The Diabetic Cycle

Diabetes Mellitus is commonly categorized into two different subsets: Type 1 diabetes (T1DM) and Type 2 diabetes (T2DM). Within the pancreas are small tissue groups called ‘islets of Langerhans’, which contain beta cells. Beta cells are responsible for the production of insulin in response to ingested glucose. At high glucose concentrations, insulin is released into the bloodstream and used by various organs to signal glucose uptake. This occurs via insulin binding to cell receptors on targeted organs, which will activate glucose transporters and move glucose into the cell. In T1DM we observe a malfunction where destruction of the beta cells in the islet of Langerhans leads to a loss of insulin production. This destruction is an autoimmune response that reacts rather quickly and is still being studied. For the majority of this summary, T1DM will be excluded in diabetic generalized statements and we will primarily discuss T2DM almost exclusively.

T2DM is classically defined by an increase in systemic insulin resistance. The dysfunction in T2DM is associated with cells that are receiving the message from insulin. While insulin is sometimes able to bind to cell insulin receptors, one theory is that downstream pathways involving secondary messengers are blocked by inflammatory cytokines and hormones caused by large concentrations of circulating fatty acids in the blood. (Hardy, 2012) When insulin signaling is being blocked between cells, a high concentration of glucose is circulating in the bloodstream. High blood glucose levels will invariably stimulate the beta cells to produce more insulin. Eventually there is enough insulin to overwhelm the cellular resistance and to push glucose through. However, this overcompensation known as hyperinsulinemia inevitably leads to a burnout of beta cells. These cells begin to dwindle and as insulin levels decrease, the cellular resistance again resumes and a detectable level of diabetes occurs. At this point we can see T2DM individuals develop insulin dependency similar to T1DM persons.

Major long-term complications due to diabetes are related to the onset of many disorders. However, the damage to the endothelial cells in the blood vessels is one of the major concerns. As glucose is responsible for the transport of all substrates into cells, hyperglycemic blood will also lead to hypertriglyceridemia and hypercholesterolemia. (Ouchi, Noriyuki. 2011) Under these conditions, the body rapidly tries to organize excess material by introduction of cholesterol into the basement membrane of endothelial cells. (Kelley, Goodpaster. 2001) With massive energy deposits into subcutaneous and visceral organ areas, an increase in both the quantity and mass of local adipocytes is observed.  This event often leads to inflammatory cytokines produced by the adipose tissue, known as adipokines. (Ouchi, 2011) These hormones are generally involved in energy metabolism and it is believed that the chronic inflammatory effects lead to a variety of systemic metabolic dysfunctions. In recent studies it has been observed that high levels of carbohydrates in the body can have significant decreasing effects on the ability of the mitochondria to metabolize fatty acids. This increase in fatty acid and carbohydrate disposal in bodily tissues, due to lack of catabolic breakdown, is perhaps one of the major causes of obesity following or seen in conjunction with T2DM. (Hardy, et. al. 2012) This will be discussed in a later part of the paper relating the link between excess triglycerides in skeletal muscle and consequent insulin resistance.

While diabetes develops alongside or because of the increase of visceral body fat, many other diseases are at high risk. In the late 19^th century, Dr. Otto Heinrich Warburg hypothesized that cancer growth is primarily caused by an overabundance in anaerobic respiration. A normal cell would use glycolysis to provide pyruvates to be oxidized within the mitochondria. However, as aforementioned, studies have shown a decreased mitochondrial performance at high levels of carbohydrates. (Goodyear, Kahn. 1998) Thus we are inclined to study his hypothesis further, as one major onset of cancer could very well be interpreted as a diabetic induced mitochondrial dysfunction. It is understood that cancer arises in many individuals who have no signs of diabetes and the secondary causes to cancer are extremely numerous and complex. Nonetheless, it is proposed that perhaps the increase in fatty acid deposits throughout the body inevitably blocks the uptake of glucose via insulin. (Kelley, Goodpaster. 2001)

Fig.1- a,b,c,d : Visual representation of lipid and cytokine production, movement, and deposition with subsequent tissue effects. (Kelley, Goodpaster. 2001)

Revisiting the process of excess carbohydrates being stored in both subcutaneous and visceral adipose tissue allows us to identify the unique problems that an overabundance of lipids can cause for different areas of the body. Insulin resistance throughout a system can be measured by the decreased glucose disposal / uptake rate in blood and metabolically active organs or tissues. Along with these two adipose tissues, two organs / tissues play key roles in systemic insulin processing. What is interesting to note is that hyperglycemia and hyperinsulinemia are not exhibiting singular symmetric effects in these different tissues. (Brown et al. 2013)

Previously we have believed that the body holds a complete systemic resistance to insulin. We now recognize tissues react to insulin almost selectively, activating some pathways and ignoring others, such as the pathway for glucose uptake. In the liver a unique response to insulin continues to produce glycogen, failing to suppress gluconeogenesis, but also continues to stimulate fatty acid synthesis. (Brown et al. 2013) This overproduction of lipid and carbohydrate energy could have indications for the obesity factor of T2DM.

In skeletal muscle, we observe a decline in glucose transport by inhibition to early parts of the GLUT chain; meanwhile also seeing a decrease in glycogen synthesis. Intriguing that the uptake of glucose via insulin is inhibited, yet the process of down-regulating gluconeogenesis via insulin is activated. Simply, insulin is not activating the glucose absorption needed by muscle, but is actively telling muscle to stop making and storing its own energy. If lipid storage is overabundant, adipose tissues surrounding muscle layers are able to overflow excess into skeletal muscle fibers. (Ouchi et al. 2011) This can be demonstrated in a visual manner by Figure 1, box (b) and box (d). Notice that in box (b) we observe lipotoxicity occurring post-tissue-deposit. However in box (d), due to the presence of inflammatory cytokines or adipokines, lipotoxicity is developing pre-tissue-deposit.  Unfortunately, both of these pathways lead to an increase in insulin resistance.       

Skeletal muscles are typically adept at oxidizing fat, a process which acute exercise can usually increase. (Melanson, Edward, Maclean 2009) The primary source of fast energy for skeletal muscles, besides muscle glycogen during exercise, is lipids; specifically circulating long chain fatty acids derived from lipolysis of subcutaneous and visceral adipocyte deposits. (Thent, et al. 2013) However, as insulin and glucose levels rise in the blood, Figure 1 (b) and (d) show that lipid levels in skeletal muscles are considered toxic.

Thus as hyperglycemic blood led to hypertriglyceridemia, skeletal muscles become trapped in a viscous cycle. Simple mechanics dictate that if a tissue has “too much” of one energy source, it would not need to accept more energy from another source. With toxic overabundant levels of lipid energy, the muscles ‘reject’ the uptake of carbohydrate energy via insulin signaling. This should lead to the oxidation of fat cells to provide muscular ATP; however as mentioned previously, extremely high levels of blood glucose causes an adverse reaction to mitochondrial fatty-acid metabolism.  (Holten, Zacho, Gaster. 2004)

Therefore as hyperinsulinemia begins to take place in efforts to reduce the hyperglycemia, some insulin signaled pathways are activated and others are ignored. This unfortunate selection of pathways then causes hypertriglyceridemia. Though, as lipids have an “out” route from adipose tissues into organs, liver and skeletal muscles, lipotoxicity occurs. (Kelley 2001) This in turn produces adipokines and signals muscle respiration of fatty acids and thereby rejecting glucose intake via insulin resistance. Coming full cycle, beta cells cannot maintain this level of hyperinsulinemic production and begin to fail.  Unfortunately this cycle shows that without intervention, small signs of diabetes can lead to cyclic processes which develop systemic insulin resistance and full symptom diabetes mellitus.  Noting that this increase in insulin resistance is due to defects in fatty-acid oxidation via mitochondrial metabolism then brings us back to Dr. Warburg’s hypothesis for cancer cells. (Ouchi 2011)

            While not investigated here, many diabetic patients develop other disorders including cancer at a higher rate than the general populous. While the cure to cancer is an unknown amount of time away, perhaps the preventative measures to cancer are now. Further research indicates that exercise as a form of preventative treatment or even ongoing conditional therapy for obese and T2DM patients is extremely effective. This is in part contributed to ongoing studies involving aerobic exercise. Aerobic exercise improves physiological parameters such as blood glucose levels, glycemic controls, and lipid profiles while also restoring endothelial function in arteries. (Balkau, et al. 2008)

            While this is still an on-going field of research, it is clearly evident that exercise, nutrition, obesity, and diabetes are unassumingly linked. For the future, research of pathways, proteins, receptors, and hormones, which dictate systemic insulin resistance, will be required to ‘cure’ the disorder. Though, it is a personal responsibility to observe healthy lifestyle habits that provide effective measures for both preventing and treating diabetes mellitus. 

REFERENCES:

Balkau, Beverley et al. “Physical Activity and Insulin Sensitivity: The RISC Study.” Diabetes 57.10 (2008): 2613–2618. PMC. Web.  Sept. 2016.

Brown, Michael S. et al. “Selective versus Total Insulin Resistance: A Pathogenic Paradox.” Med Sciences 7:2 (2013): 95-96. PMC. Web. Sept. 2016.

Goodyear LJ, Kahn BB,. “Exercise, Glucose transport, and insulin sensitivity.” Annual Review Medicine. 49: 235-261. (1998) PMC. Web. Sept 2016.

Hardy, Olga T., Michael P. Czech, and Silvia Corvera. “What Causes the Insulin Resistance Underlying Obesity?” Current opinion in endocrinology, diabetes, and obesity 19.2 (2012): 81–87. PMC. Web. Sept. 2016.

Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F. “Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes.” Sports Med. 53 (2): 294-305. (2004) PMC. Web. Sept 2016.

Kelley D, Goodpaster B, “Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance.” Diabetes Care 24.5 (2001) 933-41. PMC. Web. Sept 2016.

Melanson, Edward L, Paul S. MacLean, and James O. Hill. “Exercise Improves Fat Metabolism in Muscle but Does Not Increase 24-H Fat Oxidation.” Exercise and sport sciences reviews 37.2 (2009): 93–101. PMC. Web. Sept. 2016.

Ouchi, Noriyuki et al. “Adipokines in Inflammation and Metabolic Disease.”Nature reviews. Immunology 11.2 (2011): 85–97. PMC. Web.  Sept. 2016.

Thent, Zar Chi, Srijit Das, and Leonard Joseph Henry. “Role of Exercise in the Management of Diabetes Mellitus: The Global Scenario.” Ed. Hamid Reza Baradaran. PLoS ONE 8.11 (2013): e80436. PMC. Web.  Sept. 2016.