Physiology of the Incretin Hormones,<scp>GIP</scp>and<scp>GLP</scp>‐1—Regulation of Release and Posttranslational Modifications

Holst, Jens J.; Albrechtsen, Nicolai J. Wewer; Deacon, Carolyn F.

doi:10.1002/cphy.c180013

Cited by 47 publications

(43 citation statements)

References 455 publications

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“…The incretin hormones are peptides of 42 and 30 amino acids, respectively, and are secreted by open type endocrine cells of the intestinal epithelium, the so-called K-and L-cells [24]. The density of the K-cells is very high in the duodenum and proximal jejunum, whereas the L-cells are more numerous more distally, and are even found at high densities in the colon [25].…”

Section: Secretion Of Glp-1 and Gipmentioning

confidence: 99%

The incretin system in healthy humans: The role of GIP and GLP-1

2019

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The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.

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Section: Secretion Of Glp-1 and Gipmentioning

confidence: 99%

The incretin system in healthy humans: The role of GIP and GLP-1

2019

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“…Other bioactive compounds released into the lumen following meal ingestion, such as bile acids, are also responsible for postprandial GLP-1 secretion [ 41 , 47 ]. After its secretion, GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-4) with a half-life of 1–2 min, such that only 10–15% intact GLP-1 reaches the peripheral circulation [ 48 , 49 ]. While obesity is associated with attenuated GLP-1 secretion, accumulating evidence suggests that the latter is otherwise unaltered in patients with T2DM [ 50 , 51 ].…”

Section: Secretion and Actions Of Gastrointestinal Hormonesmentioning

confidence: 99%

“…In health, GIP stimulates insulin secretion in a glucose-dependent manner by binding to the GIP receptor expressed on the pancreatic β-cells [ 85 ], which contributes equally with GLP-1 to the augmented insulin response that is observed during enteral glucose administration when compared to an “isoglycaemic” intravenous glucose infusion, i.e., the so-called the “incretin effect”. However, the insulinotropic effect of GIP is markedly diminished in patients with T2DM [ 49 , 86 ]. Unlike GLP-1, GIP stimulates glucagon secretion from the pancreatic α-cells, particularly in the face of hypoglycaemia [ 87 ], and has little effect on appetite [ 88 ] or gastrointestinal motility [ 89 ].…”

Section: Secretion and Actions Of Gastrointestinal Hormonesmentioning

confidence: 99%

Enteroendocrine Hormone Secretion and Metabolic Control: Importance of the Region of the Gut Stimulation

et al. 2020

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It is now widely appreciated that gastrointestinal function is central to the regulation of metabolic homeostasis. Following meal ingestion, the delivery of nutrients from the stomach into the small intestine (i.e., gastric emptying) is tightly controlled to optimise their subsequent digestion and absorption. The complex interaction of intraluminal nutrients (and other bioactive compounds, such as bile acids) with the small and large intestine induces the release of an array of gastrointestinal hormones from specialised enteroendocrine cells (EECs) distributed in various regions of the gut, which in turn to regulate gastric emptying, appetite and postprandial glucose metabolism. Stimulation of gastrointestinal hormone secretion, therefore, represents a promising strategy for the management of metabolic disorders, particularly obesity and type 2 diabetes mellitus (T2DM). That EECs are distributed distinctively between the proximal and distal gut suggests that the region of the gut exposed to intraluminal stimuli is of major relevance to the secretion profile of gastrointestinal hormones and associated metabolic responses. This review discusses the process of intestinal digestion and absorption and their impacts on the release of gastrointestinal hormones and the regulation of postprandial metabolism, with an emphasis on the differences between the proximal and distal gut, and implications for the management of obesity and T2DM.

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“…The L-cells express the glucagon gene, resulting in production of proglucagon, a 160 amino acid peptide [14]. Proglucagon is stored in intracellular granules where it undergoes posttranslational processing and is cleaved by prehormone convertase 1/3 (PC1/3), to yield, amongst other peptides, GLP-1 [15][16][17]. The L-cells of the ileum and colon (but probably not of the upper small intestine) also produce and secrete peptide YY, which like GLP-1 has anorectic effects [18][19][20].…”

Section: Secretion and Metabolism Of Endogenous Glp-1mentioning

confidence: 99%

Incretin Hormones and Type 2 Diabetes – Mechanistic Insights and Therapeutic Approaches

Boer¹,

Holst²

2020

Preprint

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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.

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Physiology of the Incretin Hormones,GIPandGLP‐1—Regulation of Release and Posttranslational Modifications

Cited by 47 publications

References 455 publications

The incretin system in healthy humans: The role of GIP and GLP-1

The incretin system in healthy humans: The role of GIP and GLP-1

Enteroendocrine Hormone Secretion and Metabolic Control: Importance of the Region of the Gut Stimulation

Incretin Hormones and Type 2 Diabetes – Mechanistic Insights and Therapeutic Approaches

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