Insulin homeostasis, Hyperinsulinism, Aging, Insulin dysregulation, Insulin testing, Oxygen-insulin matrix

Picture and bio should be in August/September 2017

Insulin: The Life Span Hormone for Healthful Aging

Majid Ali, MD

Introduction

The core message of this article: Insulin is the life span hormone of human biology. To make his case for it succinctly with simple words, the author introduces three terms: (1) “oxygen-insulin signaling matrix”; (2) “oxygen-insulin matrix model of health and disease”; and (3) “insulin as the life span hormone.” The term “oxygen-insulin signaling matrix” refers to a complete bioenergetics and clinical integration of molecular biology of oxygen and insulin homeostasis. “Oxygen-insulin matrix model of health and disease” refers to a unifying model of health/dis-ease/disease continuum, which has a strong explanatory power for understanding the pathogenesis and mechanism of healing for treating chronic diseases. The term “insulin as the life-span hormone” is intended to meaningfully counter the wholly inadequate “diabetes view of hyperinsulinism,” which, in the author’s view, is the principle folly in treating metabolic disorders in the prevailing medical model. It completely ignores the core issue of insulin dysregulation and allows hyperinsulinism-to-Type 2 diabetes (T2D) transition to occur undetected and untreated.

Unmasked hyperinsulinism is permitted to inflict cellular damage of varying degrees in all cellular populations of the body for five to ten or more years before the diagnosis of T2D is made by the prevailing glycemic criteria. To underscore this crucial issue, a series of sets of insulin and glucose profiles obtained with five timed blood samples (fasting, ½-hour, 1-hour, 2-hour, and 3-hour) obtained after a 75-gram glucose challenge, are presented. For children, the glucose challenge is reduced to 50 grams. Brief clinical notes concerning individual patients are included to provide clinical context for interpreting sets of insulin and glucose.

What Is Optimal Insulin Homeostasis?

What is optimal insulin homeostasis? Most regrettably, this crucial question has been almost totally ignored in endocrinology, diabetology, bariatrics, internal medicine, and family practice. On September 11, 2017, a Google search for optimal insulin homeostasis revealed only seven entries that listed the three words in that order; all of them by the author. Notably missing were websites of the American Diabetes Association, the European Foundation for the Study of Diabetes, Diabetes Ca (Canada), the American Congress of Obstetricians and Gynecologists, and the World Health Organization. 

In the context of healthful aging and life span, an evolutionary bioenergetic optimum of human metabolism requires that (1) the lower the blood insulin concentrations following a glucose challenge accompanied by unimpaired glucose tolerance, the greater the efficiency of insulin; (2) the greater the efficiency of insulin, the closer the insulin homeostasis to its ideal; (3) hypoinsulinism by itself is of no clinical consequence since there are no known adverse effects of very low blood insulin concentrations when accompanied by unimpaired glucose tolerance; (4) hyperinsulinism sets the stage of metabolic overdrive in all cellular populations of the body; (5) insulin in excess has hepatic, endothelial, myocardial, neural, ovarian, renal, and other adverse effects; (6) the growth factor roles of insulin intensify and perpetuate inflammatory, autoimmune, and neoplastic processes. Tables 1 and 2 display two sets of insulin and glucose profiles that meet the criteria for optimal insulin homeostasis by criteria outlined here.

Optimal Insulin Homeostasis

In a survey of insulin homeostasis in 684 patients (506 of them with known T2D, (Table 3) in the general New York metropolitan area,  the authors and colleagues reported a prevalence rate of hyperinsulinism in 75.1%.

¹

 A subgroup of twelve participants was designated ‘exceptional insulin homeostasis’ for two reasons: (1) they showed an extremely low fasting insulin value of <2 uIU/mL (mean peak 14.3 uIU/mL) and peak insulin concentrations <20 uIU/mL accompanied by unimpaired glucose tolerance, and (2) ten of the twelve had no family history of diabetes (parents, siblings, grandparents, children, uncles or aunts), while the mother of the eleventh subject developed T2D in the closing months of her life at age 74 and both parents of the twelfth subject in old age had prediabetes. This subgroup appears to reflect ideal metabolic efficiency of insulin in the larger evolutionary context.

Hyperinsulinism As Pancreatic Response to Cellular Injury

In the author’s oxygen-insulin view of insulin dysregulation-to-diabetes continuum, hyperinsulinism results from the response of the pancreas to meet increased energy needs of stressed and injured cells anywhere in the body during the repair processes. This perspective does not challenge the established knowledge of dynamics of hyperglycemia and hyperinsulinism, nor does it abandon any of the regulatory roles of pro-insulin and anti-insulin hormones like glucagon, glucagon-like peptides, and others. The explanatory power of the model, however, reaches far beyond the prevailing understanding of insulin functions and their clinical significance.

The inferences drawn from the author’s large personal database and presented here form the scientific basis and rationale for his view that incremental hyperinsulinism develops as a result of growing pancreatic-bioenergetic response for meeting increasing cellular demands for energy, except in cases of ectopic insulin production in hormone-producing neoplasms.^2-5 Additional evidence for this view is drawn from an extensive body of clinical observations concerning improved clinical results of treatment of diverse disorders when hyperinsulinism accompanying them was detected and duly addressed with integrative hyperinsulinism modification plans. It is anticipated that readers, who diligently study the diverse case studies presented here and critically examine the included insulin and glucose data will find them compelling and convincing.

Hyperinsulism Begets Hyperinsulinism

As put forth here, hyperinsulinism developing as pancreatic insulin response to increased tissue demands for energy comes at a cost: a “hyper-insulin” state – so to speak – which results from metabolic and non-metabolic insulin overdrive. This insulin state is fattening, fermenting, inflaming, and self-perpetuating.^2,4,6,7 Simply stated, excess insulin begets excess insulin.  From these aspects of pathophysiology of insulin dysfunction and overdrive, abundantly documented by case studies included here and published previously,^2,3,8 hyperinsulinism is expected to play the central role in the pathogenesis and progression of most, if not all chronic metabolic, developmental, inflammatory, infectious, autoimmune, degenerative, and malignant diseases. This, indeed, is observed when insulin homeostasis is assessed in individual patients with appropriate carbohydrate challenges. This is what the author and his colleagues observed in a large survey of hyperinsulinism in a general population in metropolitan New York area.¹ Insulin dysfunction with varying levels of hyperinsulinism was found and documented in all chronic diseases so investigated – acne to dermatitis, psoriasis to sarcoidosis, autism to Alzheimer’s disease, liver steatosis to heart amyloidosis,  bronchiectasis to pulmonary fibrosis, lupus to scleroderma, rheumatoid arthritis to Lyme polyarthralgia, interstitial cystitis to recurrent prostatitis, and malignant tumors.^4-12

Tables 1 and 2 present insulin and glucose profiles of a survey subject which meet the numerical criteria of optimal insulin homeostasis. Specifically, the peak blood insulin concentration accompanied by unimpaired glucose tolerance in a female adult is below 20 uIU/mL and a male subject is below 25 uIU/mL.

The insulin and glucose profiles presented in Table 2 provide a rare insight into the dynamics of insulin homeostasis. The patient, a 58-year-old, 5’ 11” man weighing 218 Lbs. presented in December 2012 with neuropathy involving legs and an A1c value of 5.3%. The insulin profile of this patient meets the numerical criteria of optimal insulin homeostasis; specifically, the peak blood insulin concentration accompanied by unimpaired glucose tolerance is below 25uIU/mL. Two years earlier, this patient weighed 300 lbs. when he underwent radical prostatectomy for prostate cancer. Postoperatively he lost 82 Lbs. in weight (which would be expected to be associated with lower insulin levels) and experienced persistent and incremental family stresses (which would be expected to raise insulin levels). The insulin and glucose profiles of the case, then, reveal the sum total of these diverse influences. The blood insulin concentrations in all four post-glucose challenge samples were raised, with a near-fourfold rise in the 1-hr post glucose challenge blood sample (22 rising to 86 uIU/mL). The matter of hyperinsulinism associated with prostate and breast cancer breast has been discussed in the author’s two reports.^10,11

The Oxygen-Insulin Matrix Model of Health and Disease

Human life span is put in jeopardy by disruptions of molecular biology of oxygen and insulin homeostasis; life expectancy of an individual is shortened by diminished signaling of the former^1-7 as well as by excessive signaling of the latter.^2-4,8,9 Oxygen is the organizing principle of human biology and orchestrates all aging processes. In service of oxygen, insulin governs the energy economy of the body. Injured cells need more energy for repairing themselves. Glucose is the primary readily useable fuel for ATP energy generation. Insulin activates glucose transporters, drives glucose into the cells, initiates pathways of ATP energy generation, as well as energy utilization for life functions, and regulates energy transformations, producing proteins for cellular structural needs and fats for energy storage.⁸ It can be rightfully designated as the “master energy hormone” for the life span.

Oxygen signaling and insulin signaling are so inextricably intertwined throughout the kaleidoscopic bioenergetics mosaic of human biology that these two primary signaling systems of the body cannot be considered as discrete entities. In integrative medicine, clinical imperatives are commonly compelling and the scientific basis for the use of time-tested indigenous therapies with empirical benefits are not forthcoming. Under these conditions, the unifying oxygen-insulin signaling matrix model of health/dis-ease/disease continuum provides valuable and reassuring scientific rationale for integrating indigenous therapies with others, for which clear “scientific basis” has not been established.

Some readers may be interested in the author’s prior clinical and research work that led to the conceptualization of oxygen-insulin signaling matrix, disrupted oxygen-insulin matrix model of health/dis-ease/disease continuum, and insulin as the life-span hormone.” The author points out his core clinical and research work in chronic disease ranged widely and was the subject of his Townsend Letter columns on oxygen homeostasis (from 2004 to 2015) and columns on insulin homeostasis from 2016 to the present. The web site of Townsend Letter offers full details of specific subjects covered in addition to the work cited among citations in this column.

Four Dimensions of Insulin Dysregulation

The author recognizes four dimensions of insulin dysregulation: (1) the first dimension of rising blood insulin concentrations (hyperinsulinism) without raised glucose levels (hyperglycemia) that meet criteria of pre-diabetes or diabetic criteria (Table 4); (2) the second dimension of hyperinsulinism with sharp glucose and/or insulin shifts but without meeting the criteria for pre-diabetes or diabetes (Table 5); (3) the third dimension of hyperinsulinism associated with hyperglycemia that meets the criteria of Type 2 diabetes (Table 6); and (4) the fourth dimension of insulin-depletion Type 2 diabetes (T2D Subtype B)⁴ is shown in Table 7.

Insulin Dysregulation Neglected in Unwell Individuals

Unwellness is epidemic now in the United States and generally spreading worldwide. It is not attributed to insulin dysregulation, and assessment of insulin homeostasis is not included in the prevailing standards of care. A recent survey of prevalence of hyperinsulinism, as established by the survey criteria, in the general population of New York metropolitan area conducted by the author and his colleagues was 75.1%.¹ This rate was not surprising since they used insulin criteria by contrast to the Chinese who employed blood glucose-based diagnostic criteria and reported a prevalence rate of 50.1% for prediabetes and diabetes among the Chinese adults.¹³

Tables 8 and 9 present two case studies of hyperinsulinism associated with chronic symptom-complexes of unwellness, such as lack of interest and vigor, anxiety, fatigue, mood disorders, cognitive difficulties, brain fog, allergy, abdominal bloating, and digestive symptoms. These symptom-complexes were not relieved by commonly prescribed symptom-suppressive pharmacologic agents. Note the sharp drop of one-hour insulin level from 183.5 to 57.4 uIU/mL. in Table 8, which was accompanied by good clinical response.

Insulin Dysregulation Associated with Unrelenting Stress, Mood Disorders, and Weight Gain

Hyperinsulinism in patients with anxiety-depression complex, unrelenting stress, and weight gain often goes unrecognized even though hyperinsulinism is widely recognized as fattening and inflaming. Tables 10 and 11 present two such patients.

The case study presented in Table 10 reveals the weight gain aspect of insulin toxicity (rising insulin levels) well. The patient, a 46-year-old, 5 ft. 2 in. woman weighing 160 lbs. presented in 2011 with diagnoses of fibromyalgia, cognitive disorder, severe family stress, sleep disorder, constipation, cold sensitivity, and depression treated by a psycho-pharmacologist. In one 2014 office visit, she said, “Everybody at home is sick. I’m so angry, in such rage that I think I’m destroying my two daughters.” 

Hyperinsulinism Modification with Insulin Detox

Insulin in excess is potently pro-inflammatory. Chronic inflammation causes incremental hyperinsulinism, which usually responds well to robust integrative management plans. The case studies presented in Table 12 and 13 illustrates these points well. The full description of author’s hyperinsulinism modification with insulin detox is offered as a part of his free access Diabetes Course at www.alidiabetes.org. “Insulin Detox” are the search words for entry in the search box.

Polycystic Ovarian Syndrome (PCOS) Is Rooted in Insulin Dysregulation

The rising prevalence of polycystic ovarian syndrome (PCOS) among young women in the U.S. (up to 20% in some studies) is disconcerting.¹⁴ Elevated blood concentrations of insulin and testosterone are two primary hormonal abnormalities of the syndrome. These disruptions with clinical symptom-complexes of PCOS generally respond to integrative treatment plans with a focus on the bowel-liver-blood ecosystem. Table 13 presents the changes in insulin and glucose profiles which accompanied a successful pregnancy.

*Note the lower blood insulin concentration in the 2017 profile in spite of third-trimester pregnancy status. 

Insulin-Monitored Plans for Long-Term Hyperinsulinism Modification and Reversal of Type 2 Diabetes

Two insulin-based diet plans have been employed by the author for his patients with insulin dysregulation: (1) Insulin Diet Plan One for hyperinsulinism modification; and (2) Insulin Diet Plan Two for Reversal of Type 2 Diabetes. The full details of these Insulin Diet Plans are posted at www.alidiabetes.org. For free ready access to these diet plans, readers are invited to enter the following search words in the search box of the website: Insulin Diet Plans Majid Ali.

Table 14 presents a pattern of hyperinsulinism modification and reversal of Type 2 diabetes achieved with an insulin reduction diet plan.¹⁵

Insulin Profiling – Testing and Interpretation

In a previous publication, the author recognized two subtypes of T2D: (1) T2D subtype A (insulin excess diabetes) and T2D subtype (insulin-depletion diabetes), and underscored the clinical imperatives for doing so.²⁸ In companion publications, he explained why he now reads 3-hour insulin and glucose profiles of individual patients the same way he used to read diagnostic biopsy slides in his hospital based surgical pathology work, pattern recognitions fully mindful of the clinical context.²⁹ The results of insulin tests performed on randomly drawn blood samples in his opinion, should not be interpreted.

Recently, the author and his colleagues reported hyperinsulinism prevalence of 75.1% in 684 patients from a general population in New York metropolitan area.¹ The insulin database of this study permitted us to explore the following aspects of insulin homeostasis and insulin dysregulation: (1) pathogenesis of insulin resistance; (2) stratification of hyperinsulinism for optimal clinical use; (3) study of responses to carbohydrates and non-carbohydrate challenges in insulin-based care of hyperinsulinism and T2D³; (4) hyperinsulinism-to-T2D progression; (5) proinflammatory and immune-dysregulating roles of insulin dysregulation; (6) the central role of mitochondrial dysfunction in insulin dysregulation; (7) hyperinsulinism as an energetic response to chronic cellular injury; and (8) the profound therapeutic significance of insulin serving as the “minister of metabolism and energy” to “King Oxygen” of the human body.^2,3,23

The most disappointing aspect of the matter of insulin homeostasis in clinical practice is that, with very uncommon exceptions, hyperinsulinism is not detected with direct insulin testing. Insulin toxicity is allowed to inflict widespread cellular damage for years, sometimes for decades, until glycemic criteria for the diagnosis of Type 2 diabetes are met. This has been amply documented in this and past communications on the subject. Below are some specific issues concerning improper insulin testing:

1. Insulin tests are performed on randomly drawn blood tests (Results of such tests cannot be interpreted with confidence);

2. Laboratories employ utterly unusable references ranges for blood insulin concentrations; 

3. Tests for glycemic status (fasting blood glucose, two-hour postprandial glucose level, A1c levels) are performed as substitute indicators of the insulin status;

4. Cut-off points for post-glucose challenge blood insulin concentrations reported in laboratory reports are not based on actual post-glucose-challenge testing data;¹⁷

5. Gestational diabetes is a hyperinsulinism disorder before it becomes gestational diabetes by glycemic criteria;

6. Pregnant women are unscientifically and improperly assured of their metabolic health simply because their glucose tolerance tests are considered negative for gestational diabetes;

7. Insulin is the primary pro-weight gain and pro-obesity hormone, and yet insulin tests are not done in weight loss and obesity programs. 

8. Failure to assess insulin homeostasis with direct post-glucose challenge tests leaves patients and clinicians in the dark concerning the central roles of hyperinsulinism in the pathobiology of chronic inflammatory, infectious, autoimmune, metabolic, neoplastic, and degenerative disorders.

Three important concerns in this context are (1) responses to carbohydrates and non-carbohydrate challenges in insulin-based care of hyperinsulinism and related metabolic disorders⁸; (2) importance of subtyping diabetes type 2 into diabetes type 2A and diabetes type 2B⁹; and (3) hyperinsulinism modification with insulin detox (See Table 12).

It is lamentable that in the dominant medical thought, crucial health and healing aspects of chronically sluggish oxygen signaling and incrementally exaggerated insulin signaling are consistently neglected. How often is the centrality of dysoxygenosis (dysfunctional oxygen signaling) in chronic diseases recognized and effectively addressed in doctors’ offices and clinics? How often are the fattening, fermenting, and inflaming effects of simmering hyperinsulinism detected and controlled by restoring optimal insulin metabolism? Mention of mitochondrial malfunctions evokes tired yawns; the word insulin triggers Pavlovian mumbling about diabetes.

Discussion

Oxygen signaling and insulin signaling are so inextricably intertwined throughout the kaleidoscopic bioenergetics mosaic of human biology that, in the author’s view, they cannot be considered as discrete entities. He recognized this first as an integrative clinician (finding sharp therapeutic focus on oxygen and insulin equally necessary for reversing and/or controlling chronic diseases) and as a researcher in basic bioenergetics of human biology.

The author was fortunate to have undertaken clinical, bioenergetic, and histopathogical studies of broad range of chronic allergic, infectious, immune-inflammatory, gastrointestinal, reproductive, neurodevelopmental, degenerative, and neoplastic diseases. This work paved the way for his work in molecular biology of oxygen^2-7 and aging,¹³ and then to insulin homeostasis and insulin dysregulation,^{1-4,6,15,22-24} including the study of insulin dysregulation in metabolic syndromes, obesity, fatty liver disease, steatonecrosis, Type 2 diabetes, gestational diabetes, Type 1 diabetes, and the range of diabetic complications.

Insulin signaling has widespread established metabolic, developmental, and differentiative roles in human biology.^16-19,25,26 When seen within the broader evolutionary energetic perspective, the core tenet of the insulin being the life span hormone of human biology is logical, rational and completely consistent with the established aspects of the kaleidoscopic hormonal mosaic of human biology.

The author’s work in insulin homeostasis cited in this report led him to the development of a completely integrated view of molecular biology of oxygen and insulin signaling, which culminated in conceptualization of a clinico-pathologic “oxygen-insulin signaling matrix model.” This model has a strong explanatory power for diverse clinical and bioenergetics phenomena of the health/dis-ease/disease continuum, the primary strength being unrelenting focus on harnessing therapeutic benefits of all relevant oxygen-based and insulin-driven therapies in the treatment of all chronic diseases. From a didactic standpoint, this model helps in reducing many clinical complexities of human biology into workable simplicities, and facilitates presentation of a synthesis of clinical, microscopic, and bioenergetic findings concerning the essential roles of oxygen signaling and insulin homeostasis in the pathobiology of chronic diseases.

For patient education and robust patient compliance, the oxygen-insulin signaling matrix model markedly enhances understanding of the scientific underpinnings of diverse disease processes related to various patterns of impaired oxygen signaling (dysoxygenosis), insulin dysregulation, and treatment options. Specifically, this model calls for deliberating and addressing all relevant oxygen and insulin issues for individual patients.

Closing Comments

Treatment of chronic diseases that is confined to pharmacologic agents can be considered neither scientific nor ethical. Readers are invited to closely examine case studies presented in this column. They are drawn from the author’s personal insulin database of over 1100 post-glucose challenge insulin profiles. They can then determine if there is merit to his case for diligence in assessing insulin homeostasis with such laboratory tests. The matters of keeping oxygen homeostasis at the therapeutic center stage for every patient with chronic disease with documentation of clinical outcomes have been covered at length in Darwin and Dysox Triology, the 10^th, 11^th, and 12^th volumes of the Principles and Practice of Integrative Medicine.^27-29

Here, the author sees a glaring clinical deficit: a near-complete neglect of relevant oxygen and insulin issues in patient care in doctor offices and clinics in the prevailing medical model in the US. To assess the scope of this issue, he conducted an informal survey of his patients who had seen two or more physicians (primary physician, internists, endocrinologists, diabetologists, and others) during the year prior to visiting me. None of them recalled any visit in which relevant issues of insulin homeostasis or oxygen signaling were discussed and appropriate tests were performed. Nearly of all them complied with the request to review their prior medical records. He did not find 3-hour post-glucose challenge insulin studies in any patients.

References

1. Ali M, et al. Shifting Focus From Glycemic Status to Insulin Homeostasis.  Townsend Letter. 2017;402:91-96.

2. Ali M. Epidemic of Dysoxygenosis and the Metabolic Syndrome. In: The Principles and Practice of Integrative Medicine. Volume 5. Pp 246-256. Canary 21 Press. New York. 2005.

3. Ali M. Dysox Model of Diabetes and De-Diabetization Potential. Townsend Letter. 2007; 286:137-145.

4. Ali M. Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.

5. Ali M. Fayemi AO, Braun EV.  Malignant apudoma of the liver with symptomatic intractable hypoglycemia.  Cancer. 1978; 42:686-692.

6. Ali M. Oxygen, Insulin Toxicity, Inflammation, and the Clinical Benefits of Chelation. Part I. Townsend Letter. 2010;322:111-14.

7. Ali M. Oxygen, Insulin Toxicity, Inflammation, and the Clinical Benefits of Chelation. Part II. Townsend Letter. 2010;323:74-77/

8. Ali M. et al. Study of Responses to Carbohydrates and Non-Carbohydrate Challenges in Insulin-Based Care of Metabolic Disorders. Townsend Letter. 2016; 391:48-51

9. Ali M. Importance of Subtyping Diabetes Type 2 Into Diabetes Type 2A and Diabetes Type 2B. Townsend Letter. 2014; 369:56-58.

10. Ali M. Hyperinsulinism Associated with Breast and Prostate Cancer. Townsend Letter. 2017;409/410:66-69.

11. Ali M. Endothelial-Neoplastic -Dynamics, Death Receptor 6, and Ani-Metastatic Therapies. Commentary in: Nature 2016;536:215-218.

12. Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310:948-59.

13. Ali M. Oxygen and Aging. (1st ed.) New York, Canary 21 Press. Aging Healthfully Book 2000.

14. Orio F, et al. Metabolic and cardiovascular consequences of polycystic ovary syndrome. Minerva Ginecologica. 2008;60:39-51.

15. Ali M. Succinate Retention. In: Chouchani ET, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431–435.

16. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444, 840-846.

17. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116 :1793B1801.

18. Shulman G. Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease. N Engl J Med. 2014; 371:1131‑1141.

19. International Diabetes Federation. Diabetes Atlas. 2016. Seventh edition. www.diabetesatlas.org.

20. Sako Y, Grill VE. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127, 1580–1589 (1990).|

21. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit Disorders. Townsend Letter for Doctors and Patients. 2004;253:64-65.

22. Ali M. The Principles and Practice of Integrative Medicine Volume X: Darwin, Oxygen Homeostasis, and Oxystatic Therapies.  3rd. Ed. (2009) New York. Institute of Integrative Medicine Press.  

23. Ali M. Succinate Retention: The Core Krebs Dysfunction in Immune-Inflammatory Disorders. Townsend Letter. 2015;388:84-85.

24. Ali M: Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine. 1999;3:11-16.

25. Ali M. Oxygen, Insulin Toxicity, Inflammation, and the Clinical Benefits of Chelation – Part II. Townsend Letter. June 2010;323:74-79.

26. Ali M. Oxidative Cell Membrane Disorder – Leaky Cell Membrane Disorder (monograph). Teaneck, NJ, 1987

27. Ali M. The Principles and Practice of Integrative Medicine Volume X: Darwin, Oxygen Homeostasis, and Oxystatic Therapies.  3rd. Edi. (2009) New York. Institute of Integrative Medicine Press.  

28. Ali M. The Principles and Practice of Integrative Medicine Volume  XI: Darwin, Dysox, and Disease. 2000. 3rd. Edi. 2008. New York.  (2009) Institute of Integrative Medicine Press.  

29. Ali M. The Principles and Practice of Integrative Medicine Volume  XII: Darwin, Dysox, and Integrative Protocols. New York (2009). Institute of Integrative Medicine Press.