Diabetes currently afflicts 34.2 million Americans, and approximately 1 in 3 are prediabetic (CDC, 2020). Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia due to the combination of insulin resistance and insufficient insulin production. Unfortunately, the reoccurring hyperglycemia in association with long‐term insulin malfunction has been tied to damage or failure of differing organs such as kidney, nerves, and vasculature (American Diabetes Association, 2007). The renal dysfunction caused by the hyperglycemia is the causative agent of two prominent clinical signs of T2D, polydipsia and polyuria. The most substantial predispositions for T2D are obesity, poor nutrition, sedentary lifestyle, and aging, which all negatively effects an individual’s skeletal muscle mass as well. Skeletal muscle is considered the largest metabolic reservoir due to its role as a glucose sink. Skeletal muscle can be categorized into oxidative and glycolytic fibers; however, oxidative fibers are more insulin sensitive and resistant to fatigue. Peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α) is an endogenous protein and potent activator of multiple metabolic pathways including: mitochondrial biogenesis, liver gluconeogenesis, oxidative muscle fibers, and blood glucose absorption and handling. Overexpression of PGC1α is known to increase insulin‐sensitive oxidative muscle fibers, but what remains unknown is whether it is effective at preventing cardiometabolic disease and skeletal muscle dysfunction in a mouse model of T2D. Our hypothesis is that overexpression of PGC1α will improve muscle performance by preventing fatigability, will preserve glucose homeostasis, and protect against kidney function in a mouse model of T2D. The T2D mouse model utilized was the db/db mouse, which possesses a dysfunctional leptin receptor and thus is chronically hyperphagic. By 12 weeks of age, it is well characterized as a model of Type 2 diabetes. Overexpression of PGC1a was obtained by crossing the MCK‐PGC1alpha transgenic mice onto the db/db background. Adult mice were used for the duration of the experiments with a total of four mouse groups; a lean control, a lean PGC1α overexpression, an obese control, and an obese PGC1α overexpression mouse. Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), muscle function (in vivo plantarflexion of gastrocnemius muscle), and fluid dynamics (via metabolic cages). Overexpression of PGC1α improves glucose homeostasis, decreases muscle fatigability, and conserves fluid dynamics in a T2D mouse model. Furthermore, the overexpression of PGC1α returns the blood glucose levels and renal function in the T2D models back to levels of the controls, restoring them to a normal physiological state. Muscle rate of fatigue was significantly decreased in both the lean and obese mice, providing superior performance against fatigability. Altogether, this data suggests that targeting PGC1α is a possible intervention for T2D and potentially ...
Type 1 Diabetes Mellitus (T1DM) is a disease characterized by the destruction of insulin‐secreting pancreatic beta cells and results in hyperglycemia, muscle wasting, and vascular dysfunction. Patients afflicted with T1DM suffer from increased morbidity and early mortality, largely driven by an inability to appropriately maintain glucose homeostasis. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream. The myokine myostatin is a potent negative regulator of muscle growth and is upregulated in T1DM patients but downregulated following regular exercise. Physical exercise is also known to improve cardiovascular health and increase insulin sensitivity of muscle, but many T1DM patients are unable to exercise at a level that conveys benefit due to muscle atrophy. Thus, directly targeting skeletal muscle, independent of exercise, may prove beneficial for T1DM therapy. Our hypothesis is that genetic deletion of myostatin will preserve glucose homeostasis, maintain muscle function, and protect against vascular dysfunction and cardiometabolic effects in a mouse model of T1DM. T1DM was induced via streptozotocin (STZ) in adult male mice with (WT) and without myostatin (MyoKO). Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), fluid dynamics, muscle function (in vivo plantarflexion), and vascular function (ex vivo pressure myography of gracilis arteriole). Myostatin deletion inhibited STZ‐induced increases in plasma glucose, preserved fluid dynamics, and prevented decreases in muscle function, independent of insulin. Further, endothelial function was protected with myostatin deletion. Taken together, this data suggests that myostatin inhibition may be a target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1DM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.