Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction, which leads to the depletion of β-cell mass. Understanding the molecular mechanisms driving islet β-cell dysfunction is paramount for developing therapies to increase β-cell function. The mammalian target of rapamycin complex 1 (mTORC1) plays a key role in regulating β-cell function by integrating growth factors and mitogens to direct cell cycle and survival; yet, mechanistically this process is not fully understood. Synapses of amphids defective protein kinase A (SAD-A) is a member of AMP-activated protein kinase (AMPK)-related family kinases, with high expression in the pancreas. My earlier work demonstrated that SAD-A is a β-cell specific mediator of insulin secretion and islet β-cell size. Furthermore, glucose dramatically stimulated SAD-A protein translation in islets that was potently inhibited by rapamycin, an inhibitor of mTORC1. My recent preliminary studies showed that 1) SAD-A overexpression increases β-cell proliferation in the MIN6 β-cell line and islets; 2) Ablation of SAD-A in pancreas of mice (pSADKO) promotes β-cell apoptosis and attenuates compensatory islet growth in obese mice; 3) SAD-A depletion in the pancreas increases mRNA expression of cyclin D2 in islets of pSADKO mice. Based on these observations, I hypothesize that SAD-A promotes pancreatic β-cell proliferation by regulating β-cell cycle as a downstream target of mTORC1 signaling.


J. Nie: None. N. Musi: None. Y. Shi: None.

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