Change in the Amount of Body Fat and IL-6 Levels is Related to Altered Insulin Sensitivity in Type 1 Diabetes Patients with or without Diabetic Nephropathy

Abstract

Insulin resistance (IR) is found early-on in renal disease. The aim of this study was to prospectively evaluate if a change in glomerular filtration rate (GFR) or in endocrine and inflammatory factors over time alters insulin sensitivity in patients with type 1 diabetes (T1D) or without diabetic nephropathy (DN) at baseline. 20 T1D with (DN+, n=12) or without DN (DN–, n=8) were re-examined after 5.0±0.4 years. GFR was determined by ⁵¹Cr-EDTA clearance. Insulin sensitivity was assessed by hyperinsulinemic (56 mU/m²/min), euglycemic clamp (M-value at steady state during clamp) and calculated per lean body mass. Body composition was determined by bioimpedance. No association was found between change in GFR and change in M-value over time. Instead, change in M-value was associated to change in fat mass (%) and change in IL-6 levels in all subjects taken together (r=−0.55, p=0.012 and r=−0.62, p=0.006). These association were verified in the multivariate regression analyses. Findings were similar in DN − and DN +, respectively, but the change in IL-6 was only significantly associated with altered M-value in DN+ subjects. This prospective study indicates that change in amount body fat and levels of inflammatory cytokines, such as IL-6, contribute to change in insulin resistance over time in type 1 diabetes patients with and without diabetic nephropathy.

type 1 diabetes - diabetic nephropathy - glucose metabolism - insulin sensitivity - hormones - cytokines

References

• 1 Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy.  Diabetes. 1983;  32 (S 02) 64-78
• 2 Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria.  Lancet. 1993;  342 883-887
• 3 Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey.  Lancet. 1988;  2 530-533
• 4 Mykkanen L, Zaccaro DJ, Wagenknecht LE, Robbins DC, Gabriel M, Haffner SM. Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study.  Diabetes. 1998;  47 793-800
• 5 DeFronzo RA, Alvestrand A. Glucose intolerance in uremia: site and mechanism.  Am J Clin Nutr. 1980;  33 1438-1445
• 6 DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J. Insulin resistance in uremia.  J Clin Invest. 1981;  67 563-568
• 7 Eidemak I, Feldt-Rasmussen B, Kanstrup IL, Nielsen SL, Schmitz O, Strandgaard S. Insulin resistance and hyperinsulinaemia in mild to moderate progressive chronic renal failure and its association with aerobic work capacity.  Diabetologia. 1995;  38 565-572
• 8 Fliser D, Pacini G, Engelleiter R, Kautzky-Willer A, Prager R, Franek E, Ritz E. Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.  Kidney Int. 1998;  53 1343-1347
• 9 Svensson M, Yu ZW, Eriksson JW. A small reduction in glomerular filtration is accompanied by insulin resistance in type I diabetes patients with diabetic nephrophathy.  Eur J Clin Invest. 2002;  32 100-109
• 10 Becker B, Kronenberg F, Kielstein JT, Haller H, Morath C, Ritz E, Fliser D. Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study.  J Am Soc Nephrol. 2005;  16 1091-1098
• 11 Svensson M, Eriksson JW. Insulin resistance in diabetic nephropathy – cause or consequence?.  Diabetes Metab Res Rev. 2006;  22 401-410
• 12 Cooper-DeHoff RM, Pacanowski MA, Pepine CJ. Cardiovascular therapies and associated glucose homeostasis: implications across the dysglycemia continuum.  J Am Coll Cardiol. 2009;  53 S28-S34
• 13 Goicoechea M, de Vinuesa SG, Lahera V, Cachofeiro V, Gomez-Campdera F, Vega A, Abad S, Luno J. Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease.  J Am Soc Nephrol. 2006;  17 S231-S235
• 14 Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients.  Diabet Med. 2003;  20 642-645
• 15 Svensson M, Eriksson JW. No direct link between albumin excretion rate and insulin resistance – a study in type 1 diabetes patients with mild nephropathy.  Horm Metab Res. 2002;  34 254-259
• 16 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1997;  20 1183-1197
• 17 Granerus G, Aurell M. Reference values for 51Cr-EDTA clearance as a measure of glomerular filtration rate.  Scand J Clin Lab Invest. 1981;  41 611-616
• 18 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 E214-E223
• 19 DeFronzo RA, Ferrannini E, Sato Y, Felig P, Wahren J. Synergistic interaction between exercise and insulin on peripheral glucose uptake.  J Clin Invest. 1981;  68 1468-1474
• 20 Bokemark L, Froden A, Attvall S, Wikstrand J, Fagerberg B. The euglycemic hyperinsulinemic clamp examination: variability and reproducibility.  Scand J Clin Lab Invest. 2000;  60 27-36
• 21 Eriksson JW, Jansson PA, Foley K, Lithell H. Insulin sensitivity following treatment with the alpha 1-blocker bunazosin retard and the beta 1-blocker atenolol in hypertensive non-insulin-dependent diabetes mellitus patients.  J Hypertens. 1996;  14 1469-1475
• 22 Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria.  Diabetes Care. 1997;  20 1576-1581
• 23 Lender D, Arauz-Pacheco C, Adams-Huet B, Raskin P. Essential hypertension is associated with decreased insulin clearance and insulin resistance.  Hypertension. 1997;  29 111-114
• 24 Ferrannini E, Wahren J, Faber OK, Felig P, Binder C, DeFronzo RA. Splanchnic and renal metabolism of insulin in human subjects: a dose-response study.  Am J Physiol. 1983;  244 E517-E527
• 25 Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. Validation of tetrapolar bioelectrical impedance method to assess human body composition.  J Appl Physiol. 1986;  60 1327-1332
• 26 Vareesangthip K, Tong P, Wilkinson R, Thomas TH. Insulin resistance in adult polycystic kidney disease.  Kidney Int. 1997;  52 503-508
• 27 Nerpin E, Riserus U, Ingelsson E, Sundstrom J, Jobs M, Larsson A, Basu S, Arnlov J. Insulin sensitivity measured with euglycemic clamp is independently associated with glomerular filtration rate in a community-based cohort.  Diabetes Care. 2008;  31 1550-1555
• 28 Robertson L, Waugh N, Robertson A. Protein restriction for diabetic renal disease.  Cochrane Database Syst Rev. 2007;  CD002181
• 29 Trirogoff ML, Shintani A, Himmelfarb J, Ikizler TA. Body mass index and fat mass are the primary correlates of insulin resistance in nondiabetic stage 3–4 chronic kidney disease patients.  Am J Clin Nutr. 2007;  86 1642-1648
• 30 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2415
• 31 Natali A, Toschi E, Baldeweg S, Ciociaro D, Favilla S, Sacca L, Ferrannini E. Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes.  Diabetes. 2006;  55 1133-1140
• 32 Cartier A, Lemieux I, Almeras N, Tremblay A, Bergeron J, Despres JP. Visceral obesity and plasma glucose-insulin homeostasis: contributions of interleukin-6 and tumor necrosis factor-alpha in men.  J Clin Endocrinol Metab. 2008;  93 1931-1938
• 33 Astrup AS, Tarnow L, Pietraszek L, Schalkwijk CG, Stehouwer CD, Parving HH, Rossing P. Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years: association with mortality and decline of glomerular filtration rate.  Diabetes Care. 2008;  31 1170-1176

Correspondence