Insulin Resistance and Hyperglycemia : The Cellular Metabolism of What Leads to Type-2 Diabetes

This is the intro and conclusion to the paper I just handed in. I cut out all the middle /good stuff because if you aren't into cell metabolism, it is probably not of interest.

Introduction

Hyperglycemia enhances the uptake of glucose into the liver, which thus increases the metabolic pathways of glycolysis, the citric acid cycle, and the generation of energy as ATP. An additional response to hyperglycemia involves the pancreatic release of the hormone, insulin. Beta-cells of the islets of Langerhans produce insulin in the pancreas and these cells are freely permeable to glucose via the glucose transporter, GLUT-2 .1 Glucose transporters (GLUT 1, 2, 3, 4, 5) are transmembrane proteins encoded by distinct genes and have distinct kinetic properties, substrate specificities, and tissue distributions that dictate their functional roles.

The liver, which should cease to produce glucose as the level of blood glucose rises, will increase its release of insulin to lower the blood glucose concentration and increase its utilization and storage in the liver and muscle as glycogen. 1 The utilization and storage of glucose as glycogen involves the glucose transporter, GLUT-4, which is located in heart, skeletal muscle, and adipose tissue. 1 Skeletal muscle is regarded as the principal site for insulin-stimulated glucose uptake, whereas adipose tissue does not take up as much glucose as skeletal muscle. 2, 3 The research indicates that while muscle is the primary uptake site, problems in adipose uptake affect whole-body insulin resistance as well. The goal of this paper was to examine the defects that occur in signal transduction contributing to insulin resistance, hyperglycemia, and thus the defects that lead to Type-2 diabetes. In researching for this goal, two specific areas seemed to be the most significant in these defects. These two contributing factors to insulin resistance involve the GLUT-4 glucose transporter and Beta-cell failure.


It is unclear whether the research indicates that GLUT-4 defects and beta-cell failure are both required to cause hyperglycemia, or eventually cause type-2 diabetes. However, each of these defects independently contribute to insulin resistance and hyperglycemia. The combination of impaired glucose transport, increased insulin resistance, and loss of Beta-cells are all characteristics in type-2 diabetes. At first when cells in the muscle, fat and other tissues become less responsive to insulin, Beta-cells try to keep up by producing more and more insulin.8 This excess insulin in the blood can cause a bout of hypoglycemia, which is a marker for type-2 diabetes. 8 However, the over-production of insulin itself by these Beta-cells could contribute to the apoptosis discussed earlier. Insulin resistance then continues to increase due to the impairments in GLUT-4 translocation potentially caused by increased Serum RBP4 levels, and/or the loss of Beta-cells due to increased apoptosis and/or decreased islet formation.

Conclusion
The mechanisms behind increased apoptosis and decreased islet formation are only being speculated at this point in research. Similarly, the mechanism behind impaired GLUT-4 translocation is also unclear, although other studies strongly indicate that elevation in free fatty acids decrease glucose transport and impair PI(3)K in skeletal muscle.4 The elevation in free fatty acids were associated with increased levels of serum RBP4, which were inversely correlated with GLUT-4 functioning. The research did suggest solutions for reversing insulin resistance, decreasing hyperglycemia, and thus decreasing risk of type-2 diabetes. These solutions include lowering serum RBP4 levels, lowering free fatty acid levels, ( hence why Type -2 Diabetes can literally stop the disease by losing weight aka excess fat) and preserving/restoring Beta-cell function.