Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model

Diabetes affects more than 330 million people worldwide and causes elevated cardiovascular disease risk. Mitochondria are critical for vascular function, generate cellular reactive oxygen species (ROS), and are perturbed by diabetes, representing a novel target for therapeutics. We hypothesized that adaptive mitochondrial plasticity in response to nutrient stress would be impaired in diabetes cellular physiology via a nitric oxide synthase- (NOS-) mediated decrease in mitochondrial function. Primary smooth muscle cells (SMCs) from aorta of the nonobese, insulin resistant rat diabetes model Goto-Kakizaki (GK) and the Wistar control rat were exposed to high glucose (25 mM). At baseline, significantly greater nitric oxide evolution, ROS production, and respiratory control ratio (RCR) were observed in GK SMCs. Upon exposure to high glucose, expression of phosphorylated eNOS, uncoupled respiration, and expression of mitochondrial complexes I, II, III, and V were significantly decreased in GK SMCs (p<0.05). Mitochondrial superoxide increased with high glucose in Wistar SMCs (p<0.05) with no change in the GK beyond elevated baseline concentrations. Baseline comparisons show persistent metabolic perturbations in a diabetes phenotype. Overall, nutrient stress in GK SMCs caused a persistent decline in eNOS and mitochondrial function and disrupted mitochondrial plasticity, illustrating eNOS and mitochondria as potential therapeutic targets

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies

cAMP/PKA Regulates Osteogenesis, Adipogenesis and Ratio of RANKL/OPG mRNA Expression in Mesenchymal Stem Cells by Suppressing Leptin

BACKGROUND: Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into adipocytes, osteoblasts and other cells. The reciprocal relationship between adipogenesis and osteogenesis was previously demonstrated; however, the mechanisms remain largely unknown. METHODS AND FINDINGS: We report that activation of PKA by 3-isobutyl-1 methyl xanthine (IBMX) and forskolin enhances adipogenesis, the gene expression of PPARgamma2 and LPL, and downregulates the gene expression of Runx2 and osteopontin, markers of osteogenesis. PKA activation also decreases the ratio of Receptor Activator of the NF-kappaB Ligand to Osteoprotegerin (RANKL/OPG) gene expression - the key factors of osteoclastogenesis. All these effects are mediated by the cAMP/PKA/CREB pathway by suppressing leptin, and may contribute to PKA stimulators-induced in vivo bone loss in developing zebrafish. CONCLUSIONS: Using MSCs, the center of a newly proposed bone metabolic unit, we identified cAMP/PKA signaling, one of the many signaling pathways that regulate bone homeostasis via controlling cyto-differentiation of MSCs and altering RANKL/OPG gene expression

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review

The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches

Glucose Uptake by Skeletal Muscle within the Contexts of Type 2 Diabetes and Exercise: An Integrated Approach

Type 2 diabetes continues to negatively impact the health of millions. The inability to respond to insulin to clear blood glucose (insulin resistance) is a key pathogenic driver of the disease. Skeletal muscle is the primary tissue for maintaining glucose homeostasis through glucose uptake via insulin-dependent and -independent mechanisms. Skeletal muscle is also responsive to exercise-meditated glucose transport, and as such, exercise is a cornerstone for glucose management in people with type 2 diabetes. Skeletal muscle glucose uptake requires a concert of events. First, the glucose-rich blood must be transported to the skeletal muscle. Next, the glucose must traverse the endothelium, extracellular matrix, and skeletal muscle membrane. Lastly, intracellular metabolic processes must be activated to maintain the diffusion gradient to facilitate glucose transport into the cell. This review aims to examine the physiology at each of these steps in healthy individuals, analyze the dysregulation affecting these pathways associated with type 2 diabetes, and describe the mechanisms by which exercise acts to increase glucose uptake