title: Myostatin inhibition therapy for insulin-deficient type 1 diabetes.
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 Myostatin(Ln/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.
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Samantha K
authors: SK
authors: Coleman
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Irena A
authors: IA
authors: Rebalka
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Donna M
authors: DM
authors: D'Souza
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Namita
authors: N
authors: Deodhare
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Eric M
authors: EM
authors: Desjardins
authors: McMaster University, Department of Pathology and Molecular Medicine, Hamilton, ON, L8S 4L8, Canada.
authors: Thomas J
authors: TJ
authors: Hawke
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018703:Founder Effect; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000172:deficiency / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D005947:Glucose