Functional and molecular defects of pancreatic islets in human type 2 diabetes

Diabetes. 2005 Mar;54(3):727-35. doi: 10.2337/diabetes.54.3.727.

Abstract

To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • AMP-Activated Protein Kinases
  • Adult
  • Aged
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Female
  • Gene Expression
  • Glucose / metabolism
  • Glutathione / physiology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiopathology*
  • Male
  • Middle Aged
  • Multienzyme Complexes / metabolism
  • Oxidative Stress
  • Protein-Serine-Threonine Kinases / metabolism
  • Time Factors
  • Tyrosine / analogs & derivatives*
  • Tyrosine / metabolism

Substances

  • Insulin
  • Multienzyme Complexes
  • 3-nitrotyrosine
  • Tyrosine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Deoxyguanosine
  • Glutathione
  • Glucose