JCI Insight · 9 authors, 4 centres
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A 22-hour fast reduced liver glycogen by 42% and lowered glucagon levels and endogenous glucose production during both euglycemia and insulin-induced hypoglycemia in healthy adults. This suggests that fasting impairs counterregulatory hormone responses, increasing susceptibility to hypoglycemia. The findings highlight a potential mechanism for heightened hypoglycemia risk during fasting, especially relevant for individuals with type 1 diabetes.
**Background:** Intermittent fasting is increasingly practiced for weight loss and metabolic health, but it is associated with heightened hypoglycemia risk in type 1 diabetes. While reducing insulin dose can mitigate this risk, insulin-independent mechanisms may also contribute. Animal studies show that lowering liver glycogen content blunts glucagon and hepatic glucose production (HGP) responses to hypoglycemia. This study tested whether a 22-hour fast impairs counterregulatory hormone and hepatic responses to insulin-induced hypoglycemia in healthy humans.
**Methods:** Twelve healthy participants (8 F/4 M; age 27 ± 2 years; BMI 22.8 ± 0.7 kg/m²) completed two metabolic studies in random order. In the FED visit, participants consumed standardized breakfast (761 ± 33 kcal) and lunch (769 ± 30 kcal) prior to a 2-hour hyperinsulinemic-hypoglycemic clamp. In the FAST visit, they remained fasted. Liver glycogen was measured by ¹³C magnetic resonance spectroscopy at baseline, after breakfast, and before hypoglycemia. Glucose turnover was assessed using [6,6-²H₂]glucose tracer. Plasma glucose was clamped at ~55 mg/dL during hypoglycemia. Hormones (glucagon, insulin, catecholamines, cortisol, growth hormone), substrates (NEFAs, amino acids), and glucose kinetics were measured.
**Key Results:** Prior to hypoglycemia, liver glycogen was 73% higher in FED vs. FAST (P < 0.01). Fasting reduced glucagon levels under both euglycemic (pre-hypoglycemia) and hypoglycemic conditions. Peak glucagon during hypoglycemia was lower in FAST (P < 0.05), and endogenous glucose production (EGP) was significantly reduced (P < 0.05). Peak glucagon correlated positively with average EGP during hypoglycemia (r = 0.54, P < 0.01). Despite similar insulin levels, glucose rate of disappearance (Rd) was lower in FAST, and the exogenous glucose infusion rate needed to maintain glycemia was reduced (P < 0.05). Counterregulatory hormones (epinephrine, norepinephrine, cortisol, growth hormone) increased similarly in both treatments. Alanine, proline, and tyrosine were lower in FAST before and during hypoglycemia, but these differences were not considered sufficient to explain glucagon changes. No significant between-sex differences were observed.
**Clinical Implications:** This study demonstrates that a 22-hour fast reduces liver glycogen and blunts glucagon secretion and EGP during both euglycemia and hypoglycemia in healthy humans. These findings identify an insulin-independent mechanism by which fasting increases hypoglycemia susceptibility. The results suggest that interventions to maintain or increase liver glycogen (e.g., liver-specific glucokinase activators) could enhance counterregulatory responses and reduce hypoglycemia risk in vulnerable populations, such as those with type 1 diabetes. The study was limited to healthy participants and a single day of fasting; future work should examine longer fasts and patients with type 1 diabetes.