Comment on Alarcon et al. Pancreatic β-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function. Diabetes 2016;65:438-450.

Alarcon et al. (1) recently demonstrated that b-cell insulin secretory dysfunction is rapidly restored by exposure of islets to low-normal glucose ex vivo in db/db mice. The authors allude to the potential clinical relevance for “transient b-cell rest” in type 2 diabetes (T2D). Could transient b-cell rest be accomplished by manipulating diet? Lim et al. (2) have shown that a very low-calorie diet (;600 kcal/day) rapidly reverses most T2D-related metabolic dysfunction. After 1 week, fasting plasma glucose is normalized, fasting plasma insulin and C-peptide are reduced substantially, and the fasting rate of insulin secretion is lowered (i.e., evidence of b-cell rest). Stepwise hyperglycemic clamps showed that insulin secretory function was already improving after 1 week but took 8 weeks on the calorie-restricted diet to fully normalize, an effect linked to reduced pancreatic triglyceride levels. Thus, as little as 1 week of a very low-calorie diet in humans with T2D can relieve b-cell stress and achieve partial normalization of insulin secretory function, analogous to the restoration seen in islets from db/dbmice exposed to 3 mmol/L glucose by Alarcon et al. (1). Although reversal of T2D in individuals following a very low-calorie diet appears robust in some individuals (3), adherence to such extreme caloric restriction remains uncertain. Another strategy for providing b-cell rest may be to simply restrict dietary carbohydrates. Longer-term studies of low-carbohydrate diets clearly show profound effects at improving glucose control, but weight loss and triglyceride lowering (4) likely confound the interpretation of potential improvements in b-cell function. Accordingly, short-term (days to weeks) low-carbohydrate diet studies in humans with T2D could be used as a simple strategy to determine whether reducing insulin demand through diet can provide b-cell rest. b-Cell function and b-cell stress biomarkers could be key outcomes in such studies. In summary, the data from Alarcon et al. (1) suggest that transient b-cell rest may hold therapeutic potential in T2D. Evidence from human studies is available to design practical interventions to test whether short-term low-calorie and/or carbohydrate-restricted diets, perhaps applied cyclically or intermittently, can provide transient b-cell rest to relieve insulin secretory demand and reverse b-cell dysfunction in T2D.