Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.
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.
Zhang
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CY
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA 02115, USA.
Baffy
G
G
Perret
P
P
Krauss
S
S
Peroni
O
O
Grujic
D
D
Hagen
T
T
Vidal-Puig
A J
AJ
Boss
O
O
Kim
Y B
YB
Zheng
X X
XX
Wheeler
M B
MB
Shulman
G I
GI
Chan
C B
CB
Lowell
B B
BB
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
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