Abstract
While Type 1 Diabetes Mellitus (T1DM) is characterized by hypoinsulinemia and hyperglycemia, persons with T1DM also develop insulin resistance. Recent studies have demonstrated that insulin resistance in T1DM is a primary mediator of the micro and macrovascular complications that invariably develop in this chronic disease. Myostatin acts to attenuate muscle growth and has been demonstrated to be elevated in streptozotocin-induced diabetic models. We hypothesized that a reduction in mRNA expression of myostatin within a genetic T1DM mouse model would improve skeletal muscle health, resulting in a larger, more insulin sensitive muscle mass. To that end, Akita diabetic mice were crossed with MyostatinLn/Ln mice to ultimately generate a novel mouse line. Our data support the hypothesis that decreased skeletal muscle expression of myostatin mRNA prevented the loss of muscle mass observed in T1DM. Furthermore, reductions in myostatin mRNA increased Glut1 and Glut4 protein expression and glucose uptake in response to an insulin tolerance test (ITT). These positive changes lead to significant reductions in resting blood glucose levels as well as pronounced reductions in associated diabetic symptoms, even in the absence of exogenous insulin. Taken together, this study provides a foundation for considering myostatin inhibition as an adjuvant therapy in T1DM as a means to improve insulin sensitivity and blood glucose management.
Highlights
While Type 1 Diabetes Mellitus (T1DM) is characterized by hypoinsulinemia and hyperglycemia, persons with T1DM develop insulin resistance
Despite the significance of a healthy, insulin-sensitive, skeletal muscle mass in the management of circulating blood glucose, improving the health of our largest metabolic organ is often overlooked as a therapeutic target in the management of T1DM
This study demonstrates a novel means for attenuating the diabetic phenotype through improvements in muscle health via reductions in myostatin mRNA expression
Summary
While Type 1 Diabetes Mellitus (T1DM) is characterized by hypoinsulinemia and hyperglycemia, persons with T1DM develop insulin resistance. We hypothesized that a reduction in mRNA expression of myostatin within a genetic T1DM mouse model would improve skeletal muscle health, resulting in a larger, more insulin sensitive muscle mass. Reductions in myostatin mRNA increased Glut[1] and Glut[4] protein expression and glucose uptake in response to an insulin tolerance test (ITT) These positive changes lead to significant reductions in resting blood glucose levels as well as pronounced reductions in associated diabetic symptoms, even in the absence of exogenous insulin. Elevations in myostatin expression have been observed in a number of disease states associated with impaired muscle health including Type 2 and streptozotocin-induced diabetes[24,25,26,27,28]. We hypothesized that T1DM mice exhibiting reduced myostatin mRNA expression would demonstrate improved skeletal muscle health resulting in increased insulin sensitivity and reduced blood glucose.
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