Vitamin D supplementation is linked to many beneficial health outcomes in the geriatric population, such as decreased mortality, epigenetic aging, and fracture risk. Conversely, type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in glucose homeostasis among its vast target tissues across the body. Here we describe the physiological effects of vitamin D supplementation in an aged, non-obese mouse model on glucose homeostasis and associated tissue-specific gene regulation. Specifically, we found that 1) increased dietary vitamin D intake can improve glucose regulation in lean, aged male mice, and 2) these male mice also had decreased Glut4 and Insr expression in a diet low in vitamin D in various tissues indicating that dietary vitamin D may be a sex-specific key mediator in regulating glucose tolerance and protecting against insulin resistance.

The primary mechanism underlying insulin-resistant diabetes is the disruption of insulin signalling due to a relative deficiency of insulin receptor (InsR). EphB4, which forms a complex with InsR to promote lysosomal degradation, negatively regulates this pathway. Quercetin-3-O-β-D-pyranoside (Reynoutrin, Rey), a small natural compound, has garnered attention for its diverse biological activities. In this study, we demonstrated that Rey improved glycolipid metabolism in streptozotocin (STZ)-induced diabetic mice on a high-fat diet (HFD) and in palmitic acid (PA)-treated HepG2 cells. Furthermore, network pharmacology screening identified EphB4 as a potential target of Rey in the regulation of insulin resistance (IR). Surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and cellular thermal shift assay (CETSA) results confirmed that Rey directly bond to EphB4. Notably, molecular docking and CETSA analyses revealed that Rey interacted with key amino acids in EphB4, including Phe759 and Met696, thereby spatially inhibiting the interaction between EphB4 and InsR to mechanically prevent the degradation of InsR, which contributed to improve IR. In summary, our study identified Rey as a promising drug candidate for diabetes treatment, directly targeting EphB4 to improve insulin resistance and glycolipid metabolism in Type 2 diabetes mellitus.

Growing evidence links tau-related neurodegeneration with insulin resistance and type 2 diabetes (T2D), though the underlying mechanisms remain unclear. Our previous research identified HMGA1 as crucial for insulin receptor (INSR) expression, with defects in the HMGA1 gene associated with insulin resistance and T2D. Here, we explore HMGA1 deficiency as a potential contributor to tauopathies, such as Alzheimer's disease (AD), and its connection to insulin resistance. Immunoblot analyses, protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays were conducted in human and mouse neuronal cell models. Tau immunohistochemistry, behavioural studies, and brain glucose metabolism were analysed in Hmga1-knockout mice. Additionally, a case-control study investigated the relationship between HMGA1 and tau pathology in patients with tauopathy, carrying or not the HMGA1 rs146052672 variant, known to reduce HMGA1 protein levels and increase the risk of insulin resistance and T2D. We show that HMGA1 regulates tau protein expression primarily through the specific repression of MAPT gene transcription. In both human neuronal cells and primary mouse neurons, tau mRNA and protein levels were inversely correlated with HMGA1 expression. This inverse relationship was further confirmed in the brain of Hmga1-knockout mice, where tau was overexpressed, INSR was downregulated, and brain glucose uptake was impaired. Additionally, the rs146052672 variant was more common in patients with tauopathy (12/69, 17.4%) than in controls (10/200, 5.0%) (p = 0.001), and carriers of this variant exhibited more severe disease progression and poorer therapeutic outcomes. These findings suggest that HMGA1 deficiency may drive tau pathology, linking tauopathies to insulin resistance and providing new insights into the relationship between metabolic and neurodegenerative disorders. Furthermore, our observation that over 17% of individuals with tauopathy exhibit a deficit in HMGA1 protein production could have significant clinical implications, potentially guiding the development of therapeutic strategies targeting this specific defect. See acknowledgements section.

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.