Summary
The mechanisms underlying insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus are not fully understood. An enhanced lipid/non-esterified fatty acid oxidation could provide an explanation. To test this hypothesis we examined the relationship between glucose and lipid metabolism in 44 first-degree relatives (28 glucose-tolerant and 16 glucose-intolerant) of Type 2 diabetic patients and in 18 healthy control subjects. Total body glucose disposal was impaired among both glucose-tolerant and glucose-intolerant relatives compared with control subjects (36.3±3.8 and 30.4±2.7 vs 47.7±3.4 μmol · kgLBM/s-1· min−1; p < 0.05). The impairment in glucose disposal among the relatives was primarily accounted for by impaired non-oxidative glucose metabolism (14.8±3.0 and 12.5±1.8 vs 25.3±3.1 μmol · kgLBM−1 · min−1; p <0.05). Plasma non-esterified fatty acid concentrations were similar in both glucose-tolerant and glucose-intolerant relatives and control subjects (646±36,649±43 and 615±41 μmol/l) and showed the same degree of suppression by insulin (99±8, 86±7 and 84±9 μmol/l). Basal lipid oxidation was similar in all groups (1.29±0.09, 1.52±0.13 and 1.49±0.21 μmol · kgLBM−1· min−1). Furthermore, insulin suppressed lipid oxidation to the same degree in glucose-tolerant, glucose-intolerant relatives and control subjects (0.65±0.13, 0.88±0.15 and 0.59±0.09μmol · kgLBM−1 · min−1). An inverse correlation between plasma non-esterified fatty acid concentration and total body glucose disposal was observed in the group of control subjects (r=−0.540; p<0.05), but not among the relatives (r=0.002; p=N.S.). In conclusion the present data challenge the view that the “glucose-fatty acid cycle” contributes to the insulin resistance seen in first-degree relatives of patients with Type 2 diabetes.
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DeFronzo RA, Ferrannini E, Koivisto V (1983) New concepts in the pathogenesis and treatment of non-insulin dependent diabetes mellitus. Am J Med 74 [Suppl 1]: 52–81
DeFronzo RA (1988) The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687
Köbberling J, Tillil H, Lorenz HJ (1985) Genetics of Type 2A- and Type 2B-diabetes mellitus. Diabetes Res Clin Pract 11 [Suppl 1]: 311 (Abstract)
Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widén E, Schalin C, Groop L (1989) Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 321: 337–343
Kolterman O, Gray R, Griffin J, Burnstein P, Insel J, Scarlett J, Olefsky J (1981) Receptor and postreceptor defects contribute to the insulin resistance in non-insulin-dependent diabetes mellitus. J Clin Invest 68: 957–969
Olefsky J, Kolterman O (1981) Mechanisms of insulin resistance in obesity and non-insulin dependent (Type II) diabetes. Am J Med 70: 151–168
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 I: 785–789
Balasse EO, 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
Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA (1983) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747
Meylan M, Henny C, Temler E, Jéquier E, Felber JP (1987) Metabolic factors in the insulin resistance in human obesity. Metab Clin Exp 36: 256–261
Lillioja S, Bogardus C, Mott DM, Kennedy AL, Knowler WC, Howard BV (1985) Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest 75: 1106–1115
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
Felber JP, Meyer HU, Curchod B et al. (1981) Glucose storage and oxidation in different degrees of human obesity measured by continuous indirect calorimetry. Diabetologia 20: 39–44
Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jéquier E, Felber JP (1982) The effect of graded doses of insulin on total glucose uptake, glucose oxidation and glucose storage in man. Diabetes 31: 957–963
Diabetes Mellitus (1985) Technical Report Series 727. WHO, Geneva
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E223
Ferrannini E (1988) The theoretical bases of indirect calorimetry: a review. Metabolism 37: 287–301
Meriläinen PT (1987) Metabolic monitor. Int J Clin Monitor 4: 167–177
Miles JR, Glasscock J, Aikens J, Gerich J, Haymond M (1983) A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res 24: 96–99
Coleman TG, Manning RD Jr, Norman RA Jr, Guyton AC (1972) Dynamics of water-isotope distribution. Am J Physiol 223: 1371–1375
Radziuk J, Norwich KH, Vranic M (1978) Experimental validation of measurements of glucose turnover in nonsteady state. Am J Physiol 23: E84-E93
Steele R (1959) Influences of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 82: 420–430
Cobelli C, Mari A, Ferrannini E (1987) Non-steady state: error analysis of Steele's model and development for glucose kinetics. Am J Physiol 252: E679-E689
Dixon WJ (ed) (1985) BMDP Statistical software manual. 1985 reprinting. University of California Press
Shulman GI, Rothman D, Jue T, Stein P, DeFronzo RA, Shulman RG (1990) Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322: 223–228
Gulli G, Haffner S, Ferrannini E, DeFronzo RA (1990) What is inherited in NIDD? Diabetes 39 [Suppl 1]: 116A (Abstract)
Osei K (1990) Increased basal glucose production and utilization in nondiabetic first-degree relatives of patients with NIDDM. Diabetes 39: 597–601
Groop LC Bonadonna RC, Del Prato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. J Clin Invest 84: 205–213
Groop L, Petrides AS, Mainiero M (1987) Effect of insulin on FFA and total lipid oxidation in man. Diabetes 36 [Suppl 1]: 80A (Abstract)
Felber JP, Golay A, Felley C (1988) Regulation of glucose storage in obesity and diabetes: metabolic aspects. Diabetes Metab Rev 7: 691–700
Jenkins AB, Storlien LH, Chisholm DJ, Kraegen EW (1988) Effects of non-esterified fatty acid availability on tissue-specific glucose utilization in rats in vivo. J Clin Invest 82: 293–299
Argyraki M, Wright PD, Venables CW, Proud G, Taylor R (1989) In vitro study of human skeletal muscle strips: effects of nonesterified fatty acid supply on glucose storage. Metabolism 38: 1183–1187
Thiebaud D, DeFronzo RA, Jacot E et al. (1982) Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism 31: 1128–1136
Bevilacqua S, Bonadonna R, Buzzigoli G et al. (1987) Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 36: 502–506
Bevilacqua S, Buzzigoli G, Bonadonna R et al. (1990) Operation of Randle's cycle in patients with NIDDM. Diabetes 39: 383–389
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Eriksson, J., Saloranta, C., Widén, E. et al. Non-esterified fatty acids do not contribute to insulin resistance in persons at increased risk of developing Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 34, 192–197 (1991). https://doi.org/10.1007/BF00418275
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DOI: https://doi.org/10.1007/BF00418275