No abstract

Glucagon-like peptide 1 (GLP-1) [7-36 amide] is an insulinotropic hormone secreted from enteroglucagon-producing L cells in the lower gut, i. e. the ileum and colon/rectum [1,2]. , together with gastric inhibitory polypeptide (GIP) from the upper gut, acts as a physiological incretin hormone [3,4]. In pharmacological concentrations, exogenous GLP-1 [7-36 amide or 7-37] also raised insulin and lowered glucagon concentrations in Diabetologia (1996) Summary Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in noninsulin-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/m 2 ; HbA 1 c 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 ANO-VA 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 . It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia. [Diabetologia (1996[Diabetologia ( ) 39: 1546[Diabetologia ( -1553 Keywords GLP-1 [7-36 amide], incretin, insulin, glucagon, pharmacokinetics.Corresponding author: Priv.-Doz. Dr. med. M. Nauck, Department of Medicine, Ruhr-University Bochum, KnappschaftsKrankenhaus, In der Schornau ...

Exocrine pancreatic function was studied in patients with long-standing insulin-dependent diabetes mellitus using the secretin-pancreozymin test (n = 53), and estimation of immunoreactive trypsin (n = 43) and pancreatic isoamylase (n = 43). The secretin-pancreozymin test was abnormal in 23 patients (43 %). The abnormalities found were a decreased output of lipase (37%), amylase (36%) or trypsin (26%) and bicarbonate (15%). Serum immunoreactive trypsin was below normal in only 6 (14%) and pancreatic isoamylase in 29 (67%) patients. There was no correlation between impairment of the secretin-pancreozymin test and decreased serum enzyme levels. It is concluded that an impairment of exocrine pancreatic function is frequent in insulin-dependent diabetics but that a decrease in serum enzymes, especially in pancreatic isoamylase, does not reflect an impairment of pancreatic function in these patients.

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.

BAY-g-5421 is an a-glucosidase-inhibitor which inhibits intestinal absorption of carbohydrates. In a double-blind cross over study 12 diabetics taking sulphonylureas and 12 insulin-treated diabetics were treated additionally with BAY-g-5421 or a placebo for two seven day periods. In the pretreatment period and on the 7th and 14th day of the treatment periods serial blood glucose profiles were measured. In comparison to placebo BAY-g-5421 significantly lowered the mean (140 versus 157 mg/dl) and the maximal (192 versus 230 mg/dl) blood glucose values and the integrated blood glucose response (3112 versus 3421 mg/dl 24h) in the sulphonylurea-treated group as well as in the insulin-treated group (mean blood glucose 161 versus 192 mg/dl, maximal blood glucose 238 versus 283 mg/dl, integrated blood glucose response 3109 versus 3857 mg/dl-24 h). The amplitude of glycaemic excursions was significantly decreased only in the sulphonylurea-treated group (96 versus 129 mg/dl), but not in the insulin-treated diabetics. No influence on routine liver function, renal ftmction or haematological tests was observed. Side effects included hypoglycaemia in 3 patients of the insulin-treated group and meteorism in both groups. BAY-g-5421 could be a useful additional treatment for diabetic patients.