The insulin clamp technique, which is often assumed to measure the ability of insulin to stimulate glucose uptake, actually measures both insulin-independent and insulin-dependent glucose uptake. In contrast, the minimal model technique, recently introduced by Bergman, Philips and Cobelli (1981), attempts to directly estimate insulin sensitivity (insulin-dependent glucose uptake = S1) by measurement of plasma glucose and insulin values during a 3 hour intravenous glucose tolerance test (IVGTT). In the present study estimates of insulin action derived from the insulin clamp and the minimal model technique were compared in 20 humans with varying degrees of glucose tolerance. The insulin response during the IVGTT was too low to permit calculation of S1 in 5 subjects - 4 with Type II diabetes and 1 with normal glucose tolerance. Although the correlation coefficient between the two tests in the other 15 patients was statistically significant (r = 0.53, P less than 0.05), this statement is somewhat misleading. Thus, S1 in the 4/7 patients with Type II diabetes in whom it could be measured was zero, and the correlation between estimates of insulin action with the two techniques in the 11 non-diabetic patients was not statistically significant (r = 0.41, P = NS) when these 4 patients were removed from the analysis. In conclusion, these data indicate that there was only a weak correlation between estimates of insulin action assessed with the insulin clamp and the minimal model techniques. One explanation for this observation is that the insulin-independent component of total glucose disposal both varies widely among patients and contributes significantly to glucose uptake as assessed by the insulin clamp technique.(ABSTRACT TRUNCATED AT 250 WORDS)
Aims/hypothesis. This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. Methods. First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucosesupplemented liquid meal and prandial glucose and insulin profiles were compared. Results. Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC 0-210 =108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC 0-210 =298 nmol/l min) and reduced glucose excursions by 53%. Conclusion/interpretation. Nateglinide is more rapidacting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia. It has been shown convincingly that in Type 2 (noninsulin-dependent) diabetes mellitus [1,2] and even in precursors thereof [3] the kinetics of insulin secretion are disrupted despite the existence of absolute (if not relative) hyperinsulinaemia. The disrupted insulin secretory kinetics can be confirmed by either the absence of the acute insulin response to i.v. glucose [4] or a sluggish insulin response to oral glucose [5] or a meal [6]. The impaired early insulin response leads to a marked impairment of the suppression of endogenous glucose production normally seen after glucose administration or a meal [5,6] and to a lesser extent, a later decrease of peripheral glucose utilization [6].
To determine the distribution of glucose carbons to the major metabolic pathways as a function of glucose and insulin concentrations in fed rat muscle, rat hindlimbs were perfused with and without 100 nM insulin in the presence of 1-20 mM [U-14C]-D-glucose. The incorporation of radioactivity into CO2, anionic metabolites released into the medium and muscle cell fractions were determined. The results indicate that the major metabolic fate of glucose taken up by muscle in the fed rat is conversion to anions released into the medium and that this process is saturable with increasing glucose concentrations. The data suggest that saturation of the glycolytic pathway is the major cause of the previously observed saturation of the glucose disposal rate associated with increasing glucose concentration.
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