Type 2 diabetes - unmet need, unresolved pathogenesis, mTORC1-centric paradigm

Area of Science:

• Endocrinology
• Metabolic Diseases
• Molecular Biology

Background:

• The prevailing type 2 diabetes (T2D) paradigm is gluco-centric, focusing solely on glycemic control.
• Non-glycemic conditions like obesity and fatty liver are treated as comorbidities, not core T2D aspects.
• This limited view overlooks the significant role of non-glycemic factors in T2D morbidity and mortality.

Purpose of the Study:

• To propose a novel mTORC1-centric paradigm for T2D.
• To investigate the role of hyperactive mTORC1 in driving both glycemic and non-glycemic T2D manifestations.
• To offer a unifying perspective on T2D pathogenesis and treatment.

Main Methods:

• Conceptual review and synthesis of existing literature on T2D pathogenesis.
• Analysis of the proposed role of mTORC1 in insulin signaling pathways.
• Evaluation of mTORC1's proposed dual action on glycemic control and non-glycemic diseases.

Main Results:

• Hyperactive mTORC1 is hypothesized to disrupt the insulin receptor-Akt pathway, impairing glycemic control.
• Concurrently, hyperactive mTORC1 is proposed to drive non-glycemic T2D aspects such as obesity and fatty liver.
• The gluco-centric model's limitations in addressing T2D's complexity are highlighted.

Conclusions:

• An mTORC1-centric paradigm offers a unifying framework for understanding T2D's multifaceted nature.
• This new perspective may lead to improved treatment strategies targeting mTORC1.
• Rethinking T2D pathogenesis beyond glycemic control is crucial for addressing unmet clinical needs.