Centrality of Mitochondrial Dysfunction In Dysox Model of Type 2 Diabetes

Majid Ali, M.D.


 

In 2007, I put forth my dysox model of Type 2 diabetes to focus on the centrality of respiratory-to-fermentative shift in the pathogenesis of the disease (ref.8) and to recognize the need for shift of focus from glycemic status to insulin homeostasis (ref.9). The prevailing standard of treating Type 2 diabetes is to control blood sugar levels by focusing on insulin release from beta cells of the pancreas. By contrast, based on my Krebs cycle work, I treat the disease by focusing on insulin receptor embedded in the cell membrane. Specifically, my colleagues and I implement a hyperinsulinism modification plan by which we free up the insulin receptor, so to speak, to facilitate the entry of glucose in cells and so lower blood level (ref.10). I marshaled extensive evidence for shifting focus from glycemic status to insulin homeostasis for stemming the global tides of Type 2 diabetes.

Zhao et al. provide definitive answers to some fusion-fission questions with ingenious visualization of insulin-producing cells in the pancreas using confocal and super-resolution stimulated emission depletion microscopy. They show that transition to full fusion or fission is determined by competition between fusion and calcium/dynamin-dependent fission mechanisms, and that the hemi-fused intermediate is a key structure that controls fusion and fission. I look forward to the time when future advances in cell membrane dynamics based on the work of Zhao et al. will allow clinicians like me to describe our clinical and biochemical observations and attempt to explain the underlying mechanisms in light of the foundational work of Zhao et. al.

In closing, for readers interested in patterns of hyperinsulinism modification, below I include blood glucose and insulin data of three patients. The insulin and glucose profiles were obtained with blood samples drawn at fasting and 1-hour, 2-hour, and 3-hour after a 100-gram glucose load. The insulin profile of a healthy subject with unimpaired glucose tolerance is included as a control. Insulin and glucose concentrations are expressed in uIU/mL and mg/mL respectively.

Four Sets of Insulin and Glucose Profiles 

1.Healthy control subject: insulin levels: <2 uIU/mL, 18, uIU/mL, 4, and <2; glucose levels: 77, 168, 109, 74, 52.
2. Case One: a 75-yr-old woman with Type 2 diabetes. April 2013. Insulin: 16 uIU/mL, 59 uIU/mL, 113 uIU/mL, and 152 uIU/mL: Glucose: 112, 214, 241, 155?. April 2015. Insulin: 6.2, 42.9, 51.2, and 39.7; Glucose: 96, 193, 112, and 105.
3. Case Two: a 68-yr-old man with hepatitis C and dysautonomia. April 2105. Insulin uIU: 17, 721, 388, and 28; Glucose mg/dL: 95, 157, 87, and 42?. April 2016: Insulin: 8.1, 315.0, 15.88, and 4.8?. Glucose mg/dL: 90, 101, 24, 54.
4. Case Three: a 75-yr-old woman ? with coronary artery disease and Type 2 diabetes. June 2010. Insulin in uIU/mL: 9.8, 25, 39, 92.4; Glucose mg/dL: 112, 170, 241, 273?.May 2014. Insulin: 6.4, 58.2, 33.8, 6.4; Glucose: 99, 182, 139, 81.

References
1. Zhoa W-D, Hamid E, Shin W, et al. WHemi-fused structure mediates and controls fusion and fission in live cells. Nature.2016;534:548-552.
2. Ali M. Leaky Cell Membrane Disorder (monograph). Teaneck, NJ, 1987.
3. Ali M. Hypothesis: Chronic fatigue is a state of accelerated oxidative molecular injury. J Advancement in Medicine, 6:83-96; 1993.
4. Ali M. Ali M, Ali O: AA oxidopathy: the core pathogenic mechanism of ischemic heart disease. J Integrative Medicine 1997;1:6-112. Oxidopathy
5. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. 253: 64-65 (2004).
6. He W, Miao F J-P, Lin D C-H, et al. Citric acid intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:143-45.
7. Chouchani ET, Pel VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature;2014;515:431.
8. Ali M. Succinate Retention. In: Chouchani ET. et al. Nature;2014;515:431 (See comments at the end).
9. Ali M. The Dysox Model of Diabetes and De-Diabetization Potential. Townsend Letter-The examiner of Alternative Medicine. 2007; 286:137-145.
10. Ali M. Dr. Ali?s Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.

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