Human Islet Amyloid Polypeptide Oligomers Disrupt Cell Coupling, Induce Apoptosis, and Impair Insulin Secretion in Isolated Human Islets

Human Islet Amyloid Polypeptide Oligomers Disrupt Cell Coupling, Induce Apoptosis, and Impair Insulin Secretion in Isolated Human Islets Robert A. Ritzel 1 , Juris J. Meier 1 , Chia-Yu Lin 1 , Johannes D. Veldhuis 2 and Peter C. Butler 1 1 Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California 2 Endocrine Division, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota Address correspondence to Peter C. Butler, Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 24-130 Warren Hall, 900 Veteran Ave., Los Angeles, CA 90095-7073. E-mail: pbutler{at}mednet.ucla.edu Abstract Insulin secretion from the 2,000–3,000 β-cells in an islet is a highly synchronized activity with discharge of insulin in coordinate secretory bursts at approximately 4-min intervals. Insulin secretion progressively declines in type 2 diabetes and following islet transplantation. Both are characterized by the presence of islet amyloid derived from islet amyloid polypeptide (IAPP). In the present studies, we examined the action of extracellular human IAPP (h-IAPP) on morphology and function of human islets. Because oligomers of h-IAPP are known to cause membrane disruption, we questioned if application of h-IAPP oligomers to human islets would lead to disruption of islet architecture (specifically cell-to-cell adherence) and a decrease in coordinate function (e.g., increased entropy of insulin secretion and diminished coordinate secretory bursts). Both hypotheses are affirmed, leading to a novel hypothesis for impaired insulin secretion in type 2 diabetes and following islet transplantation, specifically disrupted cell-to-cell adherence in islets through the actions of membrane-disrupting IAPP oligomers. ApEn, approximate entropy ELISA, enzyme-linked immunosorbent assay h-IAPP, human IAPP IAPP, islet amyloid polypeptide r-IAPP, rodent IAPP TLVM, time-lapse video microscopy TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 29, 2006. Received May 28, 2006. DIABETES