title: Paracrinology of islets and the paracrinopathy of diabetes.
abstract: New results have brought to light the importance of the regulation of glucagon by β-cells in the development of diabetes. In this perspective, we examine the normal paracrinology of α- and β-cells in nondiabetic pancreatic islets. We propose a Sherringtonian model of coordinated reciprocal secretory responses of these juxtaposed cells that secrete glucagon and insulin, hormones with opposing actions on the liver. As insulin is a powerful inhibitor of glucagon, we propose that within-islet inhibition of α-cells by β-cells creates an insulin-to-glucagon ratio that maintains glycemic stability even in extremes of glucose influx or efflux. By contrast, in type 1 diabetes mellitus, α-cells lack constant action of high insulin levels from juxtaposed β-cells. Replacement with exogenous insulin does not approach paracrine levels of secreted insulin except with high doses that "overinsulinize" the peripheral insulin targets, thereby promoting glycemic volatility. Based on the stable normoglycemia of mice with type 1 diabetes during suppression of glucagon with leptin, we conclude that, in the absence of paracrine regulation of α-cells, tonic inhibition of α-cells improves the dysregulated glucose homeostasis. These results have considerable medical implications, as they suggest new approaches to normalize the extreme volatility of glycemia in diabetic patients.
authors.affiliation: Department of Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. roger.unger@utsouthwestern.edu
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
authors.forename: Lelio
authors.initials: L
authors.lastname: Orci
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D019899:Paracrine Communication
chemical_list: D001786:Blood Glucose; D005934:Glucagon
references.citation: Diabetes. 2002 Feb;51 Suppl 1:S117-21
references.pmid: 11815469
references.citation: J Diabetes Sci Technol. 2009 Sep 01;3(5):1109-20
references.pmid: 20144424
references.citation: J Clin Invest. 1970 Apr;49(4):837-48
references.pmid: 4986215
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4813-9
references.pmid: 20194735
references.citation: Diabetes. 2002 Aug;51(8):2637-41
references.pmid: 12145181
references.citation: N Engl J Med. 1981 Jun 18;304(25):1518-24
references.pmid: 7015132
references.citation: Clin Endocrinol Metab. 1986 Feb;15(1):33-58
references.pmid: 2869846
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14070-5
references.pmid: 18779578
references.citation: Diabetes. 2008 Nov;57(11):2899-904
references.pmid: 18971437
references.citation: N Engl J Med. 1978 Aug 31;299(9):433-6
references.pmid: 683275
references.citation: N Engl J Med. 1975 May 8;292(19):985-9
references.pmid: 804137
references.citation: Biochem Soc Symp. 1978;(43):31-45
references.pmid: 373768
references.citation: Lancet. 2010 Feb 27;375(9716):743-51
references.pmid: 20138357
references.citation: Recent Prog Horm Res. 1970;26:411-61
references.pmid: 4319350
references.citation: Diabetes. 1987 Mar;36(3):365-73
references.pmid: 3542658
references.citation: J Clin Invest. 1984 Dec;74(6):2296-9
references.pmid: 6392344
references.citation: J Clin Invest. 1971 Sep;50(9):1992-9
references.pmid: 4935445
references.citation: Science. 1975 Feb 14;187(4176):544-7
references.pmid: 1089999
references.citation: Adv Exp Med Biol. 1985;189:137-58
references.pmid: 3898762
references.citation: Diabetes. 1977 Nov;26(11):1040-51
references.pmid: 913893
references.citation: Diabetes Care. 2006 Nov;29(11):2528-38
references.pmid: 17065698
references.citation: J Clin Invest. 1974 Apr;53(4):1017-21
references.pmid: 4592597
references.citation: Physiology (Bethesda). 2004 Aug;19:183-90
references.pmid: 15304632
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2334-9
references.pmid: 16461897
references.citation: Diabetes Care. 2003 Oct;26(10):2728-33
references.pmid: 14514571
references.citation: Diabetes. 1982 Oct;31(10):883-9
references.pmid: 6759221
references.citation: Diabetes. 2010 May;59(5):1202-10
references.pmid: 20185817
references.citation: Science. 1979 Dec 14;206(4424):1323-5
references.pmid: 390711
references.citation: N Engl J Med. 1970 Jul 16;283(3):109-15
references.pmid: 4912452
references.citation: Diabetes. 1982 Jun;31(6 Pt 1):538-65
references.pmid: 6759269
references.citation: J Pharmacol Exp Ther. 2007 May;321(2):743-52
references.pmid: 17308040
references.citation: Cell Metab. 2010 Jan;11(1):11-22
references.pmid: 20074524
references.citation: J Biol Chem. 2010 May 7;285(19):14389-98
references.pmid: 20231269