Hyperglucagonemia following oral
glucose ingestion in patients with
type 1 diabetes (and
type 2 diabetes) has been claimed to result from impaired intraislet
insulin inhibition of
glucagon. We looked at plasma
glucagon responses to the oral
glucose tolerance test (OGTT) and isoglycemic intravenous
glucose infusion (IIGI) in patients with
type 1 diabetes. Nine patients without residual beta-cell function [age: 25 +/- 9 yr; body mass index (BMI): 24 +/- 2 kg/m(2); fasting plasma
glucose (FPG): 9.5 +/- 2.1 mM; Hb A(1c): 8.4 +/- 1.2% (mean +/- SD)] and eight healthy subjects (age: 28 +/- 5 yr; BMI: 24 +/- 3 kg/m(2); FPG: 5.3 +/- 0.2 mM; Hb A(1c): 5.0 +/- 0.1%) were examined on two separate occasions: 4-h 50-g OGTT and IIGI. Isoglycemia during IIGIs was obtained using 53 +/- 5 g of
glucose in patients with
type 1 diabetes and 30 +/- 3 g in control subjects (P < 0.001), resulting in gastrointestinal-mediated
glucose disposal [100% x (
glucose(OGTT) -
glucose(IIGI)/
glucose(OGTT))] of -6 +/- 9 and 40 +/- 6% (P < 0.01), respectively. Equal
glucagon suppression during the two
glucose stimuli was observed in healthy subjects, whereas patients with
type 1 diabetes exhibited less inhibition in response to OGTT compared with IIGI (AUC: 1,519 +/- 129 vs. 1,240 +/- 86 pM.4 h; P = 0.03). This difference was even more pronounced during the initial 40 min with paradoxical hypersecretion of
glucagon during OGTT and suppression during IIGI (AUC: 37 +/- 13 vs. -33 +/- 16
pM.40 min; P = 0.02). These results suggest that the inappropriate
glucagon response to
glucose in patients with
type 1 diabetes occurs as a consequence of the
oral administration way, suggesting a role of the gastrointestinal tract, possibly via glucagonotropic signaling from gut
hormones (e.g.,
glucose-dependent insulinotropic
polypeptide), in type 1 diabetic hyperglucagonemia.