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Aim: To evaluate the efficacy and safety of gliclazide modified release (MR), alone or combined with other oral antidiabetic drug(s) over 2 years in type 2 diabetic patients. Methods: Two consecutive periods: (i) a 10-month, double-blind comparative study, where 800 type 2 diabetic patients were randomized either to gliclazide MR (30–120 mg) once daily or to gliclazide (80–320 mg) twice daily. All the patients were then treated with gliclazide MR for a 2-month switch period; (ii) 549 patients were subsequently enrolled in a 12-month, open-label period on gliclazide MR alone or in combination according to glycaemic control, 507 of whom completed the study. Results: Glycated haemoglobin (HbA1c) significantly decreased from baseline over 2 years by −0.46 ± 1.08% in the whole cohort of 2-year completed patients, −0.95% in the subgroup of diet-failed patients and by −0.34% in the subgroup of patients pretreated with one oral antidiabetic drug. HbA1c was reduced by −0.43 ± 1.02% and by −0.51 ± 1.16%, when gliclazide MR was used in monotherapy and in combination therapy, respectively. The overall incidence of symptoms suggestive of hypoglycaemia was 4.8 episodes/100 patient-year, with no severe episode. This incidence was similarly low in elderly patients and patients with impaired renal function. Conclusion: Gliclazide MR alone or in combination with another oral antidiabetic drug significantly improved glycaemic control in type 2 diabetic patients over 2 years with a very good safety profile, notably in the elderly and in patients with impaired renal function.

In a double-blind, multicenter, multinational study, the long-term efficacy and safety of Diamicron(R)MR, a new gliclazide formulation taken once daily at lower dose (30-120 mg/day) was compared with Diamicron(R) (80-320 mg/day) taken twice daily in type 2 diabetic outpatients. After a 2-week run-in period, 800 patients with poor blood glucose control were randomized to Diamicron(R)MR (n=401) or Diamicron(R) (n=399). After a 4-month titration period, the efficacy and safety of Diamicron(R)MR was compared with Diamicron(R) over a 6-month fixed-dose treatment period. The ability to switch from Diamicron(R) to Diamicron(R)MR was then assessed during an additional 2-month follow-up period. Equivalence between treatment with Diamicron(R)MR and Diamicron(R) was compared by a non-inferiority test; the limit of equivalence was set at 0.5% for HbA(1c) and 1 mmol/l for fasting plasma glucose (FPG). The treatment groups were comparable at baseline. After 10 months of treatment, Diamicron(R)MR was as efficient as Diamicron(R) in controlling blood glucose, with a mean end point difference in HbA(1c) of -0.08 (0. 08)%, significantly lower than the equivalence limit (p

Insulin-dependent diabetes mellitus (IDDM) is characterized by altered composition of atherogenic lipoproteins, especially a depletion in choline-containing phospholipids (PL) of apolipoprotein (apo) B lipoproteins (LpB). To determine the effects of continuous intraperitoneal (IP) insulin infusion (CIPII) on this qualitative lipoprotein abnormality, we compared lipoprotein profiles of 14 IDDM patients treated by continuous subcutaneous insulin infusion (CSII) and at 2 and 4 months after treatment with CIPII using an implantable pump. IDDM patients were in fair metabolic control and were compared with 14 healthy control subjects matched for sex, age, body mass index, and plasma lipids. The following parameters were studies: hemoglobin A1c (HbA1c), monthly blood glucose, daily insulin dose (units per kilogram per day), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, apo A-I, and apo B. Choline-containing PL were assessed in plasma and in apo B- and no-apo B-containing lipoprotein particles (LpB and Lp no B). As compared with the control group, plasma PL and LpB-PL were significantly lower in IDDM patients treated by CSII (2.95 +/- 0.26 v 3.30 +/- 0.45 mmol/L,P

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Diabetes mellitus, a common complication of chronic pancreatitis, can disturb the metabolism of zinc, copper, and selenium. We analyzed the effects of hyperglycemia, malabsorption, and dietary intake on these factors in 35 men with alcohol-induced chronic pancreatitis complicated by insulin-treated diabetes mellitus (CP-D), 12 men with chronic pancreatitis but no diabetes (nondiabetic CP), 25 men with type 1 diabetes mellitus (type 1 DM), and 20 control subjects. Diabetes due to chronic pancreatitis was associated with decreased plasma zinc and selenium concentrations and with increased urinary copper excretion. Of the chronic pancreatitis patients, 17% had low plasma zinc, and 41% of them had low plasma selenium. None of the type 1 diabetic patients had low plasma concentrations of zinc, but 12% of them had a low selenium concentration. Hyperglycemia, as assessed by fasting plasma glucose and by plasma HbAlc, was responsible for the increased zinc excretion and the decreased superoxide dismutase activity. The perturbations of the copper, selenium, and zinc metabolism were particularly pronounced in subjects with chronic pancreatitis plus diabetes mellitus. We have yet to determine whether the differences in trace-element status contribute to the clinical expression of the disease.

The semiological value of hemoglobin A1c (HbA1c) as a retrospective and cumulative marker of glycemic balance in diabetic patients is greatly weakened in case of hemoglobinopathy. The presence of an abnormal hemoglobin raises methodological problems due to the interferences generated in most assay methods, but also alters the normal process of HbA glycation to HbA1c, and often induces a certain level of hemolysis, very variable and impossible to quantify. This paper reviews methodological and semiological problems related to the presence of abnormal hemoglobin species, and proposes a standardized strategy in case of hemoglobinopathies.

An interruption of continuous sc insulin infusion (CSII) of the insulin analog lispro should result in a more rapid metabolic deterioration of type 1 diabetic patients because of its pharmacokinetic characteristics. We analyzed the metabolic changes occurring during a 5-h interruption of CSII and the 5 h after restarting the pump in 10 type 1 diabetic patients. The study was a randomized, cross-over, open label design comparing insulin analog [Lispro (LP)] and regular insulin [Velosuline (VE)]. Plasma glucose, free insulin, glucagon, betahydroxybutyrate (beta-OHB), and nonesterified fatty acids (NEFA) were measured every hour from 0700 h (time zero) to 1700 h (600 min). After stopping CSII, the plasma glucose level was significantly higher in the LP group than in the VE group (P0.05-0.01). The plasma free insulin level decreased significantly with the two treatments, but was significantly lower with LP than with VE (P0.05-0.01). Plasma NEFA increased more rapidly and was significantly higher in the LP group than in the VE group (P0.01-0.05). Plasma beta-OHB increased earlier with LP, but was not statistically different between the treatments. After restarting the pump, plasma glucose decreased with LP, but continued to increase with VE, and the plasma free insulin peak occurred earlier and was greater with LP than with VE (P0.05). Plasma NEFA and beta-OHB levels decreased significantly with the two treatments, but more dramatically with LP treatment. Thus, a short interruption of Lispro in CSII is associated with an earlier, greater metabolic deterioration, but Lispro corrected this metabolic deterioration more effectively.

Insulin use in NIDDM is a frequent situation. Many acute clinical circumstances justify a transient insulin therapy including ketoacidosis decompensation or hyperosmolar state and severe intercurrent diseases. The problem is more complex when glycemic control is no longer obtained despite maximal doses of oral treatment. Type 2 diabetes is then defined as an insulin-requiring diabetes. There is actually no consensus, but lots of arguments advocate an intensive insulin therapy based on multiple daily injections in this clinical state. However, when patient's overweight is important or if the clinical context is unfavourable, conventional insulin therapy or combined treatment using bedtime insulin and daytime oral agents may be tried.

A mathematical model was recently developed (minimal model) to estimate insulin sensitivity from the analysis of blood glucose and insulin concentration after a modified intravenous glucose tolerance test. This approach was successfully compared with the euglycemic glucose clamp in humans. In this study, we have analysed the distribution and reproducibility of this method in 10 healthy subjects and seven obese patients. We have observed a lower insulin sensitivity (SI) in obese patients (1.96 +/- 0.38 x 10(-4)/min/microU/ml) than in healthy subjects (8.19 +/- 1.16 x 10(-4)/min/microU/ml) with a small overlap between the two groups. The test was repeated twice and good repeatability was found with the method of Blank and Altman when a log transformation was applied to the data.

The effects on lipid metabolism of a single intramuscular dose of SR 29001 (0.15 U/kg body wt), a biosynthetic human growth hormone (hGH), were explored in a double-blind randomized crossover vs a placebo study of six normal-weight and six obese subjects (Quetelet Index greater than 120%). Circulating hGH concentrations reached means of 35 and 28 ng/mL in the normal-weight and obese subjects, respectively. Free fatty acids increased in both groups (p less than 0.05); increases in beta-hydroxybutyrate and acetoacetate concentrations were more moderate (NS). Plasma glucose increased significantly despite a significant increase in insulin (p less than 0.002). The lipolytic effect persisted after a standardized 950-kcal meal eaten 5 h after hGH administration. A delayed increase in somatomedin-C and decreases in blood urea and total cholesterol were also observed (p less than 0.05). Despite increased insulin secretion, biosynthetic hGH produced a significant increase of lipolysis in both groups, which was only partially suppressed by food.

Nycthemeral variations in blood glucose (BG) and insulinemia (IRI) of four subjects with insulin-secreting pancreatic tumors were determined. Blood samples were drawn every 15 min over a 28-h period. After surgery, two of the subjects were retested. Meals were distributed during testing so that there was a minimum of eight meals per test. The meals before and after surgery were qualitatively, quantitatively and chronologically the same. Even though the circadian profiles of the glycemia and insulinemia varied greatly among the subjects, there were three common characteristics during the noctural period (24 h-8 h): Existence of one or several phases of at least 1 hour where the glycemia was less than 2.78 mmol/l, Existence of IRI peaks, without eating. Existence of a peak or of increased values (as compared to normal values) of the IRI/BG ratio, without eating. The IRI/BG ratio is a very sensitive index for insulin secretion dysfunction as compared to glycemia. The results suggest that the measurement of glycemia and insulinemia of sleeping subjects and then calculation of the IRI/BG ratio is sufficient to affirm the presence of an insulin-secreting adenoma.

The blood viscosity of 15 insulin-dependent, poorly controlled, diabetic subjects was determined by using a microviscosimeter at low shear rates, with cylindrical cuvettes of the Couette type. It was found that the blood viscosity of these diabetics was more elevated than that of control patients (p less than 0.001). In ten diabetics, the return to a strict metabolic control over a period of more than 24 h by means of an artificial pancreas resulted in a significant systematic lowering of blood viscosity. These results suggest that the metabolic control of diabetes influences blood viscosity, and they underline the importance of an artificial pancreas for the dynamic study of the factors affecting blood viscosity during the course of diabetes.

Manufacturing quality, accuracy and users opinion (i.e. medical and nurses staff and patients) were compared among five Destrostix reading reflectance-meters for home-blood-glucose-monitoring. Two machines (dextrometer and glucometer) equipped with microprocessors, integrated circuits and good quality wiring are best made. Reflectance-meter capillary blood glucose measurements were found to be accurate enough for home-blood-glucose-monitoring, compared to a reference method. However, two machines from the same brand were different in blood glucose accuracy. Glucocheck had poorest results. Users prefer small sized, battery powered machines. Glucometer appears to be best suited to home-blood-glucose-monitoring.

The euglycemic hyperinsulinaemic clamp is a means for the study of insulin sensitivity. Several techniques have been described: some are manual, others are automatic and use hypertonic glucose (50%). A semi-automatic technique is described using an artificial B cell (Biostator Miles) and a pump (Vial). The method and its reproductibility in ten healthy subjects were studied. The choice of appropriate algorithms ensure a constant and stable insulin level of 93,3 +/- 5 uU/ml and good glycemic feedback through graduated glucose perfusion. The use of a supplementary pump in series with an artificial pancreas insures basic glucose input without recourse to strong concentrations (20%); glycemic feedback of the artificial pancreas is thereby dynamically controlled. The glucose requirement is 8,08 +/- 0,73 mg/kg/min. The same values are found in the same patients three weeks later and resemble those obtained using other techniques. Automatic feedback makes the technique objective; low concentration glucose solution avoids damage to veins.

Oral tests using 50 g of sucrose and 100 g of white bread were carried out in ten insulin-dependent diabetics (four with signs of residual B-cell function and in six without). Plasma glucose and C-peptide (CPR) were estimated during the 180 minutes after ingestion. After bread intake, plasma glucose increase was significantly delayed (30 min.). Hyperglycemia (greater than 2.5 g/l) lasted significantly longer after bread then after sucrose ingestion. Blood glucose decreased more quickly in subjects with residual B-cell function than in subjects without. CPR was not significantly modified by either of the carbohydrate loads. In the controlled insulin-dependent diabetic the hyperglycemia observed results from the ease of carbohydrates hydrolysis and from the amount of available glucose. The role of fructose seems weak in the case of sucrose because its conversion to glucose would be minimized in the presence of metabolic normalization as indicated by a well controlled blood glucose.