Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse.
Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse.
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DOI：
10.7554/elife.38472
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发表时间：
2018-11-09
期刊：
影响因子：
7.7
通讯作者：
Leibowitz G
中科院分区：
文献类型：
--
作者：
Riahi Y;Israeli T;Yeroslaviz R;Chimenez S;Avrahami D;Stolovich-Rain M;Alter I;Sebag M;Polin N;Bernal-Mizrachi E;Dor Y;Cerasi E;Leibowitz G
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. Insulin is a hormone that is crucial for maintaining normal blood sugar levels and is produced by so called β-cells in the pancreas. If the body stops making insulin, or cells stop responding to it, blood sugar levels rise, leading to diabetes. A form of diabetes known as type 1 diabetes, where the body stops making insulin, usually starts in childhood and can sometimes appear during the first six months of life. Infants affected by this early onset of diabetes have mutations in one copy of the gene that encodes insulin. They can still produce half of the amount of insulin, which should be sufficient to control blood sugar to a certain extent. Instead, insulin production stops almost completely after a few months. Scientists believe that this is because the mutant insulin has a toxic effect on β-cells. Mutations in the insulin gene affect the structure of insulin. As a result, insulin builds up in the β-cells, which may eventually cause the cells to die. But the mutant insulin might also cause a problem with a molecule called mTORC1, which helps β-cells to grow. To investigate this further, Riahi et al. used a mouse model of this form of diabetes to study how stress affects β-cells from birth to adulthood. Mutant β-cells slowed down their rate of cell growth and division early after birth, but did not die more frequently. The results also revealed that β-cells had lower levels of mTORC1, which probably is the main cause of the reduced cell division and growth. When mTORC1 levels were boosted experimentally, the β-cells started to grow and produce more insulin. Understanding β-cell biology and the link between stress and growth, especially early in life, is a key step in understanding diabetes. In a separate study, Balboa et al. found that human β-cells with insulin mutations also had low mTORC1 and struggled to grow. If boosting mTORC1 could rescue β-cell growth in humans, it could lead to new ways to prevent diabetes.
