By Charlie Rumrill, V Form
Type 2 Diabetes as a Global Epidemic
Type 2 Diabetes mellitus is a group of chronic disorders caused by either the number of pancreatic beta-cells, their ability to function, or the skeletal muscle and liver cells ability to transduce insulin’s signal, all of which result in hyperglycemia. Due to genetic, environmental, and epigenetic factors, Type 2 Diabetes has rapidly become a global epidemic.
In order to understand the pathophysiology, or diseased state, of Type 2 Diabetes, a comprehension of how the body typically regulates carbohydrate metabolism is required. As shown in figure 1, the catabolism, or breakdown, of carbohydrates begins as soon as it is ingested, with salivary amylase enzymes hydrolyzing the large polysaccharides into smaller oligosaccharides. When the salivary mixture is swallowed, it continues through the esophagus to the stomach which denatures the enzymes with its highly acidic environment. Since no enzymes can function in the stomach, the digestion of the carbohydrates temporarily stops until it continues to the small intestine, where more amylase enzymes produced by the acinar cells in the pancreas meet the fluid in the small intestine and continue to hydrolyze the oligosaccharides into simpler disaccharides. As the mixture continues through the small intestine, brush border cells with enzymes attached hydrolyze the disaccharides into simpler monosaccharides, such as glucose. Only now can the once large polysaccharides be absorbed into the bloodstream. From the small intestine, the blood circulates directly to the pancreas, where the pancreatic beta-cells secrete insulin due to the elevated blood-glucose levels. Then, the blood flows to the liver and the rest of the body (Figure 1) where the liver and skeletal muscle cells bind to insulin, triggering more glucose transporters to be embedded in the cellular membrane. Due to the cells having more transporters, more glucose molecules can enter the cell, and the glycogen phosphorylase enzymes can bind them together through dehydration synthesis to form glycogen. Insulin also travels to the adipose tissue, where the glucose is then stored as fats. In addition to the effects of insulin, glucose molecules are constantly being taken into every cell in order for it to have the energy to complete its functions. Over time, due to the glycogen being produced and cells constantly needing glucose the body’s blood-glucose levels then lower. When the blood-glucose levels decrease, the pancreatic alpha-cells secrete the hormone glucagon which, when bound with the skeletal muscle and liver cells, triggers the glycogen to be hydrolyzed and released back into the bloodstream as glucose.
Type 2 Diabetes occurs when the body’s ability to anabolize the glucose into glycogen is hindered or prevented, due to either insulin resistance or a beta-cell deficiency. Type 2 Diabetes can be classified as one of two sub-disorders, the former issue, insulin resistance, being named type 2A and the latter, beta-cell deficiency, being type 2B. Type 2A Diabetes is when although the pancreatic beta-cells are properly detecting a rise in glucose levels and secreting a proper amount of insulin, skeletal muscle and liver cells do not respond to the insulin signal to take in more glucose molecules and store it. One way in which this phenomenon occurs is due to intramyocellular lipids in skeletal muscle cells, which, when hydrolyzed, can create toxic fatty breakdown products and free radicals. These radicals then block the signalling pathway process which would normally be caused by insulin binding to its receptor. Since the signal is not spread throughout the cell, the glucose transporters do not embed themselves into the cellular membrane, causing glucose to build up in the bloodstream and not be taken into the cell and converted into glycogen.
Type 2B Diabetes, on the other hand, is caused by the pancreatic beta-cell dysfunctioning and not producing enough insulin, which can be a long term effects of Type 2A Diabetes. Since the glucose in the bloodstream is not being stored as glycogen, the high levels of blood-glucose remain in the body. The high blood sugar levels in turn cause for pancreatic beta-cells to continuously produce and secrete insulin that is not being effective because of the body’s built up insulin resistance. The long term effects of the over-use of the beta-cells, such as mitochondrial stress or endoplasmic reticulum stress, can cause for them to become dysfunctional and eventually die. As more beta-cells die, the body begins to develop pancreatic beta-cell deficiency and produce even less insulin.
In the last few decades, Type 2 Diabetes mellitus has become a global epidemic, affecting every nation of the world (Figure 2). The main factors for the rapid growth are environmental, such as economic growth and access to food, epigenetic, and genetic. Although it takes thousands of years for genetic variations to become common like Type 2 Diabetes has, genetic factors can, in small part, contribute to understanding of how the disease has become so widespread. Recent genome wide investigations and studies have discovered over thirty different single-nucleotide polymorphisms (SNP) that increase the carriers’ susceptibility to Type 2 Diabetes. Despite each SNP only having a small impact on the risk of acquiring the disease, a combination of many of them can cause someone to be heavily pre-disposed. Due to evolutionary changes in geographically-based genomes, Southeast Asians and Indians have become more prone to having these predispositional SNPs. The combination of these genetic alterations has left this ethnicity to be more susceptible to beta-cell dysfunction and deficiency, making Type 2B their most prevalent form of diabetes.
Another main component for Type 2 Diabetes is the environmental factors involved. The recent economic development of the entire world in the past few generations has caused for many lifestyle changes that the human body has not necessarily been able to keep up with. Physical inactivity and dietary changes have both had severe effects on mostly Type 2A diabetes since they have caused for a sky-rocket in obesity ratings. With less people working manual labor jobs and more people working at desks all day, obesity has become a universal enemy. Obesity is also caused, in part, by dietary factors. The new Western style diet of fast food and sweetened beverages has lead to a shift from healthier lipids, like unsaturated fats, to unhealthier foods, such as trans fats. Also, diets have shifted from more natural carbohydrates such as starches to unhealthy, processed carbs that are stripped of their nutrients and fiber. The digestive system has not evolved or changed to accommodate this new diet, which has caused for obesity and being overweight to become common. Obesity causes for people to be placed at a higher risk for developing Type 2A Diabetes because it can lead to insulin resistance and excessive strain on the beta-cell.
In addition to the immediate effects of the environmental factors, they are also known to cause epigenetic modifications, changing the gene expression or phenotype. The dietary, physical, and aging factors all can cause effects on how the expression of the genes is portrayed (Figure 3). Our epigenome is subject to change many times over the course of a lifetime, especially when there are drastic changes in diets or physical activities. The epigenetics affects the development of Type 2 Diabetes since environmental factors already mentioned can cause changes beyond the physical, short lived ones. Individual’s epigenome can cause for them to stop or slow down the production or secretion of insulin for example.
In conclusion, Type 2 Diabetes can be divided into two sub-categories. Type 2A Diabetes is related to insulin resistance and it caused mostly by obesity, and dietary and physical activity factors. Whereas Type 2B Diabetes is related to beta-cell dysfunction and deficiency, and may have more genetic factors. Both types of Type 2 Diabetes have have grown exponentially in the last few decades as economic growth has lead to large changes in lifestyles and our epigenome.
Charlie Rumrill is a V form boarding student from Natick, Massachusetts.