seglitide and Diabetes-Mellitus--Type-1

To assess the pharmacologic properties and possible use in the treatment of diabetes mellitus of a recently developed analogue somatostatin (L-363,586), the analogue (2, 5, 10 or 40 micrograms/hr), somatostatin (200 micrograms/hr), or placebo were infused intravenously for 5 hours in 6 insulin-dependent diabetic subjects who were given a standard meal containing xylose. The metabolic clearance rate of the analogue (approximately 300 ml/min) was 1/6 that previously reported for somatostatin (approximately 2000 ml/min) and its half-life was approximately 20 times as great as that reported for somatostatin (45 vs 2 min). At a dose of 10 micrograms/hr, the analogue produced suppression of plasma glucagon, growth hormone, glucose, xylose and triglyceride responses to meal ingestion which were comparable to those observed when somatostatin was infused at a rate of 200 micrograms/hr. We conclude that L-363,586 is a long-acting and potent analogue of somatostatin, which has the potential for use as an adjunct to insulin in the treatment of diabetes mellitus.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Food; Glucagon; Growth Hormone; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Peptides, Cyclic; Somatostatin; Triglycerides; Xylose

Current evidence indicates that resistance to insulin due to nocturnal secretion of growth hormone plays an important role in the Dawn phenomenon and that day-to-day variability in growth hormone secretion makes this condition difficult to manage. We therefore assessed the effect of a long-acting somatostatin analog (L363,586) on overnight plasma glucose and growth hormone levels in six patients with insulin-dependent diabetes mellitus. The analog (600 micrograms) was administered intranasally at bedtime to determine whether the inconvenience of an additional injection could be avoided. Compared to control experiments, in which saline was administered intranasally, overnight increases in plasma glucose concentrations were reduced in all subjects by nearly 70% (48 +/- 19 v 148 +/- 26 mg/dL, P less than .01), plasma growth hormone was maintained at basal levels throughout the night (less than 2 v 8 to 12 ng/mL, P less than .01), and the analog was well tolerated. We conclude that pharmacologic blockade of growth hormone secretion may be a helpful approach to management of the Dawn phenomenon when it cannot be done safely and effectively by adjusting insulin doses.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Insulin; Male; Peptides, Cyclic; Somatostatin; Time Factors

L363,586 is a potent, long-acting, somatostatin derivative. Intravenous and intranasal administration to diabetic subjects was effective in reducing both fasting and postprandial hyperglycemia. Also in patients stabilized on a closed-loop insulin infusion device, the intranasal administration of L363,586 was able to improve the glucose imbalance known as dawn phenomenon. Therefore, this analogue associated to standard insulin replacement could be useful in the control of unstable diabetes.

Topics: Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Drug Administration Schedule; Humans; Peptides, Cyclic; Somatostatin