Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin.
Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
Marchetti
Piero
P
Department of Endocrinology and Metabolism and Diabetes, Transplant Unit, University of Pisa, Italy. marchant@immr.med.unipi.it.
Del Guerra
Silvia
S
Marselli
Lorella
L
Lupi
Roberto
R
Masini
Matilde
M
Pollera
Maria
M
Bugliani
Marco
M
Boggi
Ugo
U
Vistoli
Fabio
F
Mosca
Franco
F
Del Prato
Stefano
S
D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D008687:Metformin