Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

Chia-Wei Cheng; Valentina Villani; Roberta Buono; Min Wei; Sanjeev Kumar; Omer H Yilmaz; Pinchas Cohen; Julie B Sneddon; Laura Perin; Valter D Longo

doi:10.1016/j.cell.2017.01.040

Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

Cell. 2017 Feb 23;168(5):775-788.e12. doi: 10.1016/j.cell.2017.01.040.

Authors

Affiliations

¹ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; Koch Institute at MIT, 500 Main Street, Cambridge, MA 02139, USA.
² GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, Los Angeles, CA 90027, USA.
³ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, Milan 20139, Italy.
⁴ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
⁵ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
⁶ Koch Institute at MIT, 500 Main Street, Cambridge, MA 02139, USA.
⁷ Diabetes Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143.
⁸ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA; IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, Milan 20139, Italy. Electronic address: vlongo@usc.edu.

Abstract

Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models. PAPERCLIP.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Diabetes Mellitus, Type 1 / diet therapy*
Diabetes Mellitus, Type 2 / diet therapy*
Diet
Fasting*
Glucose Tolerance Test
Humans
In Vitro Techniques
Insulin / metabolism
Insulin-Secreting Cells / metabolism
Islets of Langerhans
Mice
Nerve Tissue Proteins / genetics
Pancreas / cytology
Pancreas / metabolism
Signal Transduction
Transcriptome

Substances

Basic Helix-Loop-Helix Transcription Factors
Insulin
Nerve Tissue Proteins
Neurog3 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding