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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: 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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  • 3
    ISSN: 1432-0428
    Keywords: Obesity ; insulin ; glucose ; non-esterified fatty acids ; glucose turnover ; non-esterified fatty acid turnovers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Eight obese patients and 12 normal individuals underwent a euglycaemic insulin clamp (20 and 40 mU · m2−1 · min−1) along with continuous infusion of 3-3H-glucose and 1-14C-palmitate and indirect calorimetry. Basal plasma glucose concentration (4.7±0.3 vs 4.4±0.2 mmol/l) was similar in the two groups, whereas hepatic glucose production was slightly higher in obese individuals (1.11±0.06 vs 0.84±0.05 mmol/min) in spite of higher plasma insulin levels (17±2 vs 6±1 mU/l; p〈0.01). Insulin inhibition of hepatic glucose production was impaired in obese subjects. Glucose disposal by lean body mass was markedly reduced both at baseline (11.7±1.1 vs 15.6±0.6 μmol · kg−1 · min−1; p〈0.05) and during clamp (15.0±1.1 vs 34.4±2.8 and 26.7±3.9 vs 62.2±2.8 μmol · kg−1 · min−1; p〈0.01) Oxidative (12.2±1.1 vs 17.8±1 and 16.1±1.1 vs 51.1±1.7 μmol · kg−1 · min−1; p〈0.05−0.002) and non-oxidative glucose metabolism (3.9±1.1 vs 15.0±2.8 and 12.8±3.3 vs 38.3±2.2 μmol · kg−1 · min−1; p〈0.01−0.001) were impaired. Basal plasma concentrations of non-esterified fatty acids (635±75 vs 510±71 μmol/l) and blood glycerol (129±17 vs 56±5 μmol/l; p〈0.01) were increased in obese patients. Following hyperinsulinaemia, plasma non-esterified fatty acids (244±79 vs 69±16 and 140±2 vs 36±10 μmol/l; p〈0.01) and blood glycerol levels (79±20 vs 34±6 and 73±22 vs 29±5 μmol/l; p〈0.01) remained higher in obese subjects. Baseline non-esterified fatty acid production rate per kg of fat body mass was significantly larger in normal weight subjects (37.7±6.7 vs 14.0±1.8 μmol/l; p〈0.01) and insulin inhibition was reduced in obese patients (−41±9 vs −74±3 and −53±11 vs −82±3%; p〈0.05). Basal plasma non-esterified fatty acid utilization by lean body mass was similar in the two groups (9.8±0.9 vs 8.8±2.0 μmol · kg−1 · min−1), whereas during clamp it remained higher in obese patients (6.0±1.2 vs 2.8±2.5 and 4.9±1.3 vs 1.5±0.6 μmol · kg−1 · min−1; p〈0.1−0.05). Lipid oxidation was higher in obese individuals in spite of hyperinsulinaemia (3.7±0.3 vs 2.4±0.4 and 2.3±0.4 vs 0.9±0.3 μmol · kg−1 · min−1; p〈0.05− 0.02). An inverse correlation was found between lipid oxidation and glucose oxidation (r=0.82 and 0.93; p〈0.001) and glucose utilization (r=0.54 and 0.83; p〈0.05−0.001) both in obese and control subjects. A correlation between lipid oxidation and non-oxidative glucose metabolism was present only in normal weight individuals (r=0.75; p〈0.01). We conclude that in obesity all tissues (muscles, liver, and adipose tissue) are resistant to insulin action. Insulin resistance involves glucose as well as lipid metabolism.
    Type of Medium: Electronic Resource
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