Islet amyloid inhibitors improve glucose homeostasis in a transgenic mouse model of type 2 diabetes

• Published in: Diabetes, obesity & metabolism Vol. 17; no. 10; pp. 1003 - 1006
• Main Authors: Wijesekara, N., Ahrens, R., Wu, L., Ha, K., Liu, Y., Wheeler, M. B., Fraser, P. E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2015; Wiley Subscription Services, Inc
• Subjects: Amylin; Animals; Apoptosis; Apoptosis - drug effects; Beta cells; Blood Glucose - drug effects; Cell survival; Cytotoxicity; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Disease Models, Animal; Glucose tolerance; Homeostasis; Homeostasis - drug effects; Insulin; Insulin secretion; Insulin-Secreting Cells - drug effects; islet amyloid polypeptide (IAPP); Islet Amyloid Polypeptide - antagonists & inhibitors; Islet Amyloid Polypeptide - therapeutic use; Islets of Langerhans - drug effects; Mice; Mice, Transgenic; peptide inhibitors; Rodents; Transgenic animals; Transgenic mice; type 2 diabetes; β-Amyloid; peptide inhibitors; amylin; type 2 diabetes; islet amyloid polypeptide (IAPP)
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12529

Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of β‐cell mass in type 2 diabetes. Prevention of IAPP formation represents a potential treatment to increase β‐cell survival and function. The IAPP inhibitory peptide, D‐ANFLVH, has been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D‐ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of β‐cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in β‐cell survival and validate the application of anti‐amyloid compounds as therapeutic strategies to maintain normal insulin secretion in patients with type 2 diabetes.