A Novel Use of the Hyperinsulinemic-Euglycemic Clamp Technique to Estimate Insulin Sensitivity of Systemic Lipolysis

M. Stumvoll; H. G. Wahl; K. Löblein; R. Becker; A. Volk; W. Renn; S. Jacob; H. Häring

doi:10.1055/s-2001-12403

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2001; 33(2): 89-95
DOI: 10.1055/s-2001-12403

Original Clinical

A Novel Use of the Hyperinsulinemic-Euglycemic Clamp Technique to Estimate Insulin Sensitivity of Systemic Lipolysis

M. Stumvoll¹ , H. G. Wahl¹ , K. Löblein, R. Becker, A. Volk, W. Renn, S. Jacob, H. Häring

Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, Tübingen, Germany
¹ These authors contributed equally to the study

Abstract

The aim of the present study was to assess whether a standard hyperinsulinemic-euglycemic clamp can provide an estimate for the antilipolytic insulin sensitivity. For this purpose, we infused 9 non-obese, healthy volunteers with [²H₅]glycerol and used the glycerol rate of appearance (Ra) in plasma as an index for systemic lipolysis during a standard (1 mU/kg · min, 120 min) and a 3-step (0.1, 0.25, 1.0 mU/kg · min) hyperinsulinemic-euglycemic clamp. The insulin concentration, which half-maximally suppressed lipolysis (EC₅₀) in the three-step clamp, was considered to be the gold standard for the antilipolytic insulin sensitivity. Glycerol Ra decreased from 1.53 ± 0.11 µmol/kg·min to 0.60 ± 0.09 µmol/kg · min (p < 0.001) during the standard clamp. The decrease in Ra at most time points during the standard clamp significantly correlated with the EC₅₀. The highest correlation for the % decrease of glycerol Ra from baseline was found at 60 min (r = 0.96, p < 0.001) making this parameter a useful index for the antilipoytic insulin sensitivity. Neither plasma glycerol nor plasma free fatty acid (FFA) concentrations were significantly correlated with the EC₅₀. In conclusion, the standard hyperinsulinemic-euglycemic clamp in combination with isotopic determination of glycerol Ra provides a reasonable estimate for the antilipolytic insulin sensitivity. In healthy subjects, the parameter best suited to estimate the insulin EC₅₀ (by linear correlation) was the percentage decrease of glycerol Ra at 60 min.

Key words:

Insulin Resistance - Obesity - Type 2 Diabetes - Free Fatty Acids - Glycerol

Full Text

References

1 Bonadonna R C, Bonora E. Glucose and free fatty acid metabolism in human obesity. Diabetes Rev. 1997; 5 21-51
2 Campbell P J, Carlson M G, Nurjhan N. Fat metabolism in human obesity. Am J Physiol. 1994; 266 E600-E605
3 Groop L C, Bonadonna R C, Simonson D C, Petrides A S, Shank M, DeFronzo R A. Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity. Am J Physiol. 1992; 263 E79-E84
4 Groop L C, Bonadonna R C, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo R A. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989; 84 205-213
5 Randle P J, Priestman D A, Mistry S C, Halsall A. Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biol. 1994; 55S 1-11
6 Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997; 46 3-10
7 Paolisso G, Howard B V. Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes. Diabetic Med. 1998; 15 360-366
8 Eriksson J W, Smith U, Waagstein F, Wysocki M, Jansson P. Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients. Is cellular insulin resistance a secondary phenomenon?. Diabetes. 1999; 48 1572-1578
9 Ferrannini E, Camastra S, Coppack S W, Fliser D, Golay A, Mitrakou A. Insulin action and non-esterified fatty acids. The European Group for the Study of Insulin Resistance (EGIR). Proc Nutr Soc. 1997; 56 753-761
10 Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Järvinen H, Evron W, Dailey G, Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA. 1995; 273 1855-1861
11 Pan D A, Lillioja S, Kriketos A D, Milner M R, Baur L A, Bogardus C, Jenkins A B, Storlien L H. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 1997; 46 983-988
12 Nyholm B, Qu Z, Kaal A, Pedersen S B, Gravholt C H, Andersen J L, Saltin B, Schmitz O. Evidence of an increased number of type IIb muscle fibers in insulin-resistant first-degree relatives of patients with NIDDM. Diabetes. 1997; 46 1822-1828
13 Volk A, Renn W, Overkamp D, Mehnert B, Maerker E, Jacob S, Balletshofer B, Häring H U, Rett K. Insulin action and secretion in healthy, glucose tolerant first degree relatives of patients with type 2 diabetes. Influence of body weight. Exp Clin Endocrinol Diabetes. 1999; 107 140 -147
14 Townsend R R, Klein S, Wolfe R R. Changes in lipolytic sensitivity following repeated epinephrine infusion in humans. Am J Physiol. 1994; 266 E155-E160
15 Nurjhan N, Campbell P, Kennedy F, Miles J, Gerich J. Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes. 1986; 35 1326-1331
16 Robinson C, Tamborlane W V, Maggs D G, Enoksson S, Sherwin R S, Silver D, Shulman G I, Caprio S. Effect of insulin on glycerol production in obese adolescents. Am J Physiol. 1998; 274 E737-E743
17 Stumvoll M, Jacob S. Multiple sites of insulin resistance: muscle, liver and adipose tissue. Exp Clin Endocrinol Diabetes. 1999; 107 107-110
18 Hagström-Toft E, Bolinder J, Ungerstedt U, Arner P. A circadian rhythm in lipid mobilization which is altered in IDDM. Diabetologia. 1997; 40 1070-1078
19 Campbell P J, Carlson M G, Hill J O, Nurjhan N. Regulation of free fatty acid metabolism by insulin in humans: role of lipolysis and reesterification. Am J Physiol. 1992; 263 E1063-E1069
20 DeBodo R, Steele R, Atszuler N, Dunn A, Bishop J. On the hormonal regulation of carbohydrate metabolism: studies with C14 glucose. Rec Prog Horm Res. 1963; 19 445-488
21 McCulloch A J, Johnston D G, Baylis P H, Kendall Taylor P, Clark F, Young E T, Alberti K G. Evidence that thyroid hormones regulate gluconeogenesis from glycerol in man. Clin Endocrinol Oxf. 1983; 19 67-76
22 Beylot M, Martin C, Beaufrère B, Riou J P, Mornex R. Determination of steady state and nonsteady-state glycerol kinetics in humans using deuterium-labeled tracer. J Lipid Res. 1987; 28 414-422
23 Diaconis P, Efron B. Computer-intensive methods in statistics. Scientific American. 1983; 248 116-132
24 Saggerson E D, Greenbaum A L. The regulation of triglyceride synthesis and fatty acid synthesis in rat epididymal adipose tissue. Biochem J. 1970; 119 193-219
25 Reaven G, Chang H, Hoffman B B. Impaired insulin-mediated inhibition of lipolysis and glucose transport with aging. Horm Metab Res. 1989; 21 168-171
26 Finegood D T, Bergman R N, Vranic M. Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes. 1987; 36 914-924
27 Stumvoll M, Welle S, Chintalapudi U, Perriello G, Gutierrez O, Gerich J. Uptake and release of glucose by the human kidney: Postabsorptive rates and responses to epinephrine. J Clin Invest. 1995; 96 2528-2533
28 Kellerer M, Rett K, Renn W, Groop L, Häring H U. Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity. Horm Metab Res. 1996; 28 737-743
29 Coppack S W, Persson M, Judd R L, Miles J M. Glycerol and nonesterified fatty acid metabolism in human muscle and adipose tissue. Am J Physiol. 1999; 276 E233-E240

Dr. M. Stumvoll

Medizinische Universitätsklinik

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