Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction.
Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic beta cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced beta cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on beta cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of beta cell dysfunction and type 2 diabetes.
Krauss
Stefan
S
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Zhang
Chen-Yu
CY
Scorrano
Luca
L
Dalgaard
Louise T
LT
St-Pierre
Julie
J
Grey
Shane T
ST
Lowell
Bradford B
BB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007473:Ion Channels; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010101:Oxygen Consumption; D011522:Protons; D012333:RNA, Messenger / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D000071246:Uncoupling Protein 2
D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011522:Protons; D012333:RNA, Messenger; D012235:Rhodamines; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C401833:tetramethylrhodamine methyl ester; D013481:Superoxides; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D005947:Glucose