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  • 1
    ISSN: 1432-0428
    Keywords: Streptozotocin diabetes ; hyperglycaemia ; phlorizin ; insulin treatment ; glucose utilization index ; 2-deoxy-D-glucose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The relative contribution of hyperglycaemia and hypoinsulinaemia was evaluated in rats made diabetic by streptozotocin administration. Four groups of rats were studied: untreated normal rats; streptozotocin-diabetic; streptozotocin-diabetic treated with phlorizin (0.4 mg/kg body weight per day); streptozotocin-diabetic mildly treated with insulin (0.7 IU/day). In all groups, insulin action (responsiveness) was assessed with the euglycaemic (5.3 mmol/l) hyperinsulinaemic (524 mU/l) clamp technique combined with 3H-2-deoxy-D-glucose method, enabling determination of the glucose utilization index in various tissues. Responsiveness of the overall glucose utilization process to insulin was reduced by 28% in streptozotocin-diabetic rats (12.0±1.2 vs 16.5±0.6 mg·kg−1·min−1, p〈0.001). This was associated with a significant reduction (p〈0.05) in the glucose utilization index in all muscles studied (average=17.0 vs 32.1 ng·mg of tissue−1·min−1), in the heart (19.6 vs 39.5 ng·mg−1·min−1), brown adipose tissue (98.9 vs 178.0 ng·mg−1·min−1), skin (6.4 vs 13.1 ng·mg−1·min−1). Phlorizin treatment normalized plasma glucose levels without affecting those of insulin, and restored overall glucose utilization to normal (16.6±1.0mg·kg−1·min−1). This normalization was accompanied by a normalization of the glucose utilization index in all muscle types studied (29.2 ng·mg−1·min−1), in the heart (50.0ng·mg−1·min−1), brown adipose tissue (157.2 ng·mg−1·min−1), and skin (10.0 ng·mg−1·min−1). White adipose tissue, brain and gut were not affected. Mild insulin treatment with persistent hyperglycaemia was not able to significantly ameliorate glucose disposal (14.5±0.9 mg·kg−1·min−1) or the glucose utilization index of most individual tissues (muscle=18.4; heart=36.2; brown adipose tissue=148.0; skin=7.7 ng· mg−1· min−1). These data show that correction of hyperglycaemia in streptozotocin-diabetic rats normalizes insulin action, while partial correction of the hypoinsulinaemia fails to do so.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Chronic hyperinsulinaemia ; chronic hyperglycaemia ; insulin resistance ; insulin secretion ; impaired glycogen synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two 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.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: insulin ; sulfonylurea ; combined therapy ; insulin action ; insulin secretion ; metabolic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Metabolic control, insulin secretion and insulin action were evaluated in seven Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral antidiabetic agents before and after two months of combined therapy with supper-time insulin (Ultratard: 0.4 U/kg body weight/day) plus premeal glibenclamide (15 mg/day). Metabolic control was assessed by 24 h plasma glucose, NEFA, and substrate (lactate, alanine, glycerol, ketone bodies) profile. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, hyperglycaemic clamp (+7 mmol/l) and 24 h free-insulin and C-peptide profiles. The repeat studies, after two months of combined therapy, were performed at least 72 h after supper-time insulin withdrawal. Combining insulin and sulfonylurea agents resulted in a reduction in fasting plasma glucose (12.9±7 vs 10.4±1.2 mmol/l; p〈0.05) and hepaic glucose production (13.9±1.1 vs 11.1±1.1 μmol·kgc-min−1; p〈0.05). Mean 24 h plasma glucose was also lower (13.7±1.2 vs 11.1±1.4 mmol/l; p〈0.05). Decrements in fasting plasma glucose and mean 24 h profile were correlated (r=0.90; p〈0.01). HbA1c also improved (11.8±0.8 vs 8.9±0.5%; p〈0.05). Twenty-four hour profile for NEFA, glycerol, and ketone bodies was lower after teatment, while no difference occurred in the blood lactate and alanine profile. Insulin secretion in response to glucagon (C-peptide =+0.53±0.07 vs +0.43±0.07 pmol/ml) and hyperglycaemia (freeinsulin = 13.1±2.0 vs 12.3±2.2 mU/l) did not change. On the contrary, mean 24 h plasma freeinsulin (13.2±2.6 vs 17.5±2.2 mU/l; p〈0.01) and C-peptide (0.76±0.10 vs 0.98±0.13 pmol/l; p〈0.02) as well as the area under the curve (19.1±4.1 vs 23.6±3.1 U/24 h;p〈0.01 and 1.16±0.14 vs 1.38±0.18 μmol/24 h; p〈0.02 respectively) were significantly increased. The ratio between glucose infusion (M) and plasma insulin concentration (I) during the hyperglycaemic clamp studies (M/I, an index of insulin sensitivity), was not statistically different (1.40±0.25 vs 1.81±0.40 μmol·kg−1· min−1/mU·l−1). These data suggest that, in Type 2 diabetic patients with secondary failure to oral antidiabetic agents, the combination of supper-time longacting insulin and premeal sulfonylurea agents can improve metabolic control. This positive effect is possibly mediated through an increased secretion of insulin in response to physiologic stimuli.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Key words Chronic hyperinsulinaemia ; chronic hyperglycaemia ; insulin resistance ; insulin secretion ; impaired glycogen synthesis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two 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. [Diabetologia (1994) 37: 1025–1035]
    Type of Medium: Electronic Resource
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