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

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at