Preserved GLP-1 effects in a diabetic patient with Cushing's disease.

CONTEXT: A patient with diabetes mellitus, who participated in a study with intravenous administration of GLP-1, was later found to have Cushing's disease (markedly elevated 24 h urinary cortisol excretion and inadequate suppression of fasting cortisol with 2 mg dexamethasone). His diabetic state disappeared (2 h plasma glucose after 75 g oral glucose 159 mg/dl=IGT) after successful pituitary surgery (normal 24 h urinary cortisol excretion and adequate cortisol suppression with 2 mg dexamethasone). OBJECTIVE: The present analysis was undertaken to compare GLP-1 actions on fasting glycemia in diabetes mellitus due to Cushing's disease with GLP-1 actions in typical type 2 diabetes. DESIGN AND METHODS: GLP-1 (1.2 pmol/kg/min) and placebo had been infused into ten patients with diabetes mellitus over 4 h in the fasting state. The results from the patient with Cushing's disease (C) were compared to the data from the remaining nine patients with type 2 diabetes (D). RESULTS: Within 4 h glucose decreased from basal (C: 12.9; D: 12.9+/-0.7 mmol/l) to normal fasting values (C: 5.0; D: 4.9+/-0.4 mmol/l). The stimulation of insulin secretion and suppression of glucagon secretion was similar in the patient with Cushing's disease compared to those with type 2 diabetes. CONCLUSIONS: The insulinotropic, glucagonostatic and glucose-lowering actions of GLP-1 in a patient with diabetes mellitus due to cortisol excess were similar to actions in typical type 2 diabetes. Therefore incretin mimetics might be a novel therapeutic strategy for the treatment of glucocorticoid-induced diabetes mellitus.

Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study.

AIMS: To compare the efficacy and safety of acarbose and metformin when added to sulphonylurea therapy in diabetic patients insufficiently controlled with sulphonylureas alone. METHODS: A 12-week, single-centre, placebo-controlled study, with 89 patients randomized to receive acarbose (100 mg t.d.s.), metformin (850 mg b.d.) or placebo in addition to their sulphonylurea therapy. The study was double-blinded with respect to acarbose/placebo and single-blinded for metformin/ acarbose and metformin/placebo. Patients started a strict dietary regimen 1 week before receiving their first dose of acarbose, metformin or placebo. This regimen was individually adjusted to metabolic status and energy requirements. RESULTS: The primary endpoint, HbA1c, decreased from baseline in all three groups after 12 weeks. The decrease was greater in the two groups receiving active therapy compared with placebo (acarbose -2.3+/-0.32%; metformin -2.5+/-0.16%; placebo -1.3+/-0.34%). There was no significant difference between acarbose and metformin (P=0.65). Differences between both active therapies and placebo were statistically significant (acarbose P < or = 0.01; metformin P < or = 0.004). Reductions in body weight over the treatment period were seen in all three groups and were greatest in the acarbose group (median weight reduction: acarbose 3.5 kg; metformin, 1.0 kg; placebo 1.4 kg). There were no significant differences in the incidence of gastrointestinal side-effects between the three groups and all regimens were generally well tolerated. CONCLUSION: The results of the study demonstrate the equivalence of acarbose and metformin for improving metabolic control in patients insufficiently controlled with diet and sulphonylureas.

Overnight GLP-1 normalizes fasting but not daytime plasma glucose levels in NIDDM patients.

GLP-1 (7-36 amide) normalizes fasting plasma glucose in NIDDM patients. It was the aim to study the effect of overnight intravenous GLP-1 (7-36 amide) on the following 24 h-glucose profiles. Ten NIDDM patients (7 female, 3 male; age 62 +/- 4 y., BMI (Body-Mass-Index) 29.6 +/- 3.9 kg/m2, duration 10 +/- 7 y., HbA1c 10.9 +/- 1.3% (normal 4.0-6.1%), treated with glibenclamide and/or metformin) were studied on two occasions in random order: Either GLP-1 (7-36 amide) (Saxon Biochemicals, Hannover, FRG, 1 pmol x kg(-1) x min(-1)) or placebo (0.9% NaCl with 1% human serum albumin, Behringwerke, Marburg, FRG) were infused intravenously from 22:00 to 7:00 (9 h) and plasma glucose profiles were obtained during the GLP-1 infusion and the following 24 hours. GLP-1 (7-36 amide) (plasma concentration 110 +/- 12 pmol/l) raised plasma C-peptide concentrations (p = 0.0005), suppressed glucagon (p = 0.01) and lowered plasma glucose to 5.5 +/- 0.6 and 6.3 +/- 0.4 mmol/l at 3:00 and 7:00 a.m. (vs. 10.3 +/- 0.9 and 11.3 +/- 0.6 mmol/l, p = 0.0003 and p < 0.0001, respectively, with placebo). Thereafter, starting 1 h after breakfast, no significant differences in plasma glucose, insulin, C-peptide or glucagon profiles were found between experiments with GLP-1 (7-36 amide) and placebo. Average plasma glucose concentrations over the whole 24 h period were reduced by 18% by GLP-1 administered overnight. In conclusion, (1) overnight GLP-1 (7-36 amide) normalizes fasting plasma glucose, but (2) has no sustained effect on meal-induced glucose, insulin or glucagon concentrations once its administration has been stopped. (3) Normalization of fasting plasma glucose alone does not improve daytime metabolic control in NIDDM patients on oral agents.

Glucagon-like peptide 1 and its potential in the treatment of non-insulin-dependent diabetes mellitus.

Studies examining small groups of type 2-(NIDDM) diabetic patients have shown the potential of glucagon-like peptide 1 (GLP-1) to normalize fasting hyperglycaemia. Patient characteristics determining the size of the effect have not been reported. Therefore, the results of four studies were analysed. Exogenous GLP-1 was administered i.v. or s.c. in 37 type 2-diabetic patients, age 60 +/- 8 years; BMI 28.2 +/- 5.3 kg/m2; HbA1c 10.6 +/- 1.6%; diabetes duration 10 +/- 6 years, treatment with sulfonylureas, n = 33, metformin, n = 11, acarbose, n = 3. Results were analysed using repeated measures analysis of variance and multiple regression analysis. Exogenous GLP-1 lowered fasting plasma glucose within 4-5 h from 12.8 +/- 2.5 to 5.3 +/- 1.3 mmol/l (placebo: 12.8 +/- 2.3 to 10.0 +/- 2.2; p < 0.0001 for the interaction of treatment and time). Only fasting glycaemia (p = 0.0085) and the route (i.v. vs. s.c.; p = 0.05), but not gender, age, BMI, HbA1c, diabetes duration, treatment with sulfonylureas, metformin or acarbose, were significant predictors of the plasma glucose concentrations reached after the administration of GLP-1 (variation: 3.4-8.5 mmol/l). In conclusion, GLP-1 is able to normalize plasma glucose in all type 2-diabetic patients studied. This analysis underlines the great therapeutic potential of GLP-1.

[Insulin therapy of type I diabetes]. / Insulintherapie des Typ-I-Diabetes.

Type 1 diabetes is a disease due to hormone deficiency. Therefore treatment with insulin is hormonal substitution and should be done according to physiological data with 4 injections NPH-insulin and 3 preparandial injections of regular insulin before the main meals. Intensified insulin treatment should be separate substitution of basal and prandial insulin need. The basal insulin substitution should be tested by a fasting day over 24 h giving only basal insulin. Insulin treatment has to be supplemented by diabetes education, blood glucose self control and regulation of diet and exercise. Target values are blood glucose concentrations of 80 to 120 mg/dl fasting and before the main meals, 110 to 160 mg/dl at bedtime and above 65 mg/dl after midnight. A written plan with the algorithms of insulin substitution is helpful for the care of the diabetic patient. A successful insulin treatment is assessed by a HbA1c of 7.x without hypoglycemias.

Glucagon-like peptide 1 (GLP-1) as a new therapeutic approach for type 2-diabetes.

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone in normal humans explaining in part the augmented insulin response after oral versus intravenous glucose administration. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, reduces food intake upon intracerebroventricular administration in animals, and may, in addition, enhance insulin sensitivity. Therefore, GLP-1, in many aspects, opposes the Type 2-diabetic phenotype characterized by disturbed glucose-induced insulin secretory capacity, hyperglucagonaemia, moderate insulin deficiency, accelerated gastric emptying, overeating (obesity) and insulin resistance. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in Type 2-diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in diet- and sulfonylurea-treated Type 2-diabetic patients and also in patients under insulin therapy long after sulfonylurea secondary failure. Exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological postprandial levels fully normalizes fasting hyperglycaemia in Type 2-diabetic patients. The half life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections. Current research activities aim at finding GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Another approach could be the augmentation of endogenous release of GLP-1, which is abundant in L cells of the lower small intestine and the colon. Interference with sucrose digestion using alpha-glucosidase inhibition moves nutrients into distal parts of the gastrointestinal tract and, thereby, prolongs and augments GLP-1 release. Enprostil, a prostaglandin E2 analogue, fully suppresses GIP responses, while only marginally affecting insulin secretion and glucose tolerance after oral glucose, suggesting compensatory hypersecretion of additional insulinotropic peptides, possibly including GLP-1. Given the large amount of GLP-1 present in L cells, it appears worthwhile to look for more agents that could 'mobilize' this endogenous pool of the 'antidiabetogenic' gut hormone GLP-1.

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients.

OBJECTIVE: Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients. It is not known whether GLP-1 has effects also in fasting type I diabetic patients. RESEARCH DESIGN AND METHODS: In 11 type I diabetic patients (HbA1c 9.1 +/- 2.1%; normal, 4.2-6.3%), fasting hyperglycemia was provoked by halving their usual evening NPH insulin dose. In random order on two occasions, 1.2 pmol . kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified fatty acids (enzymatic tests) were measured. RESULTS: Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P < 0.0001), but not with placebo (14.2 +/- 0.7 to 13.2 +/- 1.0). Transiently, C-peptide was stimulated from basal 0.09 +/- 0.02 to 0.19 +/- 0.06 nmol/l by GLP-1 (P < 0.0001), but not by placebo (0.07 +/- 0.02 to 0.07 +/- 0.02). There was no significant effect on nonesterified fatty acids (P = 0.34), triglycerides (P = 0.57), cholesterol (P = 0.64), cortisol (P = 0.40), or growth hormone (P = 0.53). CONCLUSIONS: Therefore, exogenous GLP-1 is able to lower fasting glycemia also in type I diabetic patients, mainly by reducing glucagon concentrations. However, this alone is not sufficient to normalize fasting plasma glucose concentrations, as was previously observed in type II diabetic patients, in whom insulin secretion (C-peptide response) was stimulated 20-fold.