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FASTING HYPERGLYCEMIA IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS - CONTRIBUTIONS OF EXCESSIVE HEPATIC GLUCOSE-PRODUCTION AND IMPAIRED TISSUE GLUCOSE-UPTAKE
No full text
Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man.
No full textHEPATIC AND PERIPHERAL INSULIN RESISTANCE FOLLOWING STREPTOZOTOCIN-INDUCED INSULIN DEFICIENCY IN THE DOG
No full textEffect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients
No full textGlycemic control and glucose metabolism were examined in 5 patients with insulin-dependent diabetes mellitus (IDDM) and 8 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients before and after 2 mo of therapy with glyburide (20 mg/day). Glycemic control was assessed by daily insulin requirement, 24-h plasma glucose profile, glucosuria, and glycosylated hemoglobin. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, and insulin sensitivity was determined by a two-step euglycemic insulin clamp (1 and 10 mU ·kg−1 · min−1) performed with indirect calorimetry and [3−3H]glucose.
In the IDDM patients, the addition of glyburide produced no change in daily insulin dose (54 ± 8 vs. 53 ± 7 U/day), mean 24-h glucose level (177 ± 20 vs. 174 ± 29 mg/dl), glucosuria (20 ± 6 vs. 35 ± 12 g/day) or glycosylated hemoglobin (10.1 ± 1.0 vs. 9.5 ± 0.7%). Furthermore, there was no improvement in basal hepatic glucose production (2.1 ± 0.2 vs. 2.4 ± 0.1 mg · kg−1 · min−1), suppression of hepatic glucose production by low- and high-dose insulin infusion, or in any measure of total, oxidative, or nonoxidative glucose metabolism in the basal state or during insulin infusion. C-peptide levels were undetectable (<0.01 pmol/ml) in the basal state and after glucagon infusion and remained undetectable after glyburide therapy.
In contrast to the IDDM patients, the insulin-treated NIDDM subjects exhibited significant reductions in daily insulin requirement (72 ± 6 vs. 58 ± 9 U/day), mean 24-h plasma glucose concentration (153 ± 10 vs. 131 ± 5 mg/dl), glucosuria (14 ± 5 vs. 4 ± 1 g/day), and glycosylated hemoglobin (10.3 ± 0.7 vs. 8.0 ± 0.4 %) after glyburide treatment (all P ≤ .05). However, there was no change in basal hepatic glucose produc-tion (1.7 ± 0.1 vs. 1.7 ± 0.1 mg kg−1 min−1), suppression of hepatic glucose production by insulin, or insulin sensitivity during the two-step insulin-clamp study. Both basal (0.14 ± 0.05 vs. 0.32 ± 0.05 pmol/ ml, P < .05) and glucagon-stimulated (0.24 ± 0.07 vs. 0.44 ± 0.09 pmol/ml) C-peptide levels rose after 2 mo of glyburide therapy and both were correlated with the decrease in insulin requirement (basal: r = .65, P = .08; glucagon stimulated: r = .93, P < .001).
These data indicate that in IDDM subjects, the addition of glyburide to insulin does not affect insulin requirement, glycemic control, or insulin sensitivity. In contrast, in insulin-treatedNIDDM patients, glyburide produces a modest decrease in insulin dose and improves glycemic control without altering insulin sensitivity. This improvement in glucose metabolism primarily reflectsan increase in endogenous insulin secretion
ADRENERGIC-BLOCKADE ALTERS GLUCOSE KINETICS DURING EXERCISE IN INSULIN-DEPENDENT DIABETICS
No full textEffect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity
No full textThe dose-response relationship between the plasma insulin concentration and
oxidative and nonoxidative pathways of free fatty acid (FFA) metabolism was
examined in 11 obese and 7 lean subjects using a stepwise insulin clamp technique
in combination with indirect calorimetry and infusion of [1-14C]palmitate. The
fasting plasma FFA concentration was elevated in obese subjects (793 +/- 43 vs.
642 +/- 39 mumol/l; P less than 0.01) and was associated with an increased basal
rate of plasma FFA turnover, FFA oxidation, and nonoxidative FFA disposal, i.e.,
reesterification (all P less than 0.01). Suppression of plasma FFA turnover by
physiological increments in plasma insulin was impaired in obese compared with
lean subjects. However, plasma FFA turnover expressed per kilogram fat mass was
normally suppressed by insulin in obese subjects. Although insulin suppressed
plasma FFA oxidation to the same extent in lean and obese subjects, inhibition of
total lipid oxidation by insulin was impaired in the obese group. Obese subjects
had an enhanced basal rate of nonoxidative FFA disposal, which was suppressed
less by physiological increments in plasma insulin compared with lean controls.
Therefore, we conclude that 1) lipolysis in uncomplicated obesity is normally
sensitive to insulin; the enhanced FFA flux is simply a consequence of the
increased fat mass. 2) Nonoxidative FFA disposal expressed per lean body mass is
enhanced in obese subjects and correlates with the increase in plasma FFA
concentration and fat mass. 3) Enhanced oxidation of intracellular lipids
contributes to the enhanced rate of total lipid oxidation in obese subjects
OXIDATIVE AND NON-OXIDATIVE GLUCOSE-METABOLISM IN NON-OBESE TYPE-2 (NON-INSULIN-DEPENDENT) DIABETIC-PATIENTS
No full textEffect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man
No full textTwo study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action
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