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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Blood Glucose / metabolism
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Body Weight
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Diabetes Mellitus / metabolism*
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Diabetes Mellitus, Type 2 / metabolism*
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Disease Models, Animal
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Gene Targeting
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Homeostasis
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Humans
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Hyperglycemia
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Insulin / blood
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Insulin / metabolism*
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Insulin Secretion
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Ion Channels
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Islets of Langerhans / metabolism*
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Male
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Membrane Transport Proteins*
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Mice
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Mice, Knockout
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Mice, Obese
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Mitochondrial Proteins*
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Models, Biological
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Obesity*
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Proteins / genetics
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Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Thermogenesis
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Uncoupling Agents / metabolism
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Uncoupling Protein 2
Substances
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Blood Glucose
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Insulin
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Ion Channels
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Membrane Transport Proteins
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Mitochondrial Proteins
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Proteins
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RNA, Messenger
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UCP2 protein, human
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Ucp2 protein, mouse
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Uncoupling Agents
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Uncoupling Protein 2
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Adenosine Triphosphate