Hormonal Control

Numerous peptide hormones play a role in the regulation of intestinal motility and gastric emptying and also directly, or indirectly, in the control of satiety and caloric intake. Some of these peptides are also involved in glycemic control. These hormones may also influence the neural control of gut motility.

Glucagon-like peptide-1 (GLP-1) arises from the differential post-transcriptional processing of the proglucagon gene that occurs in the intestinal L cells and in the hypothalamus. It is an incretin hormone because of its potentiation of glucose-induced insulin secretion. When infused in pharmacological concentrations it markedly delays gastric emptying while increasing insulin and suppressing glucagon secretion in response to meal ingestion. Because of these actions, GLP-1 can prevent postprandial hyperglycemia. These actions have led to the development of GLP-1-based therapy for type 2 diabetes. The infusion of GLP-1 in healthy subjects delays gastric emptying and increases gastric accommodation. The increase in abdominal volume is not accompanied by an increased perception of satiety suggesting that GLP-1 alters gastric compliance or the central perception of gastric distention. These actions are accompanied by the suppression of human pancreatic polypeptide (HPP) suggesting that the effects of GLP-1 on the stomach are at least partly dependent on inhibition of vagal cholinergic function (52). Indeed in people with type 2 diabetes and documented cardio-vagal neuropathy GLP-1 does not alter accommodation of the stomach in response to meal ingestion lending further support to the supposition that GLP-1 actions on the stomach are mediated by the vagus. It is interesting to note that the effects of GLP-1 on the stomach are dose-dependent and circulating concentrations encountered in the absence of GLP-1 infusion or after inhibition of its breakdown by dipeptidyl peptidase-4 (DPP-4) have no direct effect on gastric emptying or GI symptoms (53,54).

Since the intestinal L cells are dispersed in the lower small intestine and colon and GLP-1 levels rise markedly in response to nutrient ingestion, it has been hypothesized that GLP-1 may contribute to the ileal brake effect, that is, the inhibition of upper GI motility due to the presence of (unabsorbed) nutrients in the distal small intestine.

Amylin is a 37 amino-acid polypeptide that is co-secreted with insulin by the pancreatic beta cells in response to nutrient stimuli. Human studies have shown that the plasma concentrations of amylin and insulin rise and fall in parallel in both the fasted and fed states. Amylin secretion mirrors the abnormalities of insulin secretion observed in diabetes. People with type 1 diabetes typically do not have detectable amylin in the circulation during the fasting and fed states. Consequently, type 1 diabetes is a state of amylin as well as insulin deficiency. In contrast, amylin concentrations are more variable in people with type 2 diabetes. Amylin concentrations are elevated in early type 2 diabetes, but are decreased in the later stages as insulin secretion wanes.

Infusion of pharmacological concentrations of amylin or the more stable analog, pramlintide in both animals and humans has established that amylin can inhibit gastric emptying (55) and decrease glucagon secretion. The effects of amylin on gastric emptying are similar in type 1 and type 2 diabetes (56).

Studies in rats and, more recently, in humans suggest that like GLP-1, the effects of pramlintide may be centrally mediated. Pramlintide inhibits meal-induced secretion of pancreatic polypeptide a well-established marker of intestinal vagal activity (55,56). The inhibition of gastric emptying produced by pramlintide is avoided during insulin-induced hypoglycemia which is associated with vagal stimulation (57). Pramlintide is now available for clinical use to delay gastric emptying and consequently decrease postprandial hyperglycemia in people with diabetes.

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