Type II Diabetes: Review

Abstract

Type II diabetes is a chronic metabolic disorder that is characterized by very high blood sugar levels in the circulation. The disease has been known for thousands of years now. It is one of the major killer disorders, but advances in the medical field now provide for remarkable management of the condition. Type II diabetes results from insulin resistance whereby the body fails to adequately use the insulin hormone that regulates glucose levels by aiding the entry of glucose into cells where glucose is broken down to yield energy in the form of ATP. Glucose accumulates in the bloodstream to high levels (hyperglycemia) when the cells get insensitive to insulin because no glucose gets into the cells. The liver is stimulated to produce more insulin as an inflammatory response to counter this anomaly, leading to hyperinsulinemia. Eventually, Type II diabetes complications occur. They include kidney failure, heart attack, and blindness. Type II diabetes is associated with high levels of ROS, which increases oxidative stress. Programmed cell death is observed after increased oxidative stress. All these processes at the cellular level worsen the presentation of diabetes type 2.

Introduction

Diabetes is a term that is used to refer to higher blood glucose/sugar levels than normal. The term is borrowed from Greek words that mean “pass through”. This term was associated with the major symptom of the disorder, which is passing too much urine (Porter, 2013). The human body requires energy to perform normal functions. This energy is obtained from the breakdown of foods, mainly carbohydrates, to produce glucose. A hormone known as insulin aids the glucose to gain entry into the body cells from the blood circulation system (Fradkin, & Rodgers, 2013). Diabetes Type II is a condition that occurs when the body produces insufficient insulin or the body is unable to use the insulin appropriately. It is a chronic condition that is characterized by very high blood glucose levels (Das, & Elbein, 2006). Type II diabetes is the most common type of diabetes, affecting 90%-95% among the 26 million Americans suffering from diabetes (Fradkin, & Rodgers, 2013). Unlike diabetes Type I, diabetes Type II is characterized by production of insulin, but either the pancreas produces insufficient quantities or the body fails to use the insulin produced well (Porter, 2013).

Diabetes is a disease that has affected humans for thousands of years now. The disease has the potential of causing deaths due to the complications associated with it. For instance, the disease was rated as the 7th killer health condition in the US in 2011. Diabetes is also a concern for other countries in the globe. It accounts for more than 100 billion dollars in the yearly expenditure of the United States healthcare budget (So et al., 2000). It was first recognized by the Egyptians in their manuscript that dates as back as 1550BC. Diabetes was known as “sweet urine” at that time and it was tested by finding out whether the patient’s urine attracted ants (Porter, 2013). Injection of insulin in patients with the diabetes disorder at this moment managed to combat the condition remarkably, but not all patients were responsive to this treatment. It was, therefore, determined that there were two types of diabetes, which Harold Himsworth classified as “insulin-sensitive” and “insulin-insensitive” diabetes. These are now known as Type I and Type II diabetes respectively (Porter, 2013).

Cellular understanding of Type II diabetes

The normal functioning of the cell

Energy in the body is mainly produced from synthesis of carbohydrates to make glucose. Having been digested, the carbohydrates get into the blood circulation system, in the form of glucose, from where they can either be used by various tissues directly or stored in the form of glycogen for later use based on the metabolic needs of the body (Pillay, & Govender, 2013). The pancreas is signaled to produce a hormone known as insulin into the blood circulation system in situations whereby the blood sugar levels go above the normal. The hormone enables the excess glucose to penetrate into the body cells via a signaling pathway of insulin in a healthy individual (American Diabetes Association 2013). Glucose in the cells is turned into the ATP form of energy. The main process involved is called glyoclysis. However, other processes such as the citric acid cycle are important in converting glucose into a form that can be stored in body cells. In normal situations, normally about 36 ATP units are obtained from these carbohydrate/ATP conversion processes (Pillay, & Govender, 2013).

The signaling pathway of insulin is a biological process that triggers various multi-cellular functional effects on target cells, including muscle cells, fats, and liver cells. Insulin hormone regulates the levels of glucose in the blood circulation system. Besides, it is also known to take part in the metabolism of lipids and proteins. Insulin is produced via endogenous secretion into the bloodstream by cells known as beta islets located in the pancreas (Das, & Elbein, 2006).

The hormone affects the metabolism of carbohydrates in varied ways. It raises the glucose transport rate across the membrane of muscle cells and adipose tissue. This is achieved by activation of Glut4. Insulin also stimulates the muscle, fat, as well as the liver to synthesize glycogen. It increases the glycolysis rate in these cells and inhibits the breakdown of glycogen (glycogenolysis), as well as glucogeneosis in the liver. In the metabolism of protein, insulin affects this process by increasing the rate of transportation of amino acids from the circulation into tissues. It increases the synthesis of proteins in the liver, muscles, as well as the adipose tissue. It also minimizes the formation of urea and the degradation of the proteins in these cells (Fradkin, & Rodgers, 2013). The hormone further affects the lipid metabolism by minimizing the rate of oxidation of fatty acids, thereby inhibiting the breakdown of lipids. It also increases the synthesis of fatty acids and triglycerol, formation of Low-Density Lipids (LDL), and uptake of triglycerides from the circulation into the muscles (Bitar et al., 2010).

The hormone insulin performs these functions through specific receptor binding to the surfaces of cells like the liver, the muscles, and the adipose cells. The insulin activates the receptors to start self phosphorylation. This further phosphorylates other substrates like insulin receptor substrate 1 and 2, which play a central role in the proceeding sub pathways of insulin, P13k and MAP (So et al., 2000).

In human beings, carbohydrates are stored primarily in the liver and muscle cells in the form of glycogen, which is a glucose polymer with up to 12,000 units of glucose. The storage happens following a process referred to as glycogenesis (Das, & Elbein, 2006). As soon as glucose gets into the liver and muscle cells through the help of insulin, hexokinase or glucokinase immediately convert it into Glucose-6-Phosphate (G6P). The G6P is, in turn, converted into glucose-1-phosphate (G1P) by phosphoglutomutase, then into UDP-glucose by G1P-uridyltransferase, and finally UDP-glucose is removed by glycogen synthase enzyme and deposited into glycogen stores. Glycogen is broken down for energy use via the glycolysis process stimulated by glucagon enzyme produced by alpha islets in the pancreas when blood glucose levels go down and carbohydrates are unavailable for breakdown. In addition, an alternative process to obtain glucose, gluconeogenesis, can be used. The biochemical process takes place in the liver where glucose is synthesized from fats.

The normal functioning of the cell
Source: OSU (n.d.).
Type 2 Diabetes
Source: Porter (2013).

Diabetes occurs when the cells responsible for taking glucose out of the blood system into the cells for conversion into energy (liver cells, muscle cells, and adipose cells) fail to adequately react to the circulating insulin hormone. The sensitivity of these cells towards insulin is lost, a condition known as insulin resistance (Bitar et al., 2010). Consequently, the level of glucose/sugar in the bloodstream goes up. The increase in the glucose levels in the blood circulation beyond the normal range triggers a signal as a body reaction towards this change in the pancreas, which reacts suddenly by increasing the secretion of insulin hormone. Resultantly, insulin levels in the bloodstream go high, a condition that is referred to as hyperinsulinemia (Fradkin, & Rodgers, 2013). At the same time, the liver cells also gain insulin resistance. The cells are stimulated to produce a lot of glucose as a response towards insulin resistance. The sugar accumulates in the bloodstream owing to the fact that glucose is not being absorbed properly into the cells due to inadequate use of insulin hormone by the cells. This leads into very high levels of glucose, a condition that is known as hyperglycemia (Bitar et al., 2010).

The red blood cells are damaged due to the increase in blood glucose because the molecules of glucose are affixed to the exterior part of the red blood cells, resulting in the formation of a crystalline crust. The coarse crust is the one that is responsible for the damage of arteries and capillaries throughout the body (Henriksen et al., 2011). Further, the body reacts by attempting to repair this damage by signaling the liver to produce more cholesterol as an inflammatory response. However, this brings about the formation of an arterial plaque that can cause more damage to denser capillaries like those located on the hands and feet and fragile capillaries like those responsible for feeding the kidney and the eyes. All these series of occurrences lead to notable complications that characterize the major symptoms of Type II diabetes, including blindness, kidney failure, stroke of the heart, as well as heart attack and amputation. Other health issues that accompany Type II diabetes include high blood pressure, high levels of cholesterol, high inflammations, erectile dysfunction, as well as periodontal disease (Henriksen et al., 2011).

Cellular dysfunction related to Type II diabetes

The production of reactive oxygen species (ROS) in the cells of the body is primarily done by the mitochondria, although they may be produced by other cell organelles like the peroxisomes. Most pathophysiological disorders like Type II diabetes have been associated with high levels of ROS. The islet cells are the chief producers of ROS in people suffering from Type II diabetes compared to people who are non-diabetic. High levels of ROS production have been associated with obesity, as well as hyperglycemia (Pillay, & Govender, 2013). The skeletal muscles rely on ROS to remain responsive to presence of insulin. Moreover, insulin signaling may be inhibited by ROS (Das, & Elbein, 2006).

ROS support the fragmentation of DNA, cross-linking of proteins, and oxidative breakdown of phospholipids. They also activate numerous stress pathways. It is, therefore, imperative for the ROS to be promptly gotten rid of from the mitochondria. Patients suffering from Type II diabetes normally exhibit abnormalities in the morphology of their beta mitochondria islet cells, including hypertrophy, circular shape, and denser mitochondria in comparison to the beta mitochondria cells of people who are non-diabetic (Sanghera, & Blackett, 2012). High ROS levels have been associated with altered morphology seen in mitochondria of diabetic individuals. Moreover, high ROS trigger oxidative stress, which plays a role in the breakdown of lipids, as well as the damage of cell membranes and DNA. This, in turn, triggers a series of events that worsen the severity of the Type II diabetic condition (Pillay, & Govender, 2013).

Reduced beta-cell mass and function plays a role in the pathogenesis of the failure of the beta cells, which is common in individuals with Type II diabetes. Increased beta-cell death by apoptosis has been associated with decreased beta-cell volume in individuals suffering from Type II diabetes. Apoptosis is a term that is used to describe a form of programmed cell death that plays a major role in the elimination of defective, old, as well as unimportant cells from the body. Notably, Type II diabetes is characterized by a reduction in beta-cell mass as a result of high apoptosis of these cells. Cytochrome C is secreted from the mitochondria during apoptosis into the cell cytoplasm via the pro-apoptotic stimuli (American Diabetes Association, 2013). Apoptosomes that activate caspase-9 are then formed with the aid of the cytochrome C. The caspase-9, in turn, activates caspaces 3, 6, and 7, which are executioners that degrade the cell during programmed cell death (Pillay, & Govender, 2013). For instance, renal failure in Type II diabetic individuals has a very close relationship with a high apoptosis rate that accompanies hyperglycemia. In the insulin signaling pathway, hyperglycemia decreases the activation of Akt, a threonine kinase controlling metabolism of proteins, glycogenesis, synthesis of proteins, and death of cells in the P13K sub-pathway. It also raises the activity of p38 MAPK (Singh, 2011).

The formation of HbA1c, a combination of hemoglobin with glucose in the body by glycation occurring when hemoglobin is exposed to high blood glucose levels, is proportional to the amount of glucose in the circulation (American Diabetes Association 2013). Many complications that accompany Type II diabetes are associated with high HbA1c levels, which are in turn associated with the high risk of cardiovascular disorder in diabetic individuals. Lipids are stored in two forms in the muscles; extramyocellular lipid (EMCL) and intramyocellular lipids (IMCL). High levels of IMCL reduce the insulin sensitivity remarkably in human beings, especially when the functioning of mitochondria is compromised (Singh, 2011).

References

American Diabetes Association. (2013). Standards of medical care in diabetes–2013. Diabetes Care, 36(Suppl 1), S11-66. Web.

Bitar, M. S., Ayed, A. K., Abdel-Halim, S. M., Isenovic, E. R., & Al-Mulla, F. (2010). Inflammation and apoptosis in aortic tissues of aged type II diabetes: Amelioration with α-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism. Life Sciences, 86(23/24), 844-853. Web.

Das, S. K., & Elbein, S. C. (2006). The genetic basis of type 2 diabetes. Cellscience, 2(4), 100-131. Web.

Fradkin, J., & Rodgers, G. (2013). Diabetes research: a perspective from the National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes, 62(2), 320-326. Web.

Henriksen, E. J., Diamond-Stanic, M. K., & Marchionne, E. M. (2011). Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radical Biology & Medicine, 51(5), 993-999. Web.

OSU. (n.d.). Cell biology of disease and exercise. Web.

Pillay, K., & Govender, P. (2013). Amylin uncovered: a review on the polypeptide responsible for type ii diabetes. Biomed Research International, 1-17. Web.

Porter, E. (2013). Type 2 diabetes: History of type 2 diabetes. Web.

Sanghera, D. K., & Blackett, P. R. (2012). Type 2 diabetes genetics: Beyond GWAS. J Diabetes Metab, 3:198. Web.

Singh, S. (2011). The genetics of type 2 diabetes mellitus: A review. Journal of Scientific Research, 55, 35-48.

So, W. Y., Ng, M. C., Lee, S. C., Sanke, T., Lee, H. K., & Chan, J. C. (2000). Genetics of type 2 diabetes mellitus. Hong Kong Med J., 6(1), 69-76

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