Musi, Nicholas

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

AbstractAimsThe molecular mechanisms by which muraglitazar (peroxisome proliferator‐activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5′‐monophosphate‐activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle.MethodsSixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp.ResultsMuraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin‐stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5′‐monophosphate‐activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator‐activated receptor gamma coactivator–1 alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes.ConclusionsMuraglitazar increases plasma adiponectin, stimulates muscle 5′‐monophosphate‐activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator‐activated receptor agonists improve skeletal muscle insulin sensitivity.