Trends in insulin resistance 2022 nature..

[문형철]

1. nature  
2. signal transduction and targeted therapy  
3. review articles  
4. article

Trends in insulin resistance: insights into mechanisms and therapeutic strategy

Download PDF

• Review Article
• Open access
• Published: 06 July 2022

Trends in insulin resistance: insights into mechanisms and therapeutic strategy

• Mengwei Li, 
• Xiaowei Chi, 
• Ying Wang, 
• Sarra Setrerrahmane, 
• Wenwei Xie & 
• Hanmei Xu 

Signal Transduction and Targeted Therapy volume 7, Article number: 216 (2022) Cite this article

• 89k Accesses

• 59 Altmetric

• Metricsdetails

Abstract

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.

초록

인슐린 발견 100주년은 

당뇨병을 치명적인 진단에서 의학적으로 관리 가능한 만성 질환으로 전환하는 

중요한 기회를 제공합니다. 

인슐린은 

주요 펩타이드 호르몬으로 다양한 조직에서 체내 포도당 대사를 조절합니다. 

인슐린 저항성(IR)은 

표적 조직에서 다양한 분자 경로의 장애로 인해 

인슐린 자극에 대한 이상적인 생물학적 반응이 발생하는 질환입니다. 

후천적 요인과 유전적 요인이 IR과 연관되어 있습니다. 

최근 유전적 및 생화학적 연구는 

지방 조직에서 분비되는 조절되지 않은 

대사 매개체(아디포카인, 사이토카인, 케모카인, 과다 지방, 독성 지방 대사산물 등)가 

다른 조직에서의 IR을 촉진한다는 것을 제시합니다. 

IR은 

비만, 당뇨병, 대사 기능 장애 관련 지방간 질환(MAFLD), 심혈관 질환, 

다낭성 난소 증후군(PCOS) 및 기타 이상 증후군과 연관되어 있습니다. 

현재 인슐린 저항성을 치료하기 위해 특별히 승인된 약물은 없지만, 

인슐린 감수성을 개선하기 위해 효과적인 개입 방법으로 

사용된 생활 방식 변화와 약물 치료를 요약했습니다. 

궁극적으로 복잡한 메커니즘에 대한 체계적인 논의는 

인슐린 저항성과 밀접하게 연관된 대사 증후군의 잠재적 새로운 표적을 식별하고 

치료하는 데 도움이 될 것입니다.

Similar content being viewed by others

The aetiology and molecular landscape of insulin resistance

Article 20 July 2021

Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy

Article Open access02 October 2024

Insulin resistance in type 2 diabetes mellitus

Article 17 April 2025

Introduction

The discovery of insulin in 1921 was a milestone event1 that introduced the possibility of systematic research of insulin action (Fig. 1). Frederick Sanger (1918-2013) sequenced bovine insulin in 1955, identifying its exact amino-acids composition,2,3 and was awarded with the Nobel Prize for Chemistry in 1958. In 1965, a large team in the People’s Republic of China successfully synthesized the crystalline bovine insulin with full biological activity, immunogenicity and chemical property for the first time in the world.4 Subsequently, human insulin was produced using recombinant DNA methods and genetic modification of bacteria.5 Insulin therapy and understanding its mechanisms of action become important later research targets. Insulin is a peptide hormone that is produced and released by islets pancreatic β cells, that finely regulates the glucose uptake from blood into liver, fat, and skeletal muscle cells.6 Insulin also promotes several other cellular processes, in addition to glucose homeostasis, including regulation of glycogen synthesis, lipid metabolism, DNA synthesis, gene transcription, amino acid transport, protein synthesis and degradation7.

서론

1921년 인슐린의 발견은1 인슐린 작용의 체계적 연구 가능성을 열어준 기념비적인 사건이었습니다(그림 1). 프레드릭 샌거(1918-2013)는 1955년 소 인슐린의 염기서열을 해독하여 정확한 아미노산 구성을 규명했으며,2,3 1958년 노벨 화학상을 수상했습니다. 1965년 중국 인민공화국의 대규모 연구팀은 세계 최초로 완전한 생물학적 활성, 면역원성 및 화학적 특성을 갖춘 결정체 소 인슐린을 합성하는 데 성공했습니다.4 이후 재조합 DNA 기술과 세균의 유전자 변형을 통해 인간 인슐린이 생산되었습니다.5 인슐린 치료와 그 작용 메커니즘의 이해는 이후 중요한 연구 목표로 부상했습니다.

인슐린은 췌장의 베타 세포에서 생성되고 분비되는

펩타이드 호르몬으로,

혈액에서 간, 지방, 골격근 세포로 포도당 흡수를 정밀하게 조절합니다.6

인슐린은

포도당 균형 조절 외에도

글리코겐 합성,

지질 대사,

DNA 합성,

유전자 전사,

아미노산 운반,

단백질 합성 및 분해 등

여러 세포 과정을 촉진합니다.7

Insulin also promotes several other cellular processes, in addition to

glucose homeostasis, including

regulation of glycogen synthesis,

lipid metabolism,

DNA synthesis,

gene transcription,

amino acid transport,

protein synthesis and degradation

Fig. 1

A timeline of key discoveries in our understanding of insulin and insulin resistance

Full size image

Under normal physiological conditions, increased plasma glucose levels lead to increased insulin secretion and circulating insulin levels, thereby stimulating glucose transfer into peripheral tissues and inhibiting hepatic gluconeogenesis. Individuals with defected insulin-stimulated glucose uptake into muscle and adipocytes tissues, in addition to impaired insulin suppression of hepatic glucose output, are described as having ‘insulin resistance’(IR).8 Several diseases are clinically associated with IR includes obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease, MAFLD, PCOS, and cancer.9,10,11,12,13 Thus, there is an urgent need to identify the mechanisms of IR and effective interventions for treating these metabolic diseases. A relatively safe and well accepted approach in the prevention and treatment of IR is via lifestyle interventions. Nutritional intervention is an important first step that emphasizes a low-calorie and low-fat diet that stimulates excessive insulin demands. In addition, increased physical activity is recommended to help increase energy expenditures and improve muscle insulin sensitivity, this two approach represent the fundamental treatment for IR.14,15 The second step is the use of pharmacologic medications, including metformin, oral sulphonylureas, oral sodium-glucose cotransporter 2 (SGLT2) inhibitors, oral dipeptidyl peptidase 4 (DPP-4) inhibitors, oral α-Glucosidase, injectable glucagon-like peptide 1 (GLP1) receptor agonists, or injectable insulin.16,17

In this review, the mechanism of insulin action and IR are first described to promote the development of new therapeutic strategies. Further, the direct and indirect effects of insulin on target tissues are discussed to better understand the pivotal role of tissue crosstalk in systemic insulin action. Lastly, diseases associated with IR are discussed and summarized. Many methods and multiple surrogate markers have been developed to calculate the IR. We then summarize the current measurements and potential biomarkers of IR to facilitate the clinical diagnosis. Finally, we provide the general approaches including lifestyle intervention, specific pharmacologic interventions and clinical trials to reduce IR.

정상적인 생리적 조건에서 혈장 글루코스 수치가 증가하면 인슐린 분비와 혈중 인슐린 수치가 증가하여 말초 조직으로의 글루코스 이동을 촉진하고 간에서의 글루코네오게네시스를 억제합니다.

근육과 지방 세포 조직에서의 인슐린 자극에 의한 글루코스 흡수 장애와

간에서의 글루코스 배출 억제 장애를 동반한 개인은

'인슐린 저항성'(IR)을 가진 것으로 설명됩니다. 8

IR과 임상적으로 연관된 여러 질환에는

비만, 제2형 당뇨병(T2DM), 대사증후군, 심혈관 질환, MAFLD, PCOS, 암 등이

포함됩니다.9,10,11,12,13

따라서 IR의 메커니즘을 규명하고 이러한 대사 질환을 치료하기 위한 효과적인 개입 방법을 찾는 것이 시급합니다. IR의 예방 및 치료를 위한 상대적으로 안전하고 널리 수용된 접근 방식은 생활 방식 개입입니다.

영양 개입은 과도한 인슐린 요구를 자극하는 저칼로리 및 저지방 식단을 강조하는 중요한 첫 번째 단계입니다. 또한 신체 활동 증가가 에너지 소비를 증가시키고 근육 인슐린 감수성을 개선하는 데 도움이 되며, 이 두 가지 접근 방식은 IR의 기본적인 치료법을 구성합니다. 14,15

두 번째 단계는 메트포르민, 경구용 설포닐우레아, 경구용 나트륨-글루코스 코트랜스포터 2 (SGLT2) 억제제, 경구용 디펩티딜펩티다제 4 (DPP-4) 억제제, 경구용 α-글루코시다제, 주사형 글루카곤 유사 펩티드 1 (GLP1) 수용체 작용제, 또는 주사형 인슐린과 같은 약물 치료제의 사용입니다.16,17

이 리뷰에서는 새로운 치료 전략 개발을 촉진하기 위해 인슐린 작용 메커니즘과 IR의 메커니즘이 먼저 설명됩니다. 또한, 인슐린이 표적 조직에 미치는 직접적 및 간접적 효과를 논의하여 조직 간 상호작용이 전신 인슐린 작용에 미치는 핵심 역할을 이해하는 데 도움을 줍니다. 마지막으로, IR과 관련된 질환을 논의하고 요약합니다. IR을 계산하기 위해 다양한 방법과 다중 대용량 표지자가 개발되었습니다. 우리는 현재의 측정 방법과 IR의 잠재적 생물학적 표지자를 요약하여 임상적 진단을 용이하게 합니다. 마지막으로, 생활 방식 개입, 특정 약물 치료 및 임상 시험을 포함한 일반적인 접근 방법을 제시하여 IR을 감소시키는 방법을 제공합니다.

The Insulin signaling and IR

Insulin is an endocrine peptide hormone with 51 amino acids and composed of an α and a β chain linked together as a dimer by two disulfide bridges18 along with a third intrachain disulfide bridge in the α chain.19,20 Insulin is released by pancreatic beta cells and is essential for glucose and lipid homeostasis.21 Insulin binds the insulin receptor (INSR) on the plasma membrane of target cells, leading to the recruitment/phosphorylation of downstream proteins, that primarily including insulin receptor substrate (IRS), PI3-kinase(PI3K), and AKT isoforms, that are largely conserved among insulin target tissues and that initiate the insulin response.22,23 The pathway diversification of insulin signaling downstream targets of Akt activation leads to different distal signaling in target tissues response to insulin (Fig. 2). (1) AKT substrates include the inactive glycogen synthase kinase 3 (GSK3) and active protein phosphatase 1 (PP1) that promote glycogen synthesis.24,25,26 In addition, the transcription factor forkhead box O1 (FOXO1) is phosphorylated by AKT and is transported from the nucleus, thereby disabling its transcription factor activity and inhibiting gluconeogenesis.27,28 (2) Tuberous sclerosis complex 1/2 (TSC1/2) and proline-rich Akt substrate 40 (PRAS40) are inhibitors of mTORC1, thereby inducing protein synthesis and adipogenesis.29,30 (3) The upregulation of sterol regulatory element binding protein 1c (SREBP-1c), de-phosphorylation of ACC1/2 through inhibition of AMP-dependent protein kinase (AMPK), and the phosphorylation of ATP citrate lyase (ACLY) lead to constitutive increases in de novo lipogenesis (DNL);31,32,33 (4) Phosphodiesterase 3B (PDE3B) and the abhydrolase domain containing 15 (ABHD15) protein are involved in suppression of lipolysis in adipocytes by inhibiting adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL).34,35

인슐린 신호전달 및 인슐린 수용체

인슐린은

51개의 아미노산으로 구성된 내분비 펩타이드 호르몬으로,

α와 β 사슬이 두 개의 이황화 결합으로 연결된 이량체 구조를 이루며,

α 사슬 내부에 추가로 세 번째 사슬 내 이황화 결합이 존재합니다. 19,20

인슐린은 췌장의 베타 세포에서 분비되며,

포도당과 지질의 균형 유지에 필수적입니다.21

인슐린은

표적 세포의 세포막에 위치한 인슐린 수용체(INSR)에 결합하여

하류 단백질의 모집/인산화 과정을 유발합니다.

이 과정에는 주로 인슐린 수용체 서브스트레이트(IRS), PI3-키나제(PI3K), 및 AKT 이소형이 포함되며,

이러한 단백질은 인슐린 표적 조직에서 대부분 보존되어 있으며

인슐린 반응을 시작합니다. 22,23

Akt 활성화의 인슐린 신호전달 하류 표적 경로의 다양화는

인슐린에 대한 표적 조직의 반응에서

다른 원거리 신호전달을 유발합니다(그림 2).

(1) AKT의 기질에는 글리코겐 합성 키나제 3(GSK3)와 활성 단백질 인산화효소 1(PP1)이 포함되며, 이는 글리코겐 합성을 촉진합니다.24,25,26 또한 전사 인자 포크헤드 박스 O1(FOXO1)은 AKT에 의해 인산화되어 핵에서 이동되며, 이로 인해 전사 인자 활성이 억제되어 글루코네오게네시스가 억제됩니다. 27,28

(2) 결절성 경화증 복합체 1/2(TSC1/2)와 프로린 풍부 AKT 기질 40(PRAS40)은 mTORC1의 억제제로, 단백질 합성과 지방 생성을 유도합니다. 29,30

(3) 스테롤 조절 요소 결합 단백질 1c (SREBP-1c)의 발현 증가, AMP 의존성 단백질 키나제 (AMPK) 억제를 통해 ACC1/2의 인산화 제거, 및 ATP 시트르산 리아제(ACLY)의 인산화는 de novo 지방 생합성(DNL)의 지속적인 증가를 유발합니다;31,32,33

(4) 포스포디에스테라제 3B(PDE3B)와 아비드롤라제 도메인 함유 15(ABHD15) 단백질은 지방 세포에서 지방 분해를 억제함으로써 지방 세포의 지방 분해를 억제합니다. 이는 지방 세포의 지방 분해 효소인 지방 세포 트리글리세라이드 리파제(ATGL)와 호르몬 민감성 리파제(HS L).34,35

Fig. 2

1. 인슐린 결합 및 수용체 활성화
인슐린은 췌장 β 세포에서 분비됩니다.
이는 세포 표면의 인슐린 수용체 (IR)에 결합합니다.
이 과정은 수용체의 자동 인산화를 활성화하고 IRS (인슐린 수용체 기질)의 모집을 유발합니다.
🔗 2. PI3K-AKT 신호 전달 경로
IRS는 PI3K (포스포이노시타이드 3-키나제)를 활성화합니다 → PIP2를 PIP3로 전환합니다.
PIP3는 PDK1과 AKT를 막으로 모집합니다.
PDK1은 AKT(중앙 조절자)를 인산화하고 활성화합니다.
⚙️ 3. AKT의 하류 효과
✅ 글루코스 흡수
AKT는 AS160 (TBC1D4)를 인산화 → Rab-GTP를 활성화시켜 GLUT4가 막으로 이동합니다.
GLUT4는 포도당을 세포 내로 운반합니다.
✅ 글리코겐 합성
AKT는 GSK3를 억제하여 글리코겐 합성효소의 억제를 해제 → 글리코겐 저장을 촉진합니다.
또한 G6PC와 PCK1에 영향을 주어 글루코네오제네시스를 감소시킵니다.
✅ 지질 대사
AKT는 ACLY, SREBP1c, 및 ACC를 인산화하여 다음과을 촉진합니다:
지질 합성
신생 지질 합성
mTORC1 활성화 및 TSC1/2 억제는 지질 축적을 증가시킵니다.
✅ 단백질 합성
mTORC1 활성화는 리보솜 경로를 통해 단백질 합성을 촉진합니다.
✅ 지질 분해 억제
인슐린은 지질 분해를 억제합니다:
AKT는 PDE3B를 활성화하여 cAMP 수준을 감소시킵니다.
cAMP 감소 → PKA 활성화 감소 → HSL/ATGL 활성 감소, 따라서 지방 분해 억제.
🔁 교차 작용 및 조절
AMPK: 대사 효소(예: ACC)를 조절하여 인슐린 신호전달과 상호작용하며 mTORC1을 상쇄합니다.
FOXO1: AKT에 의한 인산화 작용으로 핵 내 이동이 억제되어 글루코네오겐시스 관련 유전자 발현이 감소합니다.

The insulin signaling pathway including proximal and distal segments

Full size image

Accumulation of reports have demonstrated that IR is a complex metabolic disorder with integrated pathophysiology. The exact causes of IR has not been fully determined,36,37,38 but ongoing research seeks to better understand how IR develops. Here, we focus on the underlying mechanism of IR including direct defective of insulin signaling, epidemiological factors, interorgan metabolic crosstalk, metabolic mediators, genetic mutation, epigenetic dysregulation, non-coding RNAs, and gut microbiota dysbiosis.

The direct defective of insulin signaling

As has been mentioned, the proper modulators acting on different steps of the signaling pathway ensure appropriate biological responses to insulin in different tissues. Thus, the diverse defect in signal transduction contributes to IR.

Proximal insulin receptor signaling and IR

Insulin exerts its biological effects by binding to its cell-surface receptors, therby activating specific adapter proteins, such us the insulin receptor substrate (IRS) proteins (principally IRS1 and IRS2), Src-homology 2 (SH2) and protein-tyrosine phosphatase 1B (PTP1B), eventually promoting downstream insulin signaling involving glucose homeostasis.39 Thus, changes in insulin receptor expression‎, ligand binding, phosphorylation states, and/or kinase activity accounts for many IR phenotypes.

Most individuals that are obese or diabetic exhibit decreased surface INSR content and INSR kinase (IRK) activity.40 Defective IRK activity is also implicated by decreased IRS1 tyrosine phosphorylation which is consistently observed in insulin-resistant skeletal muscles.41 In addition, the specific knockout or ablation of INSR in livers prevents insulin suppression of hepatic glucose production (HGP),42,43 suggesting a direct role for INSR in hepatic IR. Second, decreased expression‎ or serine phosphorylation of IRS proteins44,45 can reduce their binding to PI3K, thereby down-regulating PI3K activation and inducing apparent IR. Third, homozygous mice of IRS1 or IRS2 gene leading to peripheral IR and diabetes, and impaired insulin secretion through restrained PI3K/AKT signal transduction.46 Thus, pharmacological inhibitors, blocking antibodies and knockdown of PI3K abolishes the insulin stimulation of glucose transport, GLUT4 translocation and DNA synthesis.47,48,49 Additionally, deletion of Pik3r1 and Pik3r2 that encode PI3K subunit isoforms in skeletal muscle inhibits insulin-stimulated glucose transport.50 Similarly, interfering Akt mutant suppresses insulin-stimulated GLUT4 translocation,51 and inhibition of AKT expression‎, or impairment in AKT Ser473 phosphorylation are certainly detected in both muscle and liver IR.52,53 Further, there are three known isoforms of Akt1/2/3 in insulin sensitive tissues, the present study showed that the Akt2 and Akt3 defects impaired insulin-stimulated glucose transport in IR.54 In addition, elevated plasma nonesterified fatty acid (NEFA) levels impaired the insulin-induced increase in IRS-1-associated PI3K activity, but no defect in Akt phosphorylation was observed.55 Together, the combined actions of various disorders in the proximal signaling components leads to impaired glucose metabolism and IR, and a major challenge remains for understanding IR mechanisms regarding how to distinguish the causes from insulin effects or primary defects from their consequences.

보고서의 누적 결과는 IR이 통합된 병리생리학을 가진 복잡한 대사 장애임을 보여주고 있습니다. IR의 정확한 원인은 아직 완전히 규명되지 않았습니다.36,37,38 그러나 진행 중인 연구는 IR이 어떻게 발생하는지 더 잘 이해하기 위해 노력하고 있습니다. 본 연구에서는 IR의 근본적인 메커니즘에 초점을 맞추어 인슐린 신호전달의 직접적인 결함, 역학적 요인, 장기 간 대사 상호작용, 대사 매개체, 유전적 변이, 에피게놈 조절 장애, 비코딩 RNA, 장 미생물군집 불균형 등을 포함합니다.

인슐린 신호전달의 직접적인 결함
앞서 언급된 바와 같이, 신호 전달 경로의 다양한 단계에서 작용하는 적절한 조절 인자는 다양한 조직에서 인슐린에 대한 적절한 생물학적 반응을 보장합니다. 따라서 신호 전달의 다양한 결함은 IR에 기여합니다.

근위부 인슐린 수용체 신호전달과 IR

인슐린은 세포 표면 수용체에 결합하여 특정 적응 단백질(예: 인슐린 수용체 기질 단백질(IRS) 단백질(주요하게 IRS1 및 IRS2), Src-homology 2(SH2) 및 단백질 티로신 인산화효소 1B(PTP1B))을 활성화시켜 최종적으로 포도당 균형 조절을 포함한 하류 인슐린 신호전달을 촉진합니다. 39 따라서 인슐린 수용체 발현, 리간드 결합, 인산화 상태 및/또는 키나제 활성의 변화는 많은 IR 표현형을 설명합니다.
비만이나 당뇨병을 가진 대부분의 개인은 세포 표면 INSR 함량과 INSR 키나아제(IRK) 활성이 감소합니다.40 IRK 활성의 결함은 인슐린 저항성 골격근에서 일관되게 관찰되는 IRS1 티로신 인산화 감소와도 연관되어 있습니다.41 또한, 간에서 INSR의 특정 노크아웃 또는 제거는 간 포도당 생산(HGP)의 인슐린 억제를 방지합니다.42,43 이는 INSR이 간 IR에 직접적인 역할을 한다는 것을 시사합니다. 둘째, IRS 단백질의 발현 감소 또는 세린 인산화 감소44,45는 PI3K와의 결합을 감소시켜 PI3K 활성화를 억제하고 명백한 IR을 유발합니다. 셋째, IRS1 또는 IRS2 유전자의 동형접합 마우스는 말초 IR과 당뇨병을 유발하며, PI3K/AKT 신호 전달 경로의 억제를 통해 인슐린 분비 장애를 초래합니다. 46 따라서 PI3K를 차단하는 약리학적 억제제, 차단 항체 및 PI3K의 발현 억제는 인슐린 자극에 의한 포도당 운반, GLUT4 이동 및 DNA 합성을 억제합니다.47,48,49 또한 골격근에서 PI3K 서브유형 이소형을编码하는 Pik3r1 및 Pik3r2의 삭제는 인슐린 자극에 의한 포도당 운반을 억제합니다. 50 마찬가지로, Akt 돌연변이를 방해하면 인슐린 자극에 의한 GLUT4 이동이 억제되며,51 AKT 발현 억제 또는 AKT Ser473 인산화 장애는 근육과 간 모두에서 인슐린 저항성(IR)에서 확실히 관찰됩니다. 52,53 또한 인슐린 감수성 조직에서 Akt1/2/3의 세 가지 알려진 이소형이 존재하며, 본 연구에서는 Akt2 및 Akt3 결함이 IR에서 인슐린 자극에 의한 포도당 운반을 손상시킨다는 것이 밝혀졌습니다.54 또한 혈장 비에스테르화 지방산(NEFA) 수치 상승은 인슐린 유발 IRS-1 관련 PI3K 활성 증가를 손상시켰지만, Akt 인산화 결함은 관찰되지 않았습니다. 55 종합적으로, 근위 신호 전달 구성 요소의 다양한 장애가 결합되어 포도당 대사 장애와 IR을 유발하며, 인슐린 효과나 원발적 결함으로부터 그 결과를 구분하는 데 있어 IR 메커니즘을 이해하는 것이 주요 과제입니다.

Distal downstream signaling and IR

It is generally accepted that diverse downstream targets of Akt activation lead to different distal signaling in target tissues response to insulin. As mentioned above, there are more than 100 Akt substrates mainly including GLUT4, FOXO1, GSK3, mTORC1, SREBP-1c, TSC1/2, PRAS40, ABHD15, PDE3B.56 Among them, GLUT4 is the best characterized and mediates glucose uptake in skeletal muscle and white adipose cells after insulin stimulation.57,58 Impaired translocation of intracellular GSV (GLUT4 storage vesicles) caused decreased insulin-stimulated glucose uptake which are associated with IR in muscle and adipose tissues.59 This proved that heterozygous deletion of Glut4 mice reduce glucose uptake and develop metabolic disease in adipocytes.60 Similarly, defection of insulin-stimulated GLUT4 translocation to the cell surface occurs in skeletal muscle in various IR mice models61,62 and humans with T2DM.63,64 In addition, loss of Tbc1d4 in mice that phosphorylated by Akt leads to the attenuation of downstream target activation of Rab-GTPase proteins associated with GLUT4 vesicles, and completely abolishes insulin-stimulated adipocyte glucose uptake.65 Mice homozygous for the physiologically important AKT substrate TBC1D4 Thr649 knock-in exhibit impaired insulin-stimulated myocellular GLUT4 translocation and induction of glucose intolerance.66 In summary, continued discovery of novel AKT substrates involved in GLUT4 translocation indicates that many but not all of the same effectors are involved in the glucose uptake of different tissues, and further studies should be conducted to identify the molecular mediators in all phases of insulin-stimulated glucose uptake.

Akt 활성화의 원위 하류 신호전달 및 인슐린 수용체

Akt 활성화의 다양한 하류 표적은 인슐린에 대한 표적 조직의 반응에서 서로 다른 원위 신호전달을 유발한다는 것이 일반적으로 인정되고 있습니다. 위에서 언급된 바와 같이, Akt의 주요 기질 단백질로는 GLUT4, FOXO1, GSK3, mTORC1, SREBP-1c, TSC1/2, PRAS40, ABHD15, PDE3B 등이 있으며, 이 중 100개 이상의 기질 단백질이 존재합니다. 56 이 중 GLUT4는 가장 잘 연구된 기질로, 인슐린 자극 후 골격근과 백색 지방 세포에서의 포도당 흡수를 매개합니다.57,58 세포 내 GSV(GLUT4 저장 소체)의 이동 장애는 인슐린 자극에 따른 포도당 흡수를 감소시키며, 이는 근육과 지방 조직에서의 IR과 연관됩니다.59 이는 Glut4 유전자 이형접합 결손 마우스에서 지방 세포에서의 포도당 흡수가 감소하고 대사 질환이 발생함을 증명했습니다. 60 마찬가지로, 인슐린 자극에 의한 GLUT4의 세포 표면 이동 결함이 다양한 인슐린 저항성 마우스 모델61,62 및 제2형 당뇨병(T2DM) 환자의 골격근에서 관찰되었습니다.63,64 또한, Akt에 의해 인산화되는 Tbc1d4의 상실은 GLUT4 소체와 관련된 Rab-GTPase 단백질의 하류 표적 활성화가 약화되며, 인슐린 자극에 의한 지방세포의 포도당 흡수를 완전히 차단합니다. 65 생리적으로 중요한 AKT 기질 TBC1D4 Thr649 노크인 마우스는 인슐린 자극에 의한 근육 세포 GLUT4 이동 장애와 포도당 내성 장애를 나타냅니다. 66 요약하면, GLUT4 이동에 관여하는 새로운 AKT 기질의 지속적인 발견은 다양한 조직의 포도당 흡수 과정에서 동일한 효소들이 모두 관여하지는 않지만 많은 부분이 관여함을 시사하며, 인슐린 자극에 의한 포도당 흡수 과정의 모든 단계에서 분자 매개체를 식별하기 위한 추가 연구가 필요합니다.

Epidemiology studies of IR

Sex difference

Different investigations have indicated that premenopausal women exhibit many less metabolic disorders than men, including lower incidence of IR, although this effect diminishes severely when women reach the postmenopausal situation.67,68 Specifically, female sex hormones including estradiol (e.g., 17β-oestradiol)69 protect female proopiomelanocortin (POMC) neurons from IR by enhancing POMC neuronal excitability and coupling insulin receptors to transient receptor potential (TRPC) channel activation. Concomitantly, clinical and experimental observations70,71 have revealed that endogenous estrogens can protect against IR primarily through ER-α activation in multiple tissues, including in the brain, liver, skeletal muscle, and adipose tissue, in addition to pancreatic β cells. Further, female hormone estrogens are determinants that mediate body adiposity levels and body fat distribution in addition to glucose metabolism and insulin sensitivity. Specifically, insulin sensitivity and capacities for insulin responses in women is significantly higher than men.72 Women younger than 51 had a significantly lower fasting glucose and triglyceride concentration compared with men.73 Furthermore, sex differences are associated with genetic polymorphisms in the development of IR and diabetes. Male homozygous for the polymorphism of PPP1R3A gene that involved in glycogen synthase activity are significantly younger at diagnosis than female.74 The difference in regard to visceral, hepatic adiposity, hypoadiponectinemia, the insulin-sensitizing hormone-adiponectin, resting energy expenditure,67,75,76 lipid metabolism77 may also contribute to higher IR in male compared with female. Thus, additional studies are required to understand mechanisms underlying sex differences and IR development.

Ethnicity difference

T2DM is anticipated to impact nearly 600 million people globally by 2035,78 much of the investigations have recognized that the preval‎ence of T2DM are affected by different race/ethnicity, partly because of the differences in insulin sensitivity which affects plasma triglyceride levels.79,80,81 For example, Singapore Adults Metabolism Study (SAMS) performed a sub-group analysis and observed that Chinese and Malays exhibit greater insulin-sensitivity compared with Asian Indians among lean and young Singaporean males,82 the previous reports was further confirmed that the preval‎ence of T2DM in Chinese (9.7%) and Malays (16.6%) are lower than Asian Indians (17.2%).83 In the United Kingdom. South Asian children exhibit greater IR compared with white European children, while girls are more insulin resistant than boys, with sex and ethnicity differences related to insulin sensitivity and body composition.84,85 In addition, individuals of Aboriginal or South Asian descent (among Aboriginal, Chinese, and Indian populations) that also exhibit increased levels of body fat and visceral fat deposition appear to have a greater propensity for IR and type 2 diabetes.86 These interesting findings force us to reconsider the effect of the ethnic differences in IR, which is important to reduce the morbidity and mortality related to diabetes mellitus and metabolic syndrome.

인슐린 저항성(IR)의 역학 연구

성별 차이

다양한 연구 결과에 따르면, 폐경 전 여성은 남성보다 대사 장애가 훨씬 적으며, 특히 인슐린 저항성(IR)의 발생률이 낮지만, 여성들이 폐경 후 단계에 이르면 이 효과가 심각하게 감소합니다. 67,68 구체적으로, 에스트라디올(예: 17β-에스트라디올)을 포함한 여성 성호르몬은 POMC 신경세포의 흥분성을 증가시키고 인슐린 수용체를 일시적 수용체 잠재력(TRPC) 채널 활성화와 연결함으로써 여성의 프로오피오멜라노코르틴(POMC) 신경세포를 IR로부터 보호합니다. 동시에 임상 및 실험적 관찰70,71은 내인성 에스트로겐이 뇌, 간, 골격근, 지방 조직을 포함한 다양한 조직에서 췌장 β 세포 외에도 주로 ER-α 활성화를 통해 IR로부터 보호한다는 것을 보여주었습니다. 또한 여성 호르몬 에스트로겐은 체지방량과 체지방 분포, 포도당 대사 및 인슐린 감수성을 조절하는 결정 요인입니다. 구체적으로 여성의 인슐린 감수성과 인슐린 반응 능력은 남성보다 유의미하게 높습니다.72 51세 미만 여성은 남성보다 공복 혈당 및 트리글리세라이드 농도가 유의미하게 낮았습니다.73 또한 성별 차이는 인슐린 저항성과 당뇨병 발병과 관련된 유전적 다형성과 연관되어 있습니다. PPP1R3A 유전자 다형성(PPP1R3A)에 동형접합인 남성은 글리코겐 합성 효소 활성에 관여하며, 진단 시 연령이 여성보다 유의미하게 낮습니다.74 내장 지방, 간 지방, 저아디포넥틴혈증, 인슐린 감수성 호르몬인 아디포넥틴, 휴식 시 에너지 소비량,67,75,76 지질 대사77 등의 차이는 남성에서 여성보다 높은 IR에 기여할 수 있습니다. 따라서 성별 차이와 IR 발달의 기전을 이해하기 위해 추가 연구가 필요합니다.

인종 차이

2035년까지 전 세계적으로 약 6억 명이 T2DM에 영향을 받을 것으로 예상되며,78 많은 연구에서 T2DM의 유병률이 인종/민족에 따라 다르다는 점을 인정했습니다. 이는 인슐린 감수성의 차이로 인해 혈장 트리글리세라이드 수치에 영향을 미치기 때문입니다. 79,80,81 예를 들어, 싱가포르 성인 대사 연구(SAMS)는 하위 그룹 분석을 수행했으며, 싱가포르의 젊은 남성 중 중국인과 말레이인은 아시아 인도인에 비해 인슐린 감수성이 더 높다는 것을 관찰했습니다.82 이전 보고서는 중국인(9.7%)과 말레이인(16.6%)의 T2DM 유병률이 아시아 인도인(17.2%)보다 낮다는 것을 추가로 확인했습니다.83 영국에서는. 남아시아 어린이들은 백인 유럽 어린이보다 인슐린 저항성이 더 높으며, 소녀는 소년보다 인슐린 저항성이 더 높으며, 성별과 인종 차이는 인슐린 민감도와 체성분과 관련이 있습니다. 84,85 또한 원주민 또는 남아시아계 인구(원주민, 중국인, 인도인 인구 중)에서 체지방 및 내장 지방 축적 수준이 높은 개인은 인슐린 저항성과 제2형 당뇨병 발병 위험이 더 높은 것으로 나타났습니다.86 이러한 흥미로운 결과는 당뇨병 및 대사 증후군과 관련된 morbidities 및 사망률을 줄이기 위해 인슐린 저항성의 인종적 차이에 대한 영향을 재고하도록 강제합니다.

Modifiable lifestyle factors

Despite the above objective factors, some modifiable lifestyle factors including diet, exercise, smoking, sleep and stress are also considered to contribute to IR.87,88,89 For instance, irregular daily eating habits or poor sleep are connected to elevated risk for both obesity and IR. Further, circadian clocks disruption might also be an important factor to IR development via various factors including clock gene mutations, disturbed sleep cycles, shift work and jet lag.90,91 Moreover, epidemiologic studies of different institutions showed that individuals with regular exercise, healthy diet (including more soluble fiber, colorful fruit, vegetables, green tea, or less intake of added sugars, carbs, trans-fats), limiting alcohol intake, avoiding smoking cigarettes and reduced levels of stress, which indeed increase insulin sensitivity.92,93,94 Collectively, there are many relatively simple things we can do to naturally increase insulin sensitivity but ensure professional healthcare consultant first before adding medication regimen.

Different investigations suggest that vitamin D supplementation might reduce IR in some people due to increasing insulin receptor genes transcription and anti-inflammatory properties,95 while some researchers found that Vitamin D has no effect on IR.96 Thus, further studies should be performed to discover more about the mechanism and the effect of vitamin D on insulin resistance. Both experimental (animals) and clinical studies have shown that many hormones can induce IR including glucocorticoids (GCs),97 cortisol,98 growth hormone,99 and human placental lactogen,100 which may decrease the insulin-suppressive effects on glucose production and reduce the insulin-stimulated glucose uptake. Several other clinical medications including anti-adrenergic (such as salbutamol, salmeterol, and formoterol),101 HIV protease inhibitors,102,103 atypical antipsychotics104 and some exogenous insulin105 that may improve IR because of the disordered insulin signaling. All together, there may have synergistic effects of different risk factors on insulin resistance, scientific researchers should cooperate with medical experts to reduce the chances of becoming insulin resistant.

수정 가능한 생활 습관 요인

위에서 언급된 객관적 요인에도 불구하고, 식습관, 운동, 흡연, 수면, 스트레스 등 일부 수정 가능한 생활 습관 요인도 인슐린 저항성(IR)에 기여하는 요인으로 고려됩니다.87,88,89 예를 들어, 불규칙한 일상 식습관이나 수면 부족은 비만과 인슐린 저항성 모두의 위험 증가와 연관되어 있습니다. 또한, 생체 시계 장애는 시계 유전자 변이, 수면 주기 장애, 교대 근무, 시차 적응 장애 등 다양한 요인을 통해 인슐린 저항성 발달의 중요한 요인이 될 수 있습니다. 90,91 또한 다양한 기관의 역학 연구 결과, 규칙적인 운동, 건강한 식습관(용해성 식이섬유, 다양한 색상의 과일과 채소, 녹차 섭취 증가, 추가 당분, 탄수화물, 트랜스 지방 섭취 감소), 알코올 섭취 제한, 흡연 금지, 스트레스 수준 감소 등이 실제로 인슐린 감수성을 향상시키는 것으로 나타났습니다. 92,93,94 종합적으로, 인슐린 감수성을 자연스럽게 증가시키기 위해 할 수 있는 비교적 간단한 방법들이 많지만, 약물 치료를 추가하기 전에 전문 의료 상담을 먼저 받는 것이 중요합니다.

다양한 연구 결과에 따르면 비타민 D 보충제가 일부 사람에서 인슐린 저항성을 감소시킬 수 있다는 것이 제안되었습니다. 이는 인슐린 수용체 유전자 전사 증가와 항염증 작용 때문일 수 있습니다.95 반면 일부 연구자들은 비타민 D가 인슐린 저항성에 영향을 미치지 않는다는 결과를 보고했습니다.96 따라서 비타민 D가 인슐린 저항성에 미치는 메커니즘과 효과를 더 명확히 밝히기 위해 추가 연구가 필요합니다. 실험적(동물) 및 임상 연구 모두에서 글루코코르티코이드(GCs),97 코르티솔,98 성장 호르몬,99 인간 태반 락토겐,100 등이 인슐린 저항성을 유발할 수 있음을 보여주었습니다. 이러한 호르몬은 인슐린의 포도당 생산 억제 효과를 감소시키고 인슐린 자극 포도당 흡수량을 줄일 수 있습니다. 항아드레날린제(예: 살부타몰, 살메테롤, 포르모테롤)101, HIV 프로테아제 억제제,102,103 비전형적 항정신병 약물104 및 일부 외인성 인슐린105와 같은 여러 임상 약물은 인슐린 신호 전달 장애로 인해 IR을 개선할 수 있습니다. 모든 위험 요인은 인슐린 저항성에 시너지 효과를 일으킬 수 있으며, 과학 연구자들은 의료 전문가와 협력하여 인슐린 저항성 발생 위험을 줄이기 위해 노력해야 합니다.

The interorgan metabolic crosstalk in IR

As discribed above, insulin signaling calibrates glucose homeostasis by limiting hepatic glucose output via decreased gluconeogenesis and glycogenolysis activities. These processes consequently increase the glucose uptake rates in muscle and adipose tissues. In addition, insulin profoundly affects lipid metabolism by increasing lipid synthesis in liver and fat cells (Fig. 3), in addition to switching-off fatty acid release from triglycerides (TG) in fat and muscle tissues.106

인슐린 저항성(IR)에서의 장기 간 대사 교차작용

위에서 설명된 바와 같이, 인슐린 신호전달은 글루코네오제네시스 및 글리코겐 분해 활성을 감소시켜 간에서의 글루코스 배출을 제한함으로써 글루코스 균형을 조절합니다. 이러한 과정은 근육 및 지방 조직에서의 글루코스 흡수 속도를 증가시킵니다. 또한 인슐린은 간 및 지방 세포에서의 지방 합성을 증가시키는 것(그림 3) 외에도 지방 및 근육 조직에서의 트리글리세라이드(TG)로부터의 지방산 방출을 차단함으로써 지방 대사에도 심대한 영향을 미칩니다.106

Fig. 3

이 이미지는 인슐린 저항성의 분자적 기전을 간, 지방 조직, 골격근 세 가지 주요 조직에서 설명합니다. 특히 과영양 및 혈당 상승 조건 하에서입니다. 각 조직의 핵심 포인트와 전신적 영향을 살펴보겠습니다.

☀️ 중심 요인: 과영양 및 혈당 과부하
만성 대사 스트레스, 지방산 증가, 염증성 사이토킨 (TNF-α, IL-1β), 지질 독성을 유발합니다.
이것은 다양한 분자 메커니즘을 통해 인슐린 저항성을 유발합니다.

🩸 1. 간 (간 인슐린 저항성)
🔁 주요 사건:
IRS1/2 → ↓ pAKT2: 인슐린 신호전달 장애.
FOXO1 억제되지 않음 → ↑ 글루코네오제네시스.
글리코겐 합성 감소, 반면 포도당 생산 증가.
↑ 아세틸-코엔자임 A와 지방산은:
↑ DAG (디아실글리세롤) → PKCε 활성화, 인슐린 수용체 신호전달 장애.
TNFα와 JNK는 지방 조직과 대식세포에서 인슐린 수용체 기능을 억제합니다.

🧈 2. 지방 조직 (지방 조직 인슐린 저항성)
🔁 주요 사건:
↓ IRS1/2 → ↓ pAKT2 → GLUT4 이동 감소 → ↓ 포도당 흡수.
↓ PDE3B → ↑ cAMP → ↑ PKA → ↑ 지방 분해.
지방 분해는 지방산-CoA, 글리세롤, 지방산을 방출하며:
전신 인슐린 저항성을 유발합니다.
JNK 경로를 활성화합니다.
SREBP1c와 신생 지방 생합성을 억제합니다 (역설적, 인슐린 저항성 때문).

💪 3. 골격근 (근육 인슐린 저항성)
🔁 주요 사건:
↓ IRS1/2 → ↓ pAKT2 → GLUT4 이동하지 않음 → ↓ 포도당 흡수 및 글리코겐 합성.
세라마이드와 DAG/PKCθ는 지방산 과부하로 인해 축적됩니다.
이들은 PP2A (인산화효소)와 JNK를 활성화하여 인슐린 신호전달을 더욱 방해합니다.

🦠 4. 대식세포와 사이토킨
지방 조직에 침투한 대식세포는 TNF-α, IL-1β 등을 분비합니다.
이 염증성 사이토킨은 세 가지 조직 모두에서 인슐린 신호전달을 방해합니다:
JNK 활성화
IRS 단백질의 세린 인산화
지방 분해 및 이소성 지방 축적 유도.

An integrated physiological signaling on different target tissues insulin resistance

Full size image

Despite stimulated glucose uptake, insulin rapidly reduces hepatic glucose output and hepatic glucose production (HGP) by activating glycogen synthesis, and suppressing glycogenolysis and gluconeogenesis in liver.107,108 Further, gluconeogenesis suppression by insulin is mediated by inhibition of FOXO1 transcription factors.109 For example, some mouse models of profound hepatic IR exhibit increased G6pc (glucose-6-phosphatase) expression‎ suggesting increased FOXO1 activity.110 Moreover, correct hepatocellular insulin action also carries suppression of hepatic glycogenolysis and stimulation of glycogenesis.111 A remaining question is whether potential controlling factors including allosteric control of glycogen synthase (GS) and phosphorylases via glucose-6-phosphate (G6P),112 in addition to the insulin-independent transport of glucose across the hepatocellular plasma membrane by GLUT2 (as a glucose-sensitive protein in liver cells), can impact hepatic glycogen metabolism.113,114 Loss of GLUT2 leads to a typical combination of hepatic glycogen accumulation, glucose intolerance, and fasting hypoglycemia.115 In addition, liver insulin also effectively regulates lipid metabolism primarily by promoting cleavage and nuclear translocation of the sterol regulatory element binding protein 1c (SREBP-1c)116,117 that activates lipogenesis in hepatocytes. Insulin induces SREBP-1c maturation via a proteolytic mechanism started in the endoplasmic reticulum (ER), wherein hepatic IR is highly associated with hepatic steatosis.118 Over-expression‎ of liver SREBP-1c has been described in several IR models of including IRS2 knockout,119 lipodystrophic and ob/ob mice.120 In addition, hepatic glucose lead to a deficiency in the transcription factor carbohydrate responsive element binding protein (ChREBP) resulting in reduced mRNA levels of glycolytic and lipogenic enzymes, as well as SREBP-1c levels. Accordingly, restoration of nuclear SREBP-1c expression‎ in liver-specific Chrebp defective mice normalized expression‎ of some lipogenic genes, while not affecting glycolytic genes expressing. In contrast, ChREBP overexpression‎ alone failed to promote the expression‎ of lipogenic genes in the livers of mice lacking active SREBPs. Together, these data demonstrate that SREBP-1c mediates the induction of insulin lipogenic genes, but that SREBP-1c and ChREBP are both necessary for harmonious induction of glycolytic and lipogenic genes.121 ChREBP inhibition markedly decreased the expression‎ of L-PK, ACC, and FAS, but restored liver insulin sensitivity by restoring protein kinase B (Akt), and Foxo1 phosphorylation activity with insulin.122 This paradoxical response of SREBP-1c and ChREBP in hepatic IR is probably due to many branch effectors (including PI3K/AKT, AMPK, mTORC1, and FOXO1) involved in the hepatic glucose and lipid metabolism. Altogether, these above pathways and components can be used to clarify the popular pathophysiology of hepatic IR.

The lipid metabolisms including increased de novo lipogenesis and attenuation of lipolysis in the adipose tissue largely coordinate with glucose homeostasis response to insulin stimulation. De novo lipogenesis regulation in adipose is similar to that in livers, wherein adipose-ChREBP is a major determinant of adipose tissue fatty acid production and systemic insulin sensitivity, that is induced by GLUT4-mediated glucose uptake, and genetically ablating ChREBP impairs insulin sensitivity in adipose tissue123 In addition, lipogenic gene FASN and DGAT mRNA expression‎ in adipose tissue have been shown to correlate strongly and positively with insulin sensitivity, which were may reduced by larger adipocytes in adipose tissue of obese individuals. The lipogenesis stimulation of insulin is also reduced in larger, more insulin-resistant cells. Insulin suppression of lipolysis includes the hydrolytic cleavage of triglycerides, resulting in the generation of fatty acids and glycerol. The best understood effectors for this process are PDE3B and ABHD15 that operated by the suppression of cAMP to attenuate pro-lipolytic PKA signaling toward adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and perilipin (PLIN).34,124,125 Phosphorylation and activation of PDE3B at Ser273and Ser296 by AKT is a key event in antilipolysis after insulin stimulation. Further, inhibition of PDE3B inhibits insulin-induced glucose uptake and antilipolysis.126 Pde3b knockout mice exhibit impaired suppression of plasma NEFA levels and corresponding impairment in hepatic glucose production suppression during glucose tolerance tests.127 Further, mice homozygous for the Plin1 deletion exhibit high basal lipolysis and are unresponsive to adrenergic stimulation, confirm‎ing that PLIN is actively controls lipolysis128,129 Taken together, all the evidence supports that white adipose tissue (WAT) lipolysis suppression of insulin also associated with hepatic gluconeogenes, and the mechanisms of IR include complex mediators and metabolic networks.

Insulin stimulated protein synthesis is mediated by activation of the protein kinases Akt and mTOR (specifically mTORC1 and mTORC2) in numerous insulin-responsive cell types, such as hepatocytes, adipocytes, and myocytes.130 AKT also phosphorylates the TSC1-TSC2 complex to relieve its inhibition on the mTORC1. Inhibition of mTOR by rapamycin obviously impairs insulin-activated protein synthesis.131 Recent studies have identified that Akt phosphorylates and inactivates the PRAS40 (proline-rich Akt/PKB substrate 40), which abates its binding inhibition of mTOR signaling and promotes protein synthesis. Amino acids metabolic substrates enhance insulin sensitivity and responsiveness of the protein synthesis system by increasing mTOR activity and inhibiting protein degradation in liver, muscle, and heart tissues.132,133 Skeletal muscle tissue is the largest protein/amino acid (AA) reservoir in the human body, and lower muscle protein synthesis (MPS) induces fed-state anabolic resistance,134 in addition to exercise training of the Akt/mTOR pathway. These processes, in turn, promote protein synthesis and antagonize protein degradation.135 Further, PRAS40 and mTOR also exerts negative feedbacks on proximal insulin signaling, PRAS40 knockdown significantly decreases Akt phosphorylation, mTORC1 binds and inhibits INSR by inducing destabilization of IRS1.28 The signaling system of IR are multifactorial including different metabolic pathways, such as glucose, lipid, and protein, identifying new molecules will be crucial to unraveling more effective treatment of IR and associated metabolic diseases.

자극된 포도당 흡수에도 불구하고, 인슐린은 글리코겐 합성을 활성화하고 간에서의 글리코겐 분해 및 글루코네오게네시스를 억제함으로써 간 포도당 배출량과 간 포도당 생산량(HGP)을 급속히 감소시킵니다.107,108 또한, 인슐린에 의한 글루코네오게네시스 억제는 FOXO1 전사 인자의 억제를 통해 매개됩니다. 109 예를 들어, 심각한 간 인슐린 저항성(IR)을 보이는 일부 마우스 모델에서는 G6pc(글루코스-6-포스파타제) 발현이 증가하여 FOXO1 활성 증가를 시사합니다.110 또한, 정상적인 간세포 인슐린 작용은 간 글리코겐 분해를 억제하고 글리코겐 합성을 자극합니다. 111 남아 있는 질문은 글루코겐 합성효소(GS)와 포스포릴라제의 글루코스-6-포스페이트(G6P)를 통한 알로스테릭 조절,112 간세포 플라즈마 막을 통해 글루코스-2(간 세포의 글루코스 감수성 단백질)에 의해 인슐린 독립적으로 글루코스가 운반되는 것 외에도, 간 글리코겐 대사에도 영향을 미칠 수 있는 잠재적 조절 인자가 있는지 여부입니다. 113,114 GLUT2의 상실은 간 글리코겐 축적, 포도당 내성 장애, 공복 저혈당증의 전형적인 조합을 유발합니다.115 또한 간 인슐린은 주로 스테롤 조절 요소 결합 단백질 1c(SREBP-1c)의 분해 및 핵 내 이동을 촉진함으로써 지방 대사 조절에 효과적으로 작용합니다.116,117 이는 간세포에서 지방 생성을 활성화합니다. 인슐린은 내막 소포체(ER)에서 시작되는 단백질 분해 메커니즘을 통해 SREBP-1c의 성숙을 유도하며, 이 과정에서 간 인슐린 저항성(IR)은 간 지방증과 밀접하게 연관되어 있습니다. 118 간 SREBP-1c의 과발현은 IRS2 결손,119 지질이상증 및 ob/ob 마우스 등 여러 인슐린 저항성 모델에서 보고되었습니다.120 또한 간 포도당 결핍은 탄수화물 반응 요소 결합 단백질(ChREBP) 전사 인자의 결핍을 초래하여 글리코겐 분해 및 지질 생합성 효소의 mRNA 수준 감소, 그리고 SREBP-1c 수준 감소로 이어집니다. 이에 따라 간 특이적 Chrebp 결핍 마우스에서 핵 내 SREBP-1c 발현을 회복시키면 일부 지질 생합성 유전자 발현이 정상화되었으나, 글리코겐 분해 유전자 발현에는 영향을 미치지 않았습니다. 반면, 활성 SREBP가 결핍된 마우스의 간에서 ChREBP 과발현만으로는 지질 생합성 유전자 발현을 촉진하지 못했습니다. 이러한 결과는 SREBP-1c가 인슐린에 의한 지질생성 유전자 발현을 매개하지만, SREBP-1c와 ChREBP가 모두 글리코겐 분해 및 지질생성 유전자의 조화로운 발현에 필수적임을 보여줍니다.121 ChREBP 억제는 L-PK, ACC, 및 FAS 발현을 현저히 감소시켰지만, 인슐린에 의해 단백질 키나제 B (Akt) 및 Foxo1 인산화 활성을 회복시켜 간 인슐린 감수성을 회복시켰습니다. 122 간 IR에서의 SREBP-1c와 ChREBP의 역설적인 반응은 간 포도당 및 지질 대사에서 관여하는 많은 분기 효과기(PI3K/AKT, AMPK, mTORC1, FOXO1 등) 때문일 가능성이 높습니다. 전체적으로, 위의 경로와 구성 요소는 간 IR의 일반적인 병리생리학을 설명하는 데 활용될 수 있습니다.

de novo 지방 생성의 증가 및 지방 조직에서 지방 분해의 약화를 포함한 지질 대사는 인슐린 자극에 대한 포도당 항상성 반응과 크게 협응력을 보입니다. 지방에서 de novo 지방 생성의 조절은 간에서와 유사하며, 지방-ChREBP는 GLUT4 매개 포도당 흡수 및 ChREBP를 유전적으로 제거하면 지방 조직의 인슐린 감수성이 저하됩니다.123 또한 지방 조직에서 지방 생합성 유전자 FASN과 DGAT mRNA 발현은 인슐린 감수성과 강하고 양의 상관관계를 보이며, 이는 비만 환자의 지방 조직에서 더 큰 지방 세포에 의해 감소될 수 있습니다. 인슐린에 의한 지방 생합성 자극은 더 크고 인슐린 저항성이 높은 세포에서 감소됩니다. 인슐린에 의한 지방 분해 억제는 트리글리세라이드의 가수분해 분해로 지방산과 글리세롤을 생성하는 과정을 포함합니다. 이 과정의 가장 잘 이해된 조절 인자는 cAMP 억제를 통해 지방 분해 촉진 PKA 신호전달을 억제하여 지방 조직 트리글리세라이드 리파아제(ATGL), 호르몬 민감성 리파아제(HSL), 및 페릴리핀(PLIN)을 억제하는 PDE3B와 ABHD15입니다. 34,124,125 AKT에 의한 PDE3B의 세린 273 및 세린 296 위치에서의 인산화 및 활성화는 인슐린 자극 후 지방 분해 억제의 핵심 사건입니다. 또한 PDE3B 억제는 인슐린 유발 포도당 흡수 및 지방 분해 억제를 억제합니다.126 Pde3b 결손 마우스는 포도당 내성 검사 중 혈장 NEFA 수준 억제 장애 및 이에 따른 간 포도당 생산 억제 장애를 나타냅니다. 127 또한, Plin1 결손 동형접합 마우스는 기초 지방 분해가 높고 아드레날린 자극에 반응하지 않아 PLIN이 지방 분해를 적극적으로 조절한다는 것을 확인했습니다.128,129 종합적으로 모든 증거는 인슐린에 의한 백색 지방 조직(WAT)의 지방 분해 억제가 간 글루코네오게네시스(gluconeogenesis)와 연관되어 있으며, 인슐린 저항성(IR)의 메커니즘은 복잡한 매개체와 대사 네트워크를 포함한다는 것을 지지합니다.

인슐린 자극에 의한 단백질 합성은 간세포, 지방세포, 근육세포 등 다양한 인슐린 반응성 세포 유형에서 단백질 키나제 Akt와 mTOR(특히 mTORC1과 mTORC2)의 활성화에 의해 매개됩니다.130 AKT는 TSC1-TSC2 복합체를 인산화하여 mTORC1에 대한 억제를 완화합니다. 라파마이신에 의한 mTOR 억제는 인슐린 활성화 단백질 합성을 명백히 저해합니다.131 최근 연구에서는 Akt가 PRAS40(프로린 풍부 Akt/PKB 기질 40)을 인산화하고 비활성화시켜 mTOR 신호전달에 대한 결합 억제를 완화하고 단백질 합성을 촉진한다는 것이 밝혀졌습니다. 아미노산 대사 기질은 간, 근육, 심장 조직에서 mTOR 활성을 증가시키고 단백질 분해를 억제함으로써 인슐린 민감성과 단백질 합성 시스템의 반응성을 향상시킵니다.132,133 골격근 조직은 인체에서 가장 큰 단백질/아미노산(AA) 저장고이며, 근육 단백질 합성(MPS)의 감소는 식후 상태에서의 동화 저항성을 유발하며,134 Akt/mTOR 경로의 운동 훈련과 함께 작용합니다. 이러한 과정은 단백질 합성을 촉진하고 단백질 분해를 억제합니다. 135 또한 PRAS40과 mTOR는 근위부 인슐린 신호전달에 음성 피드백을 가합니다. PRAS40의 발현을 억제하면 Akt 인산화가 유의미하게 감소하며, mTORC1은 IRS1의 불안정화를 유도하여 INSR에 결합하고 억제합니다.28 인슐린 저항성(IR)의 신호전달 체계는 포도당, 지방, 단백질 등 다양한 대사 경로를 포함하는 다인자적 특성을 보입니다. 새로운 분자 식별은 IR 및 관련 대사 질환의 더 효과적인 치료법을 규명하는 데 결정적 역할을 할 것입니다.

The contribution of metabolic mediators to IR

Adipokines dysregulation and IR

Adipose tissue can secrete various bioactive circulating mediators referred as ‘adipokines’, like adiponectin, leptin, chemerin, resistin, visfatin and vaspin, in addition to cytokines and chemokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and monocyte chemoattractant protein-1.136 Dysregulation of these adipokines has been implicated in the onset of obesity, IR, type 2 diabetes, cardiovascular disease, hypertension and metabolic syndromes.137

Adiponectin is the most abundant protein secreted by adipose tissue and exhibits potent anti-inflammatory properties.138 In contrast to other adipokines, plasma adiponectin levels were reduced by pro-inflammatory factors like TNF-α, IL-6, ROS, and hypoxia in animal models of obesity and IR.139,140 Adiponectin activates the AMPK and PPAR-α signaling pathways through adiponectin receptor 1 (AdipoR1) and AdipoR2 respectively, leading to enhanced fatty acid oxidation and glucose uptake in muscle, along with suppressed gluconeogenesis in liver tissues. Moreover, targeted disruption of AdipoR1 results in halted adiponectin-induced AMPK activation, increased endogenous glucose production and increased IR. Similarly, AdipoR2 deletion results in decreased PPAR-α signaling pathway activity and IR. In addition, chemerin is a chemokine highly expressed in liver and white adipose tissue that regulates the expression‎ of adipocyte genes involved in glucose and lipid homeostasis like IRS-1 tyrosine phosphorylation activity, GLUT4, fatty acid synthase and adiponectin. Thus, chemerin may increase insulin sensitivity in adipose tissue.141,142 Adipocytes also produce apelin that is increased in insulin resistant individuals143 and morbidly obese subjects with T2DM.144 However, apelin enhances glucose uptake and Akt phosphorylation through AMPK pathway to improve glucose homeostasis and insulin sensitivity,145 apelin deficient mice are insulin resistant and have decreased skeletal muscle Akt phosphorylation.146 The precise role of anti-inflammatory adipokine in regulating IR require further investigation.

Leptin is a cytokine encoded by ob gene and produced by the adipocytes.147 Leptin binds to the leptin receptor (LepRb) and activates JAK2/STAT3 pathway to decrease body weight and normalizes blood glucose concentration, meanwhile, JAK2 stimulates the phosphorylation of insulin receptor substrate (IRS1/2), then activates PI3K/Akt pathway and directly affect insulin action.148 Leptin limits insulin synthesis and secretion from pancreatic β-cells, resulting in increased insulin sensitivity, reduced hepatic glucose production and decreased glucagon levels.149,150 In turn, insulin also plays a role in leptin production stimulation and secretion in adipose tissues.151 Leptin-deficient mice (ob/ob) causes both obesity and diabetes due to hyperphagia and blunted metabolic rate, and treatment with exogenous leptin could prevent and reverse the obese phenotype.152 Moreover, the decreased permeability of the brain-blood barrier (BBB) to leptin and impaired leptin signal transduction in neurons will lead to leptin resistance in obesity.148,153 Specifically, high serum leptin levels connected to IR likely promote the the release of pro-inflammatory compounds that include IL-6, TNF-α, and IL-12 by monocytes and macrophages.154 Together, leptin and insulin share pivotal roles in the regulating glucose metabolism, and additional studies are needed to understand the effects of leptin on glucose-insulin homeostasis. In summary, adipose tissue is a central node for distinct adipokines and bioactive mediators in IR pathophysiology. Consequently, identifying the effects of new adipokines will help in the development of new therapeutic strategies for obesity-induced diseases.

대사 매개체의 인슐린 저항성(IR)에 대한 기여

지방세포 유래 인자(adipokines)의 이상과 인슐린 저항성

지방 조직은 아디포넥틴, 레프틴, 케메린, 레지스틴, 비스파틴, 바스핀과 같은 다양한 생물학적 활성 순환 매개체인 '아디포카인'을 분비하며, 이는 사이토킨과 케모카인인 종양 괴사 인자 알파 (TNF-α), 인터루킨-6 (IL-6), IL-1β, 단핵구 화학유인 단백질-1과 함께 분비됩니다. 136 이러한 아디포카인의 조절 장애는 비만, 인슐린 저항성(IR), 제2형 당뇨병, 심혈관 질환, 고혈압 및 대사 증후군의 발병과 연관되어 있습니다.137

아디포넥틴은 지방 조직에서 가장 풍부하게 분비되는 단백질로 강력한 항염증 효과를 나타냅니다.138 다른 아디포카인과 달리, 비만 및 IR 동물 모델에서 TNF-α, IL-6, ROS 및 저산소증과 같은 염증 유발 인자에 의해 혈장 아디포넥틴 수치가 감소되었습니다. 139,140 아디포넥틴은 아디포넥틴 수용체 1(AdipoR1)과 AdipoR2를 통해 각각 AMPK 및 PPAR-α 신호전달 경로를 활성화시켜 근육에서의 지방산 산화 및 포도당 흡수 증가와 간 조직에서의 글루코네오제네시스 억제를 유발합니다. 또한 AdipoR1의 표적 파괴는 아디포넥틴에 의한 AMPK 활성화 중단, 내인성 포도당 생산 증가 및 IR 증가를 초래합니다. 同様に, AdipoR2 결손은 PPAR-α 신호전달 경로 활성 감소 및 IR을 유발합니다. 또한, 케메린은 간과 백색 지방 조직에서 고도로 발현되는 화학키닌으로, IRS-1 티로신 인산화 활성, GLUT4, 지방산 합성효소 및 아디포넥틴과 같은 포도당 및 지방 대사 조절에 관여하는 지방세포 유전자 발현을 조절합니다. 따라서 케메린은 지방 조직에서의 인슐린 감수성을 증가시킬 수 있습니다. 141,142 지방세포는 인슐린 저항성이 있는 개인143 및 제2형 당뇨병을 동반한 극심한 비만 환자에서 증가하는 아펠린을 생성합니다.144 그러나 아펠린은 AMPK 경로를 통해 포도당 흡수 및 Akt 인산화를 촉진하여 포도당 균형과 인슐린 감수성을 개선합니다.145 아펠린 결핍 마우스는 인슐린 저항성이 있으며 골격근 Akt 인산화가 감소합니다.146 항염증성 아디포카인이 인슐린 저항성 조절에 미치는 정확한 역할은 추가 연구가 필요합니다.

레프틴은 ob 유전자에 의해编码되고 지방세포에서 생성되는 사이토킨입니다.147 레프틴은 레프틴 수용체(LepRb)에 결합하여 JAK2/STAT3 경로를 활성화시켜 체중을 감소시키고 혈당 농도를 정상화합니다. 동시에 JAK2는 인슐린 수용체 서브스트레이트(IRS1/2)의 인산화를 자극하여 PI3K/Akt 경로를 활성화시키고 인슐린 작용에 직접 영향을 미칩니다. 148 렙틴은 췌장 β-세포에서의 인슐린 합성과 분비를 제한하여 인슐린 감수성을 증가시키고 간 글루코스 생산을 감소시키며 글루카곤 수치를 낮춥니다.149,150 반대로 인슐린은 지방 조직에서의 렙틴 생산과 분비를 자극하는 역할도 합니다. 151 레プチ틴 결핍 마우스(ob/ob)는 과식증과 대사율 저하로 인해 비만과 당뇨병을 유발하며, 외인성 레プチ틴 투여는 비만 형질을 예방하고 역전시킬 수 있습니다.152 또한, 뇌-혈관 장벽(BBB)의 레プチ틴 투과성 감소와 신경세포에서의 레プチ틴 신호 전달 장애는 비만에서 레プチ틴 저항성을 유발합니다. 148,153 구체적으로, 인슐린 저항성과 연관된 높은 혈청 레プチ닌 수치는 단핵구와 대식세포에서 IL-6, TNF-α, IL-12와 같은 염증성 화합물의 분비를 촉진합니다.154 레プチ닌과 인슐린은 포도당 대사 조절에 핵심적인 역할을 공유하며, 레プチ닌이 포도당-인슐린 균형에 미치는 영향을 이해하기 위해 추가 연구가 필요합니다. 요약하면, 지방 조직은 인슐린 저항성 병리생리학에서 다양한 아디포카인과 생물학적 매개체의 중심 노드입니다. 따라서 새로운 아디포카인의 효과를 규명하는 것은 비만 관련 질환의 새로운 치료 전략 개발에 기여할 것입니다.

Fatty acid/lipid metabolism in IR

The specific insulin actions in adipose tissue include activation of glucose uptake and triglyceride synthesis, suppression of triglyceride hydrolysis and free fatty acids (FFA) and glycerol release into the blood circulation.155,156,157 Among these actions, an extremely important function of adipose tissue is via the switches that favor lipids storage in adipocytes over their release into circulation upon need. Once the adipose tissue expandability exceeded limit under overnutrition, excess lipids and toxic lipid metabolites (FFA, diacylglycerol, ceramide) accumulated in non-adipose tissues, thus leading to lipid-induced toxicity (lipotoxicity) and developed IR in liver and muscle.158,159 The early mechanism of lipid accumulation pouch plasma fatty acid to induce the IR as detailed in glucose-fatty acid cycle proposed by Randle and colleagues.160,161 Their hypothesis suggested that available fatty acids promote fatty acid oxidation and cause the accumulation of mitochondrial acetyl coenzyme A (CoA) and NADH, with subsequent inactivation of pyruvate dehydrogenase. This process would in turn induce increased intracellular citrate levels, thereby inhibiting glucose-6-phosphate (G6P) accumulation. Increased G6P levels then result in decreased hexokinase activity, increased glucose accumulation, and reduced glucose uptake.

Other studies have demonstrated the relevance of the glucose-fatty acid cycle to lipid-induced IR. For example, lipid infusions combined with heparin can be used to activate lipoprotein lipase, thereby increasing plasma concentrations of fatty acids. Further, these infusions promote muscle lipid accumulation and effectively induce IR.162,163 In addition, contrary to predicted increases based on the Randle hypothesis, elevated free fatty acid levels were associated with reduced intracellular G6P levels in acute lipid-induced IR and type 2 diabetics.158,164 In parallel, lipid-induced IR in skeletal muscle leads to defected insulin signaling and decreased insulin-stimulated glucose transport mediated by GLUT4 translocation, and not by glycolysis inhibition as Randle hypothesized.165 Together, these researches suggest that lipid ectopic accumulation is directly correlated with IR.

지방산/지질 대사 및 인슐린 저항성

지방 조직에서의 인슐린의 특정 작용에는 포도당 흡수 활성화, 트리글리세라이드 합성 촉진, 트리글리세라이드 분해 억제 및 자유 지방산(FFA)과 글리세롤의 혈액 순환으로의 방출 억제가 포함됩니다.155,156,157 이 중 지방 조직의 극히 중요한 기능은 필요 시 지방 세포 내 지방 저장 대신 혈액 순환으로의 방출을 억제하는 스위치 역할을 통해 이루어집니다. 과영양 상태에서 지방 조직의 확장 한계가 초과되면 과잉 지질과 독성 지질 대사산물(FFA, 다이아실글리세롤, 세라마이드)이 비지방 조직에 축적되어 지질 유발 독성(지질 독성)을 유발하고 간과 근육에서 IR이 발생합니다.158,159 지방 축적의 초기 메커니즘은 Randle과 동료들이 제안한 포도당-지방산 사이클에 따라 지방산이 혈장 지방산을 증가시켜 IR을 유발한다는 것입니다. 160,161 그들의 가설은 이용 가능한 지방산이 지방산 산화를 촉진하고 미토콘드리아 아세틸 코엔자임 A(CoA)와 NADH의 축적을 유발하며, 이는 피루vate dehydrogenase의 비활성화를 초래한다고 제안했습니다. 이 과정은 차례로 세포 내 시트르산 수준을 증가시켜 글루코스-6-포스페이트(G6P) 축적을 억제합니다. 증가한 G6P 수준은 헥소키나제 활성 감소, 글루코스 축적 증가, 및 글루코스 흡수 감소로 이어집니다.

다른 연구들은 지방산에 의한 인슐린 저항성(IR)에 대한 글루코스-지방산 사이클의 관련성을 입증했습니다. 예를 들어, 헤파린과 결합된 지방 주입은 리포단백질 리파아제를 활성화시켜 혈장 지방산 농도를 증가시킵니다. 또한 이러한 주입은 근육 내 지방 축적을 촉진하고 효과적으로 IR을 유발합니다.162,163 또한, 랜들 가설에 따른 예측과 달리 급성 지방 유도성 IR 및 제2형 당뇨병 환자에서 자유 지방산 농도 증가와 세포 내 G6P 농도 감소가 연관되었습니다. 158,164 동시에, 골격근에서의 지질 유발성 IR은 Randle의 가설과 달리 글리코겐 분해 억제가 아닌 GLUT4 이동에 의해 매개되는 인슐린 신호 전달 장애와 인슐린 자극성 포도당 운반 감소로 이어집니다.165 이러한 연구 결과들은 지질의 이소성 축적이 인슐린 저항성과 직접적으로 관련되어 있음을 시사합니다.

Diacylglycerol and ceramide accumulation

Consistent with the above studies, elevated plasma fatty acid concentrations can result in increased intracellular diacylglycerol (DAG) levels, leading to the activation of protein kinase C isoform (PKC-θ) and PKC-ε isoforms in skeletal muscles and liver respectively. These processes, in turn, decrease insulin-stimulated IRS-1/IRS-2 tyrosine phosphorylation, PI3K activation and downstream insulin signaling that then induces IR in muscles and livers.166,167,168 Deletion of PKCθ in mice inhibits muscle IR is induced by lipid infusion.169 Moreover, knockdown of PKC-ε in rats leads to protection from fat-induced hepatic IR,170 these results confirm‎ the distinct roles of PKC-θ and PKC-ε in fat-induced IR in skeletal muscles and livers, respectively. Since diacylglycerol acyltransferase 1 (DGAT1) can increase the conversion of DAG into triacylglycerol (TAG),171 DGAT1 overexpression‎ could decrease DAG levels and improve insulin sensitivity partially attenuating the fat-induced activation of DAG-responsive PKCs.172,173 Conversely, DGAT1 ablation may result in elevated DAG levels and lipid-induced IR. Taken together, these studies strongly support that DAG as a key intermediate of TAG synthesis from fatty acids has central modulation and potential therapeutic values in IR.

Ceramide is another specific lipid metabolite that increases in concentration, along with DAG, in association with IR in obese mice.174 Accumulated ceramide mediates the activation of protein phosphatase 2 A (PP2A) and impairs insulin-dependent activation, in addition to signaling of PI3K/Akt by PKCζ,175 thereby also disrupting lipid metabolism by inhibiting oxidation and stimulating fatty acid uptake.176 In particular, C18- and C16-long-chain ceramides that are produced by ceramide synthase isoforms (CerS1, CerS5, and CerS6) have higher concentrations in insulin-resistant tissues.177,178 Consistently, C18-derived ceramides play an important role in fat-induced skeletal muscle IR.179 Likewise, C16-ceramides exist in higher concentrations in obese adipose tissue and are associated with hepatic IR.180,181 Several lines of evidence suggest that circulating adiponectin is closely related to ceramide concentrations, wherein adiponectin increases ceramidase activity associated with its two receptors AdipoR1/AdipoR2, while lower concentrations of circulating adiponectin increases ceramide concentrations in different tissues.182,183 Furthermore, inhibited ceramide synthesis or stimulation of ceramide degradation176 can prevent the effects of ceramide on Akt/PKB activation and improve insulin signaling. Thus, ectopic lipid metabolite concentrations (e.g., diacylglycerols and ceramides) may be mechanistic factors underlying liver and muscle IR. Consequently, concerted efforts to decrease lipid components in these organs are the most efficacious therapeutic targets for treating IR and metabolic diseases.

디아실글리세롤과 세라마이드의 축적

위 연구 결과와 일치하게, 혈장 지방산 농도의 상승은 골격근과 간에서 각각 단백질 키나아제 C 이소형 (PKC-θ)과 PKC-ε 이소형의 활성화를 유발하는 세포 내 디아실글리세롤 (DAG) 수치의 증가를 초래합니다. 이러한 과정은 차례로 인슐린 자극에 의한 IRS-1/IRS-2 티로신 인산화, PI3K 활성화 및 하류 인슐린 신호전달을 감소시켜 근육과 간에서 인슐린 저항성 (IR)을 유발합니다. 166,167,168 PKCθ를 제거한 쥐에서 지방 주입에 의한 근육 IR이 억제됩니다.169 또한, 쥐에서 PKC-ε를 억제하면 지방에 의한 간 IR로부터 보호됩니다.170 이러한 결과는 PKC-θ와 PKC-ε가 골격근과 간에서 지방에 의한 IR에 각각 다른 역할을 한다는 것을 확인합니다. 디아실글리세롤 아실트랜스퍼레이즈 1(DGAT1)은 DAG를 트리아실글리세롤(TAG)로 전환시키는 역할을 합니다.171 DGAT1 과발현은 DAG 수준을 감소시키고 인슐린 감수성을 개선하여 지방 유발성 DAG 반응성 PKC 활성화를 부분적으로 억제할 수 있습니다.172,173 반면, DGAT1 결손은 DAG 수준 증가와 지방 유발성 IR을 유발할 수 있습니다. 종합적으로, 이 연구들은 지방산으로부터 TAG 합성의 핵심 중간체인 DAG가 IR에서 중심적인 조절 역할을 하며 치료적 가치를 지닌다는 것을 강력히 뒷받침합니다.

세라마이드(Ceramide)는 비만 마우스에서 인슐린 저항성과 연관되어 DAG와 함께 농도가 증가하는 또 다른 특정 지질 대사산물입니다.174 축적된 세라마이드는 단백질 인산화효소 2A(PP2A)의 활성화를 매개하고 인슐린 의존성 활성화를 방해하며, PKCζ에 의한 PI3K/Akt 신호전달을 차단함으로써 지질 대사 장애를 유발합니다.175 176 특히 세라마이드 합성 효소 이소형(CerS1, CerS5, CerS6)에 의해 생성되는 C18- 및 C16-장쇄 세라마이드는 인슐린 저항성 조직에서 농도가 높습니다.177,178 일관되게 C18 유래 세라마이드는 지방 유발 골격근 IR에서 중요한 역할을 합니다. 179 마찬가지로, C16 세라마이드는 비만 지방 조직에서 더 높은 농도로 존재하며 간 IR과 연관되어 있습니다.180,181 여러 연구 결과는 순환 아디포넥틴이 세라마이드 농도와 밀접하게 관련되어 있음을 보여주며, 아디포넥틴은 두 수용체 AdipoR1/AdipoR2와 연관된 세라마이드 분해 효소 활성을 증가시키며, 순환 아디포넥틴 농도가 낮을수록 다양한 조직에서 세라마이드 농도가 증가합니다. 182,183 또한 세라마이드 합성 억제 또는 세라마이드 분해 자극176은 세라마이드가 Akt/PKB 활성화에 미치는 영향을 방지하고 인슐린 신호전달을 개선합니다. 따라서 이소성 지질 대사산물 농도(예: 디아실글리세롤 및 세라마이드)는 간과 근육의 인슐린 저항성을 유발하는 기전적 요인일 수 있습니다. 따라서 이러한 장기에서 지질 성분을 감소시키는 통합적인 노력은 인슐린 저항성과 대사 질환 치료를 위한 가장 효과적인 치료 표적이 될 수 있습니다.

Genetic mutations in IR

Some human genetic studies indicated that different genomic loci were associated with fasting insulin levels, higher triglyceride and lower HDL cholesterol levels,184,185 which are different hallmarks of IR.186 Epidemiological and family genetic studies have provided considerable evidence for the genetic basis of both IR and the individual components of the metabolic syndromes.187,188 Since 2007, genome-wide association studies (GWAS) and next-generation sequencing (NGS) have identified different genetic variants associated with IR, including PPARγ, IRS1, IGF1, NAT2, KLF14, GCKR, FTO, TCF7L2, TMEM163, MC4R, SC4MOL, TCERG1L, and ARL15184,189,190 by influencing insulin action via different regulatory mechanisms.

The peroxisome proliferator-activated receptor gamma (PPARγ) variant Pro12Ala was one of the first genetic variants identified that is involved in fatty acid and energy metabolism and that is associated with a low risk of developing T2DM.191 Variants (A allele to G allele) within IGF-1 (insulin-like growth factor 1) contribute to its low plasma levels, and cause a reduction in insulin sensitivity.192 A variant in N-acetyltransferase 2 (NAT2) was recently identified as an insulin sensitivity gene.193 Adiponectin is an adipokine involved in improving insulin sensitivity, variants within ADP ribosylation factor like GTPase 15 (ARL15) are associated with decreased adiponectin levels and nominally associated with IR.194

Despite these potential genetic correlates, variants account for only 25% to 44% of the heritability of IR.195 Consequently, the contributions of low-frequency and rare genetic variants towards the heritability of IR have also been explored through a combination of both genome and exosome sequencing.196,197 Such studies have identified a low-frequency variant of CD300LG that is associated with fasting high-density lipoprotein cholesterol (HDL-C),198 and a TBC1D4 variant that together are connected to higher fasting glucose levels and reduced insulin sensitivity.199 The rapid development of genomics methods has enabled considerable progress towards the identification of genetic loci associated with IR by direct or indirect effects. Nevertheless, additional studies are needed to assess the functional relationships between the genetic variants and IR, that are also influenced by various lifestyle and environmental factors.

IR의 유전적 변이

일부 인간 유전학 연구는 공복 인슐린 수치, 높은 트리글리세라이드 수치 및 낮은 HDL 콜레스테롤 수치와 관련된 다양한 유전적 위치가 존재함을 보여주었습니다.184,185 이는 IR의 서로 다른 특징입니다.186 역학 및 가족 유전학 연구는 IR 및 대사 증후군의 개별 구성 요소의 유전적 기반에 대한 상당한 증거를 제공했습니다. 187,188 2007년 이후로 전장 유전체 연관 연구(GWAS)와 차세대 시퀀싱(NGS)은 IR과 관련된 다양한 유전적 변이체를 식별했습니다. PPARγ, IRS1, IGF1, NAT2, KLF14, GCKR, FTO, TCF7L2, TMEM163, MC4R, SC4MOL, TCERG1L, 및 ARL15184,189,190와 같은 유전적 변이체를 포함합니다. 이러한 변이체는 다양한 조절 메커니즘을 통해 인슐린 작용에 영향을 미칩니다.

과산화체 증식 활성화 수용체 감마(PPARγ) 변이체 Pro12Ala는 지방산 및 에너지 대사 관련 유전적 변이체 중 하나로, 제2형 당뇨병(T2DM) 발병 위험이 낮은 것과 연관되어 있습니다.191 인슐린 유사 성장 인자 1(IGF-1) 내 변이체(A 알레일에서 G 알레일로)는 혈장 내 IGF-1 수치를 낮추고 인슐린 감수성을 감소시킵니다. 192 N-아세틸트랜스퍼레이스 2(NAT2)의 변이가 최근 인슐린 감수성 유전자로 확인되었습니다.193 아디포넥틴은 인슐린 감수성을 개선하는 아디포카인으로, 아디포넥틴 리보실화 인자 유사 GTP아제 15(ARL15) 내 변이는 아디포넥틴 수치 감소와 연관되며, 인슐린 저항성과 명목상 연관성이 있습니다.194

이러한 잠재적 유전적 연관성에도 불구하고, 변이체는 인슐린 저항성의 유전율 중 25%에서 44%만을 설명합니다.195 따라서, 저빈도 및 희귀 유전적 변이체가 인슐린 저항성의 유전율에 미치는 기여도는 게놈 및 엑소좀 시퀀싱을 결합한 연구를 통해 탐구되었습니다. 196,197 이러한 연구는 공복 고밀도 지단백 콜레스테롤 (HDL-C)과 연관된 CD300LG의 저빈도 변이체를 식별했으며,198 TBC1D4 변이체는 함께 공복 혈당 수치 증가와 인슐린 감수성 감소와 연관되어 있습니다.199 유전체학 방법의 급속한 발전은 직접적 또는 간접적 효과를 통해 IR과 연관된 유전적 위치를 식별하는 데 상당한 진전을 가져왔습니다. 그러나 유전적 변이와 IR 간의 기능적 관계는 다양한 생활 방식 및 환경 요인의 영향을 받기 때문에, 추가 연구가 필요합니다.

Epigenetic dysregulation in IR

Recent studies have suggested that epigenetic modifications such as DNA methylation (DNAm) and histone post-translational modifications (PTM) are implicated in the development of systemic IR.200,201

DNA methylation

Global and site-specific DNA methylation is generally mediated by DNA methyltransferases (DNMTs). These processes mainly occur in the context of CG dinucleotides (CpGs) and promoter region, while also involving covalent addition or removal of methyl groups as a means to repress or stimulate transcription, respectively.202

Firstly, DNA methylation regulates different insulin signaling genes, such as insulin (INS), insulin receptor substrate 1 (IRS1), Insulin-like growth factor-1/2 (IGF-1/2), Insulin-like growth factor-binding protein 1/2 (IGFBP-1/2), phosphatidylinositol 3-kinase regulatory subunit (PIK3R1), and Glucagon-like peptide-1 receptor (GLP-1R).203,204,205,206 The methylation status of these genes was found to be altered in obesity and IR. For example, increased INS promoter methylation levels and INS mRNA suppression were observed under over-nutrition conditions and obese T2DM patients.207 Similarly, a research with blood samples of T2DM found that increased IGF-1 DNA methylation were associated with reduced IGF-I serum levels in T2DM patients.208 Insulin-like growth factor binding proteins 1 and 2 (IGFBP1 and IGFBP2, respectively) are the most abundant circulating IGFBPs and have lower concentrations in adipose tissue in obese patients, in addition to being negatively associated with hyperinsulinemia and IR.209 Several studies have indicated that increased IGFBP-1 DNA methylation levels and decreased IGFBP-1 serum levels are associated with newly diagnosed T2DM. Another study demonstrated210 that increased IGFBP2 DNA methylation levels were are associated with lower mRNA expression‎ levels in Visceral Adipose tissue (VAT) of abdominal obesity. Moreover, the first global genome-wide epigenetic analysis in VAT211 from IR and insulin-sensitive (IS) morbidly obese patients identified a novel IR-related gene, the zinc finger protein 714 (ZNF714) exhibited the highest DNA methylation difference, and its methylation levels is lower in IR patient than in IS patient, consistent with increased transcription levels, such studies provide potential epigenetic biomarkers related to IR in addition to novel treatment targets for the prevention and treatment of metabolic disorders.

Some DNA methylation in the promoter regions of specific genes related to lipid metabolism (PPARG, PPARA),212 low-density lipoprotein receptor-related protein 1 (LRP1),213 lipoprotein lipase (LPL),214 SREBF1/2,215 and inflammation (stearoyl-CoA desaturase 1 (SCD1), chemokine C-C motif chemokine ligand 2 (CCL2), TNF-α, and TGF-β1)216,217 are associated with adipose tissue dysfunction and could lead to metabolic disorders. For example, peroxisome proliferator-activated receptor-α and -γ (PPAR-α and PPAR-γ, respectively) are encoded by PPARA and PPARG, respectively, and they are the two primary nuclear peroxisome proliferator-activated receptors involved in lipid metabolism. Higher PPARA and PPARG methylation levels were observed in association with obesity, consistent with decreased PPAR-α and PPAR-γ protein expression‎ levels,218 that lead to dyslipidemia and IR. SLC19A1, a gene encoding a membrane folate carrier, was reduced in obese WAT and induced global DNA hypermethylation of chemokine C-C motif chemokine ligand 2 (CCL2) that is a key factor in WAT inflammation,219 resulting in increased CCL2 protein secretion and the development of IR in obese.

In addition, several genes methylation involved in hypoxia stress and endoplasmic reticulum stress were regulated in obesity related metabolic diseases.220 Hypoxia-inducible factor-3α (HIF3A) belongs to the hypoxia-inducible factors family (HIFs) that play important roles in the pathogenesis of obesity-induced IR, adipose tissue-inflammation and the etiology of obesity related disease. Recent epigenetic genome-wide analysis identified low HIF3A methylation levels upregulates HIF3A expression‎ in adipose tissue, thereby leading to adipose tissue dysfunction and adiposity.221 Further, reduced HIF3A methylation and increased HIF3A levels in blood are associated with IR and higher body mass index (BMI) values in T2DM patients.222 The major function of the endoplasmic reticulum (ER) is the synthesis and folding of secreted and transmembrane proteins, increasing evidence suggests that persistent ER stress is associated with the onset and progress of chronic metabolic disorders like obesity and IR. Ramos-Lopez et al.220 found that the methylation levels of four ER genes including ERO1LB, NFE2L2, MBTPS1 and EIF2AK4 which encoded ER oxidoreductin-1β (ERO1β), nuclear factor-erythroid 2-related factor (Nrf2), site-1 protease (S1P) and eIF-2-alpha kinase (GCN2) respectively, were strongly correlated with total body fat levels. Specifically, increased insulin concentrations and HOMA-IR index were accompanied by lower ERO1LB and NFE2L2 methylation levels.223 Hence, related to hypoxia and ER stress genes could be considered as precise therapeutics to control the IR.

에피제네틱 조절 장애와 인슐린 저항성 (IR)

최근 연구들은

DNA 메틸화 (DNAm) 및 히스톤 후전사 변형 (PTM)과 같은

에피제네틱 변형이 전신성 인슐린 저항성 (IR)의 발병에 관여한다는 것을 제시했습니다.200,201

DNA 메틸화

전반적인 및 부위 특이적 DNA 메틸화는 일반적으로 DNA 메틸전달효소 (DNMTs)에 의해 매개됩니다. 이 과정은 주로 CG 이중핵산(CpG) 및 프로모터 영역에서 발생하며, 메틸 그룹의 공액적 추가 또는 제거를 통해 전사 억제 또는 촉진 역할을 합니다.202

첫째, DNA 메틸화는 인슐린(INS), 인슐린 수용체 서브스트레이트 1(IRS1), 인슐린 유사 성장 인자-1/2(IGF-1/2), 인슐린 유사 성장 인자 결합 단백질 1/2(IGFBP-1/2), 인산화 인오실리노스 3-키나제 조절 서브유닛(PIK3R1), 글루카곤 유사 펩티드-1 수용체(GLP-1R)와 같은 인슐린 신호 전달 유전자들을 조절합니다.203,204,205,206 이러한 유전자의 메틸화 상태는 비만과 인슐린 저항성(IR)에서 변화된 것으로 확인되었습니다. 예를 들어, 과영양 조건과 비만 2형 당뇨병 환자에서 INS 프로모터 메틸화 수준 증가와 INS mRNA 억제가 관찰되었습니다.207 마찬가지로, 2형 당뇨병 환자의 혈액 샘플을 대상으로 한 연구에서 IGF-1 DNA 메틸화 증가가 2형 당뇨병 환자에서 IGF-I 혈청 수준 감소와 연관되어 있음을 발견했습니다. 208 인슐린 유사 성장 인자 결합 단백질 1과 2(IGFBP1 및 IGFBP2)는 가장 풍부한 순환 IGFBP이며, 비만 환자에서 지방 조직 내 농도가 낮으며, 고인슐린혈증 및 IR과 음의 상관관계를 보입니다.209 여러 연구에서 IGFBP-1 DNA 메틸화 수준 증가와 IGFBP-1 혈청 수준 감소가 신규 진단된 T2DM과 연관되어 있음을 보여주었습니다. 또 다른 연구에서는210 IGFBP2 DNA 메틸화 수준 증가가 복부 비만 환자의 내장 지방 조직(VAT)에서 mRNA 발현 수준 감소와 연관되어 있음을 보여주었습니다. 또한, 인슐린 저항성(IR) 및 인슐린 민감성(IS)을 가진 중증 비만 환자의 VAT에서 수행된 첫 번째 전장 유전체 에피게노믹 분석211은 새로운 인슐린 저항성 관련 유전자인 아연 손가락 단백질 714(ZNF714)를 식별했으며, 이 유전자의 DNA 메틸화 수준은 IR 환자에서 IS 환자보다 낮았으며, 이는 전사 수준 증가와 일치합니다. 이러한 연구는 인슐린 저항성과 관련된 새로운 에피게노믹 바이오마커를 제공하며, 대사 장애의 예방 및 치료를 위한 새로운 치료 표적 가능성을 제시합니다. 그리고 그 메틸화 수준은 IS 환자보다 IR 환자에서 더 낮았으며, 이는 전사 수준 증가와 일치합니다. 이러한 연구는 대사 장애의 예방 및 치료를 위한 새로운 치료 표적 외에도 인슐린 저항성과 관련된 잠재적 에피제네틱 바이오마커를 제공합니다.

지질 대사 관련 특정 유전자(PPARG, PPARA)의 프로모터 지역에서 일부 DNA 메틸화가 관찰되었으며,212 저밀도 지단백 수용체 관련 단백질 1(LRP1),213 지단백 리파아제(LPL),214 SREBF1/2,215 및 염증 관련 유전자(스테아로일-코엔자임 A 탈수소효소 1(SCD1), 케모킨 C-C 모티프 케모킨 리간드 2(CCL2), TNF-α, 및 TGF-β1)216,217은 지방 조직 기능 장애와 연관되어 있으며 대사 장애로 이어질 수 있습니다. 예를 들어, 과산화체 증식 활성화 수용체-α와 -γ (PPAR-α와 PPAR-γ)는 각각 PPARA와 PPARG 유전자에 의해编码되며, 지방 대사에 관여하는 두 가지 주요 핵 과산화체 증식 활성화 수용체입니다. 비만과 연관되어 PPARA 및 PPARG 메틸화 수준이 높게 관찰되었으며, 이는 PPAR-α 및 PPAR-γ 단백질 발현 수준 감소와 일치하며,218 이는 이상지질혈증과 인슐린 저항성(IR)으로 이어집니다. SLC19A1 유전자는 막 엽산 운반체를编码하며, 비만 WAT에서 감소되어 화학키인 C-C 모티프 화학키인 리간드 2(CCL2)의 전사체 메틸화 증가를 유발합니다. CCL2는 WAT 염증의 핵심 인자로,219 비만에서 CCL2 단백질 분비 증가와 IR 발병을 초래합니다.

또한, 저산소 스트레스와 내소체 스트레스와 관련된 여러 유전자의 메틸화가 비만 관련 대사 질환에서 조절되었습니다.220 저산소 유도 인자-3α(HIF3A)는 비만 유발성 IR, 지방 조직 염증 및 비만 관련 질환의 병인에 중요한 역할을 하는 저산소 유도 인자 가족(HIFs)에 속합니다. 최근 에피제네틱 전장 유전체 분석은 지방 조직에서 HIF3A 메틸화 수준이 낮을 때 HIF3A 발현이 증가하며, 이는 지방 조직 기능 장애와 지방 축적으로 이어진다는 것을 확인했습니다.221 또한, HIF3A 메틸화 감소와 혈중 HIF3A 수준 증가가 제2형 당뇨병(T2DM) 환자에서 인슐린 저항성과 높은 체질량 지수(BMI) 값과 연관되어 있습니다. 222 내소체(ER)의 주요 기능은 분비 및 막을 통과하는 단백질의 합성과 접힘입니다. 지속적인 내소체 스트레스가 비만과 인슐린 저항성과 같은 만성 대사 장애의 발병 및 진행과 연관되어 있다는 증거가 증가하고 있습니다. Ramos-Lopez 등220은 ER 산화환원효소-1β(ERO1β), 핵인자-적혈구 2 관련 인자(Nrf2), 사이트-1 프로테아제(S1P), eIF-2-알파 키나제(GCN2)를 각각编码하는 네 가지 ER 유전자인 ERO1LB, NFE2L2, MBTPS1 및 EIF2AK4의 메틸화 수준이 이 총 체지방 수준과 강하게 연관되어 있음을 발견했습니다. 구체적으로, 인슐린 농도 증가와 HOMA-IR 지수 상승은 ERO1LB 및 NFE2L2 메틸화 수준 감소와 동반되었습니다.223 따라서 저산소증 및 ER 스트레스 관련 유전자는 IR을 조절하기 위한 정밀 치료제로 고려될 수 있습니다.

Histone modifications

The histone modification effect on gene expression‎ mainly includes histones methylation and acetylation. Histone methylation could either activate gene transcription (H3K4, H3K36, and H3K79) or silence gene expression‎ (H3K9 and H3K27), which depends on the modification site.224 Several studies have reported various histone epigenetic modifications of metabolic and mitogenic cascade-related genes of insulin signaling during IR.225 PPARG is a key transcription factors that regulates insulin sensitivity, lower histone H3 acetylation and methylation of the PPARG gene are associated with reduced PPARG expression‎ that is associated with IR.212 Further, increased expression‎ and low methylation of CDKN1A and PDE7B genes in T2DM can lead to impaired insulin release that is stimulated by glucose in T2DM patients.226 The high level of H3K4 trimethyl (H3K4me3) of Fxyd3 gene negatively regulates the glucose capacity of insulin-secreting cells in mice.227

Histone acetylation increases the accessibility and gene expression‎ of various transcription factors by reducing the positive charge and histone affinity for DNA.228 Histone deacetylation is considered to be the inhibition of DNA assembly by chromatin condensation and transcription factors, resulting in transcriptional inhibition. Increasing evidence indicates229,230 that IGFR, InsR, IRS1, Akt, GLUT4, and PPAR are more deacetylated in association with IR than in normal physiological conditions. In contrast, IRS2, FoxO, JNK, and AMPK are usually acetylated in association with IR. Castellano-Castillo, D., et al.231 utilized a chromatin immunoprecipitation (ChIP) assay to determine that the human adipose tissue H3K4me3 histone mark site in adipogenic, lipid metabolism, and inflammatory genes (such as LEP, LPL, SREBF2, SCD1, PPARG, IL6, TNF, and E2F1) is positively associated with BMI and HOMA-IR. Further, global proteomic analyses have revealed 15 histone modifications that are differentially abundant in hepatic IR.232 These observations provide evidence for diabetes-related histone modification and related impaired insulin release.

히스톤 변형

히스톤 변형이 유전자 발현에 미치는 영향은 주로 히스톤 메틸화 및 아세틸화에 포함됩니다. 히스톤 메틸화는 유전자 전사 활성화(H3K4, H3K36, H3K79) 또는 유전자 발현 억제(H3K9, H3K27)를 유발할 수 있으며, 이는 변형 부위에 따라 달라집니다. 224 여러 연구에서 인슐린 저항성(IR) 동안 인슐린 신호전달과 관련된 대사 및 증식 캐스케이드 관련 유전자의 다양한 히스톤 에피제네틱 변형이 보고되었습니다.225 PPARG는 인슐린 감수성을 조절하는 주요 전사 인자로, PPARG 유전자의 히스톤 H3 아세틸화 및 메틸화 감소는 PPARG 발현 감소와 연관되며, 이는 IR과 관련이 있습니다. 212 또한, 제2형 당뇨병(T2DM)에서 CDKN1A 및 PDE7B 유전자의 발현 증가와 메틸화 감소는 포도당에 의해 자극되는 인슐린 분비 장애를 유발할 수 있습니다.226 Fxyd3 유전자의 H3K4 트리메틸(H3K4me3) 수준이 높으면 쥐의 인슐린 분비 세포의 포도당 용량을 부정적으로 조절합니다.227

히스톤 아세틸화는 히스톤의 양전하와 DNA에 대한 친화성을 감소시켜 다양한 전사 인자의 접근성과 발현을 증가시킵니다.228 히스톤 데아세틸화는 염색질 응축과 전사 인자에 의해 DNA 조립이 억제되어 전사 억제를 초래하는 것으로 간주됩니다. 증가하는 증거는229,230 IGFR, InsR, IRS1, Akt, GLUT4, 및 PPAR가 정상 생리적 조건보다 인슐린 저항성(IR)과 연관되어 더 탈아세틸화되어 있음을 나타냅니다. 반면, IRS2, FoxO, JNK, 및 AMPK는 일반적으로 인슐린 저항성과 연관되어 아세틸화되어 있습니다. Castellano-Castillo, D. 등231은 염색질 면역침전(ChIP) 분석을 통해 인간 지방 조직의 지방 생성, 지방 대사, 염증 관련 유전자(예: LEP, LPL, SREBF2, SCD1, PPARG, IL6, TNF, E2F1)의 H3K4me3 히스톤 표지 부위가 체질량 지수(BMI) 및 HOMA-IR과 양의 상관관계가 있음을 확인했습니다. 또한, 전장 프로테오믹스 분석을 통해 간 내 인슐린 저항성에서 차등적으로 풍부한 15개의 히스톤 변형이 확인되었습니다.232 이러한 관찰 결과는 당뇨병 관련 히스톤 변형 및 관련 인슐린 분비 장애를 입증하는 증거를 제공합니다.

non-coding RNA regulation in IR

Non-coding RNAs (ncRNAs) comprise approximately 98% of human genome transcripts and are generally not translated into proteins.233 The rising studies234,235 have shown that ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are key mediators in the pathogenesis and progression of metabolic homeostasis.

MiRNAs and IR

MicroRNAs (miRNAs) are small ncRNAs (18-22 nucleotides) incorporated into Argonaute (Ago) protein to form miRISCs, which can inhibit the expression‎ of partially or completely complementary target mRMAs.236 Dysregulation of various miRNAs within different fluids (e.g., blood, saliva, and urine) is associated with obesity and IR development, including β-cell dysfunction, glucose and lipid homeostasis, and chronic inflammation.237

Firstly, pancreatic β cell mass due to dysfunction and/or death are the major cause of insufficient insulin secretion, and the main common mechanisms of T1DM and T2DM. Several miRNAs are involved in β cell differentiation and mature β cell functioning. For example, islet-specific miR-375 overexpression‎ represses glucose-stimulated insulin secretion (GSIS) and insulin gene transcription, that is then reversed upon miR-375 inhibition.238 Further, deregulated plasma levels of miR-375 together with miR-150, miR-30a-5p, and miR-15a are observed before T2DM and pre-diabetes onset. Thus, these markers may improve disease prediction and prevention in individuals at high risk for T2DM.239 Other miRNAs have been implicated in β-cell proliferation and insulin secretion regulation during IR including miR-124a2, miR-204, miR-184 and miR-24. Further, miR-124a2 targets the genes encoding cAMP-response-element binding protein (creb-1) and forkhead/winged helix transcription factor boxa2 (foxA2) mRNA.240 FoxA2 is an upstream regulator of pancreatic duodenal homeobox 1 (pdx1) that is essential for pancreatic development and glucose homeostasis. Furthermore, pdx1, neurogenin-3 (ngn3), and a transcriptional factor essential for insulin transcription (MafA) are essential transcription factors for β-cell differentiation. Thus, miR-124a2 can directly modulate insulin expression‎ through foxA2 and then pdx1. miR-204 expression‎ is induced by the cellular redox regulator thioredoxin-interacting protein (TXNIP) that then represses MafA, thereby inhibiting insulin production.241 In addition, miR-185-5p overexpression‎ enhances insulin secretion and promotes pancreatic β-cell proliferation by targeting SOCS3 and regulating the Stat3 pathway.242

Numerous studies suggest that miRNAs have pivotal roles in glucose and lipid metabolism.243,244 As we mentioned above, glucose metabolism contains different processes including glucose transport, glucose uptake, gluconeogenesis and glycogenolysis. miR-93 was first reported to directly regulate GLUT4 expression‎ in adipocytes.245 Further, miR-29 and miR-31 regulate GLUT4 expression‎ in skeletal muscle and adipose tissues of T2DM patients,246 respectively. In addition, miR-27a/b levels are higher in the sera of patients with type 2 diabetes, while miR-27a/b overexpression‎ suppresses hepatic glucose output and alleviates hyperglycemia by targeting FOXO1.247 Moreover, elevated miR-338-3p levels are responsible for decreased glycogenolysis and subsequent glycogen accumulation by directly targeting the glycogen phosphorylase brain form (PYGB).248 miR-185-5p overexpression‎ in db/db mice that represent genetic diabetes models leads to alleviated blood hyperglycemia and decreased gluconeogenesis by directly targeting glucose-6-phosphatase (G6Pase). In addition, the anti-diabetic drug metformin can up-regulate miR-185-5p expression‎ to suppress G6Pase and inhibit hepatic gluconeogenesis.249

The balance of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) molecules that are synthesized in hepatocytes is critical for lipid homeostasis. Many miRNAs have been identified as critical regulators of HDL and LDL biogenesis. For example, miR-33, miR-128-1, miR-144, and miR-148a repress expression‎ of the ATP-binding cassette transporter ABCA1 that mediates hepatic HDL generation.250,251,252 Thus, inhibition of these miRNAs increases circulating HDL levels. In addition, miR-30c targets the gene encoding microsomal triglyceride transfer protein (MTP) that is required for the lipidation of newly synthesized APOB in the liver for LD lipoprotein production. miR-30c overexpression‎ reduces the assembly and secretion of these APOB-containing lipoproteins, resulting in decreased plasma LDL levels.253 The LDL receptor (LDLR) of hepatocytes is highly expressed and binds LDLs, clearing them from circulation. miR-148a and miR-128-1 repress LDLR expression‎ and inhibition of these miRNAs results in enhanced LDLR expression‎ and clearance of circulating LDL. Further, miR-224 and miR-520d target the LDLR chaperonin PCSK9 and IDOL in addition to the rate-limiting enzyme in cholesterol biosynthesis, HMGCR.254 In addition, inhibition of PCSK9, IDOL, and HMGCR by miR-224 and miR-520d was associated with increased LDLR protein levels and increased LDL binding, resulting in decreased plasma LDL cholesterol levels.

Chronic inflammation in insulin-reactive tissues is one of the most important causes of IR and increasing evidence suggests that miRNAs has a pivotal role in the inflammatory process. Obesity inhibited miR-30 expression‎ in adipose tissue macrophages (ATMs), and miR-30 was shown to target Delta-like-4 (DLL4), a Notch1 ligand is associated with ATM inflammation.255 miR-30 inhibition triggers Notch1 signaling, pro-inflammatory cytokine (TNFα and CCL2) production, and M1 macrophage polarization, indicating that miR-30 manipulation could be a therapeutic approach for reducing obesity-induced inflammation. Conversely, Wang et al. discovered that miR-1249-3p is significantly upregulated in Natural killer (NK) cells-derived exosomes from lean mice, which directly targets SKI family transcriptional corepressor 1 (SKOR1), subsequently downregulated the expression‎ levels of pro-inflammatory cytokine factors (including IL-1β, IL-6, and TNF-α) levels and attenuated IR. Therefore, it might be that metabolism-regulating miRNAs play a vital role in the dynamics of metabolic homeostasis.256

비코딩 RNA의 인슐린 저항성 조절

비코딩 RNA(ncRNA)는 인간 유전체 전사체의 약 98%를 차지하며 일반적으로 단백질로 번역되지 않습니다.233 최근 연구들234,235는 ncRNA가 마이크로RNA(miRNA), 장쇄 비코딩 RNA(lncRNA) 및 순환 RNA(circRNA)를 포함하며, 대사 균형의 병리 발생 및 진행에서 핵심 매개체 역할을 한다는 것을 보여주었습니다.

miRNA와 인슐린 저항성

미소RNA(miRNA)는 아르고나우트(Ago) 단백질에 결합하여 miRISC를 형성하는 작은 비코딩 RNA(18-22 뉴클레오티드)로, 부분적으로 또는 완전히 보완적인 표적 mRNA의 발현을 억제합니다.236 다양한 체액(예: 혈액, 타액, 소변) 내 다양한 miRNA의 조절 이상은 비만 및 IR 발병과 연관되어 있으며, 이는 β-세포 기능 장애, 포도당 및 지질 균형, 만성 염증과 관련이 있습니다. 237

첫째, 췌장 β 세포의 기능 장애 및/또는 사멸로 인한 β 세포 질량 감소는 인슐린 분비 부족의 주요 원인이며, 제1형 당뇨병(T1DM)과 제2형 당뇨병(T2DM)의 주요 공통 메커니즘입니다. 여러 miRNA는 β 세포 분화 및 성숙한 β 세포 기능에 관여합니다. 예를 들어, 췌장 특이적 miR-375 과발현은 포도당 자극성 인슐린 분비(GSIS)와 인슐린 유전자 전사를 억제하며, 이는 miR-375 억제 시 역전됩니다.238 또한, T2DM 및 전당뇨병 발병 전 혈장 내 miR-375, miR-150, miR-30a-5p, 및 miR-15a의 조절 장애가 관찰됩니다. 따라서 이러한 표지자는 T2DM 고위험군에서의 질병 예측 및 예방을 개선할 수 있습니다.239 다른 miRNA는 인슐린 저항성(IR) 동안 β 세포 증식 및 인슐린 분비 조절에 관여하는 것으로 알려져 있으며, 여기에는 miR-124a2, miR-204, miR-184 및 miR-24가 포함됩니다. 또한, miR-124a2는 cAMP 반응 요소 결합 단백질(creb-1)과 forkhead/winged helix 전사 인자 boxa2(foxA2) mRNA를编码하는 유전자를 표적으로 합니다.240 FoxA2는 췌장 십이지장 홈박스 1(pdx1)의 상위 조절자로, 췌장 발달과 혈당 균형에 필수적입니다. 또한 pdx1, 신경발생인자-3(ngn3) 및 인슐린 전사에 필수적인 전사 인자(MafA)는 β-세포 분화에 필수적인 전사 인자입니다. 따라서 miR-124a2는 foxA2를 통해 직접적으로 인슐린 발현을 조절하며, 이는 다시 pdx1을 통해 작용합니다. miR-204 발현은 세포 내 산화환원 조절인자 티오레독신 상호작용 단백질(TXNIP)에 의해 유도되며, 이는 MafA를 억제하여 인슐린 생산을 억제합니다. 241 또한 miR-185-5p 과발현은 SOCS3를 표적화하고 Stat3 경로를 조절함으로써 인슐린 분비를 증가시키고 췌장 β-세포 증식을 촉진합니다.242

수많은 연구는 miRNA가 포도당 및 지질 대사에서 핵심적인 역할을 한다는 것을 제시합니다.243,244 앞서 언급했듯이 포도당 대사는 포도당 운반, 포도당 흡수, 글루코네오제네시스 및 글리코겐 분해 등 다양한 과정을 포함합니다. miR-93은 지방세포에서 GLUT4 발현을 직접 조절한다는 것이 처음 보고되었습니다.245 또한 miR-29와 miR-31은 각각 제2형 당뇨병 환자의 골격근과 지방 조직에서 GLUT4 발현을 조절합니다.246 또한, 제2형 당뇨병 환자의 혈청에서 miR-27a/b 수준이 높으며, miR-27a/b 과발현은 FOXO1을 표적화하여 간 포도당 배출을 억제하고 고혈당을 완화합니다.247 또한, miR-338-3p 수준이 증가하면 글리코겐 분해를 감소시키고 이후 글리코겐 축적을 유발하며, 이는 글리코겐 포스포리레이스 뇌형(PYGB)을 직접 표적화합니다. 248 유전적 당뇨병 모델인 db/db 마우스에서 miR-185-5p 과발현은 글루코스-6-포스파타제(G6Pase)를 직접 표적화하여 혈당 상승을 완화하고 글루코네오게네시스를 감소시킵니다. 또한, 항당뇨병 약물 메트포민은 miR-185-5p 발현을 증가시켜 G6Pase를 억제하고 간 글루코네오게네시스를 억제합니다.249

간세포에서 합성되는 저밀도 지단백질(LDL)과 고밀도 지단백질(HDL) 분자의 균형은 지질 대사 균형에 필수적입니다. 많은 마이크로RNA(miRNA)가 HDL과 LDL 생합성의 핵심 조절자로 확인되었습니다. 예를 들어, miR-33, miR-128-1, miR-144, 및 miR-148a는 간 HDL 생성에 관여하는 ATP 결합 캐스케이드 운반체 ABCA1의 발현을 억제합니다.250,251,252 따라서 이러한 miRNA의 억제는 순환 HDL 수치를 증가시킵니다. 또한 miR-30c는 간에서 새롭게 합성된 APOB의 지질화(lipidation)에 필요한 미소소체 트리글리세라이드 전이 단백질(MTP)을编码하는 유전자를 표적화합니다. miR-30c의 과발현은 이러한 APOB를 포함하는 지단백질의 조립과 분비를 감소시켜 혈장 LDL 수치를 감소시킵니다.253 간세포의 LDL 수용체(LDLR)는 고도로 발현되며 LDL을 결합하여 순환에서 제거합니다. miR-148a와 miR-128-1은 LDLR 발현을 억제하며, 이러한 miRNA의 억제는 LDLR 발현 증가와 순환 중인 LDL 제거를 유발합니다. 또한 miR-224와 miR-520d는 콜레스테롤 생합성의 속도 제한 효소인 HMGCR 외에도 LDLR 분자 운반체 PCSK9와 IDOL을 표적으로 합니다.254 또한 miR-224와 miR-520d에 의한 PCSK9, IDOL, HMGCR의 억제는 LDLR 단백질 수준 증가와 LDL 결합 증가를 유발하여 혈장 LDL 콜레스테롤 수치를 감소시켰습니다.

인슐린 반응성 조직에서의 만성 염증은 IR의 가장 중요한 원인 중 하나이며, miRNA가 염증 과정에 핵심적인 역할을 한다는 증거가 점점 더 증가하고 있습니다. 비만은 지방 조직 대식세포(ATMs)에서 miR-30 발현을 억제하며, miR-30은 ATM 염증과 연관된 Notch1 리간드인 Delta-like-4 (DLL4)를 표적화하는 것으로 나타났습니다. 255 miR-30 억제는 Notch1 신호전달, 염증성 사이토킨(TNFα 및 CCL2) 생산, M1 대식세포 분화를 유발하며, 이는 miR-30 조작이 비만 유발 염증을 감소시키는 치료적 접근법이 될 수 있음을 시사합니다. 반면, Wang 등 연구진은 마른 쥐의 자연살해(NK) 세포에서 유래한 엑소좀에서 miR-1249-3p가 유의미하게 상향 조절되었으며, 이는 SKI 가족 전사 억제인자 1(SKOR1)을 직접 표적화하여 염증성 사이토킨 인자(IL-1β, IL-6, TNF-α 등)의 발현 수준을 감소시키고 인슐린 저항성(IR)을 완화시켰습니다. 따라서 대사 조절 미세RNA가 대사 균형의 역학에 중요한 역할을 할 수 있습니다.256

LncRNAs and IR

Long non-coding RNAs (lncRNAs)257 are non-coding transcripts more than 200 nucleotides, and the subcellular localization of lncRNAs determines their function. LncRNAs located in the nucleus could affect chromosomal biology or interact with transcription factors to regulate gene transcription; lncRNAs located in cytosol could modulate mRNA stability and translational efficiency by acting as sponges for miRNAs or direct pairing with mRNA. Recent advances have shown that lncRNAs play crucial roles in the pathologys of IR and diabetes.213,258,259

Glucose and lipid metabolism disorders are the primary causes for the pathophysiological development of IR. The lncRNA SRA promotes insulin-stimulated glucose uptake by co-activating PPARγ, leading to increased phosphorylation of the downstream targets Akt and FOXO1 in adipocytes.260 Furthermore, glucagon-stimulated upregulation of H19 via the AMP/PKA pathway induces nuclear translocation of HNF4A and activates the transcription of G6PC and PCK that are involved in gluconeogenesis, resulting in hepatic glucose production.261 In addition, the H19 sponge cell miR-130a induces PPARγ nuclear translocation, thereby activating the transcription of adipogenic genes like those encoding acetyl coenzyme a carboxylase 1 (ACC1), fatty acid synthase (FAS), and cytochrome c oxidase (SCO1), thereby promoting intracellular lipid accumulation.262 H19 is downregulated in skeletal muscles of db/db mice and interacts with heterogeneous nuclear ribonucleoprotein (hnRNPA1) that then increases fatty acid oxidation (FFA) protein translation. These processes are closely related to the genes PGC1a and CPT1b that reverse FFA-induced lipid accumulation and improve IR.263 This suggests the complex effect of lncRNAs on the IR progression.

In addition the insulin target tissues,264 transcriptome profiling and different studies have identified several β-cell specific lncRNAs that contribute to obesity-mediated β-cell dysfunction and apoptosis. LncRNA MALAT1 downregulation may lead to pancreatic β-cell dysfunction and T2DM development by direct interaction and regulation of polypyrimidine bundle binding protein 1 (PTBP1). The lncRNA-p3134 positively regulates GSIS by promoting PI3K/Akt/mTOR signaling and the key regulators (Pdx-1, MafA, GLUT2, and Tcf7l2) in pancreatic β cells. Further, lncRNA-p3134 overexpression‎ can decrease the β cell apoptosis ratio and partially reverse the glucotoxicity effects on GSIS function.265,266 Similarly, the newly identified lncRNA β-cell function and apoptosis regulator (βFaar) ameliorates obesity-associated β-cell dysfunction and apoptosis by upregulating the islet-specific genes (Ins2, NeuroD1, and Creb1) by sponging miR-138-5p.267 In addition, a novel micropeptide TUNAR encoded by lncRNA transcripts play a critical role in pancreatic β cell functions and insulin homeostasis.268 Collectively, these studies provide new insights into the use of lncRNAs as possible biomarkers or therapeutic targets for obesity-associated IR and metabolic diseases.

Circular RNAs (circRNAs) and IR

Contrary to conventional linear RNA, circRNAs are noncoding RNAs that generated from precursor mRNAs by back-splicing circularization, which is derived from exonic circRNAs, intronic circRNAs, exonic-intronic circRNAs and ntergenic circRNAs.269 CircRNAs can affect gene transcription, splicing and translation by acting as a miRNA sponges, binding to RNA binding proteins or transcription factors (TFs). Recent studies have suggested that newly identified circRNAs are novel factors in the initiation and development of IR.270 For example, ci-Ins2 is a conserved intronic circRNA derived from insulin pre-mRNA that exhibits lower levels in the islets of rodents and humans with type 2 diabetes.271 ci-Ins2 silencing in pancreatic islets leads to decreased expression‎ of several genes important for insulin secretion (Rapgef4, Pld1, Pclo, and Cacna1c) by interacting with the TAR DNA-binding protein 43 (TDP43), thereby contributing to β-cell dysfunction during diabetes. CircHIPK3 is one of the most abundant circRNAs in β-cells and regulates hyperglycemia and IR by sequestering miR-124-3p and miR-338-3p, thereby increasing mRNA expression‎ of key β-cell genes (e.g., Slc2a2, Akt1, and Mtpn), insulin secretion, and β-cell proliferation.272 A similar effect of circHIPK3 on hyperglycemia and IR has been observed by sponging miR-192-5p and increasing FOXO1 expression‎273. In addition, Hsa_circ_0054633 suppression promotes β-cell proliferation and facilitates insulin secretion through inhibiting caspase-8 expression‎ by sponging miR-409-3p.274 These recent results point to circRNAs as novel regulators of β-cell dysfunction under diabetic conditions.

Similar to the miRNAs and lncRNAs, several circRNAs also contribute to the the regulation of glucose and lipid homeostasis.275 Li et al.276 first demonstrated that circRNA-1897 is highly downregulated in the subcutaneous tissues of two pig breeds, and that it directly targets miR-27a and miR-27b-3p that are negative regulators of adipocyte differentiation by suppressing PPARγ expression‎. Deep sequencing analysis of adipose circRNA revealed that circArhgap5-2 is highly upregulated during differentiation of human white adipocytes.277 circArhgap5-2 silencing results in inhibited lipid accumulation and adipose marker (PPARγ, AdipoQ Cebpα, and FABP4) downregulation. Thus, circRNAs likely serve as important regulators of adipocyte differentiation and lipid metabolism. Another circRNA deep sequencing analysis of sera from patients with metabolic syndrome (MetS) identified the presence of a novel circRNA, circRNF111, involved in MetS progression.278 CircRNF111 inhibition enhances IR and lipid deposition in MetS by regulating the miR-143-3p/ IGF2R pathway.

AMPK is a critical factor in energy homeostasis including glycolysis, lipolysis, and fatty acid oxidation (FAO). CircACC1 is a circRNA derived from the human acetyl-CoA carboxylase 1 (ACC1) gene and directly binds to the β and γ subunits of AMPK, facilitating its activity,279 and promoting glycolysis and fatty acid β-oxidation during metabolic stress. circMAP3K4 is another potentially important circRNA involved in glucose metabolism that is highly expressed in the placentas of patients with gestational diabetes mellitus (GDM) and the IR model.280 circMAP3K4 can suppress the insulin-PI3K/Akt signaling pathway via the miR-6795-5p/PTPN1 axis, thereby contributing to GDM-associated IR. Nevertheless, the exact roles and regulatory mechanisms of circRNAs in IR require additional clarity.

Involvement of the gut microbiota in IRInfluencing factors of Gut microbiome composition

The microbes living in the human gut are key contributors to host metabolism and immune function through mediating the interaction between the host and environment, or releasing metabolites and cytokines.281 In 2012, the Human Microbiome Project Consortium began to show that the gut microbial phyla in humans mainly consist of the gram-positive Firmicutes, gram-negative Bacteroidetes and Proteobacteria.282 Although the composition of human gut microbiota remains relatively stable from around age 3, gut microbiota undergoes the increase in diversity and altered proportions of composition.283

Different factors influencing these alterations of gut microbiome composition have been explored including diet, exercise, circadian disruption, antibiotics treatments, and genetics.284 (1) Regarding diet: David et al.285 conducted a study of human wherein volunteers were placed on either a plant-based diet (i.e., with grains, legumes, fruits, and vegetables) or an animal product-based diet (i.e., with meats, eggs, and cheeses) for five consecutive days. The gut microbial communities of the groups significantly diverged over time, with participants on animal diets experiencing proliferation of bile-tolerant microorganisms (e.g., Alistipes, Bilophila, and Bacteroides) and decreased abundances of fiber-fermenting bacteria. Furthermore, differences in gut microbiota exists between humans with western diets rich in lipids and animal proteins in comparison to African diets rich in millet/sorghum and local vegetables, with little contribution of lipids and animal proteins to diets.286 (2) With regards to exercise, recent studies have highlighted the capacity of exercise to increase the abundances of beneficial gut microbial species, increasing gut microflora diversity, improving the proliferation of commensal bacteria, and reducing inflammation in addition to intestinal permeability.287,288 (3) Circadian disruption: both human and non-human models examination indicate that insufficient sleep (less than 7 h sleep per night) and circadian misalignment (such as workforce with shift workers or social jetlag) may lead to modifications in gut microbial diversity, structure and function.289,290 (4) Antibiotics: In deed, short-time antibiotic exposures can directly perturb the gut microbiota, reduce bacterial diversity and metabolic activity, disrupt intestinal integrity,291 which is a major cause for concern in human health. (5) Host genetics also shape the composition of the gut microbiome. For example, microbiome genome-wide association studies (mGWAS) have identified that variants of different genes (for example, VDR, LCT, NOD2, FUT2, and APOA5) that are associated with distinct gut microbiome compositions.292 Furthermore, 16 S ribosomal RNA (16 S rRNA) sequencing with microbiome analysis revealed that some species (especially from the phyla Firmicutes and Verrucomicrobia) in the gut microbiome are heritable.293 Thus, how to modulate the gut microbiota based on internal and external factors is important to maintain the public health.

Gut microbiome dysbiosis involved in IR

Growing evidence in the last two decades has suggested that gut microbial dysbiosis contributes to increased risks of metabolic defects like obesity, IR, and diabetes.294 For example, several studies have shown that obese adults harbor reduced gut microbial diversity and altered microbiota compositions compared with adults exhibiting normal weight.295 Another study of sixty-eight obese young patients revealed reduced fecal bacterial richness in patients with IR and high diastolic blood pressure (BP).296 Moreover, distinct microbial population markers were associated with impaired glucose tolerance, high BP, and low high-density lipoprotein cholesterol.297 A whole-genome sequencing investigation of the intestinal microbiota from 49 obese adults revealed that low bacterial gene counts were associated with unhealthy phenotypes like higher IR, dyslipidemia, and inflammation compared to adults with higher bacterial gene counts.298 While the exact roles of gut microbiomes in IR remain incompletely understood, many studies have nevertheless begun to elucidate the mechanisms by which gut microbiome dysbiosis produces different signaling activation.299 For example, gut microbiota can influence host glucose metabolism and hormone production via the production of several metabolites like short-chain fatty acids (SCFAs, mainly including acetate, propionate, and butyrate) and bile acids.300 Hyperglycemia then increases gut permeability and subsequent translocation of bacterial lipopolysaccharide (LPS) into systemic circulation. LPS circulation then contributes to the chronic inflammation of liver and adipose tissue that is associated with the development of IR, in addition to other conditions associated with metabolic syndromes.301 The potential mechanisms related to gut microbiome activities and IR are very complex, and numerous studies with contradictory results render it difficult to identify clear mechanistic pathways. Nevertheless, some strategies have been developed to modulate microbiota, such as fecal microbiota transplants, probiotics or prebiotics supplementation, in combination with medications and/or healthy lifestyle, in hope to ameliorate microbiota composition and IR.302,303

IR related diseases in human

As we all know, IR is a state in which higher than normal concentrations of insulin are needed for a normal response, leading directly to hyperinsulinaemia and impaired glucose tolerance.304 As mentioned above, the primary characteristics of IR are inhibited lipolysis in adipose tissue, impaired glucose uptake by muscle and inhibited gluconeogenesis in liver.305 Nevertheless, IR can be linked to a cluster of abnormal syndrome (Fig. 4), which include obesity, diabetes, Nonalcoholic fatty liver disease, cardiovascular disease, polycystic ovary syndrome, and other abnormalities.306,307,308 Since obesity and diabetes have been discussed in the previous content, this part we mainly summary other related metabolic syndrome in human.

Fig. 4

Insulin resistance related diseases in human

Full size image

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) and IR

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide.309 It includes a series of diseases, such as simple fatty liver (hepatic steatosis), non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma.310 Recently, a consensus of international experts proposed that the disease acronym have to be changed from NAFLD to metabolic (dysfunction) associated fatty liver disease (MAFLD). Adipose tissue is a physiologic reservoir of fatty acids,311 when the storage capacity is exceeded, the accumulation of heterotopic lipids leads to lipotoxicity, thereby promoting low-grade inflammation and IR in the liver.312 Lipotoxicity impairs insulin signaling, induces oxidative damage, promotes inflammation and fibrosis,313 which is thought to be related to the progression of MAFLD patients from simple steatosis to NASH, hepatic fibrosis, and hepatocellular carcinoma. Lipotoxic injury appears to occur in response to excessive levels of serum free fatty acids (FFAs) in hepatocytes.314 Circulating FFAs are the primary causes of liver fat accumulation in MAFLD that mainly occur due to lipolysis of adipose tissues, and partially from excess lipoprotein.315 Patients with MAFLD have increased levels of FFAs owing to a failure of insulin-mediated suppression of lipolysis, and excess FFAs excretion into the bloodstream.314 In addition to the influence of abnormalities on lipid metabolism, IR also indirectly contributes to MAFLD through inflammation.316,317 The transcription factor NF-κB exhibits higher levels in liver and adipose tissues during IR.318 Further, activation of NF-κB translocation to the nucleus leads to upregulated of the expression‎ of target genes that encoded inflammatory mediators, like TNF-α and IL-6, which are released by hypertrophic adipocytes and elevated during MAFLD.319 In addition, adiponectin is an anti-inflammatory adipokine that mediates fatty acid β-oxidation (FAO), glucose use, and suppression of fatty acid synthesis.320,321 Hepatic adiponectin expression‎ is lower in NASH patients, while the levels of adiponectin and its receptors increase after weight loss.322 Moreover, adiponectin overexpression‎ increases subcutaneous fat levels and protects against diet-induced IR.323 Isotopic tracer studies have shown that MAFLD patients exhibit increased de novo lipogenesis (DNL), that is respectively mediated by two transcription factors SREBP-1c and ChREBP.324,325 SREBP-1c is a major regulator of fatty acid synthesis and hepatic SREBP-1c overexpression‎ increases DAG content and PKCε translocation that in turn impairs INSR tyrosine kinase activity, thereby inducing hepatic IR.326,327 While ChREBP deficiency improves IR and hepatic steatosis by inhibiting the entire lipogenic and esterification process.328,329 Thus, inhibition of DNL and related pathway may effectively alleviate MAFLD and IR.

Polycystic ovary syndrome (PCOS) and IR

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by imbalances of multiple hormones that reflect the clinical manifestations of hyperandrogenism and affects 5%–10% of women of childbearing age.330,331 It is believed that IR and obesity play preval‎ent roles in causing PCOS, and PCOS women show an higher increased comorbidities of IR, including obesity, dyslipidemia, hypertension, and T2DM than healthy women.332,333,334 Specifically, IR leads to compensatory hyperinsulinemia, which stimulates GnRH gene transcription through MAPK pathway in PCOS and increases LH pulse secretion, thereby significantly increasing ovarian androgen synthesis.12,332 In addition to directly interfering with insulin signaling, androgens may also trigger lipolysis and increase circulating FFA, thereby leading to IR.335 Moreover, androgens decrease the type I muscle fibers (TIMF) with highly oxidative and insulin-sensitive properties, while increase type II muscle fibers (TIIMF) that are glycolytic and less insulin-sensitive, further decreasing glycogen synthase expression‎ and favoring the development of IR in PCOS.336,337,338 This evidence supports that IR and hyperandrogenemia continuously stimulates each other in a vicious cycle under the condition of PCOS. At present, the molecular mechanism of insulin in PCOS has been well described. First of all, the defects downstream of insulin receptor phosphorylation, such as activation of phosphorylated IRS-1 through PKC or GLUT-4 translocation through PI3K/Akt signaling pathway, are the causes of IR in some PCOS women.41,339 Second, certain proinflammatory mediators including TNF, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and IL-18 levels are elevated in PCOS women independently of obesity.340,341,342 Furthermore, hyperglycemia may contribute to inflammation in PCOS, possibly by inducing oxidative stress via increased ROS production. Such modifications then activate NF-κB that is involved in the expression‎ of proinflammatory mediators such as TNF and IL-6,343,344 and that induces key steroidogenic molecules, like CYP11A1, CYP17A1 and StAR, leading to further aggravation of hyperandrogenemia.345,346,347 Altogether, obesity and IR play pivotal role in women with PCOS and subsequent metabolic complications, and targeting these areas may become an important therapeutic approach for effectively reducing incidence of this pathology.

Cardiovascular disease and IR

Cardiovascular diseases (CVDs) are the leading causes of death globally. The World Health Organization estimates that 17.9 million people live with CVDs each year, and CVD-related deaths accounted for 32% of all global deaths in 2019. Moreover, over 23 million people are estimated to die from CVDs each year by 2030.348,349,350 CVDs represent a general compromising abnormal conditions including any disorders of heart and blood vessels. However, the most common types of CVDs include high blood pressure, coronary artery disease (CAD), stroke, cerebrovascular disease and rheumatic heart disease (RHD).351,352 Currently, the mechanisms of IR contribute to cardiovascular diseases mainly include chronic hyperglycemia, dyslipidemia, endothelial dysfunction and inflammation.9,353,354,355 Specifically, the increased gluconeogenesis and decreased glycogen synthesis in hepatic IR results in fasting hyperglycemia that increases total TG levels and blood pressure (BP), reduces HDL-C levels, and increases the risk of thrombosis formation.43,356 Moreover, long-term follow up data from patients with type 1 and type 2 diabetes have confirmed that hyperglycemia is a risk factor for CVD.357 IR in adipose tissue leads to high FFAs levels,358 visceral fat accumulation that is associated with elevated levels of plasminogen activator inhibitor 1 (PAI-1) and BP,359 and ectopic lipid and toxic lipid metabolite accumulation (lipotoxicity) in blood vessels that alters cellular signaling and cardiac structure, thereby contributing to the increased preval‎ence of cardiovascular diseases.360,361 Furthermore, IR induces dyslipidemia characterized by elevated serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG) along with reduced HDL-C concentrations, together which enhance the incidence of CVD by 32% in men and 76% in women.362,363 IR contributes to endothelial dysfunction by decreasing nitric oxide (NO) production via PI3K/Akt pathway from endothelial cells,364 and increasing reactive oxygen species (ROS) production, prothrombotic factors and proinflammatory markers mediated by MAPK/ERK activity,365 that both increases the cardiovascular risk, increased ROS levels in turn leads to the inhibition of insulin-PI3K signaling pathway through IRS-1 phosphorylation, which may aggravate IR.366 Overall, IR is a complex syndrome, which can significantly increase the risk of cardiovascular diseases. Identifying new therapies to reduce IR may contribute to the reduced preval‎ence of CVDs.

Alzheimer’s disease and IR

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is considered the sixth leading cause of death in the United States, with most patients aged 65 or older.367 Recent epidemiological studies have suggested that IR increases the risk for AD and related dementias.368 AD is actually a brain-specific form of diabetes that exhibit increased Aβ accumulation, tau hyperphosphorylation and impaired glucose transportation, energy metabolism, hippocampus and inflammatory pathways.369 Additional research has identified that insulin receptor is expressed on almost all cell types in the brain, with expression‎ highest in the olfactory bulb, followed by the cerebral cortex, hippocampus, hypothalamus, and cerebellum.370,371,372 Thus, insulin signaling likely also carries important and diverse roles in brain functioning and AD pathogenesis. Insulin primarily enters the brain via selective, saturable transport across the blood-brain barrier (BBB)373,374,375 Peripherally produced insulin can also be actively transported into the brain via an endocytic-exocytic mechanism.376 Similar to systemic IR, brain IR can be defined as failed response to insulin by brain cells,377,378 primarily due to downregulated insulin receptors, an inability of insulin receptors to bind insulin, or dysfunction of the insulin signaling cascade.379

Current researches have demonstrated that the mechanisms of systemic IR and brain-specific IR have close links with AD pathogenesis. For example, major abnormalities in AD brains include decreased mRNA and protein expression‎ levels of insulin, insulin receptors, insulin receptor substrate 1 (IRS1) and IGF1/2, in addition to reduced protein indicators of downstream insulin signaling activity (including phosphorylated AKT (pAKT) and phosphorylated GSK3β), tau mRNA, and increased amyloid precursor protein levels.380,381 Furthermore, recent evidence indicated that inflammation and lipid metabolism might contribute to the development of AD.382 Potential targets include PPARγ, Apoliprotein E (ApoE), Apolipoprotein E receptor (LRP1), and leptin.383,384,385 Chronic inflammation exacerbates IR signaling that contributes to AD by provoking proinflammatory mediators including TNF-α, IL-6, and IL-1β.386,387,388,389 Among these mediators, IL-6 can stimulate amyloid precursor protein (APP) formation, and is often co-localized with Aβ plaques in AD patients.390,391,392 Thus, rosiglitazone has anti-inflammatory effect by decreasing levels of NFκB and inhibiting the Aβ42 production in mice, is considering as therapeutic agent for AD. Pioglitazone acts similarly as Rosiglitazone by reducing tau and Aβ deposits in the hippocampus, and improving neuronal plasticity and learning in AD.393,394,395 These studies collectively suggest that IR contributes to AD pathogenesis through multiple pathways. Moreover, overlapping pathological features exist for diabetes, IR, and AD. Thus, the development of additional therapeutic drugs including antidiabetics or IR interventions with beneficial effects against cognitive impairment and Alzheimer’s disease carry promising future application potentials.

Chronic kidney disease and IR

Chronic kidney disease (CKD) involves a gradual loss of kidney function and inability to filter blood396,397 and is a major risk factor for end-stage kidney failure (ESKF) and CVDs.398,399 And the inflammatory and glycometabolic abnormalities that closely related to IR are common features in CKD and CVD, which explain the strong relationship between them.400 In the last decades, researchers have showed that IR is an early metabolic alteration in CKD, because IR plays a primary role in metabolic syndromes characterized by abdominal obesity, high fasting glucose levels, hypertriglyceridemia, depressed serum HDL-C, and high blood pressure, that are commonly observed in CKD patients.401,402,403 Furthermore, CKD patients demonstrate systemic inflammation and elevated levels of pro-inflammatory cytokines like C-reactive protein (CRP), TNF-α, IL-6 and IL-1β.404,405 In particular, reduced renal excretion leads to abnormal plasma adipokines levels including leptin and adiponectin in CKD patients.406 Leptin may also be considered as a uremia toxin through proinflammatory effects,407,408 while adiponectin mediates insulin-sensitizing and anti-inflammatory responses.409,410,411 Indeed, an accumulation of leptin is larger than adiponectin in CKD, and this abnormal ratio may further promote IR and metabolic disorders.412 Despite these above factors, evidences persist that endothelial dysfunction, oxidative stress, and vitamin D deficiency are important in the glucose intolerance pathogenesis and IR in patients with CKD.413,414,415 Thus, newly developed methods for improving IR could lead to potential strategies for preventing excess mortality of CKD patients.

Cancer and IR

Numerous recent epidemiological studies have suggested that IR increases the risks for different cancers including colon, liver, pancreas, breast, endometrium, thyroid and gastric cancer.416,417,418 Diverse cellular and molecular mechanisms are involved in the relationship between IR and cancer. Further, a growing body of evidence suggests that increased insulin, in addition to IGF1 and IGF2 levels critically influence tumor initiation and progression in IR patients.419 Specifically, the three ligands (insulin, IGF1, and IGF2) binds the receptors (IGF-IR and INSR) and activate the insulin receptor substrates. This in turn, first activates the PI3K/Akt/mTOR, PI3K/Akt/FoxO, or Ras/MAPK/(ERK-1/2) pathways that have important roles in cancer cell growth and carcinogenesis.420,421,422 Second, these processes inactivate GSK3β through the PI3K/Akt signaling pathway, resulting in oncogenic β-catenin signaling activation, that has been associated with cancer stemness and chemoresistance.423,424 In addition, insulin and IGF1 inhibit sex-hormone binding globulin (SHBG) synthesis, although both hormones stimulate ovarian synthesis of sex steroids that can promote cellular proliferation and inhibit apoptosis in breast epithelium and endometrium.416,425 Furthermore, the increased risk of cancer in IR patients may be due to excessive ROS production that then impairs the contribution of DNA to mutation and carcinogenesis.426,427,428 With the elucidation of more new molecular mechanisms of IR and cancer, the relationship of IR with different tumors will be more complicated, and novel diagnostic and therapeutic strategies may provide a new approach for preventing cancer other related diseases.

The diagnosis and therapeutic strategy of IR

Diagnosis methods of IR

As we all know, IR is related to several metabolic abnormalities including obesity, glucose tolerance, dyslipidemia, type 2 diabetes and other metabolic syndrome.429,430 Several methods are used to measure blood insulin levels that primarily include glucose tolerance tests (GTTs), insulin tolerance tests (ITTs), hyperinsulinemic-euglycemic clamp (HEC), continuous infusion of glucose with model assessment (CIGMA), the minimal model technique (MMT), insulin suppression test (IST), and insulin release tests (IRTs) (Fig. 5), and their differences are the sensitivity, limitation, and complexity of technical procedures.35,431 Glucose tolerance test (GTT) is given to determine how quickly exogenous glucose delivered via oral, intraperitoneal, or intravenous administration is cleared from the blood.432 The GTT method is used to diagnose diabetes mellitus including T1DM, T2DM and GDM.433 The Insulin Tolerance Test (ITT) is designed to examine the systemic sensitivity of insulin receptors by measuring blood glucose levels changes before and after intravenous insulin administration.434 This method is used to assess the insulin-sensitizing efficacy of test compounds and pharmacological agents that can modify insulin sensitivity.435 However, ITT often induces adequate hypoglycemia, severe hypokalaemia, it may as the systemic counter regulatory responses following the intravenous insulin.436,437 Despite these limitations, GTT and ITT are the most widely tests for assessing insulin sensitivity, largely because they are inexpensive and easy to perform.438 The HEC has been considered as the gold-standard method to assess insulin sensitivity in vivo. Actually, IR precedes the occurrence of T2DM, so how to increase the accurate assessment of insulin sensitivity is very important to predict the risk and eval‎uate the management of impaired insulin sensitivity and metabolic syndrome in research and clinical practice.

Fig. 5

Ex vivo diagnosis methods for insulin resistance

Full size image

As the same time, some other eval‎uation indices have been developed and tested the insulin sensitivity/resistance. HOMA2 (updated HOMA model which took account of variations in hepatic and peripheral glucose resistance), homeostatic Model Assessment for IR (HOMA-IR), the oral glucose insulin sensitivity index (OGSI), fasting Insulin (FINS), and fasting plasma glucose (FPG) based on fasting glucose and insulin levels439,440,441,442,443 are widely utilized IR measurements in clinical research. Other indices based on fasting insulin include the glucose to insulin ratio (GIR), the quantitative insulin sensitivity check index (QUICKI),444,445,446 triglycerides (McAuley Index) alone or in accordance with HDL cholesterol (HDL-C),447 whole-body insulin sensitivity index (WBISI), Matsuda Index to eval‎uate whole body physiological insulin sensitivity by the above methods. Indeed, the early symptoms of IR in different individuals are not obvious, and the related symptoms are very complex, combining with screening indicators may provide more precise diagnosis for IR in the general population.

Therapeutic strategy of IRClinical approved treatment to IR

No medications exist currently that are specifically approved to treat IR, but IR management91,448,449 is possible through lifestyle changes like dietary, increased exercise, and disease prevention in addition to alternative medications (Fig. 6). Among these treatments, lifestyle changes should be the main focus for IR treatment, with nutritional intervention to decrease calories, avoidance of carbohydrates, and focusing on aliments with low glycemic index (including vegetables, fruits, whole-grain products, nuts, lean meats or beans) to provide higher fiber, vitamins, healthy fats and protein are particularly helpful for people trying to improve insulin sensitivity.450,451,452 A healthy diet and regular physical exercise including approximately 30 minutes of exercise at least five days a week leads to activation of muscle cells that increase AMPK activity, thereby inactivating TCB1D1 and promoting GLUT4 translocation to cellular membrane, in addition to increasing glucose uptake that increases insulin reactivity.453,454 Moreover, losing just 5%–7% of body weight can prevent or delay 60% of diabetes and ameliorate insulin sensitivity in obese and overweight individuals.455 Some specific pharmacological medications have been used as a preventives in type 2 diabetes by improving insulin sensitivity, primarily including Biguanides, Thiazolidinediones and GLP-1 receptor agonists, etc. (Table 1). Metformin is a first-line medication and the most widely-prescribed insulin-sensitizing agent in T2DM and PCOS patients.456,457 Metformin mediates improved insulin sensitivity by increasing insulin receptor tyrosine kinase activity, enhancing glycogen synthesis, and increasing the recruitment and activity of the glucose transporter GLUT4.458,459,460 Metformin also promotes re-esterification of free fatty acids and inhibits lipolysis, which may then indirectly increase insulin sensitivity by reducing lipotoxicity in adipose tissues.461 In addition to metformin, other targeted drugs exist for T2DM treatment and improving insulin sensitivity. For example, (1) Glucagon-like peptide 1 (GLP1) is an intestinal hormone that can enhance insulin secretion in a glucose-dependent manner by activating the GLP-1 receptor (GLP-1R) that is highly expressed on islet β cells.462,463 GLP-1 receptor agonists including Liraglutide, Semaglutide, Dulaglutide and Exenatide have now been approved for treating T2DM.464,465,466,467,468 These GLP-1 receptor agonists can suppress the inflammatory response of macrophages, thereby inhibiting IR.469 (2) Dipeptidyl peptidase-4 (DPP-4) also referred as the T-cell antigen CD26 can degrade GLP-1.470 DPP is a local mediator of inflammation and IR in adipose and hepatic tissue that interacts with the integral membrane protein, caveolin-1, then impairing the activation of down-stream AKT signaling.471,472,473 DPP-4 inhibitors (such as gemigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, vildagliptin, et al.) are now world-wide therapy of T2DM since 2006 and could improve insulin sensitivity.474,475,476 (3) A third targeted drug is sodium-glucose cotransporter (SGLT2) that is the major cotransporter involved in glucose reabsorption in kidneys.477 SGLT2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin that have been approved by the FDA for combined use with diet and exercise to lower blood sugar and excessive insulin secretion in adults with type 2 diabetes.478,479,480 In addition, SGLT2 inhibitors exhibit beneficial effects for reducing IR and protecting pancreatic β cell functioning.481,482 (4) A fourth targeted drug approach is the activation of PPAR-γ in mature adipocytes that then induces altered expression‎ of several genes (increased GLUT4 and adiponectin expression‎, along with decreased TNF-α, IL-6 and leptin expression‎) involved in the insulin signaling cascade, thereby improving insulin sensitivity.483,484,485 PPAR-γ agonists (thiazolidinediones and TZDs) used for diabetes mellitus, which enhance adipocyte lipid storage, decrease ectopic lipid accumulation and improve insulin sensitivity in liver and skeletal muscles.486,487 Unfortunately, these agents have produced limited success due to reduced efficacy, low tolerability, and significant side effects including hypoglycemia, weight gain, bone fractures, and vomiting.488,489 Thus, it is urgent to find new approaches to treat T2DM and modify insulin sensitivity.

Fig. 6

Therapeutic strategy of insulin resistance

Full size image

Table 1 Clinical medication for improving insulin resistance

Full size table

Clinical trials for insulin sensitivity management

In clinical research, scientists and physicians have explored different strategies to prevent and treat diabetes mellitus and IR. We have searched the complete clinical trials (https://clinicaltrials.gov) to reduce IR and summarized them mainly include: (1) Diet intervention, such as Low-fat vegetarian Food, high-protein food, calorie restriction, vitamin D supplementation to reduce the IR in human obesity.490,491 (2) Pharmacological Intervention, such as BFKB8488A, the anti-fgfr1/KLB agonist antibody mimics the effect of FGF21, and causes short-term weight loss and increases insulin sensitivity.492,493 Several studies have also demonstrated that chromium picolinate administration lowers glucose and insulin levels in patients with type 2 diabetes;494,495 Salsalate inhibits IKK/NF-kB and may improve insulin sensitivity.496 Besides the above drugs, structural and functional dysbiosis of intestinal microbiome are induced in obese rodents,497,498 and they may cause IR and systemic inflammation.294,499,500 Thus, synbiotic therapy on intestinal microbiota has been developed as a new treatment strategy in clinical study (NCT04642482). We present some clinical trials of IR intervention in Table 2. Over the past years, our knowledge of the pathogenesis of IR and T2DM has improved, the development of new treatments of IR and metabolic syndrome have gained certain success, while the complexity of IR and the presence of multiple feedback loops make a challenge to the specific intervention.

Table 2 Selected clinical trials for insulin resistance in recent ten years (2013–2022)

Full size table

Preclinical studies for IR intervention

In recent years, accumulating preclinical studies on the intervention of IR have been reported, which have important reference significance for the development of new drugs. We present the related studies on IR reported in recent years in Table 3, including animal models, treatment methods and results. Pre-clinical IR intervention mainly includes drug intervention, probiotic therapy and exercise supplement. Drug therapy to improve IR is the main research direction at present. Researchers found that Valdecoxib (VAL) can inhibit inflammation and endoplasmic reticulum (ER) stress through AMPK-regulated HSPB1 pathway, thus improving skeletal muscle IR under hyperlipidemia.501 The insulin signal described above has a key role in AD pathogenesis. The researchers found that the mixed nasal administration of GLP-1 receptor agonist and L-form of peneracin can effectively alleviate the cognitive dysfunction of SAMP8 mice.502 In addition, studies have found that probiotics can adjust the changes of intestinal flora to reduce inflammation and IR, so probiotics may be an important supplement for the treatment of IR. Natividad et al.503 found that HFD-fed mice intervention by Lactobacilllus reuteri strain could effectively alleviate IR. Regular exercise is an alternative intervention measure to maintain the blood sugar level in the normal range and reduce the risk factors. Hsu and colleagues504 found that exercise combined with probiotics intervention can have a positive effect on blood sugar and increase insulin sensitivity in mice. The above results show that drug intervention, probiotic supplementation and intensive exercise can improve IR but more clinical data are still needed.

Table 3 Selected preclinical studies for insulin resistance

Full size table

Overall, the increased incidence of IR and the key roles of IR plays in many diseases, urgently require a better understanding of IR pathogenesis in addition to how IR interacts with genetics and different environments. A deeper understanding of IR can be achieved with a more systematic approach involving large-scale omics to study the molecular landscape is of major importance in addition to exploring new intervention strategies to prevent abnormal IR syndrome.

References

1. Banting, F. G. & Best, C. H. The internal secretion of the pancreas. 1922. Indian J. Med. Res. 125, 251–266 (2007).

   CAS PubMed Google Scholar 

2. SANGER, F. & THOMPSON, E. O. The amino-acid sequence in the glycyl chain of insulin. The identification of lower peptides from partial hydrolysates. Biochem J. 53, 353–366 (1953).

   Article CAS PubMed PubMed Central Google Scholar 

3. SANGER, F. & THOMPSON, E. O. The amino-acid sequence in the glycyl chain of insulin. II. The investigation of peptides from enzymic hydrolysates. Biochem J. 53, 366–374 (1953).

   Article CAS PubMed PubMed Central Google Scholar 

4. Kung, Y. T., Du, Y. C., Huang, W. T., Chen, C. C. & Ke, L. T. Total synthesis of crystalline bovine insulin. Sci. Sin. 14, 1710–1716 (1965).

   CAS PubMed Google Scholar 

5. Goeddel, D. V. et al. Expression‎ in Escherichia coli of chemically synthesized genes for human insulin. Proc. Natl. Acad. Sci. USA 76, 106–110 (1979).

   Article CAS PubMed PubMed Central Google Scholar 

6. Vecchio, I., Tornali, C., Bragazzi, N. L. & Martini, M. The discovery of insulin: an important milestone in the history of medicine. Front Endocrinol. 9, 613 (2018).

   Article Google Scholar 

7. Cheatham, B. & Kahn, C. R. Insulin action and the insulin signaling network. Endocr. Rev. 16, 117–142 (1995).

   CAS PubMed Google Scholar 

8. Root, H. F. Insulin resistance and bronze diabetes. N. Engl. J. Med. 201, 201–206 (1929).

   Article Google Scholar 

9. Laakso, M. & Kuusisto, J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat. Rev. Endocrinol. 10, 293–302 (2014).

   Article CAS PubMed Google Scholar 

10. Bugianesi, E., Moscatiello, S., Ciaravella, M. F. & Marchesini, G. Insulin resistance in nonalcoholic fatty liver disease. Curr. Pharm. Des. 16, 1941–1951 (2010).

    Article CAS PubMed Google Scholar 

11. Saklayen, M. G. The global epidemic of the metabolic syndrome. Curr. Hypertens. Rep. 20, 1–8 (2018).

    Article Google Scholar 

12. Diamanti-Kandarakis, E. & Dunaif, A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr. Rev. 33, 981–1030 (2012).

    Article CAS PubMed PubMed Central Google Scholar 

13. Stenvers, D. J., Scheer, F. A., Schrauwen, P., la Fleur, S. E. & Kalsbeek, A. Circadian clocks and insulin resistance. Nat. Rev. Endocrinol. 15, 75–89 (2019).

    Article PubMed CAS Google Scholar 

14. Freeman AM, Pennings N. Insulin Resistance. 2021 Jul 10. In: StatPearls Internet. Treasure Island (FL): StatPearls Publishing. PMID: 29939616.

15. American Diabetes Association. 3. Prevention or delay of type 2 diabetes: standards of medical care in diabetes-2021. Diabetes Care 44, S34–S39 (2021).

    Article Google Scholar