Leptin Therapy Reverses Hyperglycemia in Mice With Streptozotocin-Induced Diabetes, Independent of Hepatic Leptin Signaling

被引:94
作者
Denroche, Heather C. [1 ]
Levi, Jasna [1 ]
Wideman, Rhonda D. [1 ]
Sequeira, Roveena M. [1 ]
Huynh, Frank K. [1 ]
Covey, Scott D. [2 ]
Kieffer, Timothy J. [1 ,3 ]
机构
[1] Univ British Columbia, Dept Cellular & Physiol Sci, Inst Life Sci, Vancouver, BC V5Z 1M9, Canada
[2] Univ British Columbia, Dept Biochem & Mol Biol, Inst Life Sci, Vancouver, BC V5Z 1M9, Canada
[3] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
PANCREATIC BETA-CELL; INSULIN-RESISTANCE; RECEPTOR MUTATION; GROWTH-HORMONE; ADIPOSE-TISSUE; GLUCAGON; SENSITIVITY; SUPPRESSION; PROGRESSION; INHIBITION;
D O I
10.2337/db10-0958
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type I diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes. RESEARCH DESIGN AND METHODS After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57B1/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted. RESULTS Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57B1/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wildtype littermates with STZ-induced diabetes. CONCLUSIONS These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver. Diabetes 60:1414-1423, 2011
引用
收藏
页码:1414 / 1423
页数:10
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