Abstract
Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose‐dependent insulinotropic polypeptide) und GLP‐1 (glucagon‐like peptide‐1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP‐1, L cells) gut. Together, they are responsible for the incretin effect: a two‐ to three‐fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP‐1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP‐1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP‐1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin‐based glucose‐lowering medications (GLP‐1 receptor agonists and inhibitors of dipeptidyl peptidase‐4 or DPP‐4). GLP‐1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP‐1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP‐1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux‐en‐Y gastric bypass). GIP and GLP‐1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP‐1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high‐risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well‐characterized physiological effects.
1 INTRODUCTION
Incretin hormones have received much attention because of their important role both in the physiology of glucose homeostasis and in the pathophysiology of type 2 diabetes and, potentially, of other metabolic disorders.1 Glucagon‐like peptide‐1 (GLP‐1), in particular, has moved into the focus as a suitable parent compound for glucose‐ and weight‐lowering medications.2 GLP‐1 receptor agonists and inhibitors of dipeptidyl peptidase‐4 (DPP‐4 inhibitors) offer therapeutic effects that are more or less derived from the physiological activities of incretin hormones.1, 2 DPP‐4 inhibitors exert their therapeutic effects mainly by just a moderate elevation of GLP‐1 concentrations, while effective drug concentrations of GLP‐1 receptor agonists clearly extend into the pharmacological range.2 It is the purpose of this review to summarize the state‐of‐the‐art science on incretin hormones including their role in physiology and in the pathophysiology of obesity and type 2 diabetes, and the therapeutic perspective that can be derived from these findings.
2 THE INCRETIN EFFECT
Oral glucose leads to a greater stimulation of insulin secretion than an intravenous glucose infusion even when the same plasma glucose concentration profiles (“isoglycaemia”) are achieved (Figure 1A,C,E,G).4 This phenomenon is called the incretin effect and is attributed to the fact that oral glucose leads to the release of incretin hormones (glucose‐dependent insulinotropic polypeptide, GIP, and glucagon‐like peptide‐1, GLP‐1) from specialized entero‐endocrine cells in the gut (coupled to the absorption of glucose), while intravenous glucose does not.4, 5 The gut hormones released in response to nutrient absorption are endocrine signals to the islets of Langerhans in the pancreas, augmenting insulin secretion and modulating glucagon secretion whenever plasma glucose concentrations are above a threshold value of approximately 66 mg dL−1. The physiological stimulation of insulin secretion through incretin hormones is substantial,7 while physiological degrees of hyperglycaemia are a rather weak stimulus for insulin release.4 An “isoglycaemic” intravenous glucose infusion leading to identical increments in arterial plasma glucose concentrations as does an oral glucose load causes a rise in insulin secretory responses that is approximately one‐third of that elicited by oral glucose (i.e., the combined action of hyperglycaemia and incretin hormones).8 The difference between these two insulin secretory responses, thus, represents approximately two‐thirds of the total response (Figure 1). It is usually expressed as a percentage of the response after oral glucose infusion. The estimate of the contribution of incretin hormones to insulin secretory responses after oral glucose administration depends on the dose of glucose employed, and may vary between 25% and 75%. No doubt, this quantitative contribution speaks in favour of a substantial physiological importance of incretin hormones in the maintenance of proper glucose homeostasis.4 Of the three signals originating from the gut and reaching the endocrine pancreas (substrates such as glucose, incretin hormones, and neural signals transmitted by the autonomic nervous system, Figure 2),5 incretin hormones make the most substantial contribution under physiological circumstances.
2.1 Incretin hormones (GIP, GLP‐1)
Glucose‐dependent insulinotropic polypeptide was purified using a bioassay measuring the inhibition of gastric acid secretion, and hence the old name “gastric inhibitory polypeptide”.9The main function later was identified as glucose‐dependent augmentation of insulin secretion.10 GIP is produced in K cells, which are single cells located to the mucosa in the duodenum and upper jejunum.9 GIP is synthesized as a precursor pro‐peptide (pro‐GIP), which is then cleaved to GIP by post‐translational processing.11 Glucagon‐like peptide‐1 was identified as part of the gene sequence coding for proglucagon,12 which is expressed in L cells in the small and large intestines, with a gradient from a low density in the duodenum to a higher density in the ileum, but also in the colon and rectum.13 Proglucagon contains the coding region for pancreatic glucagon and two “glucagon‐like” sequences with a predicted similarity to the glucagon amino acid sequence12 hence the names GLP‐1 and GLP‐2. Early assumptions regarding post‐translational processing were later proven wrong. Therefore, the biologically active forms of GLP‐1 are now called GLP‐1 [7–36 amide] (amidated GLP‐1) and GLP‐1 [7–37] (glycine‐extended GLP‐1). Both forms are “truncated” in comparison to the originally proposed sequences GLP‐1 [1–36 amide] and GLP‐1 [1–37] by the N‐terminal six amino acids.14, 15 The extended forms neither occur in substantial quantities nor exert insulinotropic effects. The same proglucagon gene is processed in a different manner in α cells of the endocrine pancreas (main products: “pancreatic” glucagon and a “major proglucagon fragment,”), which is not further processed to GLP‐1 and GLP‐2.11
2.2 Secretion of incretin hormones in healthy human subjects
GIP and GLP‐1 have low (basal) plasma concentrations in the low picomolar range (10−12 mol L−1) in fasting human subjects. GIP and GLP‐1 plasma concentrations start to rise a few minutes after nutrient intake, reach a peak after approximately 1 h, and reach basal concentrations again after several hours. Nutrients that stimulate the secretion of GIP and GLP‐1 are glucose and other carbohydrates including sucrose and starch, triglycerides, and some amino acids as well as proteins.4, 16 Protein is a comparatively weak stimulus. Because nutrients have to reach the location of K and L cells in the gut in order to stimulate the release of GIP and GLP‐1, respectively, a minimum rate of trans‐pyloric delivery (gastric emptying) is necessary to elicit measurable secretory responses.17 This minimum delivery rate is lower for GIP, most likely because GIP‐producing K cells are located more proximally, while nutrients are only delivered to gut areas with significant numbers of L cells, located more distally, if a greater delivery rate is achieved.17 GLP‐1 secretion from L cells occurs early after nutrient intake, almost in parallel with GIP secretion, despite the more distal location of L cells.4, 13 Whether this indicates that the low number of L cells in the duodenum and upper jejunum is sufficient as a source of GLP‐1, or whether there are signals from the upper gut that trigger release the of GLP‐1 from L cells located more distally, is a matter of debate. The gut autonomic nervous system and GIP have been proposed as signals.18 In humans, high GIP concentrations do not stimulate GLP‐1 secretion.19 Both fasting and nutrient‐stimulated plasma concentrations are higher for GIP as compared to GLP‐1.4 Secretion of the incretin hormones GIP and GLP‐1 is usually monitored using “non‐specific” immunoassays, which detect “total” GIP and GLP‐1, that is, both intact, biologically active forms and fragments such as the metabolites generated by DPP‐4‐mediated proteolysis. Both GIP and GLP‐1 are substrates of DPP‐4 and are physiologically degraded and inactivated by DPP‐4. Concentrations of “intact” (biologically active) incretin hormones are measured using sandwich immunoassays that require both the amino and carboxy termini of the peptides to be intact (unmodified) and connected. Under most physiological circumstances, intact, biologically active concentrations of GIP and GLP‐1 are substantially lower than their “total” levels: approximately 40% to 60% of the “total” concentrations in the case of GIP and approximately15% to 25% in the case of GLP‐1.20, 21 “Total” GIP concentrations usually are higher than “total” GLP‐1 concentrations, and the difference is even greater when looking at “intact” plasma concentrations.21
There is considerable inter‐individual variation in GIP as well as in GLP‐1 secretion. Interestingly, subjects that secrete little GIP tend to also secrete less GLP‐1, and vice versa.4, 22 This has been verified in independent populations, but is difficult to explain, since K cells producing GIP and L cells synthesizing GLP‐1 are not only separate entities (with the exception of some entero‐endocrine cells that appear to produce both GIP and GLP‐1)23 but also occur in different segments of the gut. At present, it is unclear whether this indicates some inter‐individual variation in the number of entero‐endocrine cells, or in more functional aspects of the mechanisms that lead to the secretion of incretin hormones (taste receptors, G‐protein coupled receptors sensing fatty acid derivatives, exposure to bile acids, the microbiome, etc.).16
2.3 Insulinotropic activitiy of incretin hormones in healthy human subjects
Both GIP and GLP‐1 stimulate insulin secretion in a glucose‐dependent manner.7, 24 ß cells have GIP and GLP‐1 receptors in their cell membranes, which, once stimulated by the binding of their respective ligands, are coupled to adenylate cyclase, which enhances cyclic AMP (adenosine monophosphate) production and thus activates protein kinase A.25 This pathway cannot initiate the release of pre‐formed insulin secretory granules from ß cells, which requires closing of potassium channels, depolarization, and calcium ion influx, as initiated by hyperglycaemia. Therefore, insulinotropic actions of incretin hormones always require a permissive degree of hyperglycaemia. The role of incretin hormones is to augment the insulin secretory responses initiated by hyperglycaemia. Therefore, incretin hormones cannot provoke episodes of hyperglycaemia. The absolute glycaemic threshold below which GLP‐1 cannot stimulate insulin secretion, even at supra‐physiological concentrations, was identified as approximately 66 mg dL−1.24 Conversely, the higher the glucose concentrations, the greater the degree of augmentation.
2.4 Incretin hormones and glucagon secretion
In addition to their insulinotropic activity, incretin hormones affect glucagon release. GIP has been found to stimulate glucagon secretion,26 especially at lower glucose concentrations, while GLP‐1 suppresses glucagon secretion, in particular at hyperglycaemia.19 The latter leads to a reduced hepatic glucose production.27 In addition, GLP‐1 appears to reduce hepatic glucose output even independent of changes in plasma glucagon.28 Since the liver does not appear to be equipped with GLP‐1 receptors, this has to be mediated indirectly, for example, through the autonomic nervous system.
Using the experimental paradigm typically used to quantify the incretin effect, it has been found that “isoglycaemic” intravenous glucose, in healthy subjects, suppresses glucagon more than oral glucose (Figure 2).6, 29 This probably is the consequence of GIP and GLP‐2 being released after oral but not intravenous glucose. Both GIP26 and GLP‐230 can stimulate glucagon secretion.
2.5 Physiological role of individual and combined incretin hormones in healthy human subject
Attempts have been made to quantify the contribution of GIP and GLP‐1 to the incretin effect by testing their insulinotropic action in the presence of a physiological glucose concentration profile (such as after oral glucose loads): GIP and GLP‐1 were infused intravenously with the aim of coming close to the physiological concentration profiles as they occur after oral glucose loads. GIP infusion rates of 1.0 pmol kg−1 min−1 led to slightly higher GIP concentrations than found after oral glucose, and GLP‐1 infusions rates of 0.15 pmol kg−1 min−1 relatively closely matched the “total” GLP‐1 concentrations after oral glucose,31 while 0.3 pmol kg−1 min−1 GLP‐1 intravenously resulted in supra‐physiological GLP‐1 concentrations. Comparing the insulin secretory responses under these circumstances suggested that GIP explains the majority of the incretin effect after oral glucose, while GLP‐1 made only a minor contribution.31 Another reason why GLP‐1 probably is not a major incretin is the fact that it slows gastric emptying.32, 33 With exogenous GLP‐1 administration, decelerating gastric emptying reduces the post‐meal rises in glucose concentrations substantially, with the consequence that insulin secretory responses are reduced despite the presence of elevated GLP‐1 concentrations.33 However, when experimental approaches are used that disregard the effects of gastric emptying, more similar contributions of GIP and GLP‐1 to meal‐induced insulin secretion can be estimated.34 We still tend to believe that GIP is responsible for the majority of the incretin effect in healthy subjects. Novel GIP peptide antagonists35 will probably help resolve this controversy.
There is no doubt that in healthy human subjects the insulinotropic effects of GIP and GLP‐1 are additive, that is, a combined administration of GIP and GLP‐1 will lead to an insulin secretory response that is equivalent to the sum of the responses elicited by GIP or GLP‐1 alone.31
Quantitative considerations as described in this paragraph suggest that, most likely, GIP and GLP‐1together explain most, if not all, of the incretin effect.31 Thus, the active search for other, hitherto undetected incretin hormones has subsided. It is not known whether hormones exist that rather limit the secretion of insulin. Gut‐derived somatostatin has been discussed as one such “decretin”.36 The “upper gut hypothesis” claims that excluding the duodenum from the passage of nutrients will explain some of the beneficial effects of bariatric surgery, which includes improvement of metabolic control in type 2 diabetic patients.37 However, the responsible factors have not been identified.
As the consequence of the dose‐dependent secretion and insulinotropic action of the incretin hormones GIP and GLP‐1, widely different oral glucose loads lead to an almost uniform plasma glucose concentration profile.38, 39 The explanation is the variation in the quantitative contribution of the incretin effect to the overall insulin secretory response after oral glucose, ranging from low (i.e., approximately 20% with small oral glucose loads, like 25 g) to high (up to 75% with large oral glucose loads, 100 g or higher).
2.6 Open questions in incretin physiology
Recently, the dogma that proglucagon processing leads to pancreatic glucagon in α cells in the endocrine pancreas and to GLP‐1 and GLP‐2 in intestinal L cells has been challenged. Intestinal production of glucagon was suggested after total pancreatectomy in human subjects,40 and GLP‐1 has been found to be present in pancreatic α cells.41 Animal studies suggest that GLP‐1 produced in pancreatic α cells may have more impact on glucose homeostasis compared to GLP‐1 produced in the gut.42 This may mean that all‐too‐simple views on the physiology of incretin hormones may need to be refined. Alternatively, the validity of these findings could be restricted to very special and rare conditions. The proposed detrimental signal form the duodenum (“upper gut hypothesis”)37 is awaiting more thorough characterization.
3 ADDITIONAL BIOLOGICAL EFFECTS OF INCRETIN HORMONES
The definition of an incretin hormone entirely relates to the secretion from the gut after nutrient intake and the insulinotropic action at physiologically stimulated concentrations.5Thus, even additional actions within the endocrine pancreas (such as the suppression of glucagon secretion, the stimulation of proinsulin biosynthesis, the stimulation of ß‐cell neogenesis or proliferation, etc.) are beyond the narrow definition of an incretin hormone. However, there is ample evidence that the incretin hormones GIP and GLP‐1 have additional biological effects that add important facets to their overall spectrum of activity. This is particularly true in the case of GLP‐1 (Table 1, Figure 3).
Organ/tissue/cell type | Incretin hormone/derivatives: | Glucose‐dependent insulinotropic polypeptide (GIP/GIP RA)) | Glucagon‐like peptide‐1/GLP‐1 receptor agonists (GLP‐1/ GLP‐1 RA) | ||
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Methodology: | GIP receptor knock‐out/polymorphisms/GIP receptor antagonists | Pharmacological studies using GIP/GIP receptor agonists | GLP‐1 receptor knock‐out/ polymorphisms/GLP‐1 receptor antagonists | Pharmacological studies using GLP‐1/GLP‐1 receptor agonists | |
Physiological function | |||||
Brain | Regulation of appetite/satiation |
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Regulation of food (calorie) intake/body weight |
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Heart | Heart rate |
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Glucose uptake |
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Ischaemia tolerance |
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Infarct size |
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Pancreas | (Pro‐)insulin biosynthesis |
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ß‐Cell apoptosis |
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ß‐Cell proliferation/neogenesis |
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Stomach | Gastric emptying |
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Acid secretion |
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Gut | Absorption |
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Adipose tissue | Glucose uptake |
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Blood flow |
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Inflammation |
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Lipoprotein lipase activity/ chylomicron elimination |
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Brown adipose tissue activity |
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Bone | Formation (osteoblasts) |
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Absorption (osteoclasts) |
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Bone mass |
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Fracture risk |
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Muscle | Glucose uptake |
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Kidney | Natriuriesis |
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Albuminuria |
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Glomerular filtration |
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Blood vessels | Vasodilation |
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Blood pressure |
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- a For effects on insulin and glucagon secretion, see Table 2.
3.1 Appetite, caloric intake, body weight
GLP‐1 administered into the central nervous system,43 but also into the general circulation,44 reduces appetite and food intake and increases satiety. The relevant GLP‐1 receptors seem to be in the hypothalamus.45 GLP‐1 may enter the brain from the blood stream through circumventricular organs, which are characterized by a leaky blood–brain barrier. GLP‐1 seems to be one of the meal‐termination signals. These effects are the basis for weight loss with prolonged stimulation of GLP‐1 receptors.1, 2 Such an activity has not been known in the case of GIP, but recently hybrid peptides (also addressing, e.g., glucagon and peptide YY receptors) have been developed for the purpose of promoting more weight loss than GLP‐1 receptor agonist alone can provide,46 by also activating GIP receptors.47
3.2 Triglyceride storage in adipose tissue
GIP receptor knock‐out mice do not develop obesity with hypercaloric feeding.48 This and the fact that GIP induces lipoprotein lipase,49 the enzyme that releases fatty acids from chylomicron triglycerides in adipose tissue and thus promotes the elimination of chylomicron triglycerides,50 has led to the hypothesis that GIP may promote fat storage in subcutaneous adipose tissue. Mostly, this is based on animal studies, and it remains uncertain whether this translates to the human situation.
3.3 Gastric emptying, intestinal transit
GIP has no effect on gastric emptying,51 while exogenous GLP‐1, both at physiological and pharmacological concentrations, slows gastric emptying.33 Studies with the GLP‐1 receptor antagonist exendin9-39 suggest that endogenous GLP‐1 also retards gastric emptying.64The consequence is a delayed and reduced delivery of nutrients into the intestinal lumen, and a delayed and reduced absorption leading to flatter rises in glycaemia and triglycerides following meals.74 Intestinal transit is also slowed.115 Secondary to slowed gastrointestinal motility, gastric acid and pancreatic exocrine secretions are reduced.32 It has been suggested that this inhibitory function on upper gastrointestinal motility and secretion may be well compatible with the (otherwise unexplained) location of L cells primarily in the lower small and large intestines.13 Under normal circumstances, nutrients never reach these areas, but in the case of, for example, diarrhoea, nutrients in the lower gut stimulate GLP‐1, which in turn halts motility and secretion to help stop symptoms. This function has been termed the “ileal brake”116 and may be another important role for GLP‐1, perhaps even the primary physiological function.
3.4 Bone metabolism
Mainly based on the phenotype of GIP and GLP‐1 receptor knock‐out mice, a role for both incretin hormones in the formation and maintenance of bone mass has been suggested (Table 1, Figure 3). GIP receptor signalling in mice seems to limit bone resorption (osteoclast number and function) and to promote bone formation (osteoblast function), especially in conjunction with meal intake.91 Examination of human polymorphisms regarding the GIP receptor gene shows significant heterogeneity in bone mass and even fracture risk,100suggesting that these animal findings have some physiological relevance in humans. The GLP‐1 receptor in mice also seems to be linked to a suppression of osteoclast function and bone resorption,117 thus increasing bone mass and decreasing fragility.117 GLP‐1 receptor agonists in animals have the potential to increase bone formation under conditions where a loss in bone mass is expected (during weight loss94 and after ovariectomy95, 96). However, no consistent effects of GLP‐1 receptor agonist treatment have been observed in clinical trials.105, 106 Physiologically speaking, the osteogenic effects of the incretin hormones GIP and GLP‐1 may be viewed as part of their overall role in anabolic processes, promoting the storage of nutrient substrates for the support and maintenance of important body functions.
3.5 Cardiovascular function
GLP‐1 has multiple effects in the cardiovascular system, which have been extensively reviewed.55, 118 Beneficial effects of GLP‐1 receptor agonists in high‐risk patients have renewed the interest in elucidating the mechanisms underlying these benefits.55, 118 There is a long list of divergent actions of GLP‐1 and of GLP‐1 receptor agonists, for example, on cardiac blood supply, on substrate uptake and performance, on ischaemia tolerance, on endothelial function (vasodilation), on inflammatory responses in adipose tissue and blood vessels and related cytokines, and on the progression of atherosclerosis and plaque stability (Table 1, Figure 3).55, 118 In most cases, these effects were shown with high doses/concentrations of GLP‐1. A physiological role of GLP‐1 in the cardiovascular system is not known. However, there is a cardiac phenotype of the GLP‐1 receptor knock‐out mice, suggesting some role for GLP‐1 in the embryonic development of the cardiovascular system.119 Since cardiovascular effects of GLP‐1 receptor stimulation are mainly described as therapeutic actions with pharmacological concentrations of GLP‐1 or GLP‐1 receptors,55such effects do not seem to be major physiological actions, and will not further be described in detail in this review.
4 INCRETIN HORMONES IN OBESITY
Interest in the role of incretin hormones in obese subjects originates from findings indicating roles for GIP as a potential mediator of increased triglyceride storage in adipose tissue and, thus, of weight gain and obesity. Conversely, the appetite‐reducing activity of GLP‐1 suggests a role in inhibiting food intake and weight gain.
4.1 Secretion and action of incretin hormones in obese, non‐diabetic subjects
Some studies suggest that there is hypersecretion of GIP in obesity,120 which might be related to compensatory insulin hypersecretion that may occur as an attempt to overcome the metabolic consequences of insulin resistance.121 Regarding the secretion of GLP‐1 in obesity, reduced increments in meal‐related GLP‐1 responses have been described with increasing body mass index,122-124 in particular in the presence of hepatic steatosis.125The incretin effect has been reported to be decreased in obesity,123 even in the absence of impaired glucose tolerance or diabetes mellitus. This may be explained by a reduced responsiveness to GIP or by a reduced contribution of GLP‐1 (achieving lower concentrations after physiological nutrient stimulation) to insulin secretory responses.123 Details have not been studied.
4.2 Role of GIP and/or GLP‐1 in the etiology of obesity
A role for GIP as an obesigenic signal from the gut is mainly based on animal studies looking at the consequences of GIP receptor knock‐out: GIP receptor knock‐out mice do not become obese when fed a high‐fat diet.48 This may be functionally related to increased hexose absorption from the gut68 and accelerated lipolysis of chylomicron triglycerides50 through enhanced adipose tissue lipoprotein lipase activity.49 Overall, this may lead to more triglycerides being taken up and stored in adipose tissue. Some human GIP receptor polymorphisms are associated with differences in body weight.126 In contrast, exogenous GLP‐1 reduces appetite, increases satiety, and reduces food intake,53 perhaps even at physiological concentrations.127 This, together with the reduced secretion of GLP‐1 in obese subjects, suggests a significant role of GLP‐1 in the pathogenesis of obesity. However, it is unclear what drives the reduced secretion of GLP‐1 in obesity and when in the course of the development of obesity these abnormalities occur.
5 ROLE OF GLP‐1 IN MEDIATING EFFECTS OF BARIATRIC SURGERY ON WEIGHT LOSS AND ON GLYCAEMIC CONTROL (DIABETES REMISSION)
Surgery is used to achieve significant reductions in body weight in obese subjects, and to induce diabetes remission, if obesity is associated with type 2 diabetes. The most frequently performed procedures are Roux‐en‐Y gastric bypass and sleeve gastrectomy. Bariatric surgery results in major changes in the pattern of gastrointestinal hormone secretion, including the secretion of GIP and GLP‐1, as well as of other gut hormones produced in the lower small intestines (e.g., peptide YY, PYY, produced in L cells like GLP‐1). The most striking change is in the secretion of GLP‐1: GLP‐1 concentrations reach levels far above the physiological range, most likely because nutrients are rapidly delivered into distal areas of the gut characterized by a high L‐cell density.128 Studies employing the GLP‐1 receptor antagonist exendin [9-39] suggest that GLP‐1 plays a role in the reduction of energy intake typically following gastric bypass. In fact, the typically increased concentrations of both GLP‐1 and PYY seem to reduce appetite and food intake synergistically.129 GLP‐1 and GIP appear to be the factors that best explain the improvement in glycaemic control following gastric bypass.130 However, weight loss after gastric bypass also occurs in GLP‐1 receptor knock‐out animals.131 These findings argue against an absolutely essential role of GLP‐1 as a mediator of the benefits of bariatric surgery like gastric bypass. Less information is available on other surgical procedures (e.g., sleeve gastrectomy).
A rare but severe adverse event after bariatric surgery is reactive hypoglycaemia, which has been observed in patients hypersecreting GLP‐1 after, for example, gastric bypass.132, 133Based on findings of studies with young rodents, a proliferative effect of GLP‐1 on ß cells was documented.134 Thus, ß‐cell hyperplasia (“nesidioblastosis”) has been viewed as a consequence of exaggerated GLP‐1 responses. However, careful studies have ruled out ß‐cell hyperplasia in such patients.135 Therefore, GLP‐1 is rather unlikely to be the primary cause of hypoglycaemia as a consequence of increased ß‐cell mass.
6 INCRETIN HORMONES IN TYPE 2 DIABETES
Type 2 diabetes is caused by insulin resistance and the inability of the endocrine pancreas to secrete enough insulin to match the increased demand. Hyperglucagonaemia is another facet in the pathophysiology of type 2 diabetes.136 Given the potential of incretin hormones to augment insulin secretor responses and of GLP‐1 to lower glucagon concentrations, there has been considerable interest to elucidate the role of incretin hormones in the pathophysiology of type 2 diabetes.
6.1 Secretion of incretin hormones in type 2 diabetic subjects
Incretin hormones are secreted in subjects with type 2 diabetes much like in healthy and obese subjects.137-139 Initial studies indicated a slightly increased secretion of GIP in type 2 diabetes at the population level140 and a reduced GLP‐1 response following mixed‐meal stimulation.21, 141 Moreover, subjects with impaired glucose tolerance had an intermediate GLP‐1 response.141 Thus, it was hypothesized that there is a progressive loss of GLP‐1 secretion with advancing stages of type 2 diabetes. Since these findings were generated during the time when incretin‐derived glucose‐lowering medications were first developed, this was considered a justification for “replacing” GLP‐1 under circumstances where there appeared to be a lack of GLP‐1. The secretion of GIP and GLP‐1 after oral glucose loads and mixed meals has been compared many times between healthy subjects and type 2 diabetic patients. Some studies confirmed slight differences (lower in type 2 diabetes), whereas others did not. Meta‐analyses suggest that there are no systematic differences in the nutrient‐induced secretion of GIP and GLP‐1 between healthy and type 2 diabetic subjects,137-139 against a background of substantial inter‐individual variation in secretory responses (vide supra). In type 2 diabetic patients, a significant correlation of GIP and GLP‐1 secretory responses has been noted as well.4, 22
6.2 Insulinotropic activitiy of incretin hormones in type 2 diabetic subjects
While the secretion of incretin hormones is more or less normal in type 2 diabetes, the characteristic abnormalities are in the insulinotropic activities of GIP and GLP‐1. As an insulinotropic agent, GIP was originally considered a drug candidate for the development of glucose‐lowering medications. While the description of insulinotropic effects in healthy human subjects was published in 1973,10 only in 1988 the first study reported much reduced insulinotropic effectiveness in both type 1 and type 2 diabetic patients.142 The original report was based on work performed with GIP of the porcine amino acid sequence, leaving some questions regarding the correspondence of GIP concentrations generated by endogenous secretion from human L cells versus exogenous administration of the porcine sequence peptide. Later studies employing synthetic human GIP fully confirmed the inability of GIP to elicit significant insulinotropic responses in subjects with type 2 diabetes.19, 143, 144 There may be a residual “early” response lasting 30 min or so,144 but certainly longer lasting exposures to elevated GIP concentrations do not lead to a significant stimulation of insulin secretion, even though the GIP concentrations achieved in these experiments clearly were far higher than physiological concentrations.
The situation is different in the case of GLP‐1. There is no doubt that physiological, and certainly pharmacological, concentrations of GLP‐1 elicit insulinotropic (and glucagonostatic) effect in subjects with type 2 diabetes.19 However, the effects are reduced in magnitude as compared to healthy subjects. Under hyperglycaemic clamp conditions, only slightly reduced insulin and C‐peptide responses to exogenous GLP‐1 have been found between type 2 diabetic and healthy subjects.19 In a careful dose–response study, Kjems et al. studied type 2 diabetic and healthy subjects with increasing intravenous infusion rates of GLP‐1.145 At each GLP‐1 dose, the insulin secretory responses to increasing glucose concentrations were determined and were described as the slope relating insulin secretion to the degree of hyperglycaemia. GLP‐1 augmented the relationship between glucose and insulin secretory responses much less (approximately 25%) compared to healthy subjects.145 In addition, GLP‐1 reduces glucagon concentrations.19 Taken together, the stimulation of insulin secretion as well as suppression of glucagon secretion with GLP‐1 is sufficient to lead to a meaningful reduction in plasma glucose, however, at pharmacological concentrations.146 A detailed account of actions of GIP and GLP‐1 on insulin and glucagon secretion, and of the important dependence on ambient glucose concentrations, in healthy as well as type 2 diabetic subjects is provided in Table 2.
Parameter | Incretin hormone | Glucose‐dependent insulinotropic polypeptide | Glucagon‐like peptide‐1/ GLP‐1 receptor agonists | ||
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Glucose tolerance Condition | Normal | Type 2 diabetes | Normal | Type 2 diabetes | |
Insulin secretion | Normal fasting plasma glucosea |
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Hyperglycaemia | |||||
Hypoglycaemiac |
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Glucagon secretion | Normal fasting plasma glucosea |
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Hyperglycaemia |
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Hypoglycaemia |
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Plasma glucose | Normal fasting plasma glucosea |
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Hyperglycaemia |
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Hypoglycaemia |
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- a Approximately 4–5.5 mmol L−1 (80–100 mg dL−1).
- b In type 2 diabetic patients, fasting hyperglycaemia is a typical finding.
- c Below 3.8 mmol L−1 (66 mg dL−1).
- d Difficult to be studied since normoglycaemia is not a typical finding in type 2 diabetic subjects.
Co‐administration of GLP‐1 and GIP in subjects with type 2 diabetes does not stimulate insulin secretion more than does GLP‐1 alone.143 Rather, the glucagon suppression seen with GLP‐1 alone is no longer there when GIP is administered as well.143
6.3 Role of incretin hormones in the pathophysiology of type 2 diabetes (reduced incretin effect)
When the incretin effect is quantified in subjects with type 2 diabetes, it is found much reduced or absent in comparison to healthy subjects (Figure 1).3, 39, 147 The most likely explanation is the inability to respond appropriately to GIP19, 144 (which in healthy subjects mediates the major proportion of the incretin effect, vide supra) and the rather minor role GLP‐1 plays in the mediation of the incretin effect in healthy subject (so that even the relatively preserved effectiveness of GLP‐1 in type 2 diabetic patients does not really matter much).31 Thus, in type 2 diabetic patients, a mechanism, which in healthy subjects contributes approximately two‐thirds to the insulin secretory response after oral glucose, is largely impaired or even no longer operative. This is likely to have functional consequences. One question arises: Does the inability to respond to GIP with an insulin secretory response represent a defect preceding (and potentially driving) the development of diabetes? Or is it a consequence of the diabetic state? Numerous studies have suggested that this defect (the inability to respond to GIP with a substantially augmented release of insulin) and a reduced incretin effect occur after the diagnosis of diabetes is established, suggesting these consequences to be secondary.148 In particular, a reduced incretin effect is seen only in those patients with chronic pancreatitis, who also develop diabetes, but not in those who have normal glucose tolerance. This indicates that it is the diabetic state itself that is associated with the reduced incretin effect, and not the disease process characterizing chronic pancreatitis.147 It is not known which facets of type 2 diabetes (hyperglycaemia, islet lipid overload, inflammatory infiltration of ß cells, etc.) trigger this development. Studies using intensive insulin treatment for optimal glycaemic control suggest that reducing hyperglycaemia into the near‐normal range of glucose concentrations will improve, yet not normalize, the insulinotropic activity of both GIP and GLP‐1 in type 2 diabetic subjects and glucose excursions after a mixed meal, perhaps indicating an improvement in their incretin effect.157, 158
Another question is whether the inability to secrete insulin in response to GIP is related specifically to abnormalities in the stimulus–secretion coupling for the GIP pathway, such as a reduced expression of GIP receptors or other components of the signal‐transduction pathway,159 or may rather be related to more general features of the type 2 diabetic endocrine pancreas, namely reductions in ß‐cell mass and functional insulin secretory capacity.4, 148 A reduced expression of GIP receptors has been described in animals with diabetic hyperglycaemia159 but, so far, not in human pancreas specimens. A reduction in ß‐cell mass and functional insulin secretory capacity can be assumed to lead to a reduced incretin effect, since oral glucose is a strong stimulus to insulin secretion, while “isoglycaemic” intravenous glucose is a weak stimulus. One can speculate that the insulin response to this weak stimulus is already close to the upper limit of the overall secretory capacity, such that a stronger stimulus can hardly elicit an even greater response.148
While the abnormalities in the incretin system, foremost the inability of the endocrine pancreas to respond to GIP, do not seem to be involved in the progression from pre‐diabetic states to manifest diabetes mellitus,148 they may well contribute to the progression that is typical for this disease. It is likely that the loss of a major physiological mechanism stimulating insulin secretion will further deteriorate glycaemic control, leading to a vicious cycle by worsening glucose toxicity, which in turn may reduce ß‐cell mass and functional capacity and the expression of GIP receptors and a progressive reduction in the incretin effect (Figure 4).
7 THERAPEUTIC POTENTIAL OF INCRETIN HORMONES IN TYPE 2 DIABETES (GLP‐1 RECEPTOR AGONISTS AND DPP‐4 INHIBITORS)
Based on the physiological effects described above in great detail, there is no obvious therapeutic potential for GIP in type 2 diabetes, because it has only negligible effects on insulin secretion in such patients, because it rather increases glucagon secretion, and because there are no measurable effects of even supra‐physiological doses/concentrations on plasma glucose concentrations. Still research is being conducted to identify conditions under which GIP may have greater beneficial effects, for example, after DPP‐4 inhibitor treatment.160 Based on findings suggesting a role for GIP in the enhanced triglyceride deposition during hypercaloric feeding (based mainly on animal studies), GIP receptor antagonists have been suggested for the treatment of the metabolic syndrome and pre‐diabetes.161 However, this has never led to clinical trials substantiating these claims.
On the contrary, the therapeutic potential of GLP‐1 for the treatment of obesity and type 2 diabetes is obvious, since the parent compound itself is able to reduce hyperglycaemia both in the fasting and postprandial state.1, 2 GLP‐1 receptor agonists had to be developed to derive agents with slower elimination than GLP‐1 itself, which has a half‐life of 1–2 min and needs to be administered continuously to fully elicit its therapeutic potential. Properties of GLP‐1 receptor agonists will be described in more detail elsewhere in this volume. The other development that originated from the characterization of in vivo degradation and inactivation of GLP‐1 was that of DPP‐4 inhibitors, which mainly preserve GLP‐1 (and, potentially, other insulinotropic peptides) in its (their) intact, biologically active state (addressed in another article in this volume). Especially, the latter therapy employs incretin hormone concentrations that closely resemble the physiological range and emphasizes the important physiological role of incretin hormones in the maintenance of glucose homeostasis.
ACKNOWLEDGEMENTS
We thank Ms. Laura Kupfer for help with retrieving literature and secretarial assistance and Dr. Sandra Ueberberg for providing microphotographs of human gut and endocrine pancreatic tissue.
Author contributions
Both authors drafted the manuscript and contributed to designing figures and tables and to writing the text. Both authors were involved in revising the manuscript for critical intellectual content and jointly made the decision to publish the final version. MAN takes full responsibility for the integrity of the information compiled and is the guarantor for the manuscript as a whole.
Conflict of interest
MAN has received compensation for lectures or advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Fractyl, GlaxoSmithKline, Intarcia/Servier, Menarini/Berlin Chemie, Merck, Sharp & Dohme, and NovoNordisk. He has received grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Menarini/Berlin‐Chemie, Merck, Sharp & Dohme, and Novartis. JJM has received compensation for lectures or advisory boards from Astra Zeneca, Boehringer‐Ingelheim, BristolMyersSquibb, Eli Lilly, Merck, Sharp & Dohme, Novo Nordisk, Servier and Sanofi. He has received research support from Boehringer‐Ingelheim, Merck, Sharp & Dohme, Novo Nordisk, and Sanofi.