Amylin-mediated control of glycemia, energy balance, and cognition

Abstract

Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. Amylin also acts centrally as a satiation signal, reducing food intake and body weight. The ability of amylin to promote negative energy balance, along with its unique capacity to cooperatively facilitate or enhance the intake- and body weight-suppressive effects of other neuroendocrine signals like leptin, have made amylin a leading target for the development of novel pharmacotherapies for the treatment of obesity. In addition to these more widely studied effects, a growing body of literature suggests that amylin may play a role in processes related to cognition, including the neurodegeneration and cognitive deficits associated with Alzheimer's disease (AD). Although the function of amylin in AD is still unclear, intriguing recent reports indicate that amylin may improve cognitive ability and reduce hallmarks of neurodegeneration in the brain. The frequent comorbidity of diabetes mellitus and obesity, as well as the increased risk for and occurrence of AD associated with these metabolic diseases, suggests that amylin-based pharmaceutical strategies may provide multiple therapeutic benefits. This review will discuss the known effects of amylin on glycemic regulation, energy balance control, and cognitive/motivational processes. Particular focus will be devoted to the current and/or potential future clinical use of amylin pharmacotherapies for the treatment of diseases in each of these realms.

Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation

“…Amylin receptors (AMYs) consist of dimerized calcitonin receptor (CTR) with receptor activity-modifying proteins (RAMPs) and belong to class B GPCR. Amylin, the endogenous peptide that binds to the amylin receptor, mediates glycemic regulation, control of energy balance, and cognitive processes and modulates innate immunity through regulatory T cells [ 16 – 18 ]. We have previously shown that the deleterious effects of Aβ on cultured human and rat neurons are expressed through the amylin receptor and that amylin receptor antagonists, such as AC253, are neuroprotective against Aβ toxicity [ 14 , 19 ].…”

Ghrelin, Amylin, Gastric Inhibitory Peptide and Cognition in Middle-Aged HIV-Infected and Uninfected Women: The Women’s Interagency HIV Study

“…While higher levels of blood amylin are associated with higher BMI, lower blood levels of amylin have been observed in adults with more severe forms of cognitive impairment, such as dementia [18]. This is congruent with the low BMI and low leptin levels observed cross-sectionally in those with dementia, and that cognition is enhanced with the amylin analog, pramlintide [19]. Similar to other reports in HIV− samples that relate anthropometric measures to gut hormone levels, our findings demonstrate that higher amylin levels were associated with higher levels of overweight and obesity [53].…”

Amylin

“…Amylin is best known as a glucoregulatory hormone that helps control glucose homeostasis through a variety of mechanisms including controlling gastric emptying, leading to reduced meal size and weight loss. There are several recent reviews on this topic, to which readers are referred for further information . In type I diabetes and in insulin‐requiring type II diabetes, there is an amylin deficit.…”

“…CGRP is principally a neuropeptide, whereas the canonical role for amylin is as an endocrine hormone that signals to the brain and acts as a satiety factor. 2,[26][27][28] The major site of expression of amylin is in the b cells of the islets of Langerhans in the pancreas, although extra-pancreatic amylin expression has also been reported. Amylin likeimmunoreactivity has been reported in the stomach and in some neurons.…”

“…There are several recent reviews on this topic, to which readers are referred for further information. 2,27,32,33 In type I diabetes and in insulin-requiring type II diabetes, there is an amylin deficit. This led to the development of an amylin analog (pramlintide, sold as the drug Symlin) to treat these conditions.…”