Skip to main content
Top
Published in: Diabetologia 5/2015

01-05-2015 | Article

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol

Authors: Heather C. Denroche, Michelle M. Kwon, Whitney L. Quong, Ursula H. Neumann, Jerzy E. Kulpa, Subashini Karunakaran, Susanne M. Clee, Roger W. Brownsey, Scott D. Covey, Timothy J. Kieffer

Published in: Diabetologia | Issue 5/2015

Login to get access

Abstract

Aims/hypothesis

Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice.

Methods

Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 μg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting.

Results

STZ–leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ–leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice.

Conclusions/interpretation

The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fasting-induced hypoglycaemia in leptin-treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin.
Appendix
Available only for authorised users
Literature
1.
go back to reference Chinookoswong N, Wang JL, Shi ZQ (1999) Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48:1487–1492CrossRefPubMed Chinookoswong N, Wang JL, Shi ZQ (1999) Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes 48:1487–1492CrossRefPubMed
2.
go back to reference Yu X, Park BH, Wang MY, Wang ZV, Unger RH (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105:14070–14075CrossRefPubMedCentralPubMed Yu X, Park BH, Wang MY, Wang ZV, Unger RH (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A 105:14070–14075CrossRefPubMedCentralPubMed
4.
go back to reference Denroche HC, Levi J, Wideman RD et al (2011) Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60:1414–1423CrossRefPubMedCentralPubMed Denroche HC, Levi J, Wideman RD et al (2011) Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes 60:1414–1423CrossRefPubMedCentralPubMed
5.
6.
go back to reference German JP, Thaler JP, Wisse BE et al (2011) Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152:394–404CrossRefPubMedCentralPubMed German JP, Thaler JP, Wisse BE et al (2011) Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology 152:394–404CrossRefPubMedCentralPubMed
7.
go back to reference Fujikawa T, Berglund ED, Patel VR et al (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431–444CrossRefPubMedCentralPubMed Fujikawa T, Berglund ED, Patel VR et al (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431–444CrossRefPubMedCentralPubMed
8.
go back to reference Jelen S, Wacker S, Aponte-Santamaria C et al (2011) Aquaporin-9 protein is the primary route of hepatocyte glycerol uptake for glycerol gluconeogenesis in mice. J Biol Chem 286:44319–44325CrossRefPubMedCentralPubMed Jelen S, Wacker S, Aponte-Santamaria C et al (2011) Aquaporin-9 protein is the primary route of hepatocyte glycerol uptake for glycerol gluconeogenesis in mice. J Biol Chem 286:44319–44325CrossRefPubMedCentralPubMed
9.
go back to reference Westergaard N, Madsen P, Lundgren K (1998) Characterization of glycerol uptake and glycerol kinase activity in rat hepatocytes cultured under different hormonal conditions. Biochim Biophys Acta 1402:261–268CrossRefPubMed Westergaard N, Madsen P, Lundgren K (1998) Characterization of glycerol uptake and glycerol kinase activity in rat hepatocytes cultured under different hormonal conditions. Biochim Biophys Acta 1402:261–268CrossRefPubMed
10.
go back to reference Mahendran Y, Cederberg H, Vangipurapu J et al (2013) Glycerol and fatty acids in serum predict the development of hyperglycemia and type 2 diabetes in Finnish men. Diabetes Care 36:3732–3738CrossRefPubMedCentralPubMed Mahendran Y, Cederberg H, Vangipurapu J et al (2013) Glycerol and fatty acids in serum predict the development of hyperglycemia and type 2 diabetes in Finnish men. Diabetes Care 36:3732–3738CrossRefPubMedCentralPubMed
11.
12.
go back to reference Rojek AM, Skowronski MT, Fuchtbauer EM et al (2007) Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice. Proc Natl Acad Sci U S A 104:3609–3614CrossRefPubMedCentralPubMed Rojek AM, Skowronski MT, Fuchtbauer EM et al (2007) Defective glycerol metabolism in aquaporin 9 (AQP9) knockout mice. Proc Natl Acad Sci U S A 104:3609–3614CrossRefPubMedCentralPubMed
13.
go back to reference Claus TH, Lowe DB, Liang Y et al (2005) Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose. J Pharmacol Exp Ther 315:1396–1402CrossRefPubMed Claus TH, Lowe DB, Liang Y et al (2005) Specific inhibition of hormone-sensitive lipase improves lipid profile while reducing plasma glucose. J Pharmacol Exp Ther 315:1396–1402CrossRefPubMed
14.
go back to reference King MT, Reiss PD, Cornell NW (1988) Determination of short-chain coenzyme A compounds by reversed-phase high-performance liquid chromatography. Methods Enzymol 166:70–79CrossRefPubMed King MT, Reiss PD, Cornell NW (1988) Determination of short-chain coenzyme A compounds by reversed-phase high-performance liquid chromatography. Methods Enzymol 166:70–79CrossRefPubMed
15.
go back to reference Neumann UH, Chen S, Tam YY et al (2014) IGFBP2 is neither sufficient nor necessary for the physiological actions of leptin on glucose homeostasis in male ob/ob mice. Endocrinology 155:716–725CrossRefPubMed Neumann UH, Chen S, Tam YY et al (2014) IGFBP2 is neither sufficient nor necessary for the physiological actions of leptin on glucose homeostasis in male ob/ob mice. Endocrinology 155:716–725CrossRefPubMed
17.
go back to reference Weir GC, Knowlton SD, Atkins RF, McKennan KX, Martin DB (1976) Glucagon secretion from the perfused pancreas of streptozotocin-treated rats. Diabetes 25:275–282CrossRefPubMed Weir GC, Knowlton SD, Atkins RF, McKennan KX, Martin DB (1976) Glucagon secretion from the perfused pancreas of streptozotocin-treated rats. Diabetes 25:275–282CrossRefPubMed
18.
go back to reference Kurose T, Tsuda K, Ishida H et al (1992) Glucagon, insulin and somatostatin secretion in response to sympathetic neural activation in streptozotocin-induced diabetic rats. A study with the isolated perfused rat pancreas in vitro. Diabetologia 35:1035–1041CrossRefPubMed Kurose T, Tsuda K, Ishida H et al (1992) Glucagon, insulin and somatostatin secretion in response to sympathetic neural activation in streptozotocin-induced diabetic rats. A study with the isolated perfused rat pancreas in vitro. Diabetologia 35:1035–1041CrossRefPubMed
19.
go back to reference Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396CrossRefPubMedCentralPubMed Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391–17396CrossRefPubMedCentralPubMed
20.
21.
go back to reference da Silva AA, Tallam LS, Liu J, Hall JE (2006) Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. Am J Physiol Regul Integr Comp Physiol 291:R1275–R1282CrossRefPubMed da Silva AA, Tallam LS, Liu J, Hall JE (2006) Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity. Am J Physiol Regul Integr Comp Physiol 291:R1275–R1282CrossRefPubMed
22.
go back to reference da Silva AA, do Carmo JM, Freeman JN, Tallam LS, Hall JE (2009) A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin. Diabetes 58:1749–1756CrossRefPubMedCentralPubMed da Silva AA, do Carmo JM, Freeman JN, Tallam LS, Hall JE (2009) A functional melanocortin system may be required for chronic CNS-mediated antidiabetic and cardiovascular actions of leptin. Diabetes 58:1749–1756CrossRefPubMedCentralPubMed
23.
go back to reference do Carmo JM, Hall JE, da Silva AA (2008) Chronic central leptin infusion restores cardiac sympathetic-vagal balance and baroreflex sensitivity in diabetic rats. Am J Physiol Heart Circ Physiol 295:H1974–H1981CrossRefPubMedCentralPubMed do Carmo JM, Hall JE, da Silva AA (2008) Chronic central leptin infusion restores cardiac sympathetic-vagal balance and baroreflex sensitivity in diabetic rats. Am J Physiol Heart Circ Physiol 295:H1974–H1981CrossRefPubMedCentralPubMed
24.
go back to reference Lin CY, Higginbotham DA, Judd RL, White BD (2002) Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 282:E1084–E1091CrossRefPubMed Lin CY, Higginbotham DA, Judd RL, White BD (2002) Central leptin increases insulin sensitivity in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 282:E1084–E1091CrossRefPubMed
25.
go back to reference Kojima S, Asakawa A, Amitani H et al (2009) Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides 30:962–966CrossRefPubMed Kojima S, Asakawa A, Amitani H et al (2009) Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides 30:962–966CrossRefPubMed
26.
go back to reference Ueno N, Inui A, Kalra PS, Kalra SP (2006) Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice. Peptides 27:2332–2342CrossRefPubMed Ueno N, Inui A, Kalra PS, Kalra SP (2006) Leptin transgene expression in the hypothalamus enforces euglycemia in diabetic, insulin-deficient nonobese Akita mice and leptin-deficient obese ob/ob mice. Peptides 27:2332–2342CrossRefPubMed
Metadata
Title
Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol
Authors
Heather C. Denroche
Michelle M. Kwon
Whitney L. Quong
Ursula H. Neumann
Jerzy E. Kulpa
Subashini Karunakaran
Susanne M. Clee
Roger W. Brownsey
Scott D. Covey
Timothy J. Kieffer
Publication date
01-05-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 5/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-015-3529-4

Other articles of this Issue 5/2015

Diabetologia 5/2015 Go to the issue