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.

Inhibition of gastric inhibitory polypeptide (GIP) release by insulin and glucose in juvenile diabetes.

The effect of glucose and insulin on fat- and glucose-induced gastric inhibitory polypeptide (GIP) release has been studied in insulin-dependent juvenile-type diabetics. Blood glucose and serum immunoreactive GIP (IR-GIP) were measured after an oral load of 100 g glucose or 100 g fat was given and during an infusion of one of the following: saline, glucose, glucose plus insulin, or insulin. The infusion of insulin alone (in the presence of elevated glucose levels) or together with glucose significantly suppressed the IR-GIP rise after fat ingestion, but it did not alter the GIP response to oral glucose. Intravenous infusion of glucose had a slight but significant inhibitory effect on fat-stimulated increase of IR-GIP, which cannot be related to endogenous insulin release in these insulin-deficient diabetics. It is suggested that an insulin-mediated increase of glucose utilization in the GIP cell interferes only with increased GIP secretion stimulated by the utilization of fatty acids but not of glucose. This could explain the existence of a negative feedback control between insulin and GIP secretion for fat but not for glucose-induced GIP release.

Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects.

To fate of exogenous glucagon-like peptide I (GLP-I)(7-36) amide was studied in nondiabetic and type II diabetic subjects using a combination of high-pressure liquid chromatography (HPLC), specific radioimmunoassays (RIAs), and a sensitive enzyme-linked immunosorbent assay (ELISA), whereby intact biologically active GLP-I and its metabolites could be determined. After GLP-I administration, the intact peptide could be measured using an NH2-terminally directed RIA or ELISA, while the difference in concentration between these assays and a COOH-terminal-specific RIA allowed determination of NH2-terminally truncated metabolites. Subcutaneous GLP-I was rapidly degraded in a time-dependent manner, forming a metabolite, which co-eluted on HPLC with GLP-I(9-36) amide and had the same immunoreactive profile. Thirty minutes after subcutaneous GLP-I administration to diabetic patients (n = 8), the metabolite accounted for 88.5 +/- 1.9% of the increase in plasma immunoreactivity determined by the COOH-terminal RIA, which was higher than the levels measured in healthy subjects (78.4 +/- 3.2%; n = 8; P < 0.05). Intravenously infused GLP-I was also extensively degraded, but no significant differences were seen between the two groups. Intact GLP-I accounted for only 19.9 +/- 3.4% of the increase in immunoreactivity measured with the COOH-terminal RIA in normal subjects (n = 8), and 25.0 +/- 4.8% of the increase in diabetic subjects (n = 8), the remainder being the NH2-terminally truncated metabolite.

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.

Cholinergic muscarinic receptor blockade suppresses arginine- and exercise-induced growth hormone secretion in type I diabetic subjects.

Stimulatory cholinergic pathways participate in the regulation of GH release, and cholinergic receptor antagonists inhibit GH secretion in normal man. Whether similar mechanisms are active in subjects with insulin-dependent diabetes is not known, yet this is of potential importance since GH hypersecretion has been implicated in both the acute and chronic complications of diabetes mellitus. To address this question we studied the effects of cholinergic receptor blockade on stimulated GH release in 18 type I diabetic men. Paired tests were performed using 1 of 2 different stimuli (30 g arginine, iv, or physical exercise for 30 min) with or without prior administration of the selective cholinergic muscarinic receptor antagonist pirenzepine (30 mg, iv). Arginine elicited a mean peak serum GH level of 9.0 +/- 1.9 (+/- SEM) micrograms/L, which was completely suppressed by pirenzepine (1.5 +/- 0.4 micrograms/L; n = 8; P less than 0.01). Blood glucose rose after arginine infusion and was not affected by pirenzepine. Serum GH levels rose during physical exercise to a mean peak of 7.3 +/- 1.6 micrograms/L, which was abolished by pirenzepine (1.2 +/- 0.3 micrograms/L; n = 10; P less than 0.01). Blood glucose was not influenced by pirenzepine. Two subjects had no serum GH response to exercise. We conclude that GH secretion in subjects with insulin-dependent diabetes, as in normal subjects, is modulated by cholinergic pathways and is responsive to pharmacological suppression by muscarinic receptor blockade. This may have implications for therapeutic trials designed to lower elevated GH levels in subjects with diabetes mellitus.

Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients.

The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.

Effect of the dopamine receptor blocking agent pimozide on the growth hormone response to arginine and exercise and on the spontaneous growth hormone fluctuations.

Pimozide, a specific blocker of dopamine receptors, was administered orally to 10 diabetics for 2 days before an arginine-hydrochloride infusion. In 8 healthy volunteers and 20 diabetics exercise tests on a bicycle ergometer were performed with a load of 100 Watts and 50 Watts respectively without or after a single dose of pimozide 30 min before the test. In 4 male diabetics day profiles of growth hormone (GH) were estimated without and during treatment with pimozide for 4 days. The arginine and exercise induced GH release was found to be significantly lowered by pimozide, whereas the marked spontaneous fluctuations in the diabetics were even enhanced by pimozide. These data support the concept of the involvement of dopaminergic stimulation in the response of GH to arginine and exercise. The spontaneous fluctuations of GH, however, seem to be regulated by other neuroendocrine mechanisms.

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.

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.

[Effectiveness and tolerance of long-term acarbose therapy in diabetic patients with threatened secondary failure of sulfonylurea drug treatment]. / Wirksamkeit und Verträglichkeit einer längerfristigen Acarbosetherapie bei Diabetikern mit drohendem Sekundärversagen einer Sulfonylharnstoffbehandlung.

The efficacy and tolerability of acarbose was studied in 14 type-2-diabetic patients poorly controlled with diet and sulfonylureas. Acarbose was given in addition to sulfonylureas in a single-blind, placebo-controlled study for three times three months (acarbose-placebo-acarbose). At the beginning of the study and every three months body weight, HbA1c and biochemical and hematological safety parameters were measured. The patients controlled their mid morning urine glucose and two to four times daily their blood glucose concentration with a memory glucometer. Diabetic control improved significantly: HbA1c was 8.5 +/- 1.4% at the beginning, 6.5 +/- 1.1% after three months with acarbose (p < 0.001), 7.2 +/- 0.9% after three months placebo (p < 0.01) and 6.7 +/- 1.3% again after three months with acarbose (p < 0.05). Thus, the effect of acarbose alone accounts for 0.7 or 0.5% respectively, whereas the effect of teaching and diet in a special diabetes unit (the difference from the study to placebo) accounts for 1.3% of HbA1c. Home monitored blood and urine glucose values were improved: The postprandial blood glucose concentrations, the postprandial differences, the mean blood glucose concentrations and the glycosuria were decreased during acarbose treatment in comparison with placebo. The preprandial blood glucose concentrations before breakfast and supper were not influenced by acarbose. Hematological and biochemical safety parameters as well as blood pressure and heart rate were unchanged. Meteorism and flatulence as typical side effects decreased during treatment. Acarbose is a safe and effective adjunct treatment for type-2-diabetic patients uncontrolled with diet and sulfonylurea alone.

[Alcohol-induced hypoglycemia in type I diabetic patients]. / Alkoholinduzierte Hypoglykämien bei Typ-I-Diabetikern.

The hypoglycemic effect of alcohol, probably caused by inhibition of gluconeogenesis in the liver, is well known. However, accurate data on the effect of usual amounts of alcohol on the blood sugar in type 1 diabetics are not available. We therefore investigated the effect of an evening dose of alcohol on the blood sugar in 23 male type 1 diabetics (age 32.8 [20 to 64] years, duration of diabetes 11.5 [0.5 to 38] years, Broca index 0.98 [0.83 to 1.34] HbAlc 8.4 [5.8 to 12.2]%). On one day, the diabetics were given 0.56 g ethanol per kg body weight to drink in the evening, corresponding to about one liter of diabetic beer, on another day, the same volume of mineral water. In addition, eleven of the 23 patients received half the amount of alcohol on a third evening. Between 7 and 11 o'clock in the morning after alcohol consumption, blood glucose levels were significantly lower. The number of hypoglycemic episodes in the morning of the day following alcohol administration was appreciably greater. Usual amounts of alcohol consumed after the evening meal thus increase the risk of hypoglycemia the following morning. Diabetics should be instructed accordingly.

[A new fructosamine test--as a routine parameter in the control of diabetes]. / Neuer Fructosamin-Test--als Routineparameter in der Diabeteskontrolle.

Measurement of protein glycation (fructosamine) has become an accepted tool in diabetes diagnostics. Among different methods available, the serum fructosamine test published by Johnson and Baker in 1983 has gained wide acceptance due to a simple and easily automated assay procedure providing clinically meaningful results. A recent modification of the Nitroblue Tetrazolium (NBT) reagent, improved by addition of tensides and uricase, exhibits lower interference by lipaemia and urate. It is also less affected by the sample matrix and yields results closer to the physiological range of glycated proteins. Furthermore, a completely new standardization protocol was used in the preparation of calibration material. The new colorimetric method for the determination of fructosamine was evaluated in 12 European clinical laboratories.

[Effect of a change in posture on the diurnal variations of fructosamine concentration in diabetic patients]. / Einfluss des Lagewechsels auf die diurnalen Schwankungen der Fructosaminkonzentration bei Diabetikern.

Daily profiles of blood glucose, HbA1c, total protein and fructosamine were measured in 10 diabetic patients and the factor fructosamine x 7/g total protein was calculated. Measurements were done at 4 a.m. to be sure that the patients were sleeping for some time, during the day and the following evening at 11 p.m., when the patients were lying again, so that the influence of orthostasis, the difference between bed rest and walking could be demonstrated. The blood glucose profile was typical whereas the HbA1c concentration was very stable and constant. Total protein and fructosamine increased significantly by orthostasis; the correction of fructosamine by total protein diminished the differences, but did not completely eliminate the effect of orthostasis. However, fructosamine should be corrected by the total protein concentration in order to increase the diagnostic value of the parameter.