Insulin resistance shows selective metabolic and hormonal targets in the elderly.

There has been no simultaneous evaluation of different aspects of insulin action in ageing. We studied 12 elderly (77 +/- 2 years) and 12 young (26 +/- 1 years) subjects with normal glucose tolerance and matched for sex, body mass index, lean body mass (LBM), blood pressure and physical activity, using a euglycaemic-hyperinsulinaemic clamp at about 350 pmol L-1 in combination with [3H]-glucose infusion. In the elderly group, hepatic glucose production was normal, fasting serum insulin and C-peptide were significantly increased (P = 0.001) and glucose utilization (34.4 +/- 2.4 vs. 44.4 +/- 3.2 mumol kg-1 LBM min-1, P = 0.02) and the percentage maximal suppression of C-peptide (58 +/- 6% vs. 79 +/- 5%, P = 0.02) during the clamp were reduced. Fasting plasma free fatty acid (FFA) and glycerol levels were similar in the two groups, but their percentage maximal suppression during the clamp was reduced in the elderly group (FFA 45 +/- 5% vs. 77 +/- 6%, P = 0.001; glycerol 43 +/- 5% vs. 76 +/- 3%, P = 0.001). Branched-chain amino acids (valine, leucine, isoleucine) and glucagon levels were similar in the two groups, both while fasting and during the clamp. Thus, insulin resistance in ageing appears selective on glucose utilization, inhibition of lipolysis and feedback inhibition of the B-cell secretion.

Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes.

In a randomized double-blind cross-over study the addition of metformin to chronic glibenclamide treatment was assessed conventionally (plasma glucose profile and HbA1c measurement) and with an euglycaemic-hyperinsulinaemic glucose clamp in ten non obese (body mass index 22.3 +/- 0.5 (+/- SE)kg.m-2) Type 2 diabetic patients with poor metabolic control. Metformin (500 mg twice a day) or placebo were added in randomized sequence for 6 weeks to their usual sulphonylurea treatment (glibenclamide 5 mg three times a day, before meals). On the last day of each administration period, an euglycaemic (glucose 5.5 +/- 0.5 mmol.l-1), hyperinsulinaemic (insulin 698.1 +/- 22.9 pmol.l-1) clamp was performed, together with a study of insulin binding to circulating monocytes. Metformin reduced fasting glucose levels (6.1 +/- 0.4 vs 6.4 +/- 0.4 mmol.l-1, P = 0.036), mean daily plasma glucose concentrations (9.2 +/- 0.4 mmol.l-1, P < 0.001), and HbA1c (8.7 +/- 0.3 vs 9.3 +/- 0.2%; P = 0.027). No variations were registered in fasting plasma insulin or body weight. A significant reduction of basal hepatic glucose production (12.8 +/- 2.7 vs 33.9 +/- 4.5 mumol.kg-1 min-1, P < 0.001), together with an increase in glucose utilization during the clamp (33.4 +/- 2.8 vs 25.9 +/- 1.1 mumol.kg-1.min-1, P = 0.033), was found after metformin, whereas residual glucose production during insulin infusion did not change. Insulin binding to circulating monocytes was higher after metformin (4.8 +/- 0.9 vs 3.2 +/- 0.6%, P = 0.020), while the lipaemic profile showed a reduction in triglycerides (1.2 +/- 0.1 vs 1.7 +/- 0.3 mmol.l-1, P = 0.039) and an increase in HDL-cholesterol (1.3 +/- 0.1 vs 1.0 +/- 0.1 mmol.l-1, P = 0.004) without variations in total cholesterol. These findings offer further evidence that metabolic control is improved after biguanide addition to sulphonylurea treatment, and support the hypothesis that biguanides improve insulin sensitivity both at the hepatic and peripheral (muscular) levels, as well as triglyceride metabolism.

Comparison of the metabolic effects of mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent diabetic subjects.

Dietary constituents other than glucose can influence insulin secretion in non-insulin-dependent diabetes mellitus and administration of a standard mixed meal has been proposed as a more physiological test in regard to human diet for evaluating the patient both at the time of diagnosis and during follow-up. This study was carried out to compare the effects of a standard meal and the oral glucose tolerance test on glucose, insulin and C-peptide plasma levels in four groups of subjects: healthy controls, subjects with impaired glucose tolerance, patients with mild non-insulin-dependent diabetes, and non-insulin-dependent diabetic patients with secondary failure to oral agents. Plasma glucose values were significantly higher after the oral glucose tolerance test than after the mixed meal in all four groups of subjects. Plasma insulin and C-peptide values were similar during the two tests in all groups of subjects except in non-insulin-dependent diabetics with secondary failure (flattened curves). Insulin and C-peptide responses per unit rise in blood glucose were significantly higher after the oral glucose tolerance test than after the mixed meal both in mild non-insulin-dependent diabetics (P less than 0.05 and P less than 0.05) and in non-insulin-dependent diabetics in secondary failure (P less than 0.01 and P less than 0.05). There was significant correlation between oral glucose tolerance test and mixed meal glucose incremental areas (r = 0.511, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind crossover study of acarbose in type 1 diabetic patients.

The addition of acarbose to insulin treatment was evaluated in 14 Type 1 (insulin-dependent) diabetic patients assessed conventionally (blood glucose profile and HbA1c measurement) and with an artificial B-cell. Their metabolic control was poor, fasting blood glucose 10.7 +/- 0.3 (+/- SE) mmol l-1, mean daily blood glucose 9.7 +/- 0.3 mmol l-1, and HbA1c 9.6 +/- 0.2% (normal range 5.0-6.1%). They were of normal body weight (body mass index 22.5 +/- 0.3 kg m-2), and were C-peptide deficient (fasting 0.08 +/- 0.02 nmol l-1). In addition to their usual insulin therapy (46.9 +/- 3.5 U day-1 in three pre-meal injections), they received 100 mg acarbose or placebo three times a day for 6 weeks in a randomized double-blind crossover design. On the last day of either acarbose or placebo treatment, the usual insulin therapy was discontinued and an artificial B-cell was used for insulin delivery, programmed for euglycaemia. Placebo or acarbose was continued before meals. Acarbose reduced mean daily blood glucose concentrations (8.5 +/- 0.3 vs 9.7 +/- 0.3 mmol l-1, p = 0.002) and HbA1c levels (8.3 +/- 0.1 vs 9.6 +/- 0.2%, p less than 0.001). A significant reduction in insulin requirement after meals was found with the artificial B-cell, 25.1 +/- 2.5 (first treatment acarbose) and 24.1 +/- 2.9 U (first treatment placebo) with acarbose and 40.0 +/- 2.5 and 35.6 +/- 2.9 U with placebo (p less than 0.001). These results suggest that acarbose could usefully be administered to Type 1 diabetic patients to ameliorate glucose control and reduce insulin requirement.