Diabetes Mellitus Type 2.

Diabetes Mellitus Type 2.

Carl Stuart.

Stuart Medical Series.

Introduction.

Diabetes mellitus is a collective designation of metabolic and endocrine disorders which share a phenotype of hyperglycemia. Studies have shown that diabetes mellitus designates a group of polygenic conditions that are caused by a complex interplay between genetics and environmental factors. Diabetes is classified into different types based on the pathophysiological processes. The two most common types are Type 1 and Type II diabetes (Poretsky, 17).

Diabetes Mellitus Type 2 (DMT2) is an endocrine disorder of glucose metabolism that is characterized by hyperglycemia due to increased gluconeogenesis, relative insulin deficiency, impaired insulin secretion and/or insulin resistance. It was formerly called adult-onset diabetes or NIDDM (noninsulin-dependent diabetes mellitus). This contrasts it to Diabetes Mellitus Type 1 which is characterized by absolute insulin deficiency and also has an early-age of onset. The cardinal symptoms of diabetes is polydipsia (excess thirst), polyphagia (constant hunger) and polyuria (frequent urination). Epidemiological studies have shown that diabetes mellitus type 2 accounts for about 90% of all cases of diabetes, with gestational diabetes and diabetes mellitus type 1 accounting for the remainder of the cases. The prevalence rate of Type II diabetes mellitus is the same in either gender. Statistics have also shown that the condition will have a global prevalence of 300 million persons by 2030. Analytical studies have shown that this can be attributed to the rapid rate of industrialization and urbanization which causes the people to adopt a sedentary lifestyle which ultimately leads to the development of obesity. Research and studies conducted by CDC (Center for Disease Control) have shown that there is a correlation between old age and diabetes mellitus type 2. Studies have also shown that type II diabetes mellitus can be controlled and managed by dietary modification and exercise (Le Roith, Taylor and Olefsky, 49).

Normal Hormonal Processes that regulate Glucose Metabolism.

Glucose metabolism is dependent on glucose uptake from the blood into cells. This uptake is regulated by insulin. Insulin is a 5800 kD hormone synthesized by B-cells of pancreatic Islets. It is made up of two chains which are labeled A and B chains which are connected by disulphide bridges. A precursor molecule for insulin, proinsulin contains a C peptide which is cleaved by specific peptidases in order to release insulin and the C-peptide. Insulin is secreted out of the cells via an exocytosis. The main physiological stimulus for insulin secretion is glucose. Other stimuli for insulin secretion are protein ingestion, gastrointestinal hormones and neural-hormonal control mechanisms. Nutrient ingestion causes substrate (glucose)-mediated insulin secretion. However, in the absence of nutrient ingestion, there is a basal rate of insulin secretion which maintains and modulates the vital intermediary metabolism, such as hepatic glucose production. Thus, circulating insulin concentration is vital in regulating fuel metabolism (Le Roith, Taylor and Olefsky, 87).

The main functions of insulin are explained hereafter. Insulin increases the expression of GLUT 1-7(glucose transporter) and SGLT 1-2 (Sodium-glucose co-transporter) receptors. GLUT 1-7 and SGLT 1-2 are the main glucose transporters which allow glucose to enter into the cell from the plasma. A plasma glucose concentration of about 70 mg/dL (3.9 mmol/L) stimulates insulin synthesis through enhancing the processes of protein translation and post-translational modification of the nascent protein. The proteins are then packaged in secretory vesicles. The process by which glucose stimulates insulin secretion is described below. To begin with, glucose is transported into the B cells via facilitative glucose transporters that are mentioned above. The glucose within the cell is phosphorylated to glucose-6-phosphate via an enzyme-mediated reaction catalyzed by glucokinase. This is the rate-limiting reaction that controls the process of glucose-regulated insulin secretion. Thereafter, the glucose-6-phosphate is channeled into a glycolytic pathway which generates the high-energy compound, ATP (Adenosine Tri-Phosphate). The ATP in turn causes an inhibition of the actions of ATP-sensitive K⁺ channels.  These K-channels are made up of two separate proteins, one of which is Kir6.2 protein, and the other protein being a binding site for specific ligands such as oral hypoglycemics. Kir6.2 protein is an intrinsically rectifying K⁺ channel receptor, and its inhibition induces depolarization of the plasma membrane which in turn opens the voltage-dependent calcium channels, thus causing an influx of Ca²⁺. The calcium ions cause the secretory vesicles containing the insulin to fuse with the cell membrane thus leading to the release of insulin into the plasma. Incretins are stimulatory chemicals released by GIT (gastrointestinal tract) neuroendocrine cells following nutrient ingestion, and they amplify the process of glucose-stimulated insulin secretion while concurrently suppressing glucagon secretion. An example of a potent incretin is GLP-1 (Glucagon-like peptide 1) which is secreted by L cells of enterocytes and they stimulate insulin secretion when blood glucose levels exceed the fasting plasma glucose levels (Le Roith, Taylor and Olefsky, 100).

Upon insulin release into the bloodstream, half of it undergoes first pass effect in the liver, while the unextracted insulin directly enters into the systemic circulation where it interacts and binds to its receptor in target tissues. The insulin receptor has an intrinsic tyrosine kinase activity which allows it to undergo autophosphorylation upon binding to insulin. Autophosphorylation of the receptors leads to the recruitment and activation of intracellular signaling molecules (for example, insulin receptor substrates) and second messengers (such as phosphatidylinositol-3′-kinase, PI-3-Kinase). Adaptor proteins such as IRS (insulin receptor substrates) do initiate complex cascades of dephosphorylation and phosphorylation reactions which lead to a myriad of mitogenic and metabolic effects. IRS causes the activation of the PI-3-Kinase pathway which causes the translocation of glucose transporters to the plasma membrane, and this ultimately results in increased glucose uptake by cells (Le Roith, Taylor and Olefsky, 171).

The other effects of insulin are described below. Insulin increases the rate of entry of amino acids into insulin-sensitive cells. Studies have also shown that insulin stimulates protein synthesis while concurrently inhibiting protein degradation. Insulin also affects enzymatic processes by inhibiting gluconeogenic enzymes while concurrently activating glycolytic enzymes such as glycogen synthase. Thus, it can be inferred that insulin has a net anabolic effect on the body by facilitating and regulating the utilization, interconversion and storage of substrates. Decrease in insulin secretion stimulates glycogenolysis and gluconeogenesis pathways (Poretsky, 67).

Thus, it can be seen that lack of insulin leads to a high plasma concentration of glucose (a condition termed hyperglycemia). In Type II diabetes Mellitus, insulin secretion is impaired but there is a circulating concentration of insulin. However, the secreted insulin does not induce post-receptor effects upon its binding to the receptor. This state of insulin resistance leads to hyperglycemia. During the early stages of Type II diabetes Mellitus, glucose tolerance remains near-normal because the B-cells increase their insulin output exponentially in order to manage the hyperglycemic state. This leads to high plasma insulin levels, and this condition is termed insulinemia. However, as the compensatory hyperinsulinemia progresses, the B cells finally become incapable of sustaining the hyperinsulinemic state. Finally, insulin secretion declines, while hepatic glucose production increases as the glucose is not transported into cells, and thus the cells are starved of glucose, and this state is termed fasting hyperglycemia. During this time, there is relative insulin deficiency. Finally, B cells failure occur (Poretsky, 91).

Works cited.

Le Roith, Derek, Simeon I. Taylor, and Jerrold M. Olefsky. Diabetes Mellitus: A Fundamental and Clinical Text. New York: Lippincott Williams & Wilkins, 2004. Print.

Poretsky, Leonid. Principles of Diabetes Mellitus. New York: Springer, 2002. Print.