title: Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.
abstract: beta cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of beta cell glucose sensing, and as a critical link between obesity, beta cell dysfunction, and type 2 diabetes.
authors: Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA 02115, USA.
authors: C Y
authors: CY
authors: Zhang
authors: G
authors: G
authors: Baffy
authors: P
authors: P
authors: Perret
authors: S
authors: S
authors: Krauss
authors: O
authors: O
authors: Peroni
authors: D
authors: D
authors: Grujic
authors: T
authors: T
authors: Hagen
authors: A J
authors: AJ
authors: Vidal-Puig
authors: O
authors: O
authors: Boss
authors: Y B
authors: YB
authors: Kim
authors: X X
authors: XX
authors: Zheng
authors: M B
authors: MB
authors: Wheeler
authors: G I
authors: GI
authors: Shulman
authors: C B
authors: CB
authors: Chan
authors: B B
authors: BB
authors: Lowell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003920:Diabetes Mellitus / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D018390:Gene Targeting; D006706:Homeostasis; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D024101:Mitochondrial Proteins; D008954:Models, Biological; D009765:Obesity; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis; D014475:Uncoupling Agents / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate