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

Abstract

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.

The metabolic impact of small intestinal nutrient sensing

“…For example, oral glucose administration with matching plasma glucose concentrations achieved by intravenous glucose administration causes up to three times more insulin to be released, and small intestinal nutrient-sensing pathways and the subsequent release of gut peptides mediate up to 80% of whole-body glucose disposal 14 . This is attributed to the glucoregulatory effect of GLP-1 and another gut peptide glucose-dependent insulinotropic polypeptide (GIP), in which the peptides are released from the small intestine in response to glucose sensing 15 . Recently, the role of the upper small intestinal GLP-1 secreting cells is highlighted by selectively knocking out Gcg expression (a gene from which GLP-1 is derived) in the lower gut (ileum and large intestine) 16 .…”

“…Direct infusion of glucose into the duodenum in humans also increases circulating insulin levels, as does jejunal infusions, while glucagon levels either decrease or remain unchanged 91 . This discrepancy in glucagon is likely due to the differing actions of GIP and GLP-1, as GIP paradoxically increases while GLP-1 inhibits glucagon secretion 15 . While both GLP-1R and GIPR knockout mice exhibit reduced insulin release in response to intestinal glucose, each model only exhibits mild glucose intolerance.…”

Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH

“…GLP-1 also has other pleiotropic effects (Figure 1), including delay in gastric emptying and glucose absorption [24,25], stimulation of brain areas involved in the regulation of glucose homeostasis and food reward [26], suppression of glucagon secretion [25], beneficial effects on cardiovascular risk factors, a natriuretic effect on the kidney and others [16,27]. Of importance, GLP-1 has been shown to have a central effect to promote satiety, to reduce appetite and food intake [28], and GLP-1 receptor agonists (GLP-1RA) have been shown to promote weight loss and decrease liver fat [28,29] (Figure 1).…”

Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice

“…34 Given the plethora of potentially translatable information acquired from GIP studies conducted in rodents, and particularly mice, it is imperative to determine an effective GIPR antagonist for such rodent-based studies. Indeed, because GIP is regarded as the major physiological incretin hormone in man, 38 as suggested over 15 years previously in rodents, 26 the need is even more imperative.…”