title: Leptin administration enhances islet transplant performance in diabetic mice.
abstract: Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice.
authors: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Heather C
authors: HC
authors: Denroche
authors: Whitney L
authors: WL
authors: Quong
authors: Jennifer E
authors: JE
authors: Bruin
authors: Eva
authors: E
authors: Tudurí
authors: Ali
authors: A
authors: Asadi
authors: Maria M
authors: MM
authors: Glavas
authors: Jessica K
authors: JK
authors: Fox
authors: Timothy J
authors: TJ
authors: Kieffer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000601:surgery*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin
references: Diabetes. 2010 Jul;59(7):1626-34
references: 20424233
references: Diabetes. 2006 Jan;55(1):171-8
references: 16380490
references: Am J Physiol Endocrinol Metab. 2002 May;282(5):E1084-91
references: 11934674
references: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2058-63
references: 14769942
references: Diabetes. 2005 Jul;54(7):2060-9
references: 15983207
references: Am J Physiol. 1998 May;274(5):R1482-91
references: 9612417
references: Autoimmunity. 2011 Mar;44(2):137-48
references: 20695765
references: Endocrinology. 2011 Feb;152(2):394-404
references: 21159853
references: J Clin Endocrinol Metab. 1999 Feb;84(2):670-6
references: 10022436
references: Diabetes. 2005 Sep;54(9):2525-32
references: 16123339
references: Science. 2002 Jul 12;297(5579):240-3
references: 12114623
references: Hepatology. 2013 Feb;57(2):543-54
references: 22941940
references: J Clin Invest. 1997 Dec 1;100(11):2729-36
references: 9389736
references: PLoS One. 2012;7(5):e36675
references: 22586489
references: J Diabetes Investig. 2012 Mar 28;3(2):115-29
references: 24843554
references: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17391-6
references: 20855609
references: Diabetes. 2012 Aug;61(8):2016-29
references: 22740171
references: Diabetologia. 2003 Oct;46(10):1329-37
references: 12928770
references: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4813-9
references: 20194735
references: Endocrinology. 2006 Mar;147(3):1480-7
references: 16339207
references: Endocrinology. 2001 Nov;142(11):4827-30
references: 11606450
references: Int J Cardiol. 2006 Mar 22;108(1):89-95
references: 16085325
references: J Clin Invest. 1995 Oct;96(4):2065-70
references: 7560100
references: J Biol Chem. 1999 Jun 18;274(25):17541-4
references: 10364187
references: Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13468-73
references: 16938896
references: FASEB J. 2002 Apr;16(6):509-18
references: 11919153
references: Diabetes. 1994 Nov;43(11):1334-9
references: 7926308
references: Diabetes. 2011 May;60(5):1414-23
references: 21464443
references: J Clin Endocrinol Metab. 2008 Jan;93(1):26-31
references: 17940115
references: Diabetes. 1999 Jul;48(7):1487-92
references: 10389859
references: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):674-9
references: 9892692
references: N Engl J Med. 2000 Jul 27;343(4):230-8
references: 10911004
references: Diabetes. 1997 Jun;46(6):1087-93
references: 9166685
references: Diabetologia. 2012 Mar;55(3):752-62
references: 22202803
references: Diabetes. 2002 May;51(5):1356-61
references: 11978630
references: Cell Metab. 2010 Jan;11(1):11-22
references: 20074524
references: Diabetes. 2007 Sep;56(9):2295-301
references: 17563069
references: World J Gastroenterol. 2007 Mar 14;13(10):1579-84
references: 17461452
references: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14070-5
references: 18779578
references: Cell Transplant. 2003;12(8):849-57
references: 14763504