The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes.
In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.
Department of Internal Medicine II, Clinical Research Unit, Clinical Center of the Ludwig Maximilians University, Campus Grosshadern, Munich, Germany. joerg.schirra@med.uni-muenchen.de
Hans Juergen
HJ
Woerle
Lucianno
L
Carneiro
Ayman
A
Derani
Burkhard
B
Göke
Jörg
J
Schirra
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004311:Double-Blind Method; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology*; D015309:Glucose Clamp Technique / Q000379:methods; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors
D001786:Blood Glucose; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D005947:Glucose