Functional and molecular defects of pancreatic islets in human type 2 diabetes.
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.
Del Guerra
Silvia
S
Department of Endocrinology and Metabolism, Metabolic Unit, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy.
Lupi
Roberto
R
Marselli
Lorella
L
Masini
Matilde
M
Bugliani
Marco
M
Sbrana
Simone
S
Torri
Scilla
S
Pollera
Maria
M
Boggi
Ugo
U
Mosca
Franco
F
Del Prato
Stefano
S
Marchetti
Piero
P
D000080242:8-Hydroxy-2'-Deoxyguanosine; D055372:AMP-Activated Protein Kinases; D000328:Adult; D000368:Aged; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D007328:Insulin; D009097:Multienzyme Complexes; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D003849:Deoxyguanosine; D005978:Glutathione; D005947:Glucose