Control of energy homeostasis by amylin

Abstract

Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.

Islet amyloid polypeptide toxicity and membrane interactions

“…The importance of postion-18 is consistent with NMR studies of IAPP fragments in the presence of model membranes (45). hIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and rIAPP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] , which differ only in the identity of residue-18, bind membranes in different orientations, and these differences are believed to correlate with the difference in the potential for membrane disruption (45,46). In summary, our data dissociate IAPP-induced leakage of standard model membranes from direct cellular toxicity, thereby indicating that further studies to identify the precise mechanism (s) of IAPP cellular toxicity are essential for the optimal development of therapeutic strategies to prevent T2D and islet graft failure.…”

“…The polypeptide plays a role in the control of adiposity, gastric emptying, glucose homeostasis, and other metabolic activities (12,13). IAPP is 37 residues in length, has a disulfide bond between Cys-2 and Cys-7, and has an amidated C terminus.…”

The physiology underlying Roux-en-Y gastric bypass: a status report

“…Amylin is cosynthesized and coreleased with insulin in response to eating. Amylin's satiating action depends on direct activation of brain centers like the area postrema (77,78,86) and perhaps the ventral tegmental area (76,80). Amylin has been shown to enhance the eating inhibitory effect of other satiating hormones like CCK (76,80).…”

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

“…Pathological aggregation of the endocrine hormone human islet amyloid polypeptide (h-IAPP, also known as amylin) is a key feature in islet amyloidosis. h-IAPP is cosecreted with insulin and plays an adaptive role in metabolism (6,(13)(14)(15)(16), but in T2D, it aggregates by an unknown mechanism and is deposited as pancreatic islet amyloid plaques associated with reduced β cell volume (2,4,7,8,17,18). Aggregation of h-IAPP into amyloid fibrils involves 3 observable stages: Preamyloid oligomers (or prefibrillar intermediates) formed in the lag phase (LP) (first phase) assemble into amyloid fibrils in the growth phase (GP) (second phase), leading to an equilibrium between amyloid fibrils and residual soluble peptide in the saturation phase (SP) (third phase) (Supplemental Figure 1, A and B; supplemental material available online with this article; https:// doi.org/10.1172/JCI85210DS1).…”