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01-09-2006 | Article

Leptin and incident type 2 diabetes: risk or protection?

Authors: M. I. Schmidt, B. B. Duncan, A. Vigo, J. S. Pankow, D. Couper, C. M. Ballantyne, R. C. Hoogeveen, G. Heiss, For the ARIC Investigators

Published in: Diabetologia | Issue 9/2006

Abstract

Aims/hypothesis

The aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance.

Subjects and methods

We conducted a case–cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA.

Results

In proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6–5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23–0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32–1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both).

Conclusions/interpretation

High leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin’s described protective effects against diabetes.

Schmidt MI, Duncan BB, Sharrett AR et al (1999) Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 353:1649–1652PubMedCrossRef

Duncan BB, Schmidt MI, Pankow JS et al (2003) Low-grade systemic inflammation and the development of type 2 diabetes: the Atherosclerosis Risk in Communities study. Diabetes 52:1799–1805PubMedCrossRef

Duncan BB, Schmidt MI (2006) The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes Technol Ther 8:7–17PubMedCrossRef

La Cava A, Matarese G (2004) The weight of leptin in immunity. Nat Rev Immunol 4:371–379PubMedCrossRef

Peelman F, Waelput W, Iserentant H et al (2004) Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases. Prog Lipid Res 43:283–301PubMedCrossRef

Yildiz BO, Haznedaroglu IC (2006) Rethinking leptin and insulin action: therapeutic opportunities for diabetes. Int J Biochem Cell Biol 38:820–830PubMedCrossRef

Ceddia RB (2005) Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis. Int J Obes (Lond) 29:1175–1183CrossRef

McNeely MJ, Boyko EJ, Weigle DS et al (1999) Association between baseline plasma leptin levels and subsequent development of diabetes in Japanese Americans. Diabetes Care 22:65–70PubMedCrossRef

Boyko EJ, de Courten M, Zimmet PZ, Chitson P, Tuomilehto J, Alberti KG (2000) Features of the metabolic syndrome predict higher risk of diabetes and impaired glucose tolerance: a prospective study in Mauritius. Diabetes Care 23:1242–1248PubMedCrossRef

10.

Franks PW, Brage S, Luan J et al (2005) Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obes Res 13:1476–1484PubMed

11.

Ceddia RB, Koistinen HA, Zierath JR, Sweeney G (2002) Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 16:1163–1176PubMedCrossRef

12.

Zhao YF, Feng DD, Chen C (2006) Contribution of adipocyte-derived factors to beta-cell dysfunction in diabetes. Int J Biochem Cell Biol 38:804–819PubMedCrossRef

13.

Shimabukuro M, Koyama K, Chen G et al (1997) Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci USA 94:4637–4641PubMedCrossRef

14.

Muoio DM, Dohm GL, Fiedorek FT Jr, Tapscott EB, Coleman RA, Dohn GL (1997) Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46:1360–1363PubMedCrossRef

15.

Shimabukuro M, Wang MY, Zhou YT, Newgard CB, Unger RH (1998) Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci USA 95:9558–9561PubMedCrossRef

16.

Minokoshi Y, Kim YB, Peroni OD et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343PubMedCrossRef

17.

Toyoshima Y, Gavrilova O, Yakar S et al (2005) Leptin improves insulin resistance and hyperglycemia in a mouse model of type 2 diabetes. Endocrinology 146:4024–4035PubMedCrossRef

18.

Munzberg H, Myers MG Jr (2005) Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8:566–570PubMedCrossRef

19.

Tong J, Fujimoto WY, Kahn SE et al (2005) Insulin, C-peptide, and leptin concentrations predict increased visceral adiposity at 5- and 10-year follow-ups in nondiabetic Japanese Americans. Diabetes 54:985–990PubMedCrossRef

20.

Huang W, Dedousis N, Bandi A, Lopaschuk GD, O’Doherty RM (2006) Liver triglyceride secretion and lipid oxidative metabolism are rapidly altered by leptin in vivo. Endocrinology 147:1480–1487PubMedCrossRef

21.

Yang XP, Schaper F, Teubner A et al (2005) Interleukin-6 plays a crucial role in the hepatic expression of SOCS3 during acute inflammatory processes in vivo. J Hepatol 43:704–710PubMedCrossRef

22.

ARIC Investigators (1989) The Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 129:687–702

23.

Lin DY (2000) On fitting Cox’s proportional hazards models to survey data. Biometrika 87:37–47CrossRef

24.

Collett D (1994) Modelling survival data in medical research. Chapman & Hall, London

25.

Duncan BB, Schmidt MI, Pankow J et al (2004) Adiponectin and the development of type 2 diabetes: the ARIC study. Diabetes 53:2473–2478PubMedCrossRef

26.

Benomar Y, Wetzler S, Larue-Achagiotis C, Djiane J, Tome D, Taouis M (2005) In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus. Mol Cell Endocrinol 242:59–66PubMedCrossRef

27.

Kirchgessner TG, Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest 100:2777–2782PubMedCrossRef

28.

Rossetti L, Massillon D, Barzilai N et al (1997) Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem 272:27758–27763PubMedCrossRef

29.

Brabant G, Muller G, Horn R, Anderwald C, Roden M, Nave H (2005) Hepatic leptin signaling in obesity. FASEB J 19:1048–1050PubMed

30.

Sagawa N, Yura S, Itoh H et al (2002) Possible role of placental leptin in pregnancy: a review. Endocrine 19:65–71PubMedCrossRef

31.

Guerre-Millo M (2003) Extending the glucose/fatty acid cycle: a glucose/adipose tissue cycle. Biochem Soc Trans 31:1161–1164PubMedCrossRef

32.

Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M (1997) Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 46:313–316PubMedCrossRef

33.

Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF (1997) Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes 46:1087–1093PubMedCrossRef

34.

Orci L, Cook WS, Ravazzola M et al (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 101:2058–2063PubMedCrossRef

35.

Cohen P, Friedman JM (2004) Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J Nutr 134:2455S–2463SPubMed

36.

Cohen P, Ntambi JM, Friedman JM (2003) Stearoyl-CoA desaturase-1 and the metabolic syndrome. Curr Drug Targets Immune Endocr Metabol Disord 3:271–280PubMedCrossRef

37.

Barzilai N, Wang J, Massilon D, Vuguin P, Hawkins M, Rossetti L (1997) Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest 100:3105–3110PubMedCrossRef

38.

Unger RH (2003) Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144:5159–5165PubMedCrossRef

39.

Park SY, Cho YR, Kim HJ et al (2005) Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice. Diabetes 54:3530–3540PubMedCrossRef

40.

Jonsson T, Olsson S, Ahren B, Bog-Hansen TC, Dole A, Lindeberg S (2005) Agrarian diet and diseases of affluence—do evolutionary novel dietary lectins cause leptin resistance? BMC Endocr Disord 5:10PubMedCrossRef

41.

Magni P, Liuzzi A, Ruscica M et al (2005) Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profile and macronutrient preference. Clin Endocrinol (Oxf) 62:189–196CrossRef

42.

Fox C, Esparza J, Nicolson M et al (1999) Plasma leptin concentrations in Pima Indians living in drastically different environments. Diabetes Care 22:413–417PubMedCrossRef

43.

Franks PW, Farooqi IS, Luan J et al (2003) Does physical activity energy expenditure explain the between-individual variation in plasma leptin concentrations after adjusting for differences in body composition? J Clin Endocrinol Metab 88:3258–3263PubMedCrossRef

44.

Cohen P, Yang G, Yu X et al (2005) Induction of leptin receptor expression in the liver by leptin and food deprivation. J Biol Chem 280:10034–10039PubMedCrossRef

45.

Unger RH (2005) Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 87:57–64PubMedCrossRef

Title: Leptin and incident type 2 diabetes: risk or protection?
Authors: M. I. Schmidt
B. B. Duncan
A. Vigo
J. S. Pankow
D. Couper
C. M. Ballantyne
R. C. Hoogeveen
G. Heiss
For the ARIC Investigators
Publication date: 01-09-2006
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 9/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0351-z

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