The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Roni Yeroslaviz
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Shoshana Chimenez
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Dana Avrahami
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
Miri Stolovich-Rain
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
Ido Alter
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Marina Sebag
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Nava Polin
The Endocrine Service, The Hebrew University-Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem, Israel
Ernesto Bernal-Mizrachi
Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, United States
Yuval Dor
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate β-cells was sufficient to rescue postnatal β-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect β-cell mass expansion due to mTOR inhibition.
