OBJECTIVE: Glucagon-like peptide 1 (GLP-1) has glucose-dependent insulinotropic and glucagonostatic actions in type 2 diabetic patients on diet and on oral agents. It is not known, however, whether after secondary sulfonylurea failure, GLP-1 is still effective. RESEARCH DESIGN AND METHODS: Therefore, 10 type 2 diabetic patients (6 women, 4 men; age 65+/-10 years, BMI 30.4+/-5.1 kg/m2, HbA1c 8.2+/-1.5%, 6+/-3 [2-13] years after starting insulin treatment) were examined in the fasting state after discontinuing NPH insulin on the evening before the two study days. GLP-1 (1.2 pmol x kg(-1) x min(-1) or placebo (NaCl with 1% human serum albumin) were infused over 6 h. Plasma glucose (glucose oxidase) insulin (IMx), and C-peptide (enzyme-linked immunosorbent assay) were measured. Statistical analysis was performed using repeated measures analysis of variance. RESULTS: Fasting plasma glucose was 9.4+/-0.5 mmol/l and was reduced by GLP-1 to 5.3+/-0.3 (3.9-7.3) mmol/l (placebo: 8.2+/-0.7 mmol/l; P < 0.0001). GLP-1 transiently increased insulin (from 115+/-31 to 222+/-64 pmol/l at 150 min; P < 0.0001) and C-peptide (from 1.00+/-0.12 to 1.90+/-0.23 nmol/l at 120 min; P < 0.0001) with no effect of placebo. Glucagon and free fatty acids were lowered transiently. After normalization of plasma glucose, insulin and C-peptide concentrations became lower again during the ongoing administration of exogenous GLP-1, and no hypoglycemia occurred. CONCLUSIONS: It is concluded that exogenous GLP-1 effectively lowers plasma glucose concentrations in advanced type 2 diabetes long after sulfonylurea secondary failure. These findings may broaden the applicability of GLP-1-derived drugs as a new treatment to nearly all type 2 diabetic patients.

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