Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in man.
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Biomedical subjects
Publications and source records attributed to D Mott.
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Previous studies have left unanswered whether human obesity, independent of glucose intolerance, is associated with a "postreceptor" defect in insulin action. We have studied the relationship between the degree of obesity (as estimated by underwater weighing) and the maximal insulin-stimulated glucose disposal rate (M) in vivo in 52 glucose-tolerant Pima Indian males. The relationship was examined independently of differences in age and maximal oxygen uptake (an estimate of "physical fitness"). The maximal insulin-stimulated glucose transport rate (MTR) was also measured in isolated abdominal adipocytes from the same subjects to determine whether differences in M could be explained by differences in glucose transport. The results showed that there was a large variance in M and MTR among these glucose-tolerant subjects. M was better correlated with glucose storage rates than with oxidation rates, as estimated by indirect calorimetry. The most obese subjects had only a 20% lower mean M and 30% lower MTR than the most lean subjects. The lower M in the obese subjects was due to both lower glucose oxidation and storage rates. There was no significant, independent correlation between age or degree of obesity and M or MTR. The maximal oxygen uptake (VO2 max) appeared to independently account for 20% of the variance observed in M. MTR was only weakly correlated with M (r = 0.36, P less than 0.02). We concluded that differences in M in these glucose-tolerant subjects must be explained by factor(s) other than maximal oxygen uptake, age, maximal insulin-stimulated glucose transport in vitro, or degree of adiposity per se.
We have studied the relationship between in vivo insulin-mediated glucose disposal rates, muscle glycogen content, and muscle glycogen synthase activity in 25 southwest American Indians with normal glucose tolerance and with varying degrees of glucose intolerance. Insulin-mediated glucose disposal (M) was measured by using the hyperinsulinemic euglycemic clamp technique at plasma insulin concentrations of 134 +/- 7 and 1709 +/- 72 microU/ml, with simultaneous indirect calorimetry to assess glucose oxidation and storage rates. Muscle glycogen content and glycogen synthase activity were measured in percutaneous muscle biopsy samples obtained from the vastus lateralis muscle before and after the euglycemic clamp procedure. The results showed that muscle glycogen synthase activity at the end of the euglycemic clamp was well correlated with insulin-mediated glucose storage rates at both low (r = 0.50, P less than 0.02) and high (r = 0.78, P less than 0.0001) insulin concentrations; and also correlated with M (r = 0.66, P less than 0.001 and r = 0.76, P less than 0.0001). Similar correlations were observed between the change in muscle glycogen synthase activity and glucose storage rates and M. The change in muscle glycogen synthase activity correlated with the change in muscle glycogen content (r = 0.46, P less than 0.03) measured before and after the insulin infusions. The change in muscle glycogen content did not correlate with glucose storage rates or M. The data suggest the possible importance of glycogen synthesis in muscle in determining in vivo insulin-mediated glucose disposal rates in man.
The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.
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Venous occlusion plethysmography was used to measure the flow of blood into the lower limbs of 30 normal volunteers. An impedance plethysmograph, using disposable point electrodes, was compared with a mercury in Silastic strain gauge plethysmograph in 20 subjects. The effect of changes in the configuration of the point electrodes was studied in 10 subjects. Impedance plethysmography was shown to be reproducible, and one particular configuration of point electrodes was shown to be superior to the others.
Simultaneous measurement of the flow of blood in the calf in 24 normal volunteers by impedance and mercury strain gauge plethysmography has revealed a systematic difference in the results from the two methods. Possible reasons for this discrepancy are discussed.