Summary
To evaluate the early metabolic alterations induced by obesity, we studied glucose turnover and lipid levels in obese children with fasting normoinsulinaemia. Two experimental protocols were carried out. Protocol I consisted of a euglycaemic glucose clamp at two rates of insulin infusion. Protocol II was similar to protocol I except for a variable lipid infusion used to maintain basal non-esterified fatty acid (NEFA) levels. During protocol I, the glucose disappearance rates were lower in obese children, while no differences were found in hepatic glucose release. NEFA response to insulin was not substantially altered in obese children either at low or high insulin infusion. During protocol II, the NEFA clamp induced a 25% reduction in peripheral insulin sensitivity in control children whereas no changes were observed in obese children. Interestingly, lipid infusion in control children was not sufficient to reproduce the same degree of insulin resistance observed in obese children, suggesting that NEFA are only one of the determinants of insulin resistance at this stage of obesity. In conclusion, the present study provides a portrait of glucose metabolism and lipid levels in normoinsulinaemic obese children. Our results document that peripheral insulin resistance is the first alteration at this stage of obesity, whereas an increase in insulin secretion and a defect in the inhibition of hepatic glucose release by insulin may develop at a later stage. In addition, primarily receptor and post-receptor defects and some alterations of NEFA metabolism are likely to coexist in the induction of insulin resistance at this stage of obesity.
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Abbreviations
- NEFA:
-
Non-esterified fatty acids
- FFM:
-
fat free mass
- APE:
-
atom percent excess
- HGR:
-
hepatic glucose release
- Ra :
-
glucose appearance
- Rd :
-
glucose disappearance
- CV:
-
coefficient of variation
References
Horton ES, Runge CF, Sims EAM (1970) Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 29: 457–496
Reaven GM, Morre J, Greefield M (1983) Quantification of insulin secretion and in vivo insulin action in non-obese and moderately obese individuals with normal glucose tolerance. Diabetes 32: 600–604
Harrison LC, Martin FIR, Melick RA (1976) Correlation between insulin recpetor binding in isolated fat cells and insulin sensitivity in obese human subjects. J Clin Invest 58: 1435–1441
Kashiwagi AC, Bogardus C, Lillioja S et al. (1984) In vitro insensitivity of glucose transport and antilipolysis to insulin due to receptor and post-receptor abnormalities in obese Pima Indians with normal glucose tolerance. Metabolism 33: 772–777
Kolterman OG, Reaven GM, Olefsky JO (1979) Relationship between in vivo insulin resistance and decreased insulin receptors in obese man. J Clin Endocrinol Metab 48: 487–494
Kolterman OG, Insel J, Saekow M, Olefsky JM (1980) Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest 65: 1272–1284
Bonadonna RC, Groop L, Kraemer N et al. (1990) Obesity and insulin resistance in humans: a dose-response study. Metabolism 39: 452–459
Del Prato S, Enzi G, Vigili de Kreutzenberg S et al. (1990) Insulin regulation of glucose and lipid metabolism in massive obesity. Diabetologia 33: 228–236
Zuniga-Guiardo S, Jimenez J, Angel A, Zinman B (1986) Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycaemic clamp technique. Metabolism 35: 278–282
Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose-fatty acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785–789
Randle PJ, Newsholme EA, Garland PB (1964) Regulation of glucose uptake by muscle. Effects of fatty acids, ketone bodies and pyruvate, and alloxan-diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscle. Biochem J 93: 652–687
Lillioja S, Foley J, Bogardus C et al. (1986) Free fatty acid metabolism and obesity in man: in vivo and in vitro comparisons. Metabolism 35: 505–514
Piatti PM, Monti LD, Pacchioni M, et al. (1991) Forearm insulin- and non-insulin-mediated glucose uptake and muscle metabolism in man: role of free fatty acids and blood glucose levels. Metabolism 40: 926–933
Vouillamoz D, Temler E, Jequier E, Felber JP (1987) Importance of substrate competition in the mechanism of insulin resistance in man. Metabolism 36: 715–720
Ferrannini E, Barrett EG, Bevilacqua S, DeFronzo RA (1983) Effects of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747
Balasse EA, Neef MA (1974) Operation of the glucose-fatty acid cycle during experimental elevations of plasma free fatty acid levels in man. Eur J Clin Invest 4: 247–252
Bevilacqua S, Bonadonna R, Buzzigoli G et al. (1987) Acute elevation of free fatty acid levels leads to hepatic resistance in obese subjects. Metabolism 36: 502–506
Thiebaud D, De Fronzo RA, Jacot E et al. (1982) Effect of long chain triglyceride infusion on glucose metabolism in man. Metab Clin Exp 31: 1128–1136
Felber JP, Ferrannini E, Golay A et al. (1987) Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes 36: 1341–1350
Golay A, Felber JP, Meyer HU et al. (1984) Study on lipid metabolism in obesity and diabetes. Metabolism 33: 111–116
Bougneres PF, Artavia-Loria E, Henry S et al. (1989) Increased basal glucose production and utilization in children with recent obesity versus adult with long-term obesity. Diabetes 38: 477–483
Le Stunff C, Bougneres PF (1993) Time course of increased lipid and decreased glucose oxidation during early phase of childhood obesity. Diabetes 42: 1010–1016
Amiel SA, Sherwin RS, Simonson DC et al. (1986) Impaired insulin action in puberty: a contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 315: 215–219
Bloch CA, Clemons P, Sperling MA (1987) Puberty decreases insulin sensitivity. J Pediatr 110: 481–487
Tanner J, Whitehouse RH (1976) Clinical longitudinal standards for height, weight and weight velocity and stages of puberty. Arch Dis Child 51: 170
Hernesniemi I, Zachmann M, Prader A (1974) Skinfold thickness in infancy and adolescence: a longitudinal correlation study in normal children. Helv Paediatr Acta 29: 523–528
Wormersley J, Durning JVGA (1977) A comparison of the skinfold method with extent of “overweight” and various weight-height relationships in the assessment of obesity. Br J Nutr 38: 271–284
Brook CGD (1971) Determination of body composition of children from skinfold measurements. Arch Dis Child 46: 182–184
Istituto Nazionale della Nutrizione (1989) Livelli di assunzione giornalieri raccomandati di energia e di nutrimenti per la popolazione italiana. Revisione 1986–87 e tabella di composizione degli alimenti. Milano: Litho Delta Ed.
Beer SF, Heaton DA, Alberti KGMM, Pyke DA, Leslie RDG (1990) Impaired glucose tolerance precedes but does not predict insulin-dependent diabetes mellitus: a study of identical twins. Diabetologia 33: 497–502
Pettitt DJ, Moll PP, Knowler WC et al. (1993) Insulinemia in children at low and high risk of NIDDM. Diabetes Care 16: 608–615
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057
Finegood DT, Bergman RN, Vranic M (1987) Estimation of endogenous glucose production during hyperinsulinemic-euglycaemic glucose clamps: comparison of unabeled and labeled exogenous glucose infusates. Diabetes 36: 914–924
Steel R (1959) Influences of glucose loading and injected insulin on hepatic glucose output. Ann NY Acad Sci 82: 420–430
Cobelli C, Toffolo G, Foster DM (1992) Tracer-to-tracee ratio for the analysis of stable isotope tracer data:the link with the radioactive kinetic formalism. Am J Physiol 262: E968-E975
Finegood DT, Bergman RN (1983) Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol 244: E471-E479
Coon PJ, Rogus EM, Goldberg AP (1992) Time course of plasma free fatty acid concentration in response to insulin: effect of obesity and physical fitness. Metabolism 41: 711–716
Carson ER, Cobelli C, Finkelstein L (1983) The mathematical modeling of metabolic and endocrine systems. Wiley, New York
Magni F, Monti LD, Brambilla P et al. (1992) Determination of plasma (6, 62 H2)-glucose enrichment by a simple and accurate gas chromatographyc mass spectrometric method. J Chromatography 573: 127–131
Knox DP, Jones DG (1984) Automated enzymatic determination of plasma free fatty acids by centrifugal analysis J Autom Chem 6: 152–154
Monti LD, Sandoli E, Costa S et al. (1993) Fluorimetric methods for the measurement of intermediate metabolites (lactate, pyruvate, alanine, Β-hydroxybutyrate, glycerol) using a Cobas Fara centrifugal analyser. J Autom Chem 15: 177–181
Gorden ES (1960) Non-esterified fatty acids in the blood of obese and lean subjects. Am J Clin Nutr 8: 740–747
Opie LH, Walfish PG (1963) Plasma free fatty acid concentrations in obesity. N Engl J Med 268: 756–760
Katz H, Butler P, Homan M et al. (1993) Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error. Am J Physiol 264: E561-E566
Penicaud L, Ferré P, Terretaz J et al. (1987) Early insulin resistance in muscles but normal sensitivity in white adipose tissue. Diabetes 36: 626–631
Penicaud L, Rohner-Jeanrenaud F, Jeanrenaud B (1986) In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions. Am J Physiol 250: E662-E668
Lee KU, Lee HK, Koh CS, Min HK (1988) Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man. Diabetologia 31: 285–290
Ferrannini E, Barrett EJ, Bevilacqua S et al. (1983) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747
Bonadonna RC, Zych K, Boni C, Ferrannini E, DeFronzo RA (1989) Time dependence of the interaction between lipid and glucose in humans. Am J Physiol 257: E49-E56
Boden G, Chen X, Ruiz J, White JV, Rossetti L (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93: 2438–2446
Keller V, Chiasson JL, Liljenquist JE et al. (1977) The roles of insulin, glucagon, and free fatty acids in the regulation of ketogenesis in dogs. Diabetes 26: 1040–1051
Berenson GS, Radhakrishnamurthy B, Srinivasan SR et al. (1981) Plasma glucose and insulin levels in relation to cardiovascular risk factors in children from biracial population — the Bogalusa heart study. J Chron Dis 34: 379–391
Groop L C, Saloranta C, Shank M et al. (1991) The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 72: 96–107
Howard BV, Klimes I, Vasquez B et al. (1984) The antilipolytic action of insulin in obese subjects with resistance to its glucoregulatory action. J Clin Endocrinol Metab 58: 544–548
Campbell PJ, Carlson MG, Nurjhan N (1994) Fat metabolism in human obesity. Am J Physiol 266: E600-E605
Bonadonna R, Groop LC, Zych K, Shank M, DeFronzo RA (1990) Dose-dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans. Am J Physiol 259: E736-E750
Olefsky JM (1981) Insulin resistance and insulin action: an in vitro and in vivo perspective. Diabetes 30: 148–162
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Monti, L.D., Brambilla, P., Stefani, I. et al. Insulin regulation of glucose turnover and lipid levels in obese children with fasting normoinsulinaemia. Diabetologia 38, 739–747 (1995). https://doi.org/10.1007/BF00401849
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DOI: https://doi.org/10.1007/BF00401849