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Recent Research Progress
IAPP, also called amylin, is secreted from pancreatic beta cells. IAPP is most studied since it has been found plays important roles in diabetes and Alzheimer’s disease (AD), both of which cannot be cure yet. IAPP is a prevalent autoantigen in diabetes cause several of its epitopes can activate either CD4 or CD8 T cells in NOD mice and T1D subjects. In addition, recently evidences show that IAPP aggregates elicit interleukin-1B (IL1B) secretion from innate immune cells as strong proinflammatory stimuli. Moreover, the pro-inflammatory properties and toxic effects on beta cells of IAPP are implicated in the pathology of Type 2 diabetes (T2D). Besides, IAPP is the main constituent of insoluble amyloid deposits in T2D. Intriguingly, IAPP deposits also be found in the brain tissue of patients with AD, contributing to the pathophysiology of the disease. Researches show that human IAPP has high binding affinity to Aβ, an important factor in AD. What’s more, they also share many biophysical and physiological properties, and exert similar cytotoxic mechanisms when they aggregate.
Thus, IAPP seems a novel link between T2D and AD. Increasing evidences reveal that there are many possible pathways by which IAPP aggregates accelerate the progression of AD in diabetic patients, such as the interaction with Aβ, instigation generic toxic cellular responses, interaction with lipid components of cell membrane, triggering inflammatory responses, inducing a pattern of oxidative stress genes which lead to cell apoptosis, and working with the pro-apoptotic c-Jun N-terminal kinase (JNK) signaling pathway. People speculated that cerebral IAPP is derived from pancreatic islet b-cells during the progression of T2D, and then flows into the Central nervous system (CNS) via the circulation. Result that parts of IAPP deposits are detected in blood vessel walls and pericapillary spaces in the brain has further supported this hypothesis. Additionally, as shown as Figure 1, IAPP oligomers can cross the blood brain barrier (BBB) by inducing inflammatory cytokines to destroy the integrity of the BBB.
Figure 1. The potential mechanisms of amyloidogenic IAPP-induced AD development.
(Zhang Y, et al. 2018)
IAPP plays many physiological roles in diabetes and AD with its heterodimer receptor, distributing in the brain widely. Among those roles, one of the most significant role of IAPP is to be a physiologic regulator of food consumption. Besides its effects on appetite, studies also demonstrated that IAPP is to serve as an adiposity signal in the brain to control body weight. It has been showed that IAPP activates the sympathetic nerve, increasing brown adipose tissue (BAT) activity and regulating total energy expenditure. With the overexpression of RAMP1, a component of the IAPP receptor complex, this metabolic effect of IAPP is enhanced in the mice. However, the BAT response to IAPP abolished when pretreatment with the IAPP receptor antagonist AC187, indicating that the sympathetic effects of IAPP are receptor- mediated. Previous studies have demonstrated that IAPP contributes to glucose homeostasis by suppressing glucagon secretion in the postprandial state, which indicates the beneficial effects of IAPP on glucose homeostasis. On the other side, IAPP delays absorption of glucose from the small intestine into the circulation by signaling the stomach to slow gastric emptying.
Figure 2. Physiological role of amylin. (Michaela Press, et al, 2018)