Fasting lowers glucagon levels under basal conditions and during insulin-induced hypoglycemia in people with type 1 diabetes

<p dir="ltr">Short-term fasting (<24 hrs) is common in people with type 1 diabetes (T1D) but associated with increased risk of hypoglycemia. Current strategies to mitigate this risk include changing the timing and/or dose of insulin, but it is unclear if counterregulatory hormone secretion is diminished, which would also contribute to this elevated risk. The current experiments were conducted to determine if short-term fasting impacts the hormonal and hepatic responses to insulin-induced hypoglycemia in people with T1D. Nine C-peptide negative people with T1D gave their informed consent to participate in a randomly assigned cross-over designed metabolic study. During one study subjects ate an isocaloric breakfast and lunch prior to undergoing a hyperinsulinemic/ hypoglycemic metabolic challenge in the evening (FED); during the other, they remained fasted prior to the hypoglycemic challenge (FAST). Immediately prior to insulin-induced hypoglycemia, glucagon concentrations were 43% lower in FAST compared to 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 AUC for glucagon remained lower by 42% in FAST compared to FED (1598±229 and 2768±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 people with T1D and should be considered when developing strategies to avoid hypoglycemia.</p>