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.

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.

Lipoprotein and apoprotein levels in different types of dialysis.

Cardiovascular disease is common in chronic renal failure and its progression during dialysis has been described. We evaluated lipoprotein and apoprotein profiles in 30 male and 28 female uremic patients on dialysis in order to compare the results with 30 male and 19 female non-uremic controls and to detect any differences in lipemic pattern due to different types of dialysis. The dyslipidemic picture typical of uremia was observed in both sexes, coupled with significant hypertriglyceridemia and an increase in the lipid components of the very low density lipoprotein (VLDL). There was also a significant reduction in high density lipoproteins (HDL) cholesterol and HDL2 cholesterol. Apo C levels were increased, whereas Apo AI and AII were diminished. Apo B levels were unchanged. We also evaluated their lipid profile in relation to three types of dialysis: hemodialysis, hemofiltration and continuous ambulatory peritoneal dialysis. Analysis of variance of three different types of dialysis performed for comparable periods of time showed that the parameters typically altered in uremia (Tg, VLDL, ApoC, ApoE) were uniform, whereas differences were observed in the variables indicative of cholesterol and phospholipid metabolism. The alterations of cholesterol metabolism in some subjects, in addition to the specific alterations of Tg metabolism, help explain the elevated prevalence of atherosclerotic complications in dialysed uremic patient.

Effects of sodium and potassium adenosine-triphosphatase on circulating lymphocytes: an approach to human obesity.

The methodological aspects of (Na+, K+)-ATPase-dependent uptake of 86Rb, a potassium analog, were examined on human lymphocytes isolated from peripheral blood. The study of the time-course, the kinetic parameters, i.e., maximum velocity (Vmax) and Michaelis constant (Km) and the ouabain inhibition curve of 86Rb+ uptake confirm that circulating lymphocytes represent a suitable model for the study of (Na+,K+)-ATPase in human diseases. An application to human obesity is reported: the results indicate that 86Rb+ uptake on circulating lymphocytes is similar in obese and non-obese subjects. Therefore, (Na+,K+)-ATPase does not seem to be involved in the pathogenesis of human obesity.

Moderate guar-gum addition to usual diet improves peripheral sensitivity to insulin and lipaemic profile in NIDDM.

The addition of vegetable fibres to the diabetic diet has been reported to ameliorate glycaemic and plasma lipid profiles, and Guar flour seems to obtain the best results. At its usual dose, Guar produces several gastro-intestinal side effects. A lower dose (4 + 4 g/day) was therefore employed in 10 non-insulin dependent diabetics (NIDD). The following parameters were measured at the end of treatment and after a control period: HbA1 levels, hepatic glucose production (3H-Glucose infusion), peripheral sensitivity to insulin and insulin secretion (hyperglycaemic clamp), and specific insulin binding to isolated monocytes. The ultracentrifugal plasma lipid pattern was also measured. No significant body weight change was recorded during the study. A significant glycaemic and insulinaemic decrease in the fasting state was observed after Guar, together with a significant decrease of HbA1 levels (from 8.5 +/- 0.4 to 7.9 +/- 0.4%, p less than 0.05) and amelioration of peripheral sensitivity to insulin (M/I = 14.3 +/- 6.6 versus 24.3 +/- 8.8, p less than 0.025; 50% increase of insulin binding to circulating monocytes) without significant variation of the fasting hepatic glucose production. Decreased B-cell stimulation by flattening post-prandial glycaemic peaks may be an explanation of the reduction of insulin resistance via down-regulation mechanism. As far as the lipid profile is concerned, a significant reduction in total and LDL cholesterol (p less than 0.05 and p less than 0.01) and an increase in HDL-phospholipids (p less than 0.05) were recorded after Guar. These results suggest that Guar in low doses is well accepted and can contribute to a better glycaemic and lipaemic control in NIDDM.

The treatment of unstable type I diabetes: conventional versus portable pump insulin administration.

The treatment of unstable insulin-dependent diabetics (UIDD) is still an unsolved problem. A comparison was made between optimized conventional treatment (OCT) (Ultralente + Actrapid at breakfast, Actrapid at lunch and Actrapid at dinner) and continuous s.c. insulin infusion (CSII) for 30 days in 10 UIDD outpatients. Continuous 24-h blood glucose monitoring with an artificial pancreas, fasting values of HbA1, plasma lipids, growth hormone, glucagon, daily urinary glucose and protein excretion were recorded after each treatment; a daily blood glucose profile was determined every week. Daily mean blood glucose values dropped significantly (p less than 0.01): from 187.2 +/- 66.6 (OCT) to 111.6 +/- 27.0 mg/dl (CSII), and hypoglycemic and ketotic events disappeared during CSII. A significant improvement (p less than 0.01 - p less than 0.001) in all other parameters was also observed. It is suggested that CSII may help to improve metabolic control and the quality of life in UIDD.

Metformin reduces insulin requirement in Type 1 (insulin-dependent) diabetes.

The effect of metformin on Type 1 (insulin-dependent) diabetes has been assessed with the artificial pancreas. Fourteen Type 1 diabetic patients of normal body weight received in addition to their usual insulin therapy 850 mg metformin or placebo three times a day for 4-6 weeks. The sequence was placebo-metformin in eight patients and metformin-placebo in the other six. On the last day of metformin or placebo treatment, an artificial pancreas was used for about 36 h to assess insulin requirement. There was a 25.8% reduction in insulin requirement during metformin management despite slightly lower blood glucose levels (5.25 +/- 0.20 versus 5.98 +/- 0.18 mmol/l, p less than 0.01). Maximum reduction (about 50%) occurred 2 h after both lunch and dinner. There was no nocturnal effect. A marked decrease in specific insulin binding before metformin was found (0.56 +/- 0.27% to 10(7) monocytes versus 2.82 +/- 0.75 of control subjects) and significant increase after metformin (1.36 +/- 0.36%, p less than 0.05). There were no significant changes in blood lactate, total and HDL-cholesterol, triglycerides and C-peptide levels. These results show that insulin receptor binding is diminished in Type 1 diabetes, perhaps as a consequence of higher peripheral blood insulin levels and that metformin can improve binding, and so reduce the amount of insulin needed to reach euglycaemia. The insulin sparing effect is greatest after meals, and interference with intestinal absorption of sugars may also be important. It follows that metformin could be usefully administered to Type 1 diabetic patients with unimpaired liver and renal function to reduce their insulin requirement.

Effect of a somatostatin analog on insulin requirement and hormone levels in 6 insulin-dependent juvenile-onset diabetics subjected to artificial pancreas.

This study was performed in order to investigate the effect of a 12-h infusion of the somatostatin selective analog D-Trp8, D-Cys14 Serono, (SRIF-A), on insuli requirement and C-peptide (CP), growth hormone (GH) and glucagon (IRG) levels in 6 insulin-dependent diabetics submitted to 60-h artificial pancreas (Biostator Miles) metabolic control from 2000 of the first day to 0800 of the fourth day. Meals were given at 1200 and 1700 of the second and third day. Before meals and 1-2 h after meals, plasma levels of CP, GH and IRG were measured. The two 12-h periods (midday-midnight) with and without continuous SRIF-A 12-h infusion (40 microgram/h) were considered. The SRIF-A infusion caused a 20% reduction in insulin requirement (p < 0.05) and a slight but significant reduction of GH levels (p < 0.05). CP and IRG were unaffected.