Type 2 diabetes (T2DM) is characterized by impaired postprandial insulin secretion and glucagon suppression. Recent work suggests that α-cell dysfunction is independent of β-cell dysfunction. The effect of diabetes-associated variation in TCF7L2 on α-cell function also suggests a direct role in the pathogenesis of T2DM. To quantify the interaction between a lack of glucagon suppression with intact, mildly or moderately impaired insulin secretion we studied 45 nondiabetic subjects with and without suppressed glucagon. On both occasions, an intravenous glucose infusion mimicking the systemic appearance of 50g oral glucose was administered in the presence of a pancreatic clamp. Glucagon was infused at a rate of 0.65ng/kg/min, starting at 0 min or 120 min (non-suppressed vs. suppressed respectively). In one group (100%) a nondiabetic insulin profile was infused; another group received 80% of this profile and the third group received 60% of the insulin infused in the first group. We observed that a lack of glucagon suppression increased peak (p < 0.05) and area above basal (AAB) glucose (p < 0.02) in all groups (1.5 ± 0.1 vs. 1.1 ± 0.1; 1.6 ± 0.1 vs. 1.1 ± 0.1; 1.5 ± 0.1 vs.1.3 ± 0.1 Mol per 5hr, 100%, 80%, 60% respectively). These increases were explained by delayed suppression of endogenous glucose production (EGP) so that EGP at 120 minutes was higher (p < 0.05) in the presence of non-suppressed glucagon (6.6 ± 1.0 vs. 4.2 ± 0.6; 7.2 ± 0.8 vs. 5.1 ± 0.5; 7.7 ± 0.8 vs. 5.9 ± 0.6 μmol/kg/min, 100%, 80%, 60% respectively) as was integrated EGP (p < 0.05) over the postprandial period (-1.9 ± 0.4 vs. -2.1 ± 0.1; -1.8 ± 0.1 vs. -1.9 ± 0.2; -1.6 ± 0.3 vs. -1.8 ± 0.1 mmol/kg per 5hr, 100%, 80%, 60% respectively). These data indicate that impaired postprandial glucagon suppression contributes to postprandial hyperglycemia through increased EGP even when insulin secretion is intact as can occur early in prediabetes. These effects are exacerbated by increasing degrees of insulin deficiency.
J. Adams: None. M.C. Laurenti: Employee; Self; GlySens Incorporated. R.A. Rizza: Advisory Panel; Self; Lilly Diabetes, Metavention, Novo Nordisk A/S, vTv Therapeutics. A.M. Egan: None. C. Cobelli: None. C. Dalla Man: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc.
National Institutes of Health