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

S Del Guerra, R Lupi, L Marselli, M Masini… - Diabetes, 2005 - Am Diabetes Assoc
S Del Guerra, R Lupi, L Marselli, M Masini, M Bugliani, S Sbrana, S Torri, M Pollera, U Boggi
Diabetes, 2005Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc