Abstract. The present study was designed to quantitate the interaction between the decrease in target tissue insulin action seen in subjects with Type II diabetes and the mass action effect of glucose exerted via the prevailing hyperglycemic state. To this end, euglycemic glucose clamp studies were performed in 26 control subjects using insulin infusion rates of 15, 40, 120, 240, and 1,200 mU/M2 per min and in 10 Type II diabetic subjects using insulin infusion rates of 120 and 1,200 mU/M2 per min.The results of these euglycemic studies indicated that insulin-stimulated peripheral glucose disposal was decreased in the Type II diabetics due to a combined receptor (rightward shift in the dose-response curve) and postreceptor defect in insulin action (decreased maximal response), whereas the decrease in insulin-mediated suppression of hepatic glucose output (HGO) was consistent with a defect in insulin binding (rightward shift in dose-response curve).Hyperglycemic glucose clamp studies were also performed in the Type II diabetics at their respective fasting serum glucose levels (mean [±SE]

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Elevated basal and stimulated insulin levels have been previously demonstrated in elderly human subjects. To see whether these elevated insulin levels are due to alterations in either the metabolic clearance rate (MCR) for insulin or the feedback inhibition of insulin secretion, we have studied 14 elderly and 19 nonelderly subjects, mean age 70 +/- 2 and 35 +/- 2 yr, respectively. Fasting serum insulin and C-peptide levels were elevated in the elderly compared with the nonelderly, 17 +/- 2 versus 11 +/- 1 microU/ml, P less than 0.01 and 0.95 +/- 0.12 versus 0.47 +/- 0.07 pmol/ml, P less than 0.001. Euglycemic hyperinsulinemia created by insulin infusion rates of 15, 40, and 1200 mU/m2/min with glucose held constant resulted in steady-state serum insulin levels of 65 +/- 4, 109 +/- 8, and 11,316 +/- 890 versus 34 +/- 2, 96 +/- 5, and 11,083 +/- 1079 microU/ml in the elderly and nonelderly subjects, respectively. The MCR of insulin was decreased by 46% in the elderly compared with the nonelderly (10.1 +/- 0.7 versus 18.7 +/- 1.4 ml/kg/min) at the insulin infusion rate of 15 mU/m2/min with no difference observed between the two groups at the higher insulin infusions. Steady-state suppression of C-peptide by exogenous insulin was similar, 73 +/- 2% versus 72 +/- 2% and 70 +/- 3% versus 64 +/- 5% in the nonelderly and elderly groups during the 15 and 40 mU/m2/min insulin infusions, respectively. However, 50% suppression was achieved within 30 min in the nonelderly group compared with 70 min in the elderly group during the low-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

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We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 microgram/m2/min) or proinsulin (2.75 micrograms/m2/min), achieving steady-state serum levels of 32 +/- 3 microU/ml (equivalent to 0.23 +/- 0.02 pmol/ml) and 3.7 +/- 0.2 pmol/ml, respectively. Suppression of HGO was similar (83-84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 +/- 0.43 versus 1.98 +/- 0.28 mg/kg/min, P less than 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.