Abstract
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.
Highlights
Introduction bCell failure is the fundamental pathophysiological factor of both type 1 (T1D) and type 2 diabetes (T2D) (Cerasi and Luft, 1967; Accili et al, 2010; Rhodes, 2005; Mathis et al, 2001)
Apoptotic cells are rapidly cleared by macrophages; the true rate of apoptosis is very difficult to assess in all models of diabetes
We cannot exclude that cumulative low-grade apoptosis throughout life contributes to b-cell loss in adult animals; this finding was somewhat surprising, considering the fact that irreparable proinsulin misfolding generates severe endoplasmic reticulum (ER) stress associated with b-cell loss and insulin deficiency mimicking T1D
Summary
Introduction bCell failure is the fundamental pathophysiological factor of both type 1 (T1D) and type 2 diabetes (T2D) (Cerasi and Luft, 1967; Accili et al, 2010; Rhodes, 2005; Mathis et al, 2001). There exist less frequent, monogenic forms of diabetes resulting from loss-of-function mutations in b-cell function genes. An example is proinsulin mutations which lead to proinsulin misfolding, inducing bcell ER stress and permanent neonatal diabetes, called mutant-insulin diabetes of the young (MIDY); its animal counterpart is the Akita mouse (Liu et al, 2010; Weiss, 2013). The proinsulin burden on the ER is increased and proinsulin folding is impaired due to altered b-cell redox state, leading to accumulation of misfolded proinsulin and to ER stress. Clarifying how ER stress leads to b-cell failure in Akita diabetes can have important implications for the common forms of diabetes
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