Neuroendocrine hormone amylin in diabetes

Abstract

The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and co-secreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.

Keywords: Amylin; Diabetes; Neuroendocrine hormone.

Figure 1

Overview of physiological actions of amylin. (1) Amylin suppresses glucagon secretion from islet alpha cells at mealtime and thus, inhibits glucagons-induced glucose release from the liver; (2) Amylin delays nutrient delivery from the stomach to the small intestine for absorption; (3) Amylin reduces food intake by a signal mediated through the central nervous system; (4) Renal amylin may stimulate Renin-Angiotensin System; and (5) Amylin and insulin coordinate storage of carbohydrate.

Figure 2

Amino acid sequence and diagrammatic representations of human amylin and pramlintide. A: Amino acid sequence alignment of human (WT, S20G), rat, mouse amylin and pramlintide. Only the amino acids that differ are shown. The sequence between amino acids 20 to 29 represents the amyloidogenic domain; B: The synthetic amylin analog pramlintide differs from human amylin at three amino acid sites (proline at 25, 28, and 29) and this molecule overcomes these disadvantages of human amylin.

Figure 3

Three conformations of human amylin. Monomers of amylin with physiological functions mainly contribute to glucose and lipid homeostasis and tend to misfold into the cytotoxic oligomers. A self-driven process is accumulating the misfolded oligomers into insoluble nontoxic amylin fibrils with a β-sheet structure.