Cardiovascular diseases (CVDs) are the leading cause of death globally as well as the leading cause of mortality and morbidity in type 2 diabetes (T2D) patients. Results from large interventional studies have suggested hyperglycemia and poor glycemic control to be largely responsible for the development of CVDs. However, the association between hypoglycemia and cardiovascular events is also a key pathophysiological factor in the development of CVDs. Hypoglycemia is especially prevalent in T2D patients treated with oral sulfonylurea agents or exogenous insulin, increasing the susceptibility of this population to cardiovascular events. The adverse cardiovascular risk of hypoglycemia can persist even after the blood glucose levels have been normalized. Hypoglycemia may lead to vascular disease through mechanisms such as enhanced coagulation, oxidative stress, vascular inflammation, endothelial dysfunction, and platelet activation. In the following review, we summarize the evidence for the role of hypoglycemia in platelet activation and the subsequent effects this may have on the development of CVD. In addition, we review current evidence for the effectiveness of therapies in reducing the risk of CVDs.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and post-menopausal women. PCOS is a multifactorial heterogeneous disorder associated with a variety of etiologies, outcomes, and clinical manifestations. However, the pathophysiology of PCOS is still unclear. Heat shock proteins (HSPs) have recently been investigated for their role in the pathogenesis of PCOS. HSPs are a class of proteins that act as molecular chaperones and maintain cellular proteostasis. More recently, their actions beyond that of molecular chaperones have highlighted their pathogenic role in several diseases. In PCOS, different HSP family members show abnormal expression that affects the proliferation and apoptotic rates of ovarian cells as well as immunological processes. HSP dysregulation in the ovaries of PCOS subjects leads to a proliferation/apoptosis imbalance that mechanistically impacts follicle stage development, resulting in polycystic ovaries. Moreover, HSPs may play a role in the pathogenesis of PCOS-associated conditions. Recent studies on HSP activity during therapeutic interventions for PCOS suggest that modulating HSP activity may lead to novel treatment strategies. In this review, we summarize what is currently known regarding the role of HSPs in the pathogenesis of PCOS and their potential role in the treatment of PCOS, and we outline areas for future research.

Objective: Rat sarcoma (Ras) proteins, Kirsten, Harvey, and Neuroblastoma rat sarcoma viral oncogene homolog (KRAS, HRAS, and NRAS, respectively), are a family of GTPases, which are key regulators of cellular growth, differentiation, and apoptosis through signal transduction pathways modulated by growth factors that have been recognized to be dysregulated in PCOS. This study explores Ras signaling proteins and growth factor-related proteins in polycystic ovary syndrome (PCOS). Methods: In a well-validated PCOS database of 147 PCOS and 97 control women, plasma was batch analyzed using Somascan proteomic analysis for circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins. The cohort was subsequently stratified for BMI (body mass index), testosterone, and insulin resistance (HOMA-IR) for subset analysis. Results: Circulating KRas, and RASA1 did not differ between PCOS and control women (p > 0.05). EGF1, EGFR, and EGFRvIII were decreased in PCOS (p = 0.04, p = 0.04 and p < 0.001, respectively). FGF8, FGF9, and FGF17 were increased in PCOS (p = 0.02, p = 0.03 and p = 0.04, respectively), and FGFR1 was decreased in PCOS (p < 0.001). VEGF-D (p < 0.001), IGF1 (p < 0.001), IGF-1sR (p = 0.02), and PDGFRA (p < 0.001) were decreased in PCOS compared to controls. After stratifying for BMI ≤ 29.9 kg/m², EGFR FGF8, FGFR1 VEGF-D, IGF1, and IGF-1sR differed (p < 0.05) though EGF1, EGFRvIII, FGF8, FGFR1, and VEGF-D no longer differed; after subsequently stratifying for HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed between groups (p < 0.05). Conclusions: Several growth factors that activate Ras differ between women with and without PCOS, and when stratified for BMI and HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed; these appear to be inherent features of the pathophysiology of PCOS.

Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca²⁺ release with mitochondrial Ca²⁺ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER–mitochondria crosstalk sustains β-cell health through Ca²⁺ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP₃) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca²⁺ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.

Studies in obese polycystic ovary syndrome (PCOS) have shown growth factors that activate rat sarcoma (Ras) proteins, which regulate intracellular signaling pathways, differ in PCOS; however, it is difficult to account for obesity, insulin resistance, and systemic inflammation that are linked to many of the features found in PCOS. This study explores Ras signaling proteins and related growth factors in non-obese women with and without PCOS. Somascan proteomic analysis of circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins that signal through Ras was undertaken in a non-obese population of women with (n=44) and without (n=78) PCOS, groups matched for age and body mass index (BMI), without insulin resistance (HOMA-IR) or systemic inflammation (normal CRP; C-reactive protein). There was an increase in the free androgen index (FAI, p<0.0001) and anti-Müllerian hormone (AMH, p<0.0001) in PCOS. Cohen’s d showed a moderate effect size for 3 proteins, of which Vascular endothelial growth factor-A (VEGFA) and EGFR were increased and EGFR1 was decreased in PCOS (all FDR p<0.05). EGFR and VEGF pathways interact closely and when EGFR signaling decreases, VEGFA may increase to maintain angiogenic balance, suggesting that in non-obese PCOS there may be a signal for compensatory angiogenesis in a dysfunctional endothelial environment.