Cover Story Current Issue
Glucose is a ubiquitous and essential source of energy for all living organisms. Although mammals have evolved ways to convert other nutritional molecules to ATP, the preference for dietary glucose appears to be preserved. In rodents, the immediate detection of ingested glucose potently reinforces intake, hierarchically organizing behaviors towards glucose-yielding substances, and away from other types of food including other sugars. Taste is the primary sense linked to nutrient selection. Until recently, it was thought that most mammalian species utilize a single broadly tuned receptor to detect all simple sugars. Indeed, this “sweet” receptor, which comprises a heterodimer of the T1R2 and T1R3 proteins, binds multiple natural sugars (e.g., glucose, fructose, sucrose, maltose), as well as various other chemicals that yield little to no energy (e.g., low calorie sweeteners, sugar alcohols) and some d-amino acids. The neural signal originating from the sweet receptor is hardwired into brain circuits that drive eating and drinking behaviors, but it is an unreliable indicator of nutrient quality and quantity.
Current Issue
Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions
Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions
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.
Articles in Press
Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions
Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions
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.
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Helmholtz Diabetes Conference
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You are what you eat
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