a) Background and Significance
Type 2 Diabetes Mellitus is a chronic disorder characterized by two main features: high blood glucose level (hyperglycemia) and insulin resistance. The disorder was formerly referred to as non-insulin-dependent diabetes mellitus. The pathophysiology of type 2diabetes is progressive, characterized by decreased insulin sensitivity, deteriorating cell function, and decreased incretion function (Phielix and Mensink, 2008; Misra, 2008).
In human studies, people with type 2 diabetes have a decreased PGC-1α expression compared to healthy subjects (Wagner et al., 2008; Cantó and Auwerx, 2009; Kang, 2012). The skeletal muscles of people with type 2 diabetes and those of their relatives who are asymptomatic have a decrease in mRNA expression for PGC-1α. Due to increase in sedentary lifestyle and obesity, there has been consistence increase in the prevalence of type 2 diabetes (Cantó and Auwerx, 2009).
Influence of changes in expression of PGC-1α on oxidative metabolism in non-diabetic mellitus control, insulin resistance, and patients with type 2 diabetes has been extensively studied. Firstly, one study shows that increase in expression of PGC-1α within normal physiological limits leads to improvement in oxidation of fatty acids (Benton, Wright, and Bonen 2008). It further states that the increase causes increase in insulin sensitivity. However, this is not the case when PGC-1α is over expressed beyond normal limits (Benton, Wright, and Bonen 2008; Dillon, Rebelo, and Moraes, 2012). Another study on mice also shows that over expression of PGC-1α beyond normal physiological limits in vivo induces insulin resistance (Kang and Li, 2012). . This is attributed to accumulation of fatty acid translocase-mediated lipid (Phielix, and Mensink, 2008; Ramjiawan, 2010).
Development of IR in the context of type 2 diabetes is highly linked to reduction in the oxidative capacity of mitochondria (Dillon, Rebelo, and Moraes, 2012). A study by Hayat (2013) also shows that skeletal muscle plays a major role in development of insulin resistance hence diabetes mellitus type 2. According to Hayat, most people with diabetes mellitus type 2 also exhibit high lipid accumulation in their skeletal muscle cells. Besides, they tend to present with decline in the activity of skeletal muscles. He points out that exercise is instrumental in increasing lipid oxidation of skeletal muscles as well as increasing mitochondrial activity. Exercise also helps increase the expression of PGC-1 alpha. Consequently, Hayat states that exercise is very important in managing diabetes mellitus type 2. In this study, Hayat observed increased mitochondrial activity among the subjects following an intense training (SPIRIT) (Hayat, 2013).
Several Programs that promote healthier diet and more active lifestyles have been put in place. However, Exercise and caloric restrictions alone as a way of treating type2 diabetes have failed to achieve adequate glycemic control within one year for the majority of patients. It is so difficult for patients to modify their long term habits. Most of them will ultimately require pharmacotherapy to restore normoglycemia. This leaves majority of the patients with poor glycemic control. Insulin therapy is the only medication which has been currently approved by medics as able to bring back patient to glycemic target at any point in the progression of the disease. It is always prescribed after OADs have failed, and to make it worst, often later than the ideal. Unfortunately, several characteristics that are conventionally linked to human insulin limit its potential for this purpose. When original human insulin is injected intravenously, it can have a half-life of 17minutes. It can also exhibit a short duration of action (Phielix and Mensink, 2008).
The induction of PGC1α levels can therefore be the best strategy to boost mitochondrial biogenesis (Krishnan, 2012; Um, 2012). PGC-1α helps in metabolism of multiple energy substrates. It promotes mitochondrial biogenesis and has been associated with increased skeletal muscle and mitochondrial transcription factor (tFAM) of expressed mice. This shows a color change and increase in mRNA in laboratory testing unlike the unexpressed mice (Cantó and Auwerx, 2009). Studies show that PGC-1α has a decrease in mRNA and lower protein content of ATP synthase and mitochondrial respiratory chain proteins .This reduction in ATP synthase and mitochondrial respiratory chain proteins is also used in the defense against antioxidants (Andreux, Houtkooper, and Auwerx, 2013). There is better control of reactive oxygen species with increase in oxidative capacity of mitochondrial.
Since this study aims at providing insight into the role of PGC-1 alpha expression in regulation of mitochondrial activity, it will give way to other studies aimed at producing an appropriate pharmacological therapy for disorders associated with mitochondrial dysfunction. Insulin resistance can be reduced through improvement of PGC-1 alpha expression. This study may also give to studies that may lead to production of medications that enhance increase in PGC-1 alpha expression. This would be very instrumental in managing diabetes especially among people with obesity whose occupations do not provide enough opportunity for exercise which is a way of improving PGC-1 alpha expression.
This study provides the significance of considering manipulation of expression of PGC-1alpha as a therapy to address mitochondrial dysfunction. The study will lead to a more efficient therapy for treatment of many mitochondrial defects that will eventually help in the treatment of diabetes. By altering the level of expression of PGC-1 alpha, improved function of mitochondria would be achieved.
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