Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions

TL;DR

Blocking a protein called PKD in pancreatic cells causes signs of aging but improves blood sugar control in mice on a high-fat diet.

Contribution

This study reveals that PKD regulates beta-cell aging and function, and its inhibition unexpectedly improves glucose tolerance.

Findings

PKD inhibition in beta-cells leads to a senescence-like phenotype with enlarged cells and increased β-galactosidase activity.

Reduced PKD activity improves glucose-stimulated insulin secretion and glucose tolerance in aged mice.

PKD inhibition lowers SOD2 and increases ROS, linking PKD to redox control in beta-cells.

Abstract

Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.

Image 1

•PKD inhibition induces hallmarks associated with β-cell senescence.•PKD loss improves GSIS and glucose tolerance in aged mice.•PKD loss lowers SOD2 and raises ROS, linking it to redox control in β-cells.•Inhibition of PKD Improves Glucose Homeostasis under HFD conditions.

PKD inhibition induces hallmarks associated with β-cell senescence.

PKD loss improves GSIS and glucose tolerance in aged mice.

PKD loss lowers SOD2 and raises ROS, linking it to redox control in β-cells.

Inhibition of PKD Improves Glucose Homeostasis under HFD conditions.

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