Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans

Abstract

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

Trial registration: ClinicalTrials.gov NCT04392843.

Keywords: Diabetes; Endocrinology.

Figure 1. Hormone and substrate responses and glucose kinetics prior to and during insulin-induced hypoglycemia.

Plasma glucose (A), insulin (B), and nonesterified fatty acid (C) levels, and endogenous glucose production (D), glucose rate of disappearance (E), and the exogenous glucose infusion rate (F) during the 30 minutes prior to hypoglycemia (Pre-Hypo) and during the final hour of the hyperinsulinemic-hypoglycemic clamp period (Hypo). n = 12 (8 F/4 M). *P < 0.05 compared with FAST. Two-way repeated measures ANOVA was used to analyze the data in A–E, whereas a paired t test (2-tailed) was used to analyze the data in F.

Figure 2. Glucagon levels prior to and during the hyperinsulinemic-hypoglycemic clamp.

Plasma glucagon concentrations (A) and peak plasma glucagon levels (B) during the hyperinsulinemic-hypoglycemic clamp. n = 12 (8 F/4 M). *P < 0.05 compared with FAST; ^†P ≤ 0.10 compared with FAST. Two-way repeated measures ANOVA was used to analyze the data in A, whereas a paired t test (2-tailed) was used to analyze the data in B.