A 75% insulin lispro/25% NPL mixture provides a longer duration of insulin activity compared with insulin lispro alone in patients with Type 1 diabetes.

AIMS: To compare a new insulin formulation, high mix (HM) [75% lispro (LP) and 25% neutral protamine lispro (NPL)], to regular human insulin (HR) and LP with respect to glucose response and pharmacokinetics following a test meal in patients with Type 1 diabetes. METHODS: After fasting overnight, patients received an intravenous insulin infusion to standardize blood glucose (BG) to 7.5 mmol/l (135 mg/dl). In a randomised, three-way crossover study, HR was injected 30 min before, and LP or HM was injected immediately before the test meal on three separate occasions. For each patient, LP and HR were administered at identical doses; the HM dose was one and one third times that of HR and LP to maintain the same dose of short or rapid-acting insulin. The insulin infusion was stopped 15 min after the insulin injection. Free insulin and BG concentrations were measured frequently for 7 h following the test meal. RESULTS: HM and LP resulted in better glycaemic control than HR during the observation period. BG concentrations during the first 4-5 h did not differ between HM and LP. However, HM exhibited prolonged insulin activity relative to LP beyond 5 h, extending the duration of action by approximately 1 h, and resulting in lower overall BG concentrations when the 0-6- and 0-7-h intervals were considered. CONCLUSIONS: Compared with LP, HM provided similar glycaemic control for up to 5 h and superior glycaemic control from 5 to 7 h following a standard test meal.

Metabolic effects of mealtime insulin lispro in comparison to glibenclamide in early type 2 diabetes.

The efficacy and safety of the preprandial injection of insulin lispro was compared with the oral administration of glibenclamide in patients with early type 2 diabetes. In this open-label, multicenter study, 143 patients with a glucagon-stimulated increase in C-peptide of at least 0.4 nmol/L were randomized to receive preprandial insulin lispro (LP) or glibenclamide (GB) for 26 weeks. Seventy-five patients received LP (51 male/24 female; age 40 to 70 years, duration of diabetes 4.4 +/- 2.9 years) and 68 patients received GB (39 male/29 female; age 39 to 70 years; duration of diabetes 4.3 +/- 3.4 years). After 12 weeks, mean 90 minute blood glucose excursions were 0.9 +/- 1.0 mmol/L for LP and 1.8 +/- 1.2 mmol/L for GB (p < 0.0001). After 24 weeks, mean blood glucose excursions were 1.0 +/- 1.1 mmol/L for LP and 1.7 +/- 1.2 mmol/L for GB (p = 0.002). Body weight decreased slightly from 87.2 +/- 2.3 to 86.5 +/- 12.2 kg in the LP group and increased from 84.1 +/- 13.7 to 84.4 +/- 13.3 kg in the GB group. LP versus GB induced changes from baseline to endpoint in fasting C-peptide (nmol/L), proinsulin and insulin levels (pmol/L) were - 0.2 +/- 0.4 versus - 0.1 +/- 0.6 (p = 0.04), - 11.2 +/- 26.0 versus - 1.1 +/- 17.3 (p = 0.03), and - 27.8 +/- 147.4 versus + 32.6 +/- 286.2 (not significant), respectively. HbA 1c at baseline was 7.5 +/- 1.0 % for LP and 7.7 +/- 1.2 % for GB and did not change significantly in either group during the investigation. No significant difference was observed between the groups with respect to hypoglycemic episodes. Treatment with LP improved postprandial blood glucose control more than GB without increasing body weight or hypoglycemic episodes. In addition, use of LP was associated with a decrease in fasting C-peptide and proinsulin levels, suggesting a potential down regulation of endogenous insulin production and improved proinsulin processing efficiency.

Cessation of insulin infusion at night-time during CSII-therapy: comparison of regular human insulin and insulin lispro.

Development of hyperglycemia with subsequent ketoacidosis is one of the potential risks of a sudden cessation of insulin delivery during continuous insulin infusion therapy with insulin pumps in patients with IDDM. To evaluate differences in the development of ketoacidosis after a sudden pump stoppage between regular human insulin and insulin lispro, we performed an open label randomized crossover investigation with 7 patients (6 male/1 female, mean age (SD: 40.9 +/- 12.9 years). At 10 p.m., 4 hours after a light dinner with a preprandial injection of the corresponding insulin, the catheter was pulled out of the skin. During the observation period, blood glucose (every hour), pH-values and base excess values (every two hours) were measured until 7 a.m. One patient, in the insulin lispro treatment arm, discontinued because early interruption criteria were met after 7 hours. With insulin lispro, the metabolic changes developed 1.5 to 2 hours earlier than with regular human insulin (after 3 hours: difference in base excess (BE) mean +/- SD: regular human insulin: -0.41 +/- 1.04 mmol/l; insulin lispro: -1.69 +/- 0.83 mmol/l, p < 0.05; blood glucose: regular human insulin: 4.93 +/- 2.87 mmol/l, insulin lispro: 8.97 +/- 3.48, p < 0.05; pH values: regular human insulin: 7.38 +/- 0.02, insulin lispro: 7.36 +/- 0.02, n.s.). In general, metabolic deterioration tended to be more pronounced with insulin lispro than with regular human insulin (deltaBE after 7 h: regular human insulin: -2.39 +/- 1.30 mmol/l; insulin lispro: -3.27 +/- 2.43 mmol/l, n.s.). In conclusion, if patients want to be treated with insulin lispro in an insulin pump, they have to be well-educated about the pharmacokinetic properties of the insulin analogue and about the possibility that ketoacidotic deterioration after an interruption of the insulin delivery may occur earlier in comparison to regular human insulin. It is anyway recommendable to perform a pump stop test when starting CSII-treatment in patients with diabetes mellitus.

Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin.

OBJECTIVE: To study the pharmacodynamic properties of three premixed formulations of the rapid-acting insulin analog insulin lispro and its protamine-retarded preparation, neutral protamine lispro (NPL) insulin. RESEARCH DESIGN AND METHODS: In this open, single-center, euglycemic glucose clamp study, 30 healthy volunteers (12 women, 18 men) aged 27 +/- 2 years (mean +/- SD), whose BMI was 23.0 +/- 2.3 kg/m2, received subcutaneous injections of 0.3 U/kg body wt of insulin mixture (high-mixture 75/25, mid-mixture 50/50, or low-mixture 25/75 insulin lispro/NPL insulin), insulin lispro, or NPL insulin on one of the five study days in randomized order. Glucose infusion rates were determined over a period of 24 h after administration. RESULTS: Maximal metabolic activity decreased after subcutaneous injection of the mixtures with lower insulin lispro content; however, the time point of maximal and of early half-maximal metabolic activity was comparable among the three mixtures. Higher proportions of insulin lispro resulted in higher values for area under the curve within the first 360 min after injection and a more rapid decline to late half-maximal activity. Serum insulin concentrations showed a similar pattern. CONCLUSIONS: This study shows that the pharmacodynamic and pharmacokinetic properties of insulin lispro are preserved in stable mixtures with NPL insulin.

The blood glucose lowering effects of exercise and glibenclamide in patients with type 2 diabetes mellitus.

Physical exercise is associated with a fall in serum insulin levels, whereas sulphonylurea administration increases insulin release. To date, the opposing effects of exercise and sulphonylurea administration have not been systematically studied in Type 2 diabetic patients, who are not infrequently treated with sulphonylureas. In this study nine patients with Type 2 diabetes mellitus were subjected to four treatments in random order on separate days: (A) endurance exercise after the administration of 3.5 mg glibenclamide; (B) as A but given only 1.75 mg glibenclamide; (C) as A but with placebo; (D) rest and administration of 1.75 mg glibenclamide. Exercise and placebo resulted in only a small decrease in glycaemia. Rest and administration of 1.75 mg glibenclamide led to a moderate but steady fall in blood glucose concentrations. If glibenclamide administration and exercise were combined, blood glucose concentrations declined more markedly. Serum insulin concentrations showed a physiological decrease during exercise and placebo administration. If patients rested after administration of glibenclamide serum insulin levels rose and remained elevated. When exercise and glibenclamide were combined the rise in serum insulin levels was blunted and insulin levels fell once exercise was begun. Thus, exercise attenuates the glibenclamide induced increase in serum insulin in moderately hyperglycaemic Type 2 diabetic patients. Nevertheless, exercise has a substantial hypoglycaemic effect in glibenclamide treated Type 2 diabetic patients.

Metformin and exercise: no additive effect on blood lactate levels in health volunteers.

Metformin administration has been associated with substantial rises in blood lactate concentrations in individual Type 2 diabetic patients. Exercise also leads to increases in blood lactate levels. The objective of this study was to determine whether metformin administration augments the rise in plasma lactate concentrations during intermittent exercise in healthy subjects, when compared to placebo. Twelve healthy males (age 28 +/- 5 years, body mass index 22.7 +/- 1.3 kg m-2) took either 1.7 g metformin or placebo daily for 4 consecutive days before being subjected to strenuous intermittent exercise. On the morning of the fourth day exercise was performed on an upright bicycle ergometer at a work load of 200 W for 2 min alternating with 2 min rest for an overall duration of 60 min. Maximal plasma lactate levels during exercise (metformin: 4.1 +/- 2.6 mmol l(-)1, placebo: 4.5 +/- 2.6 mmol (l-1)), areas under the plasma lactate curve (207 +/- 121 vs 222 +/- 133 mmol l(-1) h(-1), blood pyruvate levels at the end of exercise (0.06 +/- 0.04 vs 0.07 +/- 0.04 mmol l(-1)), lactate/pyruvate ratio (65 +/- 41 vs 60 +/- 36), serum insulin (25.4 +/- 8.9 vs 32.3 +/- 13.0 pmol l(-1)), and plasma glucose (4.4 +/- 0.3 vs 4.5 +/- 0.3 mmol l(-1)) did not differ significantly between metformin and placebo administration. Administration of metformin did not lead to an augmented rise in endogenous plasma lactate concentrations during intermittent exercise in healthy fasting subjects under the experimental design chosen.

Ø[The effect of physical exercise on glycemia on healthy subjects following administration of glimepiride]. / Einfluss von körperlicher Belastung auf die Glykämie von stoffwechselgesunden Probanden nach Einnahme von Glimepirid.

Sulfonylureas predispose to hypoglycaemia during and after exercise. The hypoglycaemic effect of the novel sulfonylurea glimepiride (G; CAS 93479-97-1) in male healthy volunteers under these conditions. Each subject was exposed to three experimental situations, administration of 3 mg G and rest, administration of 3 mg G and 60 min of bicycle ergometry (E) (work load adjusted to a heart rate of 120 bpm), or placebo (P) and bicycle ergometry as mentioned. Each of these was preceded and followed by 60 min of physical rest. Base line glycaemia was comparable (PE 83 +/- 8 mg/dl, GR 84 +/- 5 mg/dl, GE 86 +/- 7 mg/dl) and fell during GR to 63 +/- 6 mg/dl after 150 min. During GE glycaemia ceased to decline after 30 min exercise, and rose thereafter reaching values comparable to PE after 150 min (80 +/- 8 vs. 82 +/- 7 mg/dl). Serum insulin concentrations rose during exercise following administration of G to 6-7 microU/ml (AUC during the period 60-120 min after administration: GE 371 +/- 81 microU/ml.60 min, GR 414 +/- 77 microU/ml.60 min), and fell during PE to 4 microU/ml (265 +/- 49 microU/ml.60; p < 0.001 vs. GE and GR). During GE serum insulin concentrations fell to 6 microU/ml at the end of exercise and thereafter (AUC during the period 120-180 min after administration: 340 +/- 82 microU/ml.60 min), whereas they remained at 7 microU/ml during GR (399 +/- 109 microU/ml.60 min; p = 0.087 vs. GE). In conclusion, exercise blunts the hypoglycaemic effect of glimepiride in healthy individuals.