Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes enhanced mortality in people with metabolic and cardiovascular diseases. Other highly infectious RNA viruses have demonstrated dependence on glucose transport and utilization, so we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole-body glucose metabolism. Twenty-four healthy domestic cats were intratracheally inoculated with B.1.617.2 (delta) SARS-CoV-2 and samples were collected at 4- and 12-days post-inoculation (dpi). Blood glucose and circulating cortisol concentrations were elevated at 4 and 12 dpi. Serum insulin concentration was statistically significantly decreased, while angiotensin 2 concentration was elevated at 12 dpi. SARS-CoV-2 RNA was detected in the pancreas and skeletal muscle at low levels; however, no change in the number of insulin-producing cells or proinflammatory cytokines was observed in the pancreas of infected cats through 12 dpi. SARS-CoV-2 infection statistically significantly increased GLUT protein expression in both the heart and lungs, correlating with increased AMPK expression. In brief, SARS-CoV-2 increased blood glucose concentration and cardio-pulmonary GLUT expression through an AMPK-dependent mechanism, without affecting the pancreas, suggesting that SARS-CoV-2 induces the reprogramming of host glucose metabolism. A better understanding of host cell metabolism and virus crosstalk could lead to the discovery of novel metabolic therapeutic targets for patients affected by COVID-19.

Our study on a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, mirroring human COVID-19, revealed alterations in whole body and cellular glucose metabolism. Infected cats developed mild hyperglycemia, increased protein levels of glucose transporters in the lung, and AMPK activation in the heart. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming in the cardiorespiratory system to support viral replication. Understanding these mechanisms could lead to novel antiviral therapeutic strategies.

Type 1 Diabetes Mellitus (T1D) is a disease characterized by the destruction of pancreatic beta cells. The subsequent loss of insulin production results in hyperglycemia, muscle wasting, and vascular dysfunction. Due to an inability to appropriately maintain glucose homeostasis, patients afflicted with T1D suffer from increased morbidity and early mortality. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream and physical exercise is known to improve and prevent the progression of pathological outcomes, but many T1D patients are unable to exercise at a level that conveys benefit. Thus, directly targeting muscle mass and function may prove beneficial for improving T1D patient outcomes, independent of exercise. A potent negative regulator of skeletal muscle has been identified as being upregulated in T1D patients, namely the myokine myostatin. Our hypothesis is that targeting myostatin (via genetic deletion) will prevent glucose dysfunction in a T1D model, preserve skeletal muscle function, and protect against vascular and renal dysfunction. Our methods utilized adult male mice with (WT) and without myostatin (Myo KO), in combination with the chemical induction of T1D (streptozotocin). Experimental outcomes included the assessment of glucose homeostasis (plasma glucose, HbA1c, IGTT), metabolism, muscle function (in vivo plantarflexion), and skeletal muscle vascular function (ex vivo pressure myography). Our results described systemic benefits from myostatin deletion in the T1D model, independent of insulin, including the following: inhibition of T1D-induced increases in plasma glucose, prevention of functional deficits in muscle performance, and preservation of fluid dynamics. Further, endothelial function was preserved with myostatin deletion. Taken together, these data inform upon the use of myostatin inhibition as a therapeutic target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1D.