Effects of acute and recurrent clamp-induced hypoglycemia on resting metabolic rate in healthy adults

<i>Background:</i> Hypoglycemia is a common and serious side effect to insulin treatment, which has been studied extensively. However, resting metabolic rate during hypoglycemia, and its potential adaptions to recurrent hypoglycemia, has not been characterized. Therefore, we assessed resting metabolic rate before, during, and after recurrent clamped hypoglycemia in healthy males, conjecturing, by evolutionary reasoning, that energy would be conserved during and after recurrent hypoglycemia. <i>Methods:</i> We recruited 31 subjects, who underwent a four-day experiment. Day 1 and 4 with adrenaline infusion and day 2 and 3 with recurrent clamped hypoglycemia (2.8 mmol/l). Indirect calorimetric measurements of O₂ consumption, CO₂ production, respiratory exchange rate (RER), energy expenditure (EE), and glucose oxidation (GO) were made with a ventilated hood system. <i>Results:</i> We found that subjects undergoing acute hypoglycemia increased O₂, CO₂, RER, EE, and GO (e.g., first hypoglycemia: mean difference of 10.7 ml/min, 18.2 ml/min, 0.03, 89.6 kcal/day, and 0.05 g/min in O₂, CO₂, and EE, respectively; all p-values <0.05) compared to euglycemia. Further, the baseline values of O₂, CO₂, RER, EE, and GO increased after recurrent hypoglycemia (day 4 vs day 1): O₂:9.22 ml/min (p-value = 0.036); CO₂:40.30 ml/min (p-value < 0.0001); RER: 0.12 (p-value < 0.0001); EE: 117.0 kcal/day (p-value = 0.001); GO: 0.105 g/min; (p-value < 0.00001). <i>Conclusion:</i> Resting metabolic rate and glucose oxidation increased acutely in response to insulin-induced hypoglycemia. More notably, a similar increase in resting metabolic rate was observed following recurrent hypoglycemia, suggesting a sustained stress response the day following the last hypoglycemic episode.