Diet-induced diabetes driven by proinsulin misfolding reversed by β-cell rest

Diet modification can be beneficial in the treatment of type-2 diabetes; but different dietary management approaches can have different impact on pancreatic islet β-cells. Congenic male mice carrying one Ins2-R(B22)E allele (encoding a proinsulin that is predisposed to misfolding, plus three alleles encoding WT proinsulin) develop diabetes prompted by high fat diet-induced weight gain, with exacerbation of β-cell ER stress. Here we sought to understand how β-cell rest could bring about reversal of diabetes. For this, we transitioned two groups of diabetic mice for 5-weeks of a lower caloric-density diet (normal chow ad lib) or alternatively, the same high fat diet alternating with fasting every other day. Both approaches yielded sets of animals that consumed the same total calories; both blocked further body weight gain leading to the same final body weight; both maintained the same energy expenditure; and both exhibited the same whole-body insulin sensitivity. However, diabetes was selectively reversed in animals fed high fat diet alternating with fasting, accompanied by significantly increased islet insulin content, and increased circulating insulin. Blood glucose and serum insulin levels oscillate in animals fed every other day; our data suggest β-cell rest on the fasting day. Mechanisms associated with recovery included decreased islet phospho-eIF2α, accompanied by increased proinsulin synthesis without a corresponding increase of the ER chaperone BiP. We conclude that one of the key features leading to the phenotype of enhanced β-cell maturity involves enhanced insulin biosynthesis without a concomitant increase in β-cell ER stress.