How Does The Undergo Muscle Insulin Resistance?

Insulin is a hormone that is produced from what is known as the “islets of Langerhans”, discovered by German Histologist Paul Langerhans, and is required for the utilization of glucose in muscle cells for energy. If the muscles are deprived of glucose for energy conversion, the muscles begin to utilize fat for energy (Roth). This however has toxic side effects, such as the production of high blood levels of Ketone bodies or otherwise known as Acetone. In high quantities, Acetone will accumulate in the blood, leading to brain damage and the possibility of brain death (Roth).

Several upstream kinases have been reported to activate AMPK, including liver kinase B 1 (LKB1) [12]. LKB1 is predominately localized in the nucleus under normal physiological condition, and is translocated to cytosol in response to stimulation, which leads to subsequent AMPK phosphorylation and activation [13]. When activated, AMPK decreases fatty acid levels by phosphorylating and thus inhibiting acetyl-CoA carboxylases (ACC), a critical enzyme for controling fatty acid biosynthesis and oxidation [14]. The activation of AMPK also decreases total cholesterol (TC) and triglyceride (TG) levels by inhibiting the activity of glycerol-3-phosphate acyltransferase (GPAT) and HMG-CoA reductase, respectively [15]. AMPK has therefore been proposed as a major therapeutic target for obesity and obesity-linked metabolic disorders such as hyperlipidemia and atherosclerosis [16]. 5-Aminoimidazole-4-carboxamide-1-b-D- ribofuranoside (AICAR) is one of the activators of AMPK

Type 2 diabetes results from a multitude of defects: impaired insulin secretion, insulin resistance, and defects in GLP-1 secretion and action. Prior to the onset and throughout the course of the disease, beta cell function and pancreatic mass deteriorate; causes may be lipotoxicity, glucose toxicity, increased age, genetics, insulin resistance, and incretin deficiency. Insulin resistance takes place in the liver, adipose, and skeletal tissues (1), ultimately leading to decreased peripheral uptake and hyperglycemia. In the liver, lack of insulin action results in gluconeogenesis and glycogenolysis, further potentiating the hyperglycemia. In fat cells, decreased GLUT4 leads to excessive release of free fatty acids and adipocytokines (2). Because

Insulin resistance is a fundamental aspect of Type 2 diabetes. Insulin lowers blood glucose by suppressing liver glucose production and increases glucose uptake into muscle and fat cells. The majority of glucose gets largely stored in the muscle and adipose tissue contributes little to glucose disposal. Insulin is a critical regulator of adipocytes as it promotes adipocyte triglyceride storage by helping preadipocytes get differentiated to adipocytes. Adipocytes are over 1 billion cells that specialize storing energy as fat and together they constitute the largest endocrine system that communicates to other tissues by adipocyte-released secretagogues including proteohormones lectin, adiponectin, and visfatin. (Redinger, R., 2007) Along

By definition insulin is refer as a hormones which assumes a key in the regulation of blood glucose levels and an absence of insulin can lead to the improvement of the symptoms of diabetes (The global diabetes community, 2014). Decrease insulin concentrations trigger adipose tissue lipase causing lipolysis of triglycerides in glycerol and free fatty with consequent elevation of fatty acid transport into mitochondria where ketone body development happens (Keays, 2007). Understanding the significance of insulin serves to know more about how the body utilizes it for energy. As we know our body is made up of millions of cells, thusly to create energy, this cells need food in exceptionally straightforward structure (Type 2 diabetes, 2014). When we eat or drink, a great part of the nourishment is broken down into a straightforward sugar called ‘glucose’. Basically, glucose is transported through the circulatory system to these body cells where it can be utilized to provide the energy the body requirements for daily exercise. The decrease of glucose levels in blood is caused when the amount of glucose in the blood ascents to certain level; hence, the pancreas discharge more insulin to push more glucose into cells. While to keep blood glucose levels from getting

Manipulation of the myostatin pathway will not only affect degenerative diseases, but it can also help with obesity and type II diabetes. (Lee 2004)

Obesity also affects insulin resistance by having an elevated number of free fatty acids (McCance & Huether, 2014). When these levels are elevated it causes a chain reaction with the body being able to get insulin and making tissues not sensitive to insulin (McCance & Huether, 2014). These alterations can cause not only changes to

Oxidative stress is widely accepted to be associated with dysfunction of pancreatic β-cells as well as insulin resistance in type 2 diabetes (Henriksen et al., 2011). Experimental evidences suggest the involvement of free radicals in the onset of diabetes and more importantly in the development of diabetic complications (Lipinsky, 2001). Studies have revealed decreases in expression of genes for antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase, and catalase in diabetic models (Lenzen et al., 1996). Also a decrease in the activities of the antioxidant/ antioxidant enzyme systems in diabetics are linked to the progressive glycation of the enzyme proteins (Hartnet et al., 2000). The interrelationship between the antioxidative potentials and antidiabetic activities of bioactive compounds is still unclear. In the present study, the extent of free radical damage orchestrated by STZ administration was significantly reduced by the antioxidant composition and combination treatment in a dose-dependent manner; thereby reducing the extent of pancreatic β-cell damages among the rats co-treated with combination therapy and STZ, relative to normal and STZ-only rats. The HFD/STZ-induced diabetic control rats had significantly lower (p< 0.05) of total SOD, CAT, GST and GPx activities among the extracts, cell gevity, antioxidant composition and combination therapy co-treated rats (Figure 4.2.34, Figure 4.2.35, Figure 4.2.36, Figure 4.2.37). HFD/STZ decreased the

The study of oxidative stress and obesity has stimulated several attempts in recent times to define the contribution of the individual components of the metabolic syndrome to oxidative stress as it is in metabolic syndrome patients. Although there have been recent attempts to do so, studies have revealed the role of obesity as a critical and core component in the development of metabolic syndrome. Essentially, obesity plays an integral role in amplifying oxidative stress. It has been proven that patients who are obese show oxidative stress-induced decreased vasodilatory response to acetylcholine. This response inversely relates to body mass index, waste to hip ratio, fasting insulin and insulin resistance [70]. This situation remains to be

do not in themselves enhance muscle growth in all individuals who are following their usual diet and exercise habits. The decline in insulin that occurs during prolonged exercise further increases this challenge. These data emphasize the importance of the

Insulin secretion is further regulated by several hormones and neurotransmitters. Acetylocholine and cholecystokinin promote phosphoinositide breakdown with a consequent mobilisation of Ca+2 from intracellular stores leading to activation of PKC. Other factors including glucagon-like peptide 1 or glucose-dependent insulinotropic peptide raise cyclic AMP (cAMP) levels and activate PKA. Insulin secretion can also be regulated by chemical compounds. Tolbutamide is a sulphonylurea inhibitor that inhibit the ATP-sensitive K+ channels, thus stimulating insulin secretion even at low glucose concentration, whereas nifedipine is a blocker of Ca+2 channels resulting in inhibition of insulin release at inducible glucose concentration [(Henquin, 2000), see Fig. 5. Whereas, insulin is the only hormone that decrease blood glucose level, there are a group of hormones that can elevate blood glucose levels, such as glucagon, cortisol, adrenaline, growth hormone and thyroid

Several studies described that a significant increase in lipid peroxidation were noted in diabetic rats (Limaye et al., 2003). The present findings are in accordance also with previous report indicated significant increase in TBARS in STZ diabetic rats (Murugan and Pari, 2006). The lipid peroxidation may attribute to the hypoinsulinemia caused by STZ progressive deterioration of normal pancreatic β-cell function. This hypoinsulinemia induced an increase in the activity of fatty acyl Co-A oxidase that initiate the β-oxidation of fatty acids resulting in lipid peroxidation (Baynes and

Insulin referred to as hormone is secreted using the pancreas which control glucose levels in the blood. Without insulin, cells cannot use the energy from glucose to perform the numerous functions within the body. The main metabolic fuel for cell utilization used in energy production are glucose and fatty acids. In addition, equilibrium between food intake and energy expenditure may depend on energy homeostasis and metabolism. However, glucose is the most important fuel with a normal level ranging from 4-3-6.5mmol/l needed for cell function and is controlled by multifaceted system between the pancreas, liver, adipose tissue, muscle and brain.

This is due to a few mechanisms including accumulation of intracellular fatty acid metabolites, inflammatory signaling, oxidative stress, mitochondrial dysfunction, and the Randle cycle. With an increase in FFAs the ability of adipose tissue to store fatty acids can be exceeded, which leads to FFA accumulation in the liver and skeletal muscle. (35) This accumulation of intracellular content of fatty acid metabolites subsequently diminishes insulin-receptor signaling, decreasing translocation of GLUT4 and subsequent glucose uptake. (31, 35) FFAs also increase inflammatory signaling via Toll-like receptors (TLR) and increased secretion of cytokines. TLR detect microbes and transmit inflammatory signaling and FFAs can signal through TLR-2 and -4 to induce pro-inflammatory gene expression. A loss of TLR-2 and -4 has been shown to resolve high fat induced insulin resistance in mice.

Insulin deficiency also causes protein metabolism in skeletal muscle.This leads to increased release of alanine to the circulation.These substances then enter the liver where they are used as substrates for gluconeogenesis which is overly stimulated in the absence of insulin and the elevated glucagon.The increased rate of glucose production in the liver,coupled with the glucagon-mediated inhibition of glucose storage into glycogen results in the overproduction of glucose release from the liver and leads consequent hyperglycemia.