Matrix metalloproteinases (MMPs) are M2 macrophage markers that are modulated by inflammation. A disintegrin and metalloproteinases (ADAMS) and those with thrombospondin motifs (ADAMTS) regulate the shedding of membrane-bound proteins, growth factors, cytokines, ligands, and receptors; MMPs, ADAMS, and ADAMTS may be regulated by tissue inhibitors of metalloproteinases (TIMPs). This study aimed to determine whether these interacting proteins were dysregulated in PCOS. A Somascan proteomic analysis of 12 MMPs, three of their inhibitors (TIMP-1, 2, 3), two ADAMS (9, 12), five ADAMTS (1, 4, 5, 13, 15), insulin-like growth factor binding protein-1 (IGFBP-1), and insulin-like growth factor-1 (IGF-1) was undertaken in a well-validated PCOS database of 143 women with PCOS and 97 controls. Women with PCOS had significantly higher levels of MMP-9 and lower levels of MMP-2, MMP-14, TIMP-2, IGFBP-1, and IGF-1 compared to the controls (p < 0.0001, p < 0.005, p < 0.04, p < 0.05, p < 0.0001, and p < 0.0001, respectively). No differences were observed for any other MMPs. The ADAMS or ADAMTS levels did not differ between groups. Body mass index (BMI) was correlated with MMP-9 (p < 0.01), MMP-1 (p < 0.05), MMP-2 (p < 0.05), MMP-10 (p < 0.005), MMP-12 (p < 0.005), ADAM-9 (p < 0.05), and IGFBP-1 (p < 0.0001), but only MMP-9 still differed after accounting for BMI. MMP-9/TIMP-1, MMP-9/TIMP-2, and MMP-9/TIMP-3 ratios were higher in the PCOS group (p < 0.01), whilst MMP-17/TIMP-1 and MMP-17/TIMP-2 were lower (p = 0.01). MMP-2/TIMP ratios showed no difference between groups. TIMP-2 was positively correlated with CRP (p < 0.01). MMP changes in PCOS are largely driven by BMI, though increased MMP-9 is BMI-independent, suggesting that any deleterious effects of MMP-9 would be potentially exacerbated by a concomitantly increased BMI. The significant increases in the MMP-9/TIMP ratios suggests MMP-9 overactivity in PCOS.

Evidence suggests that endocrine disrupting chemicals (EDCs), commonly used in plastics and personal care products, may be associated with reduced levels of vitamin D. Therefore, this study examined the relationship between phthalate metabolites, 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan; TCS) and bisphenols (BPs) with vitamin D₃ (25(OH)D₃) and active 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), and their relationship to calcium homeostasis. 57 female participants (age 31.8 ± 4.6 years; BMI 25.6 ± 3.7 kg/m²) were analyzed for urinary levels of phthalate metabolites, TCS and BPs, and serum levels of 25(OH)D₃ and 1,25(OH)₂D_3, determined by isotope-dilution liquid chromatography tandem mass spectrometry. Serum calcium/calmodulin-dependent (CaM) associated proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan. In the study cohort, 25(OH)D₃ and 1,25(OH)₂D₃ levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively: mono-3-carboxypropyl-phthalate (MCPP) correlated negatively with 25(OH)D₃ (ρ = -0.53, p = 0.01). 28 of the 57 women recruited were 25(OH)D₃ deficient, <20 ng/mL (50 nmol/L): in this group, mono-iso-butylphthalate (MiBP) and mono-butylphthalate (MBP) negatively correlated with 25(OH)D₃; (ρ = -0.47, p = 0.049) and (ρ = -0.64, p = 0.005), respectively. EDCs did not correlate with 1,25(OH)₂D₃, measures of renal function or CaM proteins. These putative data indicate that MCPP is related to 25(OH)D₃, while MiBP and MBP were related to vitamin D deficiency; however, no correlations were observed with TCS and BPs. No phthalate metabolites correlated with 1,25(OH)₂D₃, CaM associated proteins or renal function, suggesting that effects occur earlier in the vitamin D pathway and not through modulation of cellular calcium flux. The observed correlations are surprisingly strong compared to other predictors of 25(OH)D₃, and larger studies adjusting for potential confounders are warranted.

Diabetes mellitus, both type 1 (T1D) and type 2 (T2D), has become the epidemic of the century and a major public health concern given its rising prevalence and the increasing adoption of a sedentary lifestyle globally. This multifaceted disease is characterized by impaired pancreatic beta cell function and insulin resistance (IR) in peripheral organs, namely the liver, skeletal muscle, and adipose tissue. Additional insulin target tissues, including cardiomyocytes and neuronal cells, are also affected. The advent of stem cell research has opened new avenues for tackling this disease, particularly through the regeneration of insulin target cells and the establishment of disease models for further investigation. Human-induced pluripotent stem cells (iPSCs) have emerged as a valuable resource for generating specialized cell types, such as hepatocytes, myocytes, adipocytes, cardiomyocytes, and neuronal cells, with diverse applications ranging from drug screening to disease modeling and, importantly, treating IR in T2D. This review aims to elucidate the significant applications of iPSC-derived insulin target cells in studying the pathogenesis of insulin resistance and T2D. Furthermore, recent differentiation strategies, protocols, signaling pathways, growth factors, and advancements in this field of therapeutic research for each specific iPSC-derived cell type are discussed.

Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary syndrome (PCOS), where it is strongly related to obesity, insulin resistance (IR) and risk of cardiovascular disease. To determine if the inherent pathophysiology of PCOS or vitamin D levels are linked to dysregulation of cardiovascular risk proteins (CVRPs), a study in non-obese women with PCOS and without IR was undertaken. Our hypothesis was that the levels of vitamin D₃ and its active metabolite would be associated with CVRPs comparably in women with and without PCOS. In women with PCOS (n = 29) and controls (n = 29), 54 CVRPs were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement and correlated to 25-hydroxyvitamin D₃ (25(OH)D₃) and the active 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Women with PCOS had comparable IR and systemic inflammation (normal C-reactive protein) to control women, though had higher free androgen index and anti-Mullerian hormone levels. 25(OH)D₃ and 1,25(OH)₂D₃ levels did not differ between groups. Nine CVRPs were higher in PCOS (p < 0.05) (Galectin-9, Brother of CDO, C-motif chemokine 3, Interleukin-18 receptor-1, Thrombopoietin, Interleukin-1 receptor antagonist protein, Programmed cell death 1 ligand-2, Low-affinity immunoglobulin gamma Fc-region receptor II-b and human growth hormone), whilst 45 CVRPs did not differ. 25(OH)D₃ correlated with five CVRPs in PCOS and one in controls (p < 0.05). Despite the women with PCOS not exhibiting overt systemic inflammation, 9 of 54 CVRPs were elevated, all relating to inflammation, and 5 of these correlated with 25(OH)D_3, suggesting an ongoing underlying inflammatory process in PCOS even in the absence of obesity/IR.

Diabetes mellitus encompasses a heterogeneous group of metabolic disorders defined by abnormalities in insulin secretion, function, or both. Exogenous insulin therapy has long been the principal treatment strategy for patients with type 1 diabetes and for those in advanced stages of type 2 diabetes. Stem cell therapy has gained significant attention in recent years as a potential curative approach for several life-threatening disorders. In this review, we focus on the use of induced pluripotent stem cells as an alternative source for beta-cell generation, offering a solution to organ scarcity and providing a sustainable supply of insulin-producing cells. We further evaluate current developments in encapsulation technologies and transplantation sites, while noting that the issue of immune-mediated graft rejection continues to be widely debated. The aim of this review is to outline encapsulation techniques and transplantation approaches explored in animal models, and to discuss the risks and challenges anticipated in human clinical trials.

In human population studies, organochlorine pesticides (OCPs) have been linked to vitamin D deficiency. Therefore, this study examined the association between OCPs, vitamin D₃ (cholecalciferol, 25(OH)D₃), and the active metabolite 1,25-dihydrovitamin D₃ (1,25(OH)₂D₃) in a cohort of non-obese women. The serum samples of 58 female participants (age—31.9 ± 4.6 years; body mass index (BMI)—25.7 ± 3.7 kg/m²) were screened for 10 indicator OCPs. 25(OH)D₃ and 1,25(OH)₂D₃ levels were determined via isotope dilution liquid chromatography tandem mass spectrometry. In this cohort, the 25(OH)D₃ and 1,25(OH)₂D₃ levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively, with 28 participants classified as 25(OH)D₃-deficient (<50 nmol/L). In the study cohort, no correlations were found between individual or total OCPs (ƩOCPs) and 25(OH)D₃. p,p′-dichlorodiphenyldichloroethylene (DDE) and ƩOCPs correlated positively with 1,25(OH)₂D₃, with the latter being negatively correlated with estimated glomerular filtration rate (eGFR). In women with sufficient 25(OH)D₃ levels, p,p′-dichlorodiphenyltrichloroethan (DDT) was positively correlated with 1,25(OH)₂D₃, whilst in the deficient group, hexachlorobenzene (HCB) and p,p′-(DDE) were positively correlated with 1,25(OH)₂D₃, β-Hexachlorocyclohexane (HCH) was positively correlated with 25(OH)D₃, and none of the OCPs were associated with measures of renal function. Overall, OCPs and ƩOCPs were not associated with 25(OH)D₃, suggesting that they are unrelated to vitamin D deficiency, but p,p′-DDE and ƩOCPs correlated positively with active 1,25(OH)₂D₃, while ƩOCPs correlated negatively with eGFR, suggesting a possible renal effect. Analysis of vitamin D deficiency revealed an association between β-HCH and 25(OH)D₃, and between HCB and p,p′-DDE and 1,25(OH)₂D₃, suggesting that OCP effects may be enhanced in cases of vitamin D deficiency.