Antidiabetic Actions of Endogenous and Exogenous GLP-1 in Type 1 Diabetic Patients With and Without Residual β-Cell Function

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 5; pp. 1599 - 1607
• Main Authors: KIELGAST, Urd, HOLST, Jens J, MADSBAD, Sten
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-05-2011
• Subjects: Adult; Biological and medical sciences; Blood Glucose - drug effects; C-Peptide - blood; Comparative analysis; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gastric Emptying - drug effects; Gastric Inhibitory Polypeptide; Gastrointestinal hormones; Glucagon - blood; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - therapeutic use; Health aspects; Hemodialysis patients; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; Insulin - pharmacology; Insulin-Secreting Cells - drug effects; Male; Medical sciences; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides; Pharmacology and Therapeutics; Physiological aspects; Triglycerides - blood; Young Adult; Denmark; Endocrinopathy; Human; Immunopathology; Type 1 diabetes; Langerhans islet; Autoimmune disease; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-1790

To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function.
Eight type 1 diabetic patients with (T1D+), eight without (T1D-) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.
Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D- patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D- patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.
Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.