Two of the many gastrointestinal hormones have significant effects on insulin secretion and glucose regulation. These hormones are the glucagon-like peptides (principally glucagon-like peptide-1, GLP-1) and glucose-dependent insulinotropic peptide (GIP). Both of these gut hormones constitute the class of molecules referred to as the incretins. Incretins are molecules associated with food intake-stimulation of insulin secretion from the pancreas.
Details of the actions of GLP-1 and GIP can be found in the Gut-Brain Interactions page. Briefly, GLP-1 is derived from the product of the proglucagon gene (gene symbol = GCG). This gene encodes a preproprotein that is differentially cleaved dependent upon the tissue in which it is synthesized. For example, in pancreatic α-cells prohormone convertase 2 action leads to the release of glucagon. In the gut prohormone convertase 1/3 action leads to release of several peptides including GLP-1. Upon nutrient ingestion GLP-1 is secreted from intestinal enteroendocrine L-cells that are found predominantly in the ileum and colon with some production from these cell types in the duodenum and jejunum. Bioactive GLP-1 consists of 2 forms; GLP-1(7-37) and GLP-1(7-36)amide, where the latter form constitutes the majority (80%) of the circulating hormone.
The primary physiological responses to GLP-1 are glucose-dependent insulin secretion, inhibition of glucagon secretion and inhibition of gastric acid secretion and gastric emptying. The latter effect will lead to increased satiety with reduced food intake along with a reduced desire to ingest food. The action of GLP-1 at the level of insulin and glucagon secretion results in significant reduction in circulating levels of glucose following nutrient intake. This activity has obvious significance in the context of diabetes, in particular the hyperglycemia associated with poorly controlled type 2 diabetes. The glucose lowering activity of GLP-1 is highly transient as the half-life of this hormone in the circulation is less than 2 minutes. Removal of bioactive GLP-1 is a consequence of N-terminal proteolysis catalyzed by dipeptidylpeptidase IV (DPP IV or DPP4). For more complete information on the activities of DPP4 go to the DPP4 page.back to the top
Although much of the research that has led to a detailed understanding of the signal transduction pathways initiated by Wnts was carried out in models of early development, evidence has been accumulating demonstrating a significant role for the Wnts in the control of metabolism. In particular Wnt action has been shown to be involved in metabolic control via its actions in both the gut and pancreas. In addition, Wnt signaling has been shown to interact with signaling pathways induced by insulin.
In the gut Wnt has been shown to be involved in regulated expression of the GCG gene. In intestinal enteroendocrine L cells the expression of the GCG gene results in the production of GLP-1. As indicated above, GLP-1 exerts its effects on the gut, the pancreas and in the brain. In the gut its effects lead to a reduced rate of gastric acid secretion and reduced gastric emptying. In the pancreas GLP-1 induced β-cell proliferation and inhibition of β-cell apoptosis. In the brain GLP-1 actins result in increased satiety leading to reduced desire for food intake.
The GCG gene promoter region contains an enhancer that harbors a canonical Wnt response element that binds TCF factors, in particular the TCF7L2 protein. Genome wide screens for polymorphisms associated with type 2 diabetes demonstrated that two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene were the most frequently occurring SNPs associated with this disease. The significance of Wnt in the control of GLP-1 production was demonstrated by the fact that reduction/loss of either β-catenin or TCF7L2 function completely blocks insulin-stimulated expression of the intestinal GCG gene. In addition, the effects of GLP-1 on the pancreas (i.e. proliferation and anti-apoptosis) are effected via the actions of β-catenin and TCF7L2. In the pancreas insulin inhibits expression from the GCG gene leading to reduced production of glucagon. This action has physiological significance because glucagon is the major counter-regulatory hormone to insulin action. The important role of TCF7L2 in pancreatic function can be demonstrated in experiments that lead to reduction in the levels of TCF7L2. In these types of experiments there is an increased rate of pancreatic β-cell apoptosis, reduced β-cell proliferation, and reduced glucose-dependent insulin secretion.
The demonstration of cross-talk between the Wnt and insulin signaling pathways is important as these observations may eventually lead to novel approaches to the treatment of type 2 diabetes.back to the top