Increased glycolysis affects β-cell function and identity in aging and diabetes

Area of Science:

• Endocrinology
• Metabolic Research
• Aging Biology

Background:

• Age is a significant risk factor for developing type 2 diabetes (T2D).
• Understanding the alterations in pancreatic beta-cell function with aging is crucial for T2D pathogenesis.
• Investigating shared mechanisms between aging and T2D in beta cells can reveal therapeutic targets.

Purpose of the Study:

• To determine if beta-cell glucose metabolism changes with aging.
• To investigate the contribution of these metabolic changes to T2D development.
• To identify common molecular and metabolic signatures between aged and diabetic beta cells.

Main Methods:

• Utilized senescence-accelerated mice (SAM), C57BL/6J (B6), ob/ob, and db/db mice as aging and diabetes models.
• Assessed glucose-stimulated insulin secretion and [U-¹³C]-glucose metabolic flux in isolated islets.
• Analyzed beta-cell identity markers and utilized Got1 knockout (KO) beta cells as a model for increased glycolysis.

Main Results:

• Aged and diabetic mouse beta cells exhibit shared dysfunctional phenotypes: glucose hyperresponsiveness and compromised cellular identity.
• Both aged and diabetic beta cells show hyperactive glycolysis, linked to increased expression of Nmnat2 (nicotinamide mononucleotide adenylyl transferase 2).
• Got1 KO beta cells mimicked aging and diabetes phenotypes, with increased glycolysis, dysfunction, and impaired identity; glycolysis or Nmnat2 attenuation restored function.

Conclusions:

• Hyperactive glycolysis is a key metabolic signature in aged and diabetic beta cells, contributing to dysfunction and identity loss.
• These findings suggest Nmnat2 suppression as a potential strategy to combat age-related T2D.
• The study highlights shared metabolic pathways in beta-cell aging and diabetes.