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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.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/protein-kinase-d-deficiency-induces-a-senescence-like-phenotype-in-cells-and-improves-glucose-and-insulin-tolerance-under-high-fat-diet-conditions/455684/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/protein-kinase-d-deficiency-induces-a-senescence-like-phenotype-in-cells-and-improves-glucose-and-insulin-tolerance-under-high-fat-diet-conditions/455684.png","ImageObject",300,407,{"name":92,"@type":93},"Rowan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-08","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does the study connect PKD to β-cell function during aging?","Question",{"text":112,"@type":113},"It identifies protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What cellular changes occur when PKD activity is inhibited in mature adult mice?",{"text":117,"@type":113},"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.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is glucose tolerance improved even though PKD inhibition promotes a senescence-like phenotype?",{"text":121,"@type":113},"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.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455684,1790792219,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099514067415,"https://ap-avatar.wpscdn.com/avatar/100002539d78ffe74a7?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779092875211072502","Original Article  \nProtein kinase D deficiency induces asenescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions  \nWolfgang S. Lieb1, Carlos O. Oueslati Morales1, Kornelia Ellwanger1, Claudia Koch1, Sylke Lutz1, Stephan A. Eisler 2, Annika M. Möller1, Veronika Leiss3, Angelika Hausser1, 2, *  \nABSTRACT  \nInsulin 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.  \n© 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/).)  \nKeywords PKD; HFD; Aging; Diabetes; β-cell; Senescence  \n1. INTRODUCTION  \nAging 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  \nfide 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.  \nThe 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","cbCaisXLfrgh2VaO","https://ap.wps.com/l/cbCaisXLfrgh2VaO","pdf",6170987,15,"English","# Abstract\n# Introduction\n## Aging, obesity, and type 2 diabetes risk\n## Cellular senescence and p16Ink4a\n## PKD family roles and pancreatic expression\n## PKD1 and insulin secretion under stress conditions","[{\"question\":\"How does the study connect PKD to β-cell function during aging?\",\"answer\":\"It identifies protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence.\"},{\"question\":\"What cellular changes occur when PKD activity is inhibited in mature adult mice?\",\"answer\":\"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.\"},{\"question\":\"Why is glucose tolerance improved even though PKD inhibition promotes a senescence-like phenotype?\",\"answer\":\"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.\"}]","Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions | PDF",1790743878,38]