위 배출시간의 탐구!!

[문형철]

Neurogastroenterol Motil

. 2019 Feb 10;31(4):e13546. doi: 10.1111/nmo.13546

Advances in the physiology of gastric emptying

Raj K Goyal 1,✉, Yanmei Guo 1, Hiroshi Mashimo 1

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PMCID: PMC6850045  PMID: 30740834

Abstract

There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits.

The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP‐1 inhibit gastric emptying via the GIVMC, and in the inter‐digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.

초록
최근 위 운동과 위 배출의 생리학에 대한 다양한 측면에 대한 이해에 많은 발전이 있었습니다. 이전 연구에서는 위가 섭취한 음식 성분의 비우는 시기와 속도를 조절하는 놀라운 능력과 근본적인 운동 활동을 발견했습니다. 

최근 연구에 따르면 두 개의 병렬 신경 회로인 

위 억제 미주 운동 회로(GIVMC)와 

위 흥분성 미주 운동 회로(GEVMC)가

 위 억제와 흥분, 

따라서 위 배출 속도를 매개하는 것으로 나타났습니다. 

gastric inhibitory vagal motor circuit (GIVMC) and the

gastric excitatory vagal motor circuit (GEVMC)

GIVMC에는 

DMV의 신경절 전 콜린성 뉴런과 산화질소, 

ATP 및 펩타이드 VIP를 방출하여 작용하는 

장신경총의 신경절 후 억제 뉴런이 포함됩니다. 

GEVMC는 

DMV의 위 흥분성 신경절 전 콜린성 뉴런과 

장 신경총의 신경절 후 흥분성 콜린성 뉴런을 포함합니다. 

평활근은 

이러한 회로의 최종 목표입니다. 

신경근 전달에서 

카잘의 근육 내 간질 세포의 역할은 

아직 논란의 여지가 있습니다. 

두 개의 운동 회로는 NTS와 미주 구심체의 서로 다른 뉴런 세트에 의해 차등적으로 조절됩니다. 

소화기에는 

콜레시스토키닌과 GLP-1을 포함한 많은 호르몬이 

GIVMC를 통해 위 배출을 억제하고, 

소화기 간에는 그렐린과 모틸린 호르몬이 GEVMC를 자극하여 위 배출을 촉진합니다. 

GIVMC와 GEVMC는 

각각 거식성 및 식욕성 신경 경로와도 연결되어 있습니다. 

위 배출의 제어 회로를 규명하면 

비정상적인 위 배출의 병리 생리와 포만 신호 및 음식 섭취와의 관계를 더 잘 설명할 수 있습니다.

Keywords: digestive and inter‐digestive periods, gastric emptying, gastric motility, intestinal hormones, neural control, satiety and food intake, the interstitial cell of Cajal, vagal circuits

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Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.

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Key Points

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요점

• 최근 위 배출 조절에서 신경 회로, 위장 호르몬, 카잘 간질 세포 및 평활근의 역할에 대한 이해에 큰 발전이 있었습니다.
• 이 리뷰는 위 배출의 제어 시스템과 포만감, 배고픔 및 에너지 대사와의 연관성에 대한 통합 모델을 제시합니다.
• 이 정보는 위 배출과 당뇨병의 관계를 이해하고, 고혈당증, 제2형 당뇨병의 발병 기전 및 비만을 조절하기 위한 전략을 개발하는 데 유용할 것입니다.

1. INTRODUCTION

The gastric emptying rate is a measure of the speed of delivery of gastric contents into the duodenum. Gastric contents to be delivered include liquids, digestible solids, and indigestible food residues. Over the years, advances in understanding the different physiological components of gastric emptying have been facilitated by the development of reliable, noninvasive techniques in humans.1 The understanding of the biomechanics of the stomach helped to understand the relationship between gastric motility and gastric emptying.2, 3 These advances began with the appreciation that gastric emptying is regulated by the physical and chemical nature of the food4, 5 through neuro‐hormonal control mechanisms. Recent, ongoing studies have shown that inhibitory and excitatory vagal motor circuits and their regulatory neurons located in the solitary tract nucleus (nucleus tractus solitarius [NTS]) are responsible for the precise control of gastric emptying.6 The NTS neurons have widespread connections with neurons in the other parts of the CNS. Gastric inhibitory and gastric excitatory hormones released from the intestine and pancreas also actively regulate gastric emptying. Many of these hormones are also involved in immediate satiety signals, and long‐term food intake, energy metabolism, and bodyweight, thereby linking these metabolic changes to gastric emptying.

The precise regulation of the rate of gastric emptying of chyme (semifluid mass of partly digested food) into the duodenum is critical for further digestion and absorption in the small intestines. This regulation is provided by feedback from the intestines via a variety of gastrointestinal hormones. The rate of gastric emptying of carbohydrates and sugars is particularly an important determinant of postprandial glycemia. Slow gastric emptying may cause postprandial hypoglycemia, whereas fast gastric emptying may cause postprandial hyperglycemia. However, fast gastric emptying also upsets the release of intestinal hormones and has complex effects on glucose homeostasis. Fast gastric emptying is now recognized as a major factor in postprandial hyperglycemia and in the pathogenesis and management of diabetes mellitus (DM).7, 8, 9

The purpose of the present review is to synthesize the advances in the understanding of gastric motility and its neurohormonal control into an integrated model of gastric emptying.

1. 소개

위 배출 속도는

위 내용물이 십이지장으로 전달되는 속도를 측정하는 수치입니다.

위 내용물에는

액체, 소화가 가능한 고형물 및 소화가 불가능한 음식 잔류물이 포함됩니다.

수년에 걸쳐 위 배출의 다양한 생리적 구성 요소에 대한 이해는 신뢰할 수 있는 비침습적 인체 검사 기술의 개발로 촉진되었습니다.1 위의 생체 역학에 대한 이해는 위 운동과 위 배출 사이의 관계를 이해하는 데 도움이 되었습니다.2, 3 이러한 발전은 위 배출이 신경 호르몬 조절 메커니즘을 통해 음식의 물리적, 화학적 특성에 의해 조절된다는 인식4, 5에서 시작되었습니다.

최근 진행 중인 연구에 따르면,

억제성 및 흥분성 미주 운동 회로와

그 조절 뉴런이 단독 관핵(nucleus tractus solitarius [NTS])에 위치하여

위 배출을 정밀하게 제어하는 것으로 밝혀졌습니다.6

NTS 뉴런은

중추 신경계의 다른 부분의 뉴런과 광범위하게 연결되어 있습니다.

장과 췌장에서 분비되는

위 억제 호르몬과 위 흥분 호르몬도 위 배출을 적극적으로 조절합니다.

이러한 호르몬 중 다수는

즉각적인 포만 신호와 장기적인 음식 섭취,

에너지 대사 및 체중에도 관여하여

이러한 대사 변화를 위 배출과 연결합니다.

소장에서의 추가 소화 및 흡수를 위해서는

십이지장으로의 키임(부분적으로 소화된 음식의 반유체 덩어리) 위 배출 속도를 정확하게 조절하는 것이 중요합니다.

이 조절은 다양한 위장 호르몬을 통한 장의 피드백에 의해 이루어집니다.

특히

탄수화물과 당분의 위 배출 속도는

식후 혈당을 결정하는 중요한 요인입니다.

위 배출이 느리면

식후 저혈당증이 발생할 수 있고,

위 배출이 빠르면

식후 고혈당증이 발생할 수 있습니다.

그러나

빠른 위 배출은 장 호르몬의 방출을 방해하고 포도당 항상성에 복잡한 영향을 미칩니다.

빠른 위 배출은

이제 식후 고혈당증과 당뇨병(DM)의 발병 및 관리의 주요 요인으로 인식되고 있습니다.7, 8, 9

본 리뷰의 목적은

위 운동성과 신경 호르몬 조절에 대한 이해의 진전을

위 배출의 통합 모델로 종합하는 것입니다.

2. GASTRIC EMPTYING

The stomach performs a remarkable function of accepting large quantities of foods of different physical and chemical compositions over a short period. In humans, the stomach can expand 10‐15 times its empty state volume without a significant increase in intragastric pressure (called accommodation). Water may leave the stomach promptly.10 Digestible solids empty after they are pulverized to form chyme, which contains particles less than 2‐3 mm in size.5 Liquids and digestible solids are emptied in the digestive period that lasts 2‐3 hours after a meal. However, stomach retains large food particles that escape mincing during the digestive period, and then forcefully dumps them into the small bowel during the inter‐digestive period11 (Figure 1A).

2. 위 비우기

위는 단기간에 다양한 물리적, 화학적 성분의 음식을

대량으로 받아들이는 놀라운 기능을 수행합니다.

사람의 경우

위는 위내압이 크게 증가하지 않고도

비어 있는 상태 부피의 10-15배까지 팽창할 수 있습니다(이를 조절이라고 합니다).

물은

즉시 위를 떠날 수 있습니다.10

소화 가능한 고형물은 분쇄되어

크기가 2-3mm 미만인 입자를 포함하는 chyme를 형성한 후

비워집니다.5

액체와 소화 가능한 고형물은

식사 후 2-3시간 동안 지속되는 소화 기간에 비워집니다.

그러나

위는

소화 기간 동안 잘게 부서지지 않은 큰 음식물 입자를 유지한 다음

소화 간 기간 동안 소장으로 강제로 배출합니다11 (그림 1A).

Figure 1.

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Gastric emptying rates vary with the physical characteristic and caloric density of food. (A) Effect of physical characteristics of food on the rate of gastric emptying. Note that water or 5% glucose leaves the stomach at a fast rate, and digestible solids begin to leave after a lag period and leave the stomach slowly. Large pieces of indigestible solids are retained in the stomach during the digestive period and are then rapidly emptied. (B) Effect of caloric density of the liquid meal. Note that water leaves the stomach very fast and only 50% remains in the stomach at 10 min. High‐calorie liquids empty at a slower rate with 50% remaining in the stomach at 2 h. Low‐calorie liquids empty at an intermediate rate so the 50% leave the stomach by 1 h.

Hunt and others in the1950s and early 1960s also showed that the gastric emptying rate in the digestive period is highly dependent on volume, osmolality, the chemical composition, and caloric density of the food.4 The average stomach empties approximately 1‐4 kcal/min12 (Figure 1B).

위 배출 속도는 음식의 물리적 특성과 칼로리 밀도에 따라 달라집니다.

(A) 음식의 물리적 특성이 위 배출 속도에 미치는 영향.

물이나 5% 포도당은 빠른 속도로 위를 떠나고,

소화 가능한 고형물은 시차를 두고 천천히 위를 떠나기 시작합니다.

소화되지 않는 큰 고형물은 소화 기간 동안 위장에 남아 있다가 빠르게 비워집니다.

(B) 유동식의 칼로리 밀도에 따른 영향.

물은 매우 빠르게 위를 떠나며 10분이 지나면 50%만 위장에 남아 있습니다.

고칼로리 액체는 더 느린 속도로 비워져 2시간이 지나면 50%가 위장에 남습니다.

저칼로리 액체는 중간 속도로 비워져 1시간이 지나면 50%가 위장을 떠납니다.

1950년대와 1960년대 초에 헌트 등은 소화기의 위 배출 속도가 음식의 부피, 삼투압, 화학 성분 및 칼로리 밀도에 따라 크게 달라진다는 것을 보여주었습니다.4

평균적으로

위는

약 1~4kcal/min 12 (그림 1B)을 비우는 것으로 나타났습니다.

Because of the complex regulation of gastric emptying, proper assessment of all phases of gastric emptying requires separate studies of liquids and digestible solids of defined caloric density in the digestive period and of large indigestible particles in the inter‐digestive period. Moreover, earlier tests of gastric emptying were invasive and not repeatable. Development of noninvasive imaging and isotope techniques has now facilitated studies of gastric emptying in animals and humans.3 Scintigraphy using technetium (99m)‐sulfur colloid‐ or technetium (99m)‐diethylenetriaminepentaacetic acid‐labeled food remains the “gold standard.” Time taken to empty 50% of the ingested contents (t1/2) has often been used to describe gastric emptying rate for the purposes of comparison.13 Recently, low‐fat egg white meal with measurements at 0, 1, 2, and 3 or 4 hours has been used. Gastric retention of <30 at 1 hour is indicative of fast gastric emptying, and retention of >30% at 4 hours suggests slow gastric emptying.14 More recently, the 13C breath test that indirectly measures gastric emptying has been developed. In the absence of liver or kidney disease, the results of these tests correlate well with the results of the scintigraphy. These developments have facilitated the assessment of gastric emptying in disorders of gastric emptying.1

위 배출의 복잡한 조절로 인해 위 배출의 모든 단계를 적절히 평가하려면 소화기에는 칼로리 밀도가 정의된 액체와 소화 가능한 고형물을, 소화기 간에는 소화하기 어려운 큰 입자에 대한 별도의 연구가 필요합니다. 또한, 이전의 위 배출 검사는 침습적이고 반복할 수 없었습니다. 비침습적 영상 및 동위원소 기술의 발달로 동물과 사람의 위 배출 연구가 용이해졌습니다.3 테크네튬(99m)-황 콜로이드 또는 테크네튬(99m)-디에틸렌트리아민펜타아세트산 표지 음식을 사용한 신티그래피는 여전히 “황금 표준”으로 남아 있습니다. 섭취한 내용물의 50%를 비우는 데 걸리는 시간(t1/2)은 비교 목적으로 위 배출 속도를 설명하는 데 자주 사용되어 왔습니다.13 최근에는 0, 1, 2, 3 또는 4시간에 측정하는 저지방 난백 식사가 사용되고 있습니다. 1시간 후 위 잔류량이 30 미만이면 위 배출이 빠른 것으로, 4시간 후 위 잔류량이 30%를 초과하면 위 배출이 느리다는 것을 나타냅니다.14 최근에는 위 배출을 간접적으로 측정하는 13C 호흡 검사도 개발되었습니다. 간 또는 신장 질환이 없는 경우 이 검사 결과는 신티그래피 결과와 잘 일치합니다. 이러한 발전으로 위 배출 장애에서 위 배출을 평가하는 것이 용이해졌습니다.1

3. BIOMECHANICS OF GASTRIC EMPTYING

Earlier studies also defined how a single‐chamber stomach can serve multiple functions such as flexible storage, grinding of food, and controlled delivery of chyme into the duodenum.

In humans, the anatomic fundus and proximal corpus of the stomach serve as a flexible reservoir and a pressure pump. The distal corpus and proximal antrum constitute the peristaltic pump that primarily serves as a mixer. The terminal antrum and the pyloric sphincter form the functional grinder and filter2, 15, 16 (Figure 2). The gastric emptying during the digestive and inter‐digestive periods is differently regulated.

3. 위 배출의 생체 역학

초기 연구에서는 단일 챔버 위가 유연한 저장, 음식물 분쇄, 십이지장으로의 침 전달 조절 등 다양한 기능을 수행할 수 있는 방법에 대해서도 정의했습니다.

사람의 경우 해부학적 안저와 위 근위부는

유연한 저장소이자 압력 펌프 역할을 합니다.

anatomic fundus and proximal corpus of the stomach

원위부와 근위부는

주로 믹서 역할을 하는 연동 펌프를 구성합니다.

peristaltic pump that primarily serves as a mixer

말단 antrum과 유문 괄약근은

기능성 분쇄기 및 필터2, 15, 16를 형성합니다 (그림 2).

terminal antrum and the pyloric sphincter 

소화기 및 소화기 간 기간 동안의 위 배출은

다르게 조절됩니다.

Figure 2.

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Anatomic and functional parts of the human stomach, the gastric tunnel (Magenstrasse), and the pylorus. (A) Anatomic and functional parts of the stomach. The stomach includes three multifunctional, interconnected structures: pressure pump, peristaltic pump, and a grinder. The pressure pump includes anatomic fundus and proximal corpus. The peristaltic pump includes anatomic distal corpus and pyloric antrum. The pressure and peristaltic pumps form the propulsive unit. The anatomic correlate of the grinder is the pylorus that includes the anatomic pyloric canal and pyloric sphincter. Modified from Adler.15 (B) A functional tunnel along the lesser curvature of the stomach, called Magenstrasse, that may allow liquids to bypass the slower movement of the solid food through the stomach to accomplish a very fast gastric emptying. The figure identifies the initial location of particles emptied during 10 min, gray shaded with the time period of emptying, t emptying. From Pal et al10 (C) Details of the pyloric complex which includes the proximal muscle loop and the distal muscle loop formed by the pyloric sphincter. The proximal and distal muscle loops are ~2 cm away from each other on the greater curvature but merge together on the lesser curvature of the stomach. The loops enclose a triangular cavity with the merged muscle loops forming a torus at the lesser curve. The pyloric torus fits into the groove left between the proximal and distal muscle loops along the greater curvature, like a pastel and mortar, to form a perfect grinder. Pylorus provides mechanical grinding and food that has been tenderized by acid‐pepsin, to form chyme. The proximal muscle loop and the pyloric sphincter are separately regulated and can work independently

인체 위의 해부학적 및 기능적 부분, 위 터널(마겐슈트라세) 및 유문.

(A) 위의 해부학적 및 기능적 부분.

위에는 압력 펌프, 연동 펌프, 분쇄기라는 세 가지 다기능의 상호 연결된 구조가 있습니다. 압력 펌프에는 해부학적 안저와 근위부가 포함됩니다. 연동 펌프에는 해부학적 원위 코퍼스와 유문부가 포함됩니다. 압력 펌프와 연동 펌프는 추진 장치를 형성합니다. 그라인더의 해부학 적 상관 관계는 해부학 적 유문관과 유문 괄약근을 포함하는 유문입니다. Adler에서 수정됨.15

(B) 마겐슈트라고 하는 위의 곡률이 낮은 부분을 따라 있는 기능적 터널로, 액체가 위를 통과하는 고형 음식의 느린 이동을 우회하여 매우 빠른 위 배출을 달성할 수 있습니다. 그림은 10분 동안 비워진 입자의 초기 위치를 회색 음영으로 표시하고, 비워지는 시간인 t 비워짐을 나타냅니다. Pal 등10

(C) 유문 괄약근에 의해 형성된 근위 근육 루프와 원위 근육 루프를 포함하는 유문 복합체의 세부 사항.

근위와 원위 근육 루프는 곡률이 큰 쪽에서는 서로 약 2cm 떨어져 있지만, 곡률이 작은 쪽에서는 합쳐집니다. 루프는 삼각형의 구멍을 둘러싸고 있으며, 합쳐진 근육 루프는 더 작은 곡률에서 토러스를 형성합니다. 유문 토러스는 파스텔과 모르타르처럼 큰 곡률을 따라 근위와 원위 근육 루프 사이에 남은 홈에 맞물려 완벽한 그라인더를 형성합니다.

유문은

산-펩신에 의해 부드러워진 음식물을 기계적으로 분쇄하여

키임을 형성합니다.

근위 근육 루프와 유문 괄약근은 개별적으로 조절되며 독립적으로 작동할 수 있습니다.

4. GASTRIC EMPTYING DURING THE DIGESTIVE PERIOD

As the food is ingested and fills the stomach, fundic compliance increases so that a large volume of food is accommodated without an increase in pressure. In this filling phase, the pressure and peristaltic pumps remain inhibited and show no contractions. The filling phase is followed by a pumping phase, which is associated with a slow tonic contraction of the fundus and increased peristaltic contractions in the peristaltic stomach. This allows mixing of ingested food with gastric acid and pepsin and its transfer to the pylorus. The peristaltic pump also accepts food that escapes proper pulverization for recycling. The antrum fills to a certain level before food begins to enter the duodenum. This is reflected as the lag phase on the whole stomach‐emptying curve.

The stomach forms a functional tunnel named “Magenstrasse,” along with the lesser curvature of the stomach, that shunts liquids directly into the duodenum and bypasses the main stomach10 (Figure 2).

The tenderized food is propelled into the pyloric grinder by contractions that become forceful in the antrum. The pylorus relaxes to receive food from the proximal antrum.17 Pyloric contractions generate a powerful retrograde jet of food that escapes pulverization, and an anterograde jet of chyme into the duodenum. On intraluminal manometry, these events correspond with the antropyloric pressure waves (APPW) that are intimately associated with a pulsatile flow into the duodenum18 and “sieving function”.16 Closure of the pyloric sphincter that causes complete closure of gastroduodenal communication corresponds with the isolated pyloric pressure waves (IPPW) on intraluminal manometry in humans.19

Enhanced or impaired relaxation of the pressure pump leads to slow or fast gastric emptying, respectively. Loss of strength or organization of contractions of the peristaltic pump leads to poor mixing and slow gastric emptying, while the increased strength of peristaltic contractions leads to the fast gastric emptying of the digestible solids20 (Table 1).

4. 소화 기간 동안 위 비우기

음식물이 섭취되어 위를 채우면

위 순응도가 증가하여

압력의 증가 없이 많은 양의 음식물을 수용할 수 있습니다.

이 충전 단계에서는

압력 및 연동 펌프가 억제된 상태로 유지되며 수축이 나타나지 않습니다.

충전 단계가 끝나면 펌핑 단계가 이어지며,

이 단계에서는 안저의 강직성 수축이 느려지고

연동 위의 연동 수축이 증가합니다.

이를 통해

섭취한 음식물이 위산 및 펩신과 혼합되어

유문으로 이동합니다.

연동 펌프는 또한 재활용을 위해

적절하게 분쇄되지 않은 음식물을 받아들입니다.

음식물이 십이지장으로 들어가기 시작하기 전에

전정부가 일정 수준까지 채워집니다.

이것은 전체 위 비우기 곡선에서 지연 단계로 반영됩니다.

위는 “마겐스트라세”라는 기능적 터널을 형성하고

위의 곡률이 낮아져 액체를 십이지장으로 직접 보내고 주 위를 우회합니다10 (그림 2).

부드러워진 음식물은

유문부의 강력한 수축에 의해 유문 분쇄기로 밀려 들어갑니다.

유문은 이완되어 근위부 항문에서 음식물을 받습니다.17

유문 수축은 분쇄를 빠져나가는 강력한 역행 분출과 십이지장으로 유입되는 전역행 분출을 생성합니다.

내강 내 압력계에서 이러한 이벤트는 십이지장으로의 맥동성 흐름18 및 “체질 기능”과 밀접한 관련이 있는 유문 괄약근의 폐쇄와 일치합니다.16 위십이지장 소통의 완전한 폐쇄를 유발하는 유문 괄약근의 폐쇄는 사람의 내강 내 압력계에서 고립 유문 압력파(IPPW)와 일치합니다.19

압력 펌프의 이완이 강화되거나 손상되면 위 배출이 각각 느리거나 빨라집니다.

연동 펌프의 수축 강도나 조직이 약해지면 혼합이 잘 되지 않고 위 배출이 느려지며,

연동 수축의 강도가 증가하면 소화 가능한 고형물의 위 배출이 빨라집니다20 (표 1).

Table 1.

Anatomic parts, muscle type, the presence of ICC‐MY, type of contraction, and effect of inhibition or excitation on different functional parts of the stomach

Pressure pumpPeristaltic pumpGrinder

Anatomic parts	Fundus + proximal corpus	Distal corpus and proximal antrum	Terminal antrum + pyloric sphincter. Pylorus
Muscle type	Tonic	Phasic	Phasic + tonic
ICC‐MY	Absent	Present	Present
Type of contractions	Tonic	Phasic, peristaltic	Strong, phasic, nearly simultaneous
Effect of increased inhibition/decreased excitation	Slow gastric emptying	Impaired mixing Slow gastric emptying of solids	Impaired grinding Duodeno‐gastric reflux
Effect of reduced inhibition/increased excitation	Impaired accommodation and fast gastric emptying	Fast gastric emptying of solids	Outlet obstruction

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The pyloric sphincter and the duodenum work in a well‐coordinated way to regulate gastric emptying. As the pyloric complex acts as both a grinder and a variable filter, it can facilitate or inhibit gastric emptying in the digestive period. The duodenum relaxes during antral contractions—a phenomenon called “antroduodenal coordination.” After accepting injections of chyme, the duodenal bulb contracts to expel the chyme in a steady flow into the second portion of the duodenum. Studies have shown that slow gastric emptying with a high‐fat test meal was associated with decreased antral and increased duodenal contractile activity.21 Moreover, duodenal contractions may cause closure of the pyloric sphincter that in turn corresponds with the isolated pyloric pressure waves (IPPW) on intraluminal manometry.19, 22

유문 괄약근과 십이지장은 위 배출을 조절하기 위해 잘 조율된 방식으로 작동합니다.

유문 복합체는 분쇄기이자 가변 필터 역할을 하므로

소화 기간 동안 위 배출을 촉진하거나 억제할 수 있습니다.

십이지장은 항문 수축 중에 이완되는데, 이를 “항십이지장 조정”이라고 합니다.

십이지장 구근은 키메 주사를 받은 후 수축하여 십이지장의 두 번째 부분으로 키메를 일정한 흐름으로 배출합니다.

연구에 따르면 고지방 시험 식사로 위를 천천히 비우는 것은 항문 수축 활동 감소 및 십이지장 수축 활동 증가와 관련이 있는 것으로 나타났습니다.21

또한 십이지장 수축은 유문 괄약근의 폐쇄를 유발할 수 있으며, 이는 내강 내 압력계에서 고립 유문 압력파(IPPW)와 일치합니다.19, 22

5. GASTRIC EMPTYING IN THE INTER‐DIGESTIVE PERIOD

In the inter‐digestive (fasting) period, gastric motility designed to clear the stomach of undigestible residues. It is characterized by a cyclical motor activity called the migrating motor complex (MMC).23 The MMC is divided into four phases. Phase I lasts approximately 45‐60 minutes, during which the peristaltic pump exhibits electrical slow waves that are not associated with muscle contractions. Motor quiescence is due to tonic inhibition of the motor activity. Phase II is associated with slow waves associated with frequent phasic contractions. Phase III (also called “activity front”) is characterized by a front of large amplitude contractions, lasting 5‐15 minutes that march toward the pyloric sphincter. The phase III of the MMC is neurally mediated and is independent of the slow waves.24 During the migrating front, the pylorus and duodenum remain relaxed and open to allow phase III activity to sweep food residues out of the stomach.25 Loss of pyloric relaxation leads to gastric outlet obstruction and gastric stasis.26, 27 However, enhanced relaxation of the pylorus may facilitate duodeno‐gastric reflux.27 Phase IV includes inhibition of contractile activity that merges with the next phase of digestive period activity. Vagal stimulation immediately abolishes the gastric motor and neurohormonal activity during the digestive and inter‐digestive periods23 (Table 2).

5. 소화 간 기간의 위 비우기

소화간(공복) 기간에는 소화되지 않은 잔류물을 위장에서 제거하기 위한 위 운동이 이루어집니다. 이는 이동 운동 복합체(MMC)라고 하는 주기적인 운동 활동이 특징입니다.23 MMC는 네 단계로 나뉩니다.

1단계는 약 45~60분 동안 지속되며,

이 기간 동안 연동 펌프는 근육 수축과 관련이 없는 전기적 느린 파동을 나타냅니다.

운동 정지는 운동 활동의 강장제 억제로 인한 것입니다.

2단계는 잦은 위상성 수축과 관련된 느린 파동과 관련이 있습니다.

3단계(“활동 전선”이라고도 함)는 유문 괄약근을 향해 5-15분 동안 지속되는 큰 진폭의 수축 전선이 특징입니다. MMC의 3단계는 신경적으로 매개되며 느린 파동과는 무관합니다.24 이동 전선 동안 유문과 십이지장은 이완된 상태로 열려 있어 3단계 활동이 음식 잔여물을 위 밖으로 쓸어낼 수 있습니다.25 유문 이완의 손실은 위 출구 폐쇄와 위 정체를 유발합니다.26, 27 그러나 유문의 이완이 강화되면 십이지장-위 역류를 촉진할 수 있습니다.27

4단계에는 다음 단계의 소화기 활동과 합병되는 수축 활동의 억제가 포함됩니다. 미주 자극은 소화기 및 소화기 간 기간 동안의 위 운동 및 신경 호르몬 활동을 즉시 폐지합니다23 (표 2).

Table 2.

Neuro‐hormonal activity during the digestive and inter‐digestive periods

Digestive periodInter‐digestive periodImmediateLaterPhase IPhase IIPhase IIIPhase IV

Vagal activity	Increased inhibitory/reduced excitatory	Reduced inhibitory/increased excitatory	Increased inhibitory/reduced excitatory	Reduced inhibitory/increased excitatory	Non‐vagal, peripheral neuro‐hormonal	Increased inhibitory/reduced excitatory
Hormonal activity	Leptin, cholecystokinin, GLP‐1			Ghrelin	Motilin
Fundus	Increasing compliance	Decreasing compliance	No pressure	Increased tonic pressure	Increased tonic pressure	Increasing compliance
Antrum	Reduced phasic contractions	Increased phasic contractions	Reduced phasic contractions	Increased phasic contractions	Migrating motor complex	Reduced phasic contractions
Pylorus	Contraction	Relaxation		Relaxation	Relaxation	Contraction

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6. REGULATION OF GASTRIC MOTILITY AND EMPTYING

Gastric motility is regulated by the neural circuits that affect the activity of its final target, the smooth muscles. The interstitial cells of Cajal (ICC) may also be involved in the control of gastric emptying in multiple ways, including afferent mechanosensing,28 certain types of neuromuscular transmissions (NMT),29, 30 and phasic contractions in the antrum.31, 32 However, the multifunctional role of ICC has been questioned.33

6. 위 운동성 및 비움의 조절

위 운동성은 최종 목표인 평활근의 활동에 영향을 미치는 신경 회로에 의해 조절됩니다.

카잘 간질 세포(ICC)는 구심성 기계감지,28 특정 유형의 신경근 전달(NMT),29, 30 및 전위부의 단계적 수축 등 다양한 방식으로 위 배출 조절에 관여할 수 있습니다.31, 32 그러나 ICC의 다기능적 역할에 대해서는 의문이 제기되고 있습니다.33

7. NEURAL CONTROL OF GASTRIC MOTILITY

It is now generally accepted that autonomic nerves regulate gastric motility.34, 35, 36 Traditionally, parasympathetic and sympathetic motor nerves were thought to exert an excitatory and inhibitory effect on the stomach, respectively. However, studies showed that sympathetic nerves do not have an important role in physiological regulation of gastric motility, while the vagus nerves exert both inhibitory and excitatory effects on the stomach via the gastric inhibitory vagal motor circuit (GIVMC) and a gastric excitatory vagal circuit (GEVMC).37, 38, 39

Gastric inhibitory vagal motor circuit consists of preganglionic cholinergic and postganglionic non‐cholinergic inhibitory neurons. The GEVMC consists of preganglionic cholinergic and postganglionic cholinergic neurons. Moreover, the GIVMC and GEVMC are regulated by other connected neurons and, together, they constitute the gastric inhibitory vagal circuit (GIVC) and a gastric excitatory vagal circuit (GEVC), respectively. Because the neurons of the same chemical nature may be present at different locations of the circuit and even in two opposing circuits, we have identified them by their location, chemical nature, and the functional circuitry in the descriptive table (Table 3).

7. 위 운동의 신경 조절

자율 신경이 위 운동을 조절한다는 것은

이제 일반적으로 인정되고 있습니다.34, 35, 36

전통적으로 부교감 신경과 교감 운동 신경은

각각 위장에 흥분 및 억제 효과를 발휘하는 것으로 여겨졌습니다.

그러나

연구에 따르면 교감 신경은 위 운동의 생리적 조절에 중요한 역할을 하지 않는 반면

미주 신경은

위 억제 미주 운동 회로(GIVMC)와 위 흥분성 미주 회로(GEVMC)를 통해

위장에 억제 및 흥분 효과를 모두 발휘하는 것으로 나타났습니다.37, 38, 39

위 억제 미주 운동 회로는

신경절 전 콜린성 및 신경절 후 비콜린성 억제 뉴런으로 구성됩니다.

GEVMC는 신경절 전 콜린성 뉴런과 신경절 후 콜린성 뉴런으로 구성됩니다.

또한, GIVMC와 GEVMC는 서로 연결된 다른 뉴런에 의해 조절되며, 이들은 각각 위 억제 미주 회로(GIVC)와 위 흥분성 미주 회로(GEVC)를 구성합니다. 동일한 화학적 성질을 가진 뉴런이 회로의 다른 위치에 존재할 수 있고 심지어 서로 반대되는 두 개의 회로에 존재할 수도 있으므로 설명 표(표 3)에서 위치, 화학적 특성 및 기능적 회로에 따라 뉴런을 식별했습니다.

Table 3.

Abbreviated identity of neurons involved in gastric emptying as identified by three parameters, namely, anatomic location, chemical nature, and their participation in the gastric inhibitory or gastric excitatory and hunger or satiety neural circuits

Triangular parameters

Neuron identity	Location	Chemical nature	Neural circuit
NG‐GLUT‐i	Nodose Ganglion	Glutaminergic	Gastric inhibitory
NTS‐CC‐i	Nucleus tractus solitarius	Catecholaminergic	Gastric inhibitory
NTS‐GLUT‐e	Nucleus tractus solitarius	Glutaminergic	Gastric excitatory
NTS‐GABA‐e	Nucleus tractus solitarius	Gamma‐aminobutyric acid‐ergic	Gastric excitatory
NTS‐PPG‐i	Nucleus tractus solitarius	Pre‐proglucagon	Gastric inhibitory
NTS‐POMC‐s	Nucleus tractus solitarius	Pro‐opiomelanocortin	Satiety
DMV‐C‐e	Dorsal motor nucleus of vagus	Cholinergic	Gastric excitatory
DMV‐C‐i	Dorsal motor nucleus of vagus	Cholinergic	Gastric inhibitory
DMV‐GABA‐e	Dorsal motor nucleus of vagus	Gamma‐aminobutyric acid‐ergic	Gastric excitatory
MP‐C‐e	Myenteric Plexus	Cholinergic	Gastric excitatory
MP‐NANC‐i	Myenteric Plexus	Non‐cholinergic, non‐adrenergic	Gastric inhibitory
H‐POMC‐s	Hypothalamus	Pro‐opiomelanocortin	Satiety
H‐NPY/GABA‐h	Hypothalamus	Neuropeptide Y/Gamma‐aminobutyric acid	Hunger
H‐Gh‐h	Hypothalamus	Ghrelin	Hunger
H‐OREX‐h	Hypothalamus	Orexigenic	Hunger
H‐ANOREX‐s	Hypothalamus	Anorexigenic	Satiety

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8. GASTRIC INHIBITORY VAGAL MOTOR CIRCUIT (GIVMC)

Gastric inhibitory vagal motor circuit consists of preganglionic cholinergic neurons in the DMV (DMV‐C‐i) and postganglionic, non‐adrenergic non‐cholinergic (NANC) inhibitory neurons in the myenteric plexus (MP‐NANC‐i) (Figure 3A). The DMV‐C‐i neurons are distinct from the DMV‐C‐e neurons and are located in rostro‐lateral and caudomedial areas of the DMV.40 Moreover, DMV‐C‐i neurons are segregated into distinct groups and may have different chemical markers, so that they regulate the different regions of the stomach separately.41

8. 위 억제 미주 운동 회로(GIVMC)

위 억제 미주 운동 회로는

DMV의 신경절 전 콜린성 뉴런(DMV-C-i)과 장 신경총의 신경절 후 비아드레날린성 비콜린성(NANC) 억제 뉴런(MP-NANC-i)으로 구성됩니다(그림 3A).

DMV-C-i 뉴런은 DMV-C-e 뉴런과 구별되며 DMV의 등측 및 꼬리 쪽 영역에 위치합니다.40

또한, DMV-C-i 뉴런은 서로 다른 그룹으로 분리되어 있으며 화학 마커가 다를 수 있으므로 위장의 다른 영역을 개별적으로 조절합니다.41

Figure 3.

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A simplified gastric inhibitory vagal circuit (GIVC) and the gastric excitatory vagal circuit (GEVC). (A) The GIVC includes GIVMC and its inputs. GIVMC consists of preganglionic DMV‐C‐i neuron and postganglionic, NANC inhibitory neuron in the myenteric plexus (MP‐NANC‐i). See text for details of the neurotransmission. The DMV‐C‐i neurons receive excitatory input directly from the NTS‐CC‐i neurons via the α1‐receptors and through NTS‐PPG neurons via GHSR or GLP‐1 receptors. The NTS‐CC‐i neurons receive glutaminergic input from low‐threshold vagal afferents whose neurons are in the nodose ganglion (NG). (Arrow—stimulation; flat—inhibition). (B) The GEVC includes GEVMC and its inputs. GEVMC consists of preganglionic DMV‐C‐e neurons and postganglionic, cholinergic excitatory myenteric plexus (MP‐C‐e) neurons. DMV‐C‐e neurons receive strong inhibitory input from NTS‐GABA‐e neurons and NTS‐CC‐e neurons, and excitatory input from NTS‐GLUT‐e neurons. The NTS‐GABA‐e, NTS‐CC‐e, and NTS‐GLUT‐e neurons are interconnected and send integrated inhibitory input to the DMV‐C‐e neurons. NTS‐CC neurons also send inhibitory input to DMV‐C‐e neurons via the α2‐receptors. The inhibitory inputs from the NTS to DMV‐C‐e suppress spontaneously active DMV‐C‐e and cause gastric relaxation. On the other hand, suppression of the NTS‐GABA neurons NTS‐CC‐i disinhibits the spontaneously active DMV‐C‐e neurons leading to gastric excitation and fast gastric emptying as in acute hypoglycemia. See text for other details. (Arrow—stimulation; flat—inhibition)

Motor axons of the DMV‐C‐i neurons travel in the vagus nerve and exert a tonic inhibitory effect on the lower esophageal sphincter42 and the stomach.43, 44 The tonic inhibitory neural effect is also evidenced by the observation that an isolated guinea pig stomach is spontaneously contracted so that small gastric distension causes a steep increase in intragastric pressure and increases the amplitude of pressure waves. The resting tonic contraction may be due to the removal of tonic gastric inhibitory vagal influence. In contrast, larger distension volumes cause a decrease in the intragastric pressure indicating that the response is mediated by a local inhibitory reflex.45

Vagal motor fibers to different regions of the stomach assemble in different branches of the vagus that innervate the gastric fundus, corpus, and antrum and the pyloric sphincter.46 Various types of vagotomy performed for the treatment of peptic ulcer disease have provided important information on vagal control of motility of different parts of the stomach. Proximal gastric vagotomy leads to vagal denervation of the fundus and the proximal corpus and impairs receptive relaxation and accommodation of the fundus. These changes increase the fundic tone and lead to a fast emptying of liquids.43 Because proximal vagotomy spares the distal stomach, a regular pattern of trituration, sieving, and solid emptying is preserved. Truncal vagotomy and selective vagotomy denervate most of the stomach including the pylorus. Denervation of the pylorus causes a decrease in compliance and loss of relaxation that leads to pyloric obstruction and gastric stasis.44 On the other hand, stimulation of vagal motor fibers has been shown to decrease pyloric resistance.47 Clinically, truncal or selective vagotomy is always combined with pyloroplasty in the surgical treatment of peptic ulcer, to prevent gastric stasis.

The vagal motor axons of DMV‐C‐i neurons synapse onto the postganglionic, MP‐NANC‐i neurons via nicotinic (N) and muscarinic (M1) receptors.48 Stimulation of the MP‐NANC‐i neurons relaxes the smooth muscle by releasing NO, ATP, and VIP.49, 50 NO. causes smooth muscle relaxation in part by causing membrane hyperpolarization (nitrergic IJP) via sGC‐cGMP signaling; ATP causes relaxation mainly by causing membrane hyperpolarization via P2Y1 receptors‐SK channel signaling (purinergic IJP); VIP acts by increasing intracellular cAMP.51 Out of these different inhibitory transmissions, muscle relaxant effect of NO. is most prominent.52, 53, 54

Stimulation of nitrergic neuromuscular transmission (NMT) in the pressure and peristaltic pumps causes slow gastric emptying, while its suppression causes fast gastric emptying in the digestive period.55, 56 On the other hand, loss of nitrergic NMT in the tubular pylorus causes delayed gastric emptying in the inter‐digestive period.27 ICC‐IM and PDGFRα+ fibroblasts have been proposed to be necessary for nitrergic and purinergic NMT, respectively.29, 57 However, this proposal is open to question.56, 58

The regulatory part of the GIVC includes vagal afferents and second‐order neurons in the NTS for vagovagal reflex and other neurons that provide input to the NTS neurons. Esophagogastric relaxation and gastric accommodation reflexes are well‐studied gastric inhibitory vagovagal reflexes.40, 52, 53, 54 The vagal afferents have their cell bodies in the nodose ganglion. Originally, neural input to the DMV‐C‐i was thought to be from vagal afferents leading to monosynaptic vagovagal reflexes. However, it is now clear that the vagal afferents do not directly synapse on the DMV‐C‐i neurons but project onto second‐order neurons in the NTS (Figure 3A).

The vagal afferents provide glutaminergic excitatory input to the NTS‐CC‐i neurons.59 The afferent terminals are a site of action of multiple hormones that act presynaptically to modulate these synapses.60, 61 The NTS‐CC‐i neurons inhibit gastric motility by multiple pathways,62 including direct stimulation of DMV‐C‐i neurons via α1‐receptors63 and indirectly via stimulation of NTS‐PPG neurons that release glucagon‐like peptide‐1 (GLP‐1) onto the DMV‐C‐i neurons.64 Stimulation of NTS‐CC‐i neurons also inhibits DMV‐C‐e neurons via α2‐catecholaminergic receptors and further enhances the gastric inhibitory effect.63 It has been estimated that the GIVMC mediates fundic relaxation in the esophagogastric reflex.53

DMV-C-i 뉴런의 운동 축삭은 미주 신경을 따라 이동하며 하부 식도 괄약근42과 위에 강장 억제 효과를 발휘합니다.43, 44 강장 억제 신경 효과는 고립된 기니피그 위가 자발적으로 수축하여 작은 위 팽창이 위내 압력을 급격히 증가시키고 압력 파의 진폭을 증가시키는 관찰에서도 입증됩니다. 휴식 강장 수축은 강장성 위 억제 미주 영향의 제거로 인한 것일 수 있습니다. 반대로, 팽창량이 클수록 위내압이 감소하여 국소 억제 반사에 의해 반응이 매개된다는 것을 나타냅니다.45

위의 다른 부위에 대한 미주 운동 섬유는 위 안저, 소체 및 항문과 유문 괄약근을 자극하는 미주 신경의 다른 가지에 모입니다.46 소화성 궤양 질환 치료를 위해 수행 된 다양한 유형의 미주 절개술은 위의 다른 부분의 운동성에 대한 미주 조절에 대한 중요한 정보를 제공했습니다. 근위 위 미주신경절개술은 안저와 근위 소체의 미주신경 탈신경을 초래하고 안저의 수용성 이완과 조절을 손상시킵니다. 이러한 변화는 안저 톤을 증가시키고 액체의 빠른 배출로 이어집니다.43 근위부 질절개술은 원위부를 보존하기 때문에 삼투, 체질 및 고체 배출의 규칙적인 패턴이 보존됩니다. 근위부 질절개술과 선택적 질절개술은 유문을 포함한 대부분의 위를 탈신경화합니다. 유문의 탈신경화는 순응도를 감소시키고 이완을 상실하게 하여 유문 폐쇄와 위 정체를 유발합니다.44 반면에 미주 운동 섬유의 자극은 유문 저항을 감소시키는 것으로 나타났습니다.47 임상적으로, 소화성 궤양의 외과적 치료에서 항상 위 정체를 예방하기 위해 유문 또는 선택적 질 절개술은 유문 성형술과 결합됩니다.

DMV-C-i 뉴런의 미주 운동 축삭은 니코틴(N) 및 무스카린(M1) 수용체를 통해 신경절 후 신경절, MP-NANC-i 뉴런에 시냅스합니다.48 MP-NANC-i 뉴런의 자극은 NO, ATP 및 VIP를 방출하여 평활근을 이완시킵니다.49, 50 NO는 부분적으로 sGC-cGMP 신호 전달을 통해 막 과분극(질산성 IJP)을 일으켜 평활근 이완을 유발하고, ATP는 주로 P2Y1 수용체-SK 채널 신호 전달(퓨린성 IJP)을 통해 막 과분극을 유발하여 이완을 유발하며, VIP는 세포 내 cAMP를 증가시켜 작용합니다.51 이러한 다양한 억제 전달 중에서 NO의 근육 이완 효과가 가장 두드러집니다.52, 53, 54

압력 및 연동 펌프에서

질소성 신경근 전달 (NMT)의 자극은 느린 위 배출을 유발하는 반면,

그 억제는 소화 기간에 빠른 위 배출을 유발합니다 .55, 56

반면에, 관 유문에서 질소성 NMT의 손실은 소화기 간 위 배출을 지연시킵니다 .27 ICC-IM 및 PDGFRα + 섬유 아세포는 각각 질소성 및 퓨린 성 NMT에 필요한 것으로 제안되었습니다 .29, 57 그러나이 제안은 의문의 여지가 있습니다 .56, 58

GIVC의 조절 부분에는 미주성 반사를 위한 미주 구 심체와 NTS의 2차 뉴런 및 NTS 뉴런에 입력을 제공하는 기타 뉴런이 포함됩니다. 식도 위 이완 및 위 조절 반사는 잘 연구된 위 억제 미주 반사입니다.40, 52, 53, 54 미주 구심원은 결절 신경절에 세포체를 가지고 있습니다. 원래 DMV-C-i에 대한 신경 입력은 미주 구심성에서 단일 시냅스 미주 미주 반사로 이어지는 것으로 생각되었습니다. 그러나 이제는 미주 구심체가 DMV-C-i 뉴런에 직접 시냅스를 형성하지 않고 NTS의 2차 뉴런에 투사된다는 것이 분명해졌습니다(그림 3A).

미주 구심성은 NTS-CC-i 뉴런에 글루타민성 흥분성 입력을 제공합니다.59 구심성 단자는 이러한 시냅스를 조절하기 위해 시냅스 전 작용을 하는 여러 호르몬의 작용 부위입니다.60, 61 NTS-CC-i 뉴런은 여러 경로를 통해 위 운동성을 억제합니다.62 여기에는 α1 수용체를 통한 DMV-C-i 뉴런의 직접 자극63과 글루카곤 유사 펩타이드-1(GLP-1)을 DMV-C-i 뉴런으로 방출하는 NTS-PPG 뉴런의 자극을 통한 간접적 자극이 포함됩니다.64 NTS-CC-i 뉴런의 자극은 또한 α2-카테콜라민성 수용체를 통해 DMV-C-e 뉴런을 억제하고 위 억제 효과를 더욱 강화합니다.63 GIVMC는 식도 위 반사에서 기저 이완을 매개하는 것으로 추정되었습니다.53

9. GASTRIC EXCITATORY VAGAL MOTOR CIRCUIT (GEVMC)

Gastric excitatory motor circuit (GEVMC) consists of preganglionic cholinergic neurons (DMV‐C‐e) and postganglionic cholinergic (MP‐C‐e) neurons (Figure 3B). The DMV‐C‐e neurons of the GEVMC are distinct from the DMV‐C‐i neurons of the GIVMC.37 The DMV‐C‐e neurons are located in the more rostral and medial divisions of the DMV and are spontaneously active and may cause tonic excitation of the stomach muscle.40 Their motor axons are carried in the vagus nerve in the company of the fibers of the GIVMC and vagal afferents. The preganglionic efferent fibers synapse on the MP‐C‐e neurons involving nicotinic receptors. The postganglionic excitatory myenteric neuron releases acetylcholine to contract the smooth muscles via M3 receptors. ICC‐IM has also been proposed to be included in the transduction of cholinergic neural signals to smooth muscles.29, 30, 32, 65 However, the role of ICC‐IM in cholinergic NMT is questionable.33, 58, 66

The vagal excitatory circuits are a dominant regulator of gastric acid secretion and hormonal release, but GEVMC plays a less dominant role in gastric motility.36 Cholinergic excitatory motor responses are usually masked by the stronger inhibitory responses.67 Moreover, cholinergic responses are highly dependent on the sensitivity of the smooth muscle that is related to the activity of the RhoA/ROCK signaling.51, 68

The regulatory part of the GEVC includes GABAergic neurons that exert a tonic inhibitory influence on the DMV‐C‐e neurons and neutralize their excitatory tonic effect.69, 70 Stimulation of the NTS‐GABA‐e neurons suppresses the activity of DMV‐C‐e leading to a decrease in the gastric tone and the motility of the gastric corpus and antrum.71 A recent study using optogenetic stimulation suggested that somatostatin‐positive GABA neurons in the DMV are responsible for the gastric inhibitory effect of vagus‐mediated gastric antral motility.72 However, further studies are needed to elucidate the distinct roles of GABA neurons in NTS and DMV in gastric motility. NTS‐GABA and NTS‐non‐GABA inhibitory neurons and NTS‐GLUT excitatory neurons exert an inhibitory and excitatory effect, respectively, on the DMV‐C‐e neurons.73

Moreover, within the NTS, the GABA, non‐GABA, and GLUT neurons are interconnected.74 NTS‐CC‐e neurons may also act to inhibit DMV‐C‐e neurons via the α2‐receptors.62, 75 Thus, NTS neurons exert a precise inhibitory regulation of the GEVC. DMV‐C‐e neurons also receive GABAergic inhibitory input from area postrema.76 Interestingly, vagal afferent input to GEVMC has not been described.

A variety of neurotransmitters and endogenous chemicals may exert different effects on vagal circuits, based on the receptor type and the neural input. For example, dopamine may use either stimulatory effect via the dopamine 1 (DA1) receptors or inhibitory effect via the dopamine 2 (DA2) receptors on the DMV neurons of the GEVC.

Moreover, DA2 receptor‐mediated effect is more prominent than the DA1 receptor‐mediated effects.77 Thus, stimulation of dopaminergic projections of substantia nigra pars compacta (SNpc) causes some gastric excitation due to stimulation of DA1 receptors on the DMV‐C‐e neurons.77 However, gastric inhibitory effect and delayed gastric emptying in Parkinson's disease associated with loss of dopamine in substantia nigra may not be due to loss of DA1 receptor‐mediated excitatory effect on the DMV‐C‐e neurons but may be due to the increase in dopaminergic input from other neurons that primarily act to stimulate inhibitory DA2 receptors.77 Moreover, in animal models of Parkinson's disease a decrease in DA1 and increase in DA2 receptors in the DMV have been reported.78 Thus, degeneration of SNpc‐DMV dopaminergic pathway neurons in Parkinson's disease may cause delayed gastric emptying primarily due to a gain of DA2 receptor‐mediated neurotransmission in the DMV.79 It is intriguing to consider that prokinetic agents such as DA2 receptor antagonists may accelerate gastric emptying in Parkinson's disease.80 Although domperidone does not readily cross blood‐brain barrier, it may act on areas that have deficient blood‐brain barrier.81

10. MOTOR BEHAVIOR OF DIFFERENT SEGMENTS OF THE STOMACH

The different segments of the stomach may be regulated by distinct sub‐circuits of the GIVC and GEVC, the nature of their smooth muscles and presence of the ICC‐MY.

The smooth muscles of the pressure pump, the peristaltic pump, and the grinder‐filter have distinct mechanical behaviors. Smooth muscle of the pressure pump, fundus, and proximal corpus is primarily of tonic phenotype. In response to cholinergic stimulation, fundic smooth muscle elicits a strong tonic contraction.51, 68 The muscles of the peristaltic pump, distal corpus, and the proximal antrum are primarily of phasic phenotype, and cholinergic stimulation elicits phasic contractions.82 Muscle of the pyloric complex possesses both phasic and tonic muscles.

The phasic muscles are paired with the myenteric type of interstitial cells of Cajal (ICC‐MY). ICC‐MY generate propagates electrical slow waves in the distal stomach at a rate of 3‐5 per minute. That serve to set the pace for the phasic contraction and have been called pace‐setter potentials. The pylorus exhibits nearly simultaneous and strong slow waves that are associated with forceful contractions.83

Slow waves recorded by surface electrodes in vivo have often been assumed to represent phasic contractions. However, it has been reported that (a) extracellularly recorded slow waves in vivo may not represent true slow waves recorded intracellularly,84 (b) slow waves recorded by surface electrodes are strongly influenced by neural stimuli and may not represent mechanical contractions,85, 86 and (c) Klotho‐deficient progeric mice that have a profound loss of ICC and reduced amplitude of slow waves manifest no change in gastric emptying of solids.87 Therefore, the role of ICC‐MY and the slow waves recorded by surface electrodes remains unclear.

11. HORMONAL CONTROL OF GASTRIC MOTILITY

One of the most characteristic features of normal gastric emptying is its large variability, depending on the chemical composition of the food (Figure 1). The effect of different foods on gastric emptying is in large part due to the hormones released from the gastrointestinal tract that provides feedback regulation of gastric emptying. These hormones are released from the stomach, intestines, pancreas, and other tissues and act at various levels of the neural circuits including vagal afferents, NTS, area postrema (AP), preganglionic vagal neurons in the DMV, and myenteric plexus and the smooth muscle. It is noteworthy that the dorsal vagal complex (DVC, including NTS, AP, and DMV) is located outside the blood‐brain barrier, has a large network of fenestrated capillaries, and contacts specialized neurons lining the ependymal layer of the central canal and fourth ventricle.81 Some of these hormones, along with other mediators, act on other control centers to coordinate gastric motility with satiety, food intake, and energy balance. Some GI hormones serve as a brake to slow gastric emptying and are called “braking hormones,” while others serve to accelerate gastric emptying and are called “accelerating hormones” (Table 4).

Table 4.

Hormones that cause slow gastric emptying and that cause fast gastric emptying

Slow gastric emptyingFast gastric emptying

Cholecystokinin	Ghrelin
Leptin	Motilin
Glucagon‐like peptide‐1
Glucagon
Oxyntomodulin
Peptide YY
Gastrin‐releasing peptide
Enterostatin
Pancreatic amylin
Pancreatic polypeptide

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12. GASTRIC “BRAKING” HORMONES

Ingestion of a meal causes a release of a large number of hormones that act to put “brakes” on gastric emptying.88 These hormones are active during the digestive period and include cholecystokinin (CCK), GLP‐1, and leptin.

Cholecystokinin is a prototype of gastric braking hormones. It is released from neuroendocrine cells in the duodenum by stimuli such as hydrochloric acid, amino acids, and fatty acids. CCK acts to stimulate the GIVC at multiple levels. CCK stimulates vagal afferent endings of the vagal inhibitory circuit in a paracrine fashion,89, 90 may act on nodose ganglion,91 and may enhance synaptic neurotransmission at the vagal afferent second‐order NTS‐CC‐i neurons by enhancing release of glutamate in the NTS.89, 92 Furthermore, intraperitoneal application of CCK‐8 induces c‐FOS immunoreactivity in the catecholaminergic (CC), pro‐opiomelanocortin (POMC), and pre‐proglucagon (PPG) neurons.93 CCK stimulation of the NTS‐CC‐i neurons may, in turn, stimulate NTS‐POMC and NTS‐PPG neurons. Thus, CCK may excite DMV‐C‐i neurons using multiple pathways including the projections of the NTS‐CC‐i neurons via the α1‐receptor89, 94 and projections of the NTS‐PPG neurons via GLP‐1. CCK also exerts its gastric inhibitory effect by stimulating the myenteric non‐adrenergic non‐cholinergic (NANC) inhibitory neurons95 (Figure 4A).

12. 위 “제동” 호르몬

음식을 섭취하면 위 배출에 “브레이크”를 거는 역할을 하는 많은 호르몬이 분비됩니다.88 이러한 호르몬은 소화 기간 동안 활성화되며 콜레시스토키닌(CCK), GLP-1 및 렙틴을 포함합니다.

콜레시스토키닌은 위 제동 호르몬의 원형입니다. 염산, 아미노산, 지방산과 같은 자극에 의해 십이지장의 신경 내분비 세포에서 방출됩니다. CCK는 여러 수준에서 위장관 자극 호르몬으로 작용합니다. CCK는 미주 억제 회로의 미주 구심성 말단을 파라크린 방식으로 자극하고,89, 90 결절 신경절에 작용할 수 있으며,91 NTS에서 글루타메이트의 방출을 강화하여 미주 구심성 2차 NTS-CC-i 뉴런에서 시냅스 신경전달을 향상시킬 수 있습니다.89, 92 또한, CCK-8의 복강 내 적용은 카테콜아민성(CC), 프로-오피오멜라노코르틴(POMC) 및 프리-프로글루카곤(PPG) 뉴런에서 c-FOS 면역 반응성을 유도합니다.93 NTS-CC-i 뉴런의 CCK 자극은 차례로 NTS-POMC 및 NTS-PPG 뉴런을 자극할 수 있습니다. 따라서 CCK는 α1 수용체89, 94 를 통한 NTS-CC-i 뉴런의 투영과 GLP-1을 통한 NTS-PPG 뉴런의 투영 등 여러 경로를 통해 DMV-C-i 뉴런을 흥분시킬 수 있습니다. CCK는 또한 장 비아드레날린성 비콜린성(NANC) 억제 뉴런을 자극하여 위 억제 효과를 발휘합니다95 (그림 4A).

Figure 4.

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Main sites of action of CCK and ghrelin. (A) Cholecystokinin (CCK) is a prototype breaking hormone. It acts to stimulate vagovagal circuit at multiple levels. CCK stimulates vagal afferents endings by paracrine effect and enhances glutamate release from the vagal afferent endings projecting onto NTS‐CC‐i neurons. CCK also directly or indirectly stimulates NTS‐CC‐i neurons, PPG‐i neurons, and NTS‐POMC‐S neurons. CCK stimulation of NTS‐CC‐i neurons activates DMV‐C‐i via the α1‐adrenergic receptor; stimulation of the NTS‐PPG‐i neurons via the GLP‐1 receptor on the DMV‐C‐i. CCK has also been shown to directly stimulate MP‐NANC‐i neurons, and may also stimulate DMV‐C‐i neurons. Thus, CCK acts at multiple sites to stimulate GIVC. Stimulation of NTS‐CC‐i neurons also inhibits DMV‐C‐e neurons via the α2‐adrenergic receptors. Thus, CCK also acts to inhibit GEVC. All these actions further augment the inhibitory effect of CCK on the gastric muscle. CCK also stimulates NTS‐POMC‐s neurons to generate satiety signals. (Arrow—stimulation; flat—inhibition). (B) Ghrelin is a gastric accelerating hormone. Ghrelin acts at multiple central and peripheral sites to stimulate gastric motility. Centrally, ghrelin inhibits NTS‐CC‐i neurons thereby inhibiting DMV‐C‐i. Ghrelin also inhibits NTS‐CC‐e to disinhibit DMV‐C‐e neurons. Ghrelin also disinhibits DMV‐C‐e neurons by inhibiting AP‐GABA‐e neurons that project onto DMV‐C‐e neurons. Ghrelin also acts on myenteric plexus and the smooth muscle. All these actions lead to strong gastric excitation. (Arrow—stimulation; flat—inhibition)

CCK also interacts closely with GLP‐1 and bile salts. CCK releases GLP‐1 that is an important gastric inhibitory hormone. It has been reported that entry of chyme in the gut releases nesfatin‐1 that stimulates CCK secretion that causes gallbladder emptying and rise in bile salts.96 Bile salts stimulate Takeda G‐protein‐coupled receptor‐5 (TGR5) on the basolateral aspect of the enteric endocrine L cells to elicit GLP‐1 secretion.97 CCK activation of NTS‐CC‐i neurons may also inhibit DMV‐C‐e via the α2‐adrenergic receptors. All these actions of CCK lead to robust gastric inhibition and slowed gastric emptying.

Gastric emptying is also slowed by the products of posttranslational modifications of pre‐proglucagon, which act to slow gastric emptying and serve as braking hormones.98 In the pancreatic alpha cells, these products include glucagon, proglucagon 1‐61, and the so‐called major proglucagon factor (MPGF, ie, fused GLP‐1 and GLP‐2). Following ingestion of a meal, the L cells of the intestinal wall and PPG neurons in the NTS produce pre‐proglucagon gene products including GLP‐1 and its amide, GLP‐2, oxyntomodulin, and glicentin. GLP‐1 is the most studied in this group. However, GLP‐1 is rapidly degraded by N‐terminal degradation by dipeptidyl peptidase IV (DPP IV, CD26). DPP IV inhibitors and DPP IV‐resistant incretin analogs have been used to prolong its activity.99

GLP‐1 released from the intestines acts to stimulate vagal afferents that stimulate the second‐order NTS‐CC‐i neurons that activate DMV‐C‐i neurons. GLP‐1 released from NTS‐PPG neurons also stimulates DMV‐C‐i neurons.89 By stimulating NTS‐CC‐e, GLP‐1 may also inhibit DMV‐C‐e neurons. These multiple actions account for a strong inhibitory effect of GLP‐1 on gastric motility.89, 100 In functional studies, intravenous GLP‐1 has been shown to retard gastric emptying and decrease the number and volume of flow pulses in the trans‐pyloric flow. This was associated with an inhibition of antropyloric pressure waves, but stimulation of isolated pyloric pressure waves, and an increase in basal pyloric tone.101 Interestingly, decreased gastric contraction but increased intestinal contractions have been reported to cause delayed gastric emptying in response to nutrients.21

Other pancreatic hormones such as insulin and islet amyloid peptide (amylin) are co‐secreted from the beta cells. Both these hormones act to slow gastric emptying and reduce appetite. Pancreatic polypeptide (PP) is secreted by PP cells of the pancreas during the cephalic phase of gastric acid secretion via cholinergic excitatory pathway.102 PP has been shown to act on the area postrema and stimulate a gastric inhibitory vagovagal reflex and slow gastric emptying.76

Gastric leptin is released from the chief cells along with pepsin in the gastric juice by protein load and vagal stimulation. It is reprocessed in the small bowel to be released as a hormone. Leptin may produce its peripheral effect via the CCK1 receptors. However, the primary source of leptin is white fat cells (adipokine leptin). Gastric leptin slows gastric emptying in response to a protein meal. Secretion of adipokine leptin is constitutive and exerts its primary effect on hypothalamic nuclei to inhibit food intake and gastric emptying.103 It is interesting to note that intragastric infusion of nutrient rapidly inhibits hunger‐promoting, agouti‐related peptide/neuropeptide Y (AgRP/NPY, orexigenic) neurons in awake mice. This inhibition is proportional to the number of calories but independent of the type of food and is mediated by CCK, peptide YY, and 5‐hydroxytryptamine (5HT). Leptin induces a slow modulation that develops over hours and is required for the inhibition of feeding.104

13. GASTRIC “ACCELERATING” HORMONES

Ghrelinand motilin act to accelerate gastric emptying and are released in the inter‐digestive (fasting) period.105 No gastric accelerating hormones are released in the digestive period. Ghrelin is released from G cells in the stomach and the ghrelin‐containing neurons in the hypothalamus. Ghrelin acts on the growth hormone secretagogue receptor (GHSR) to stimulate the release of growth hormone. Ghrelin increases food intake, fat deposition, and weight gain.106 It is a primary stimulant of appetite and is called the “hunger hormone” (Table 4).

Ghrelin serves as a neurotransmitter as well as a hormone, exerts its effects centrally as well as peripherally, and acts on afferent as well as efferent pathways (Figure 4B). Ghrelin inhibits vagal afferent activity at the level of the sensory endings,107 nodose ganglion,108 and the afferent terminal to NTS‐CC synapses.59, 61 Suppression of NTS‐CC neurons leads to inhibition of the DMV‐C‐i and disinhibition of DMV‐C‐e neurons. Ghrelin also disinhibits DMV‐C‐e neurons by activating AP‐GABA neurons109, 110 and facilitates excitatory transmission to DMV‐C‐e neurons.111 Moreover, ghrelin also directly stimulates MY‐C‐e neurons. These actions lead to the gastric stimulatory effect of ghrelin. Functional in vitro studies have shown that ghrelin augments electrically stimulated contractions of fundic strips in mice.112 In vivo, ghrelin increases gastric myoelectrical activity and gastric emptying in the rats.113 Ghrelin activates phase II activity in the antrum of the fasting stomach by a central action.111 The peripheral action of ghrelin facilitates motilin to induce the activity in front of the MMC.114 By inhibiting the vagal afferents, ghrelin also suppresses anorexigenic signals and stimulates hunger at the NTS and hypothalamic levels.107, 115

Motilin is released from M cells during the inter‐digestive phase.114 Motilin release is due to duodenal alkalization that occurs as a compensatory response to duodenal acidification during the digestive phase. Acidification of the duodenum causes a release of prostaglandin E2 (PGE2) and 5HT. PGE2 inhibits further acid secretion and contributes to duodenal alkalization. 5HT acts on 5HT4 receptors to cause a release of duodenal bicarbonate that further alkalinizes the duodenal mucosa. 5HT4 receptor stimulation also causes duodenal contractions that activates a gastro‐stimulatory ascending vagal reflex.19

Motilin acts on multiple sites including the myenteric neurons and smooth muscles in a species‐dependent fashion.116 Its action on myenteric plexus neurons initiates phase III of the gastric MMC that promotes gastric emptying of indigestible food residues. Phase III of the MMC is strongly inhibited by the gastric inhibitory vagovagal reflex that is activated upon ingestion of food. It is worth pointing out that rodents do not exhibit typical MMC pattern because they lack motilin owing to a defective motilin gene.117 However, dogs and the house musk shrew (Suncus murinus) exhibit MMC pattern similar to that seen in humans. Therefore, these animal species have been used to investigate the mechanism of action of ghrelin and motilin in MMC.114

14. LINKING GASTRIC EMPTYING TO SATIETY SIGNALS, FOOD INTAKE, AND GLUCOSE METABOLISM

Gastric emptying is linked to sensations of satiety, appetite, and hunger and their hedonic aspects as well as to chronic food intake and energy homeostasis. This linkage involves connections of the GIVC and GEVC with the NTS‐CC‐i and NTS‐CC‐e neurons connected with satiety‐ and hunger‐associated neural pathways, respectively, in the hypothalamic, limbic, and cortical areas of the brain118 and the NTS.94, 119

15. CONCLUSION

The primary function of the stomach is to prepare ingested food into chyme and provide regulated delivery into the small bowel that is measured as gastric emptying. Earlier studies had identified two remarkable characteristics of gastric emptying: (a) ability to regulate the timing and rate of emptying of ingested food of different physical compositions; and (b) ability to regulate emptying based on the caloric density of food. Studies on the biomechanics of gastric emptying revealed that activity of different anatomic parts of the stomach was integrated to form functional “pressure” and “peristaltic” pumps and a grinder‐filter that played well‐defined roles in gastric emptying. The peristaltic pump is mainly involved in gastric emptying of solids.

The pattern and the rate of gastric emptying have been shown to be regulated by two parallel circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), which mediate gastric inhibition and excitation, respectively. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic NANC inhibitory neurons, in the myenteric plexus. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neuron in the DMV and postganglionic excitatory, cholinergic neurons in the myenteric plexus. It was proposed but remains unproven that ICC‐IM were required to transduce nitrergic and cholinergic neural signals to the gastric smooth muscles. The circuits for different parts of the stomach are distinct, so that different parts of the stomach can be differentially regulated. Currently, ongoing studies also show that some intestinal and pancreatic hormones released during the digestive period inhibit gastric motility by stimulating the GIVC and inhibiting the GEVC.

On the other hand, in the inter‐digestive period, hormones ghrelin and motilin and motilin act by stimulating gastric pumps and inhibiting pyloric contraction. Studies have also shown that the GIVC is linked to anorexigenic neurons in the NTS and hypothalamus, and GEVC may be linked to the orexigenic signals. Therefore, neurohormonal controls link disorders of gastric emptying with satiety signal, food intake, and energy metabolism as well as postprandial hyperglycemia in the pathogenesis and management of diabetes mellitus.

15. 결론
위의 주요 기능은 섭취한 음식물을 소화액으로 준비하고 위 배출로 측정되는 소장으로 조절된 전달을 제공하는 것입니다. 초기 연구에서는 위 배출의 두 가지 주목할 만한 특징, 즉 (a) 섭취한 음식의 물리적 구성이 다른 경우 배출 시기와 속도를 조절하는 능력과 (b) 음식의 칼로리 밀도에 따라 배출을 조절하는 능력을 확인했습니다. 위 배출의 생체역학에 대한 연구에 따르면 위의 여러 해부학적 부분의 활동이 통합되어 위 배출에서 잘 정의된 역할을 하는 기능적 “압력” 및 “연동” 펌프와 그라인더 필터를 형성하는 것으로 나타났습니다. 연동 펌프는 주로 고형물의 위 배출에 관여합니다.

위 배출의 패턴과 속도는 각각 위 억제와 흥분을 매개하는 두 개의 병렬 회로, 즉 위 억제 미주 운동 회로(GIVMC)와 위 흥분성 미주 운동 회로(GEVMC)에 의해 조절되는 것으로 나타났습니다. GIVMC에는 DMV의 신경절 전 콜린성 뉴런과 장 신경총의 신경절 후 NANC 억제 뉴런이 포함됩니다. GEVMC는 DMV의 위 흥분성 신경절 전 콜린성 뉴런과 장 신경총의 신경절 후 흥분성 콜린성 뉴런을 포함합니다. 위 평활근으로 니트린성 및 콜린성 신경 신호를 전달하는 데 ICC-IM이 필요하다는 것이 제안되었지만 아직 입증되지 않았습니다. 위의 다른 부위에 대한 회로는 구별되므로 위의 다른 부위가 차별적으로 조절될 수 있습니다. 현재 진행 중인 연구에 따르면 소화 기간 동안 분비되는 일부 장 및 췌장 호르몬은 GIVC를 자극하고 GEVC를 억제하여 위 운동성을 억제하는 것으로 나타났습니다.

반면, 소화기 사이 기간에는 그렐린과 모틸린 및 모틸린 호르몬이 위 펌프를 자극하고 유문 수축을 억제하는 방식으로 작용합니다. 연구에 따르면 GIVC는 NTS 및 시상하부의 거식성 뉴런과 연결되어 있으며, GEVC는 식욕 자극 신호와 연결되어 있을 수 있습니다. 따라서 신경 호르몬 조절은 당뇨병의 발병 및 관리에서 위 배출 장애와 포만 신호, 음식 섭취 및 에너지 대사, 식후 고혈당증을 연결합니다.

CONFLICT OF INTEREST

The authors report no conflict of interest relevant to this article.

AUTHOR CONTRIBUTIONS

RKG conceived and designed the study and wrote the manuscript; YMG made all the illustrations, conducted literature search, and wrote this review; HM provided critical input in the organization and writing of this review.

ACKNOWLEDGMENTS

We thank Maryrose Sullivan, PhD, and Vivian Cristofaro, PhD, for their critical comments and helpful suggestions. We also appreciate Frances Achee, PhD, for administrative help.

Goyal RK, Guo Y, Mashimo H. Advances in the physiology of gastric emptying. Neurogastroenterol Motil. 2019;31:e13546 10.1111/nmo.13546

Goyal R.K. Advances in the physiology of gastric emptying. First Wylie J Dodds and Sushil K Sarna Endowed Lecture of the American Neurogastroenterology and Motility Society, presented at 13th Postgraduate Course on Gastrointestinal Motility, and Neurogastro‐enterology in Clinical Practice, July 29, 2018, Milwaukee, Wisconsin

Funding information

This study was supported by (a) Merit Award from the VA Medical Research Service, Department of Veterans Affairs, Washington, DC (RKG); and (b) William S Middleton Award from the Department of Veterans Affairs, Office of Research and Development, Biomedical Research Laboratory, and Development Service (RKG).

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