Glucagon-Like Peptide-1 (GLP-1) potentiates insulin secretion in response to an oral challenge. Exendin-(9,39) a competitive antagonist of GLP-1, has been used to quantify the contribution of endogenous GLP-1 to glucose tolerance. In nondiabetic subjects, Exendin-(9,39) infused for three hours altered the subsequent β-cell response to an i.v. glucose challenge. Similar results were observed using perifused human islets from nondiabetic donors. We hypothesized that the effects of fasting GLP-1 secretion on β-cell response would be similar in people with type 2 diabetes (T2D). We studied 9 subjects with T2D in random order. Glucose containing [3-3H]-glucose was infused to mimic the systemic appearance of glucose after a meal. On one occasion, saline, was infused for 3 hours prior (-180 to 0 minutes) to the I.V. challenge, while on the other Exendin-(9,39) was infused at 750pmol/kg/minutes. Exendin-(9,39) infusion prior to the i.v. challenge increased fasting (8.7 ± 0.6 vs. 7.8 ± 0.5 mmol/l, p < 0.01) and peak (13.3 ± 0.8 vs. 12.5 ± 0.6 mmol/l, p = 0.05) glucose concentrations. These differences were not explained by altered insulin secretion: insulin and C-peptide concentrations did not differ between study days. On the other hand, fasting glucagon concentrations were increased (70 ± 8 vs. 53 ± 1 ng/l, p = 0.01) by Exendin-(9,39) and this was accompanied by increased endogenous glucose production (23 ± 1 vs. 20 ± 1 μmol/kg/minutes, p = 0.02). In separate experiments using perifused isolated human islets from diabetic donors, pretreatment with Exendin-(9,39) did not alter integrated insulin secretion in response to hyperglycemia (0.6 ± 0.2 vs. 0.9 ± 0.4 nmol/Islet/30 minutes, p = 0.49). Taken together these results suggest that in T2D fasting GLP-1 receptor activation may augment glucagon suppression in response to subsequent challenges. This may represent an adaptive mechanism not seen in nondiabetic subjects that restrains α-cell function to decrease postprandial hyperglycemia.
M.D. Hurtado: None. A.M. Egan: None. M.C. Laurenti: Employee; Self; GlySens Incorporated. J. Adams: None. R.A. Rizza: Advisory Panel; Self; Lilly Diabetes, Metavention, Novo Nordisk A/S, vTv Therapeutics. C. Cobelli: None. A. Matveyenko: None. C. Dalla Man: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc.
Endocrine Fellows Foundation; National Institutes of Health