Leptin and INSULIN
(adipoinsular axis)
ObRb "the long form of the Leptin receptor" is essential for the actions of Leptin. ObRb receptor is present in the pancreatic beta cells, and thus a regulation of Insulin secretion from the pancreas is made possible, resulting in an adipoinsular axis. Insulin is adipogenic and hence it is logical that a fat-regulatory hormone like Leptin should influence Insulin secretion, in addition to multiple other factors including ingested nutrients, glucagon, incretins and autonomic responses. On the other hand of the axis, Leptin secretion could be regulated by Insulin. Leptin varies in the long term in relation to fat mass, but short term changes (in response to fasting and diurnally) also occur, and hence regulators other than fat mass, clearly exist
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Leptin levels may be influenced by insulin. Leptin has been shown to correlate with insulin levels independent of fat mass. J Clin Endocrinol Metab. 1996 Dec;81(12):4433-8; Diabetes Care. 1997 Sep;20(9):1476-81 Insulin injections into rats increases ob mRNA in adipose tissue with increased serum Leptin levels. Nature. 1995 Oct 12;377(6549):527-9 Rats made insulin-deficient with streptozotocin Metabolism. 1998 May;47(5):584-91. as well as naturally diabetic rats show reduced Leptin levels, but respond with Leptin rise on insulin administration. The Human adipocytes treated with insulin increases mRNA expression and secretion of Leptin. Diabetes. 1996 Oct;45(10):1435-8. Hyperinsulinaemia induced by clamp technique in humans is associated with a rise in Leptin levels. Diabetes. 1996 Oct;45(10):1364-6 High levels of insulin as in an insulinoma patient, Clin Endocrinol (Oxf). 1997 Jun;46(6):751-7 as well as treatment with insulin in type 1 Metabolism. 1998 Nov;47(11):1391-6 and type 2 diabetics J Clin Endocrinol Metab. 1997 Feb;82(2):654-7 are associated with increases in Leptin levels. Removal of the insulin stimulus as in treatment of the insulinoma results in normalisation of Leptin levels. Eur J Endocrinol. 1998 Jan;138(1):86-8. SREBP-1 is a transcription factor that is increased on treatment of adipocytes with insulin which could transactivate the Leptin gene. J Clin Invest. 1998 Jan 1;101(1):1-9. Other transcription factors as PPAR Curr Opin Cell Biol. 1998 Apr;10(2):165-73 and C/EBP may also be involved in this insulin mediated Leptin regulation. Annu Rev Cell Dev Biol. 1997;13:231-59.
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Leptin in turn, can influence insulin levels. Leptin administration to ob/ob mice corrects all the metabolic disturbances (insulin resistance and hyperglycaemia) Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14804-8 with acute fall in insulin levels occurring within 10 minutes, well before weight loss occurs. J Clin Invest. 1997 Dec 1;100(11):2729-36. The reduction in insulin with Leptin administration is associated with rise in glucose levels suggesting that the regulation is indeed Leptin mediated rather than by glucose. Biochem Biophys Res Commun. 1998 Apr 17;245(2):502-9. In normal mice in the fed state, Leptin administration thus decreases insulin and increases glucose levels. In normal mice in the fasting state, Endocrinology. 1997 Aug;138(8):3395-401 and on chronic treatment, Biochem Biophys Res Commun. 1998 Apr 17;245(2):502-9. Leptin reduces both insulin and glucose, suggesting improved insulin sensitivity. The reduction of insulin levels could be mediated via sympathetic activation, or direct action on the Leptin receptors demonstrated on the pancreatic beta cells Biochem Biophys Res Commun. 1996 Jul 16;224(2):522-7. In keeping with the former notion is the fact that the effect of Leptin is abolished after chemical sympathectomy in vagotomised rats. Endocrinology. 1998 Sep;139(9):3863-70. Leptin may also decrease insulin secretion through inhibition of Neuropeptide Y secretion. Science. 1996 Dec 6;274(5293):1704-7. Although Leptin decreases insulin in the fasting state, this effect is over-ridden by factors that increase cAMP concentrations as glucose stimulation and GLP-1, J Clin Invest. 1998 Sep 1;102(5):869-73. both of which increase with feeding. Thus Leptin may act by antagonizing cAMP signalling. Leptin seems to decrease insulin secretion by facilitating opening of the K-ATP channels- possibly mediated by increase in long-chain acyl-CoA J Biol Chem. 1996 May 3;271(18):10623-6 in beta cells- thus preventing depolarisation in the islet beta cells, an effect that can be reversed by adminstration of potassium channel closing agents as sulphonylureas. Diabetes. 1997 Jun;46(6):1087-93. Not only release of insulin, but also the synthesis of insulin by beta cells has been shown to be reduced by Leptin, Biochem Biophys Res Commun. 1997 Sep 8;238(1):267-70, which could be mediated by the STAT3 protein pathway. J Mol Endocrinol. 1999 Apr;22(2):173-84. In fact, high doses of Leptin (6.25 nM) inhibits even GLP-1 stimulated expression of pre-proinsulin mRNA in human islets incubated with glucose. J Clin Endocrinol Metab. 1999 Feb;84(2):670-6.
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Target tissues for insulin action namely liver, skeletal muscle and adipose tissue, all demonstrate Leptin receptors. Leptin infusion in rats increases glucose utilization with improved peripheral insulin sensitivity. Endocrinology. 1997 Aug;138(8):3395-401. ob/ob mice treated with Leptin showed lower glucose and insulin levels than pair fed ob/ob mice which lost similar weight without Leptin therapy, Diabetes. 1996 Apr;45(4):531-5 suggesting improved insulin sensitivity induced by Leptin independent of fat loss. Leptin decreased glucokinase expression and decreased glycogenolysis, thus facilitating insulin induced inhibition of hepatic glucose output in the postprandial state. J Biol Chem. 1997 Oct 31;272(44):27758-63 The role of Leptin in the aetiology of the type 2 diabetic state (adipogenic diabetes) is controversial. Improved insulin sensitivity and glucose utilization has been demonstrated with Leptin on one hand, while decreased insulin secretion from the pancreas and increased peripheral insulin resistance has been demonstrated in hyper-Leptinaemic states on the other. More confusing studies are awaited before any categorical statements can be made! Relative Leptin resistance in tissues is considered beneficial according to one view as Leptin promotes foam cell formation in macrophages with predilection for atherosclerosis. J Biol Chem. 2002 Nov 8;277(45):42557-62.