Prolonged fasting outperforms short-term fasting in terms of glucose tolerance and insulin release: A randomized controlled trial.

Fasting is related to glucose intolerance and insulin resistance, but it is unknown whether the duration of fasting influences these factors. We explored whether prolonged fasting increases norepinephrine and ketone concentrations, and decreases core temperature to a greater extent than short-term fasting; if so, this should lead to improved glucose tolerance. Forty-three healthy young adult males were randomly assigned to undergo a 2-day fast, 6-day fast, or the usual diet. Changes in rectal temperature (T R) , ketone and catecholamine concentrations, glucose tolerance, and insulin release in response to an oral glucose tolerance test were assessed. Both fasting trials increased ketone concentration, and the effect was larger after the 6-day fast ( p < 0.05). T R and epinephrine concentration increased only after the 2-day fast ( p < 0.05). Both fasting trials increased the glucose area under the curve (AUC) ( p < 0.05), but the AUC remained higher than the baseline value after participants returned to their usual diet in the 2-day fast group ( p < 0.05). Neither fasting had an immediate effect on the insulin AUC, although it increased after return to their usual diet in the 6-day fast group ( p < 0.05). These data suggest that the 2-day fast elicited residual impaired glucose tolerance, which may be linked to greater perceived stress during short-term fasting, as shown by the epinephrine response and change in core temperature. By contrast, prolonged fasting seemed to evoke an adaptive residual mechanism that is related to improved insulin release and maintained glucose tolerance. Trial registration: ClinicalTrials.gov, NCT05545943.