Paracrinology of islets and the paracrinopathy of diabetes.
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.
Unger
Roger H
RH
Department of Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. roger.unger@utsouthwestern.edu
Orci
Lelio
L
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
D001786:Blood Glucose; D005934:Glucagon
Diabetes. 2002 Feb;51 Suppl 1:S117-21
11815469
J Diabetes Sci Technol. 2009 Sep 01;3(5):1109-20
20144424
J Clin Invest. 1970 Apr;49(4):837-48
4986215
Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4813-9
20194735
Diabetes. 2002 Aug;51(8):2637-41
12145181
N Engl J Med. 1981 Jun 18;304(25):1518-24
7015132
Clin Endocrinol Metab. 1986 Feb;15(1):33-58
2869846
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14070-5
18779578
Diabetes. 2008 Nov;57(11):2899-904
18971437
N Engl J Med. 1978 Aug 31;299(9):433-6
683275
N Engl J Med. 1975 May 8;292(19):985-9
804137
Biochem Soc Symp. 1978;(43):31-45
373768
Lancet. 2010 Feb 27;375(9716):743-51
20138357
Recent Prog Horm Res. 1970;26:411-61
4319350
Diabetes. 1987 Mar;36(3):365-73
3542658
J Clin Invest. 1984 Dec;74(6):2296-9
6392344
J Clin Invest. 1971 Sep;50(9):1992-9
4935445
Science. 1975 Feb 14;187(4176):544-7
1089999
Adv Exp Med Biol. 1985;189:137-58
3898762
Diabetes. 1977 Nov;26(11):1040-51
913893
Diabetes Care. 2006 Nov;29(11):2528-38
17065698
J Clin Invest. 1974 Apr;53(4):1017-21
4592597
Physiology (Bethesda). 2004 Aug;19:183-90
15304632
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2334-9
16461897
Diabetes Care. 2003 Oct;26(10):2728-33
14514571
Diabetes. 1982 Oct;31(10):883-9
6759221
Diabetes. 2010 May;59(5):1202-10
20185817
Science. 1979 Dec 14;206(4424):1323-5
390711
N Engl J Med. 1970 Jul 16;283(3):109-15
4912452
Diabetes. 1982 Jun;31(6 Pt 1):538-65
6759269
J Pharmacol Exp Ther. 2007 May;321(2):743-52
17308040
Cell Metab. 2010 Jan;11(1):11-22
20074524
J Biol Chem. 2010 May 7;285(19):14389-98
20231269