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mTORC2 Signaling: A Path for Pancreatic β Cell's Growth and Function
Ting Yuan1, Blaz Lupse1, Kathrin Maedler1
1University of Bremen, Centre for Biomolecular Interactions Bremen, Bremen, Germany.
Abstract:
The mechanistic target of rapamycin (mTOR) signaling pathway is an evolutionary conserved pathway that senses signals from nutrients and growth factors to regulate cell growth, metabolism and survival. mTOR acts in two biochemically and functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in terms of regulatory mechanisms, substrate specificity and functional outputs. While mTORC1 signaling has been extensively studied in islet/β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in β cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. β cell-selective mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion. Thereby, many mTORC2 targets, such as AKT, PKC, FOXO1, MST1 and cell cycle regulators, play an important role in β-cell survival and function. This indicates mTORC2 as important pathway for the maintenance of β-cell homeostasis, particularly to sustain proper β-cell compensatory response in the presence of nutrient overload and metabolic demand. This review summarizes recent emerging advances on the contribution of mTORC2 and its associated signaling on the regulation of glucose metabolism and functional β-cell mass under physiological and pathophysiological conditions in type 2 diabetes.
Insights
Mechanistic target of rapamycin complex 2 (mTORC2) is crucial for pancreatic beta-cell function and mass. Declines in mTORC2 accelerate type 2 diabetes by impairing insulin secretion and beta-cell survival.
Area of Science:
- Cellular signaling pathways
- Metabolic regulation
- Endocrinology
Background:
- The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and metabolism via mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
- While mTORC1 is well-studied in beta-cells, mTORC2's role in pancreatic beta-cell function and mass is emerging.
- mTORC2 signaling is reduced in beta-cells during type 2 diabetes.
Purpose of the Study:
- To review the role of mTORC2 in regulating pancreatic beta-cell function and mass.
- To highlight mTORC2's contribution to glucose metabolism and beta-cell homeostasis.
- To discuss mTORC2's significance in type 2 diabetes pathophysiology.
Main Methods:
- Literature review of recent advances in mTORC2 signaling.
- Analysis of mTORC2's impact on beta-cell biology.
- Examination of mTORC2 targets and their role in diabetes.
Main Results:
- Beta cell-selective mTORC2 inactivation impairs glucose tolerance and accelerates diabetes.
- Reduced beta-cell mass, proliferation, and insulin secretion are consequences of mTORC2 deficiency.
- mTORC2 targets like AKT and FOXO1 are vital for beta-cell survival and function.
Conclusions:
- mTORC2 is essential for maintaining beta-cell homeostasis and compensatory responses.
- Dysregulation of mTORC2 contributes to the pathogenesis of type 2 diabetes.
- Targeting mTORC2 signaling may offer therapeutic strategies for type 2 diabetes.