Fasting Lowers Glucagon Levels Under Basal Conditions and During Insulin-Induced Hypoglycemia in Individuals With Type 1 Diabetes

Abstract

Short-term fasting (<24 h) is common in individuals with type 1 diabetes (T1D), but it is associated with increased risk of hypoglycemia. Current strategies to mitigate this risk include changing the timing and/or dose of insulin; however, it is unclear whether counterregulatory hormone secretion is diminished, which would also contribute to this elevated risk. The current experiments were conducted to determine whether short-term fasting affects the hormonal and hepatic responses to insulin-induced hypoglycemia in those with T1D. Nine C-peptide–negative individuals with T1D gave their informed consent to participate in a randomly assigned crossover-design metabolic trial. In one study, participants ate an isocaloric breakfast and lunch before undergoing a hyperinsulinemic/hypoglycemic metabolic challenge in the evening (FED); in the other, they fasted before the hypoglycemic challenge (FAST). Immediately before insulin-induced hypoglycemia, glucagon concentrations were 43% lower in FAST compared with FED (31 ± 5 and 54 ± 6 pg/mL, respectively; P < 0.001), and endogenous glucose production (EGP) was 28% lower (3.4 ± 0.2 and 4.6 ± 0.3 mg/kg/min, respectively; P < 0.01). During insulin-induced hypoglycemia, the area under the curve for glucagon remained lower by 42% in FAST compared with FED (1,598 ± 229 and 2,768 ± 422 pg/mL ∗ 60 min, respectively; P < 0.01), as did EGP (41 ± 4 and 78 ± 12 mg/kg ∗ 60 min, respectively; P = 0.01). These data demonstrate that fasting lowers glucagon concentrations and EGP under euglycemic/normoinsulinemic metabolic conditions and during insulin-induced hypoglycemia. This reduction in metabolic flexibility, in addition to hyperinsulinemia, enhances susceptibility to fasting-induced low blood glucose in individuals with T1D and should be considered when developing strategies to avoid hypoglycemia. Article Highlights Fasting is associated with increased risk of hypoglycemia in patients with type 1 diabetes (T1D); however, little is known about how the counterregulatory responses to low blood sugar are affected under these metabolic conditions. During insulin-induced hypoglycemia, fasting (compared with eating normal meals for breakfast and lunch) glucagon concentrations were lower by 42% and endogenous glucose production by 47% in individuals with T1D. The secretion of other counterregulatory hormones during hypoglycemia was not affected by fasting (e.g., epinephrine, norepinephrine, cortisol). Fasting diminishes glucagon levels under hypoglycemic conditions in those with T1D, which may increase their susceptibility to hypoglycemia.