Role of Amylin in Type 1 and Type 2 Diabetes

Abstract

Amylin, formed primarily in pancreatic islet β cells, is cosecreted with insulin in response to caloric intake. Patients with type 1 diabetes have lower baseline amylin serum concentrations, and amylin response to caloric intake is absent. Patients with type 2 diabetes requiring insulin also have a diminished amylin response to caloric intake, potentially related to the degree of β-cell impairment. Key physiologic functions of amylin in maintaining glucose homeostasis include suppressing glucagon release in response to caloric intake, delaying the rate of gastric emptying, and stimulating the satiety center in the brain to limit caloric intake. Pramlintide is indicated for adults with type 1 and 2 diabetes who have not achieved adequate glucose control despite optimal insulin therapy. As an adjunct to insulin therapy, pramlintide demonstrated significant reductions in A1C in patients with type 1 and 2 diabetes, with favorable effects on body weight. It is administered subcutaneously before each major meal. There is an increased risk of hypoglycemia with insulin when used in combination with pramlintide. Other adverse effects may include nausea, vomiting, anorexia, reduced appetite, and headache. Proper patient selection and education are essential to successful pramlintide use.

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).…”

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

“…Since any protein needs to adopt an appropriate conformation in order to perform its function, protein unfolding into the cross-β conformation accompanied by phase transformation into solid fibrils generally abolishes the native function of the protein. Proteins such as lipoproteins, antibodies and IAPP (also called amylin) are not able to perform their homeostatic, immunological, or hormonal functions in their pathological amyloid forms in Apo-AI amyloidosis, lightchain amyloidosis and diabetes, respectively (Hieronymus and Griffin, 2015;Muchtar et al, 2016;Lu et al, 2017). The same applies to Aβ, prion protein (PrP) and α-syn, which are the most studied in the context of neurodegenerative disorders.…”

“…The LOF framework might also explain the failure of therapeutic approaches aiming only to reduce the amyloid forming proteins and open new directions in treatment that include restoring protein homeostasis via replacement therapy with functional, non-aggregating forms of the protein (Mockett et al, 2017). Indeed, synthetic IAPP (amylin) analogs such as pramlintide are clinically used as replacement therapy in diabetes (Hieronymus and Griffin, 2015). Furthermore, overexpression of soluble amyloid precursor protein alpha (APPsα) has been shown to restore synaptic plasticity, and rescue spatial memory in an AD mouse model with preexisting pathology and amyloidosis (Fol et al, 2016).…”

The role of pericytes in brain disorders: from the periphery to the brain

“…Amylin, or islet amyloid polypeptide, is a hormone which is synthesized by pancreatic islet b cells and secreted alongside insulin (Hieronymus and Griffin 2015). Amylin's main role is to regulate glucose homeostasis by inhibiting secretion of glucagon, prolonging gastric emptying, and stimulating satiety (Hieronymus and Griffin 2015).…”