Glucose-induced Beta Cell Production of IL-1beta Contributes to Glucotoxicity in Human Pancreatic Islets

J Clin Invest. 2002 Sep;110(6):851-60. doi: 10.1172/JCI15318.

Abstract

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antioxidants / pharmacology
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Gerbillinae
  • Glucose / metabolism*
  • Glucose / toxicity
  • Humans
  • Hyperglycemia / metabolism
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Male
  • Middle Aged
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Proline / analogs & derivatives*
  • Proline / pharmacology
  • Receptors, Interleukin-1 / metabolism
  • Thiocarbamates / pharmacology

Substances

  • Antioxidants
  • Interleukin-1
  • Receptors, Interleukin-1
  • Thiocarbamates
  • prolinedithiocarbamate
  • Proline
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Glucose