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Mechanism for leptin's acute insulin-independent effect to reverse diabetic ketoacidosis.
Citation | “Mechanism For Leptin's Acute Insulin-Independent Effect To Reverse Diabetic Ketoacidosis.”. The Journal Of Clinical Investigation, pp. 657-669. . |
Center | Yale University |
Author | Rachel J Perry, Liang Peng, Abudukadier Abulizi, Lynn Kennedy, Gary W Cline, Gerald I Shulman |
Abstract |
The mechanism by which leptin reverses diabetic ketoacidosis (DKA) is unknown. We examined the acute insulin-independent effects of leptin replacement therapy in a streptozotocin-induced rat model of DKA. Leptin infusion reduced rates of lipolysis, hepatic glucose production (HGP), and hepatic ketogenesis by 50% within 6 hours and were independent of any changes in plasma glucagon concentrations; these effects were abrogated by coinfusion of corticosterone. Treating leptin- and corticosterone-infused rats with an adipose triglyceride lipase inhibitor blocked corticosterone-induced increases in plasma glucose concentrations and rates of HGP and ketogenesis. Similarly, adrenalectomized type 1 diabetic (T1D) rats exhibited decreased rates of lipolysis, HGP, and ketogenesis; these effects were reversed by corticosterone infusion. Leptin-induced decreases in lipolysis, HGP, and ketogenesis in DKA were also nullified by relatively small increases (15 to 70 pM) in plasma insulin concentrations. In contrast, the chronic glucose-lowering effect of leptin in a STZ-induced mouse model of poorly controlled T1D was associated with decreased food intake, reduced plasma glucagon and corticosterone concentrations, and decreased ectopic lipid (triacylglycerol/diacylglycerol) content in liver and muscle. Collectively, these studies demonstrate marked differences in the acute insulin-independent effects by which leptin reverses fasting hyperglycemia and ketoacidosis in a rodent model of DKA versus the chronic pleotropic effects by which leptin reverses hyperglycemia in a non-DKA rodent model of T1D. |
Year of Publication |
2017
|
Journal |
The Journal of clinical investigation
|
Volume |
127
|
Issue |
2
|
Number of Pages |
657-669
|
Date Published |
02/2017
|
ISSN Number |
1558-8238
|
DOI |
10.1172/JCI88477
|
Alternate Journal |
J. Clin. Invest.
|
PMID |
28112679
|
PMCID |
PMC5272181
|
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