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

Sep 30, 2026

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Insulin secretion from pancreatic β-cells maintains glucose homeostasis and helps prevent type 2 diabetes, a disease linked to aging. This study identifies protein kinase D (PKD) as a key regulator of β-cell function during aging via control of cellular senescence. β-cell–specific dominant-negative PKDkd-EGFP expression and selective PKD inhibition with CRT0066101 induced a senescent-like phenotype with enlarged cells and increased β-galactosidase activity. The phenotype coincided with reduced superoxide dismutase 2 and higher reactive oxygen species. Despite senescence-like changes, PKD inhibition improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance, preserving β-cell function under metabolic stress.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

Aging, obesity, and type 2 diabetes risk

Cellular senescence and p16Ink4a

PKD family roles and pancreatic expression

PKD1 and insulin secretion under stress conditions

Original Article Protein kinase D deficiency induces asenescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions Wolfgang S. Lieb1, Carlos O. Oueslati Morales1, Kornelia Ellwanger1, Claudia Koch1, Sylke Lutz1, Stephan A. Eisler 2, Annika M. Möller1, Veronika Leiss3, Angelika Hausser1, 2, * 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 asenescent-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. © 2025 The Author(s) . Published by Elsevier GmbH. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/).)[).](http://creativecommons.org/licenses/by/4.0/).) Keywords PKD; HFD; Aging; Diabetes; β-cell; Senescence 1. INTRODUCTION Aging and obesity are major risk factors for the development of type 2 diabetes (T2D) and are closely associated with impaired glucose homeostasis [1—3] . During aging, pancreatic β-cells lose the ability to proliferate in response to higher metabolic demands [4 ,5] . Consequently, the regenerative potential of β-cells declines markedly in both mice and humans [6—8] . This results in a reduction in functional β-cell mass that contributes to dysregulated insulin secretion, reduced glucose tolerance, and an increased risk of T2D at later stages of life [9] . A key factor underlying the loss of replicative capacity in β-cells is the cyclin-dependent kinase (CDK) inhibitor p16Ink4a (hereafter referred to as p16), a master regulator of cellular senescence. p16 expression increases with age in mouse islets and predisposes animals to diabetes [8 ,10 ,11] . Additionally, elevated circulating free fatty acids, such as those induced by a high-fat diet (HFD), suppress β-cell proliferation by inducing p16 expression [12] . Although increased p16 expression is known to limit β-cell regenerative potential, it remained unclear whether this also results in bona fide cellular senescence, and whether such senescent β-cells remain functionally active. Surprisingly, a study demonstrated that p16 promotes β-cell senescence during physiological aging and enhances glucose-stimulated insulin secretion (GSIS) [13] . This finding suggests that p16-dependent β-cell senescence may act as a compensatory mechanism to preserve glucose homeostasis despite a reduced β-cell regenerative capacity. However, the signaling pathways that govern β-cell senescence during aging and their impact on β-cell function remain poorly understood. The protein kinase D (PKD) family comprises three isoforms, PKD1, PKD2, and PKD3, best known for their roles in dynamic actin remodeling and regulation of vesicle fission at the Trans-Golgi Network (TGN) [14 ,15] . In the pancreas, PKD isoforms are differentially expressed: PKD

FAQs

How does the study connect PKD to β-cell function during aging?

It identifies protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence.

What cellular changes occur when PKD activity is inhibited in mature adult mice?

PKD inhibition induces a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity, along with reduced superoxide dismutase 2 and increased reactive oxygen species.

Why is glucose tolerance improved even though PKD inhibition promotes a senescence-like phenotype?

Although PKD inhibition promotes senescent-like β-cells, it still significantly improves glucose tolerance, enhances glucose-stimulated insulin secretion, and protects against high-fat diet–induced glucose and insulin intolerance.

Sep 30, 2026

Upload by Rowan