James R Sowers’s research while affiliated with University of Missouri and other places

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild type (ECCD36 +/+ ) and knock out (ECCD36 -/- ) mice, aged six weeks, were provided with either a WD or a standard chow diet for a duration of 16 weeks. ECCD36 +/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that were blunted in ECCD36 -/- mice. Improved insulin sensitivity in ECCD36 -/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 weeks of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36 -/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36 -/- mice. These findings demonstrate that endothelial specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.

Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin–aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.

Type 1 and type 2 diabetes account for up to 90% of all cases of diabetes. However, the remaining “atypical” cases, while rare, appear frequently enough that every practitioner should be aware of them. Some forms of diabetes, distinct from type 1 or type 2 diabetes, are caused by single gene mutations. In addition to monogenic diabetes, other atypical causes of diabetes include: genetic defects in insulin action; diseases of the exocrine pancreas; and endocrinopathies. Atypical Diabetes is divided into three parts, each exploring distinct categories of atypical diabetes, and each part includes case studies that illustrate the clinical challenges presented by different forms of atypical diabetes. This book is a comprehensive resource for the successful diagnosis and treatment of these rare, but significant, forms of diabetes.

Background Excess dietary salt increases vascular stiffness in humans, especially in salt- sensitive populations. While we recently suggested that the endothelial sodium channel (EnNaC) contributes to salt-sensitivity related endothelial cell (EC) and arterial stiffening, mechanistic understanding is incomplete. This study thus aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a regulator of sodium channels, in EC and arterial stiffening. Methods and Results A mouse model of salt sensitivity-associated vascular stiffening was produced by subcutaneous implantation of slow-release deoxycorticosterone acetate (DOCA) pellets, with salt (1% NaCl, 0.2% KCl) administered via drinking water. Preliminary data showed that global SGK1 deletion caused significantly decreased blood pressure, EnNaC activity and aortic endothelium stiffness as compared to control mice following DOCA-salt treatment. To probe EC signaling pathways, selective deletion of EC-SGK1 was performed by cross-breeding cadherin 5-Cre mice with sgk1 flox/flox mice. DOCA-salt treated control mice had significantly increased blood pressure, EC and aortic stiffness in vivo and ex vivo, which were attenuated by EC-SGK1 deficiency. To demonstrate relevance to humans, human aortic ECs were cultured in the absence or presence of aldosterone and high salt with or without the SGK1 inhibitor, EMD638683 (10uM or 25uM). Treatment with aldosterone and high salt increased intrinsic stiffness of ECs, which was prevented by SGK1 inhibition. Further, the SGK1 inhibitor prevented aldosterone and high salt induced actin polymerization, a key mechanism in cellular stiffening. Conclusion EC-SGK1 mediates salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation actin polymerization. Graphical Abstract

Disclosure: C. Homan: None. J. Habibi: None. D. Chen: None. A. Whaley-Connell: None. J.R. Sowers: None. G. Jia: None. Skeletal muscle is an important organ in the storage and release of lipids in response to physiological changes in free fatty acid (FFA) supply and demand. Once fat tissue mass expansion exceeds its blood supply excess lipids are stored ectopically as small lipid droplets in non-adipose tissues such as skeletal muscle. Recently, our data found that mineralocorticoid receptors (MRs) mediate Western diet (WD)-induced lipid infiltration of skeletal muscle and insulin resistance. Related to this, MRs, the principal receptors for the hormone aldosterone in the kidney, also exist in vascular cells, including endothelial cells (ECs). Moreover, enhanced MR signaling in ECs (ECMR) induces arterial stiffening and impairs microcirculation. However, our understanding of the precise mechanisms by which enhanced ECMR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles of ECMR in soleus lipid accumulation and corresponding insulin resistance in diet-induced obesity. Six-week-old ECMR wild type (ECMR+/+) and knockout (ECMR-/-) mice were fed either a mouse chow diet or WD for 16 weeks. 16 weeks of WD induced increases in glucose intolerance, fasting plasma insulin levels, HOMA-IR and insulin resistance index were found to be blunted in ECMR-/- mice. ECMR-/- prevented WD-induced increase in soleus FFA levels without changing serum FFA levels. Meanwhile, WD also increased soleus intramyocellular lipid content, plasma EC derived exosomal CD36 and soleus CD36 protein levels. These abnormalities were related to reduced soleus insulin metabolic signaling in PI3K/Akt pathways, as these pathways were blunted in ECMR-/- mice. These findings indicate that EC specific MR activation contributes to diet-induced increases in CD36 expression, soleus fat infiltration, as well as systemic and skeletal muscle insulin resistance. Presentation: Saturday, June 17, 2023

Metabolic syndrome is a group of risk factors that increase the risk of developing metabolic and cardiovascular disease (CVD) and include obesity, dyslipidemia, insulin resistance, atherosclerosis, hypertension, coronary artery disease and heart failure. Recent research indicates that excessive production of aldosterone and associated activation of mineralocorticoid receptors (MR) impair insulin metabolic signaling, promote insulin resistance, and increase the risk of developing metabolic syndrome and CVD. Moreover, activation of specific epithelial sodium channels (ENaC) in endothelial cells (ECs) (EnNaC), which are downstream targets of endothelial specific MR (ECMR) signaling, are also believed to play a crucial role in the development of metabolic syndrome and CVD. These adverse effects of ECMR/EnNaC activation are mediated by increased oxidative stress, inflammation and lipid metabolic disorders. It is worth noting that ECMR/EnNaC activation and the pathophysiology underlying metabolic syndrome and CVD appears to exhibit sexual dimorphism. Targeting ECMR/EnNaC signaling may have a beneficial effect in preventing insulin resistance, diabetes, metabolic syndrome and related CVD. This review aims to examine our current understanding of the relationship between MR activation and increased metabolic syndrome and CVD, with particular emphasis placed on the role for endothelial specific ECMR/EnNaC signaling in these pathological processes.

Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induces CD36 expression, increases ectopic lipid accumulation, and results in systemic and tissue insulin resistance. Here, we further investigated whether endothelial cell (EC) specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16-weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 (Glut4) expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.