A Fasting-Mimicking Diet Reverses Type 1 and Type 2 Diabetes in Mice

A fasting-mimicking diet (FMD) reversed type 1 diabetes (T1D) and type 2 diabetes (T2D) in mice by promoting beta cell regeneration and restoring beta cell function, according to a study recently published in Cell. The FMD’s ability to regenerate beta cells through cellular reprogramming suggests “a therapeutic intervention to treat diabetes and other degenerative diseases,” the authors wrote.

Previous studies have reported stem cell—based regeneration of hematopoietic and nervous system cells when animals resume a normal diet after fasting. Whether fasting and refeeding promote pancreatic cell reprogramming and regeneration remains a question.

The current study’s FMD was low in calories, protein, and carbohydrates, and high in fat. Mice ate the FMD for 4 days, then ate ad libitum mouse chow for up to 10 days before beginning another FMD cycle. Control mice ate the ad libitum mouse chow throughout the study.

FMD in Type 2 Diabetes

The authors evaluated mice induced with T2D. Mice developed severe hyperglycemia by 12 weeks of age and began dying around 16 weeks of age. To “rescue” mice from late-stage T2D, the authors fed them FMD in weekly cycles starting at 12 weeks of age. The authors observed a reversal of T2D, indicated by:

• A return to near-normal blood glucose levels
• Increased insulin secretion and plasma insulin levels

• Increased beta cell number and proliferation

FMD in Type 1 Diabetes

Mice were treated with streptozotocin to deplete beta cells and induce T1D. They became hyperglycemic starting 5 days after treatment. Multiple cycles of FMD reversed T1D, indicated by:

• A return to normal insulin and blood glucose levels
• Improved glucose tolerance
• Increased beta cell number and proliferation

Cytokine levels in mice with T1D were also measured. The FMD decreased levels of inflammatory cytokines (eg, tumor necrosis factor—α, interleukin [IL]-12) and increased levels of cytokines that promote beta cell regeneration (eg, IL-2, IL-10).

FMD in Non-Diabetic Mice

The authors also investigated the effect of FMDs on diabetes-independent beta cell regeneration. During the 4-day FMD feeding, non-diabetic mice experienced decreased pancreatic islet size and a 35% decrease in beta cells; within 3 days of refeeding, islet size and beta cell levels returned to normal. Notably, beta cells remained very proliferative after their levels returned to normal.

FMD and Gene Expression

The genes NGN3 and SOX2 regulate embryonic cell differentiation. NGN3 controls embryonic differentiation of endocrine cells, including beta cells. In this study, the authors observed an expansion of NGN3-lineage cells with the FMD; this in turn increased the beta cell pool.

The authors also analyzed gene expression in cultured pancreatic islets from humans that were healthy or had T1D. The islets were first treated with serum from patients enrolled in an FMD clinical trial; SOX2 and NGN3 expression were observed. Next, a fasting-mimicking medium (short-term starvation [STS]) was added to the islets. STS induced SOX2 and NGN3 expression, stimulated insulin secretion, and reduced activity of the protein kinase A (PKA) and mammalian target of rapamycin (TOR) pathways; these pathways play roles in pancreatic cell reprogramming.

Interestingly, adding insulin growth factor—1 (IGF-1) to STS reduced SOX2 expression and insulin secretion and increased PKA pathway activity in the islets from humans with T1D; IGF-1 did not, however, reduce NGN3 expression in these islets.

The authors also observed SOX2 and NGN3 expression when cultures were treated with PKA and mTOR inhibitors.

These gene expression findings suggest the ability of fasting to promote, the authors wrote, “lineage reprogramming and insulin generation in pancreatic islet cells, in part by reducing IGF-1 and inhibiting TOR and PKA signaling.”

Taken together, the study’s findings provide support for the potential of fasting to reverse T1D and T2D through restored beta cell proliferation and function.

Dr. JoAnna Pendergrass received her doctorate in veterinary medicine from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, LLC.