Type 2 Diabetes Mellitus Treatment

  Diabetes mellitus (DM) is a complex metabolic disorder affecting more than 400 million people worldwide.^8,11 There are currently two types of diabetes, designated Type 1 and Type 2. Type 1 diabetes mellitus (T1DM) is characterized by deficient insulin production within the body due to the autoimmune destruction of pancreatic insulin-producing β-cells. ^8,11 Type 2 diabetes mellitus (T2DM) is defined by hyperglycemia in individuals due to a myriad of pathological changes within the body, the three key defects being increased hepatic glucose production, diminished insulin production and development of insulin resistance. ^{5, 8} Insulin resistance is defined as suppressed or delayed responses to insulin, and generally refers to “post-receptor” effects, meaning the complication lies in cellular response to insulin in contrast to insulin production. ⁵ A major point of diversion between the two forms of diabetes pertains to the production of insulin. T2DM patients retain the ability to naturally produce insulin, though production declines as the disease progresses, while T1DM patients are physically incapable of producing their own insulin following the loss of pancreatic β-cells. ^{8, 11}

T2DM accounts for the vast majority of people diagnosed with DM, and this disease takes a massive toll on patients and healthcare systems alike. ^8,9 Patients with T2DM have a 15% increase in all-cause mortality, along with complications that include macrovascular and microvascular diseases, such as cardiovascular disease, stroke, retinopathy, nephropathy, neuropathy and others (see Figure 1). ^2,13 The medical and socioeconomic burden on healthcare systems is enormous due to the need for persistent care arising from the numerous associated pathological complications, not to mention the immense cost to patients and insurance companies paying for these treatments. ^8,9

     

Figure 1 Symptoms and Affected Areas of Diabetes.¹³

The current understanding of T2DM pathophysiology involves several organs that contribute to the development and progression of the disease, summarized in Figure 2.^{5, 8} The most prevalent risk factors contributing to the development of T2DM are obesity, an unhealthy diet and physical inactivity.⁸

Figure 2: Current theories contributing to pathogenesis of T2DM.⁵ 

In the early and intermediate disease stages of T2DM, hyperglycemia occurs in the presence of hyperinsulinemia, which indicates that insulin resistance is the driving force of this disease.⁹ The current treatment guidelines, per the American Diabetes Association (ADA), highlight glycemic control as the main criteria to determine efficacy of therapy, stating that “clinical trials…support decreasing glycemia as an effective means of reducing long-term microvascular and neuropathic complications.” ⁷ The core initial treatment for patients diagnosed with T2DM is lifestyle intervention and metformin administration, followed by insulin or sulfonylurea medication.⁷ These are considered well-validated treatment options by the ADA and are the first line of therapy following diagnosis. The ADA also states that it is uncommon for lifestyle interventions to achieve or maintain metabolic goals, thus metformin is the immediate pharmacological treatment option in addition to lifestyle intervention strategies.⁷ If lifestyle and metformin treatment fail, the next step is insulin administration.⁷ If the disease continues to progress, there are a multitude of other pharmacological agents that can be introduced and tested in different combinations.

Despite the introduction of new classes of medications along with numerous combination therapies, techniques that target glycemic control for treatment have ultimately failed to produce positive health outcomes or prevent progression of the disease.^{7, 3} This is where Dr. Jason Fung and his idea of therapeutic fasting for T2DM patients come into play. Dr. Fung states that the prevailing view of insulin resistance theorizes a pathology within the cell that derails the normal mechanism of glucose absorption. As stated earlier, T2DM patients still produce insulin. In early and intermediate stages of the disease, this production is at normal, or even excessive, levels.⁹ In a healthy individual, increased blood glucose levels – for example, following a meal – cause an increase in insulin levels, which interact with insulin receptors on the surface of cells within tissues in the liver, muscle and fat. This signal relays that high concentrations of glucose within the blood need to be absorbed into cells for use as fuel or packaged and stored for later use, as demonstrated in Figure 3 (Upper panel).¹²

Cells then respond by presenting glucose transporters at the cell membrane to allow glucose entry. In insulin-resistant individuals, the cells no longer elicit a response to normal levels of circulating insulin, thus the cells must be resistant to the insulin, shown in Figure 3 (Lower panel).¹² Dr. Fung terms this the “lock-and-key paradigm,” where the insulin receptor is a “locked” door and insulin-binding is a “key” that unlocks and open the door, allowing glucose to exit the bloodstream and enter the cell.¹ There is evidence that supports regular function of the insulin receptor and normal insulin composition and action in T2DM – so the “lock” and “key” are both unaffected. Thus, it is assumed that there must be something jamming the lock, arresting glucose entry into the cell, and causing an internal starvation state within. To counteract this, insulin is administered to T2DM patients as a way to force the door open and allow glucose entry.

Figure 3.  (Upper) Normal glucose response.  (Lower) T2DM insulin resistance.¹²

Herein lies a paradox: insulin has many functions within the body, only one of which contributes to glucose absorption.¹ For example, insulin is also responsible for lipogenesis within the liver, a process that takes excess carbohydrates (i.e. glucose), packages it into fat molecules and stores it for later use. However, lipogenesis is not reduced in T2DM patients, despite a supposed starvation state within the cells, and it is even well supported that lipogenesis in T2DM is in fact hyperactive.¹ This means that in the same liver tissue, there is a contradictory state of both resistance and super-sensitivity to the same hormone, creating the paradox wherein insulin-resistant patients are accomplishing the process of insulin-mediated fat production despite apparent cellular starvation as a result of insulin resistance.¹ Going back to the lock-and-key paradigm, there could be another, more fitting explanation for the blockage of glucose entry: either the lock is jammed shut, or the space behind the door is jammed too full.¹ In other words, the cells may have already reached their limit for glucose storage and cannot let any more in. This perspective resolves the paradox within the currently accepted view of insulin resistance. That is, the problem is not actually insulin resistance, but hyperinsulinemia.¹ Thus, the administration of insulin as a core treatment method for T2DM is a lot like filling a suitcase that has space for 20 t-shirts with 40 t-shirts, then coming back with a t-shirt cannon and blasting in 40 more, when only 10 t-shirts were needed for the trip in the first place. One novel way to solve this dilemma of needing to manage the cardiovascular risks of hyperglycemia without forcing an already overloaded liver to process more glucose, is to naturally reset the entire process through fasting.

Therapeutic fasting as a treatment for T2DM is a relatively new, and not widely accepted, option for diabetic patients. Revisiting the suitcase analogy, fasting is like dumping out all 80 t-shirts, packing the required 10 and enjoying a nice vacation. The idea is that there is already so much excess energy stored within the abundant adipose tissue of obese diabetic patients, that constantly eating is not really necessary. The body is not only able to easily utilize fat as energy, but it possesses a remarkable ability to readily do so when entering a fasted state. Dr. Fung published a case study on three T2DM patients that underwent therapeutic fasting therapy, defined as “the controlled and voluntary abstinence from all calorie-containing food and drinks [for] a specified period of time”.³ All patients within this trial not only had subjective reports of positive affect and higher energy levels during fasting periods, they also had reductions in serum A1C levels and waist circumference, and experienced 10-18% weight loss over the course of 10 months.³ Additionally, Patients 1 and 3 were able to discontinue all diabetic medications, and Patient 2 discontinued 3 out of 4.³ All patients were able to discontinue insulin therapy within the first 20 days of their fasting regiment, one patient in as little as five days, with no occurrences of symptomatic hypoglycemia reported.³ The results of this trial demonstrated that the therapeutic fasting can significantly reverse or eliminate the need for diabetic medication, as well as improve other clinically significant health measures such as serum A1C levels, body mass index and waist circumference.³ Therapeutic fasting may be a viable therapy for T2DM patients, aiding in the remission of the disease, reduction of cardiovascular risk factors through weight loss, decrease the need for glycemic control medication and possibly improve additional diabetic-related complications, reducing the need for those medications as well.³ This would not only improve patient outcomes but lighten the socioeconomic burden on the healthcare system contributed by diabetic patients due to the wide range of subsidiary pathologies arising from the disease.⁹

By Andrew Yakzan, A Post Baccalaureate Student at the University of Kentucky

References

¹Attia, Peter, and Jason Fung. “#59 - Jason Fung, M.D.: Fasting as a Potent Antidote to Obesity, Insulin Resistance, Type 2 Diabetes, and the Many Symptoms of Metabolic Illness.” Edited by Gary et al., Peter Attia MD, Peter Attia, MD, 24 June 2019, peterattiamd.com/jasonfung/.

²Chatterjee, Sudesna, et al. “Type 2 Diabetes.” The Lancet, vol. 389, no. 10085, 2017, pp. 2239–2251., doi:10.1016/s0140-6736(17)30058-2.

³Furmli, Suleiman, et al. “Therapeutic Use of Intermittent Fasting for People with Type 2 Diabetes as an Alternative to Insulin.” BMJ Case Reports, 2018, doi:10.1136/bcr-2017-221854.

⁴Kalra, Sanjay, et al. “Defining Disease Progression and Drug Durability in Type 2 Diabetes Mellitus.” European Endocrinology, vol. 15, no. 2, 2019, p. 67., doi:10.17925/ee.2019.15.2.67.

⁵Lin, Yi, and Zhongjie Sun. “Current Views on Type 2 Diabetes.” Journal of Endocrinology, vol. 204, no. 1, 2009, pp. 1–11., doi:10.1677/joe-09-0260.

⁶Madenidou, Anastasia-Vasiliki, et al. “Comparative Benefits and Harms of Basal Insulin Analogues for Type 2 Diabetes.” Annals of Internal Medicine, vol. 169, no. 3, 2018, p. 165., doi:10.7326/m18-0443.

⁷Nathan, D. M., et al. “Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes.” Diabetes Care, vol. 32, no. 1, 2008, pp. 193–203., doi:10.2337/dc08-9025.

⁸Roglic, Gojka. Global Report on Diabetes. World Health Organization, 2016.

⁹Stumvoll, Michael, et al. “Type 2 Diabetes: Principles of Pathogenesis and Therapy.” The Lancet, vol. 365, no. 9467, 2005, pp. 1333–1346., doi:10.1016/s0140-6736(05)61032-x.

¹⁰Weir, G. C., and S. Bonner-Weir. “Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes.” Diabetes, vol. 53, no. Supplement 3, 2004, doi:10.2337/diabetes.53.suppl_3.s16.

¹¹Zaccardi, Francesco, et al. “Pathophysiology of Type 1 and Type 2 Diabetes Mellitus: a 90-Year Perspective.” Postgraduate Medical Journal, vol. 92, no. 1084, 2015, pp. 63–69., doi:10.1136/postgradmedj-2015-133281.

¹²Harvard Health Publishing. “Type 2 Diabetes Mellitus.” Harvard Health, Dec. 2018, www.health.harvard.edu/a_to_z/type-2-diabetes-mellitus-a-to-z.

¹³Gulati, Martha, et al. “Diabetes (Type 2 Diabetes).” Global, Mar. 2019, www.cardiosmart.org/diabetes.