Category Archives: Diabetes Basics

Is Diabetes A Sugar Problem? No.

Majid Ali, M.D.

Suite 3 C, 344 Prospect Avenue

Hackensack, New Jersey 07601



Is diabetes mellitus (Type 2 Diabetes) a sugar problem? No. The abnormalities of blood sugar seen in diabetes are the consequences of the derangements of cellular energetics and toxicity that collectively create what is commonly called diabetes. Is diabetes an insulin problem? No. The abnormalities of insulin functions are the consequences of plasticized (chemicalized) and hardened cell membranes that immobilize the insulin receptors embedded in them. Is diabetes a problem of blood vessels that causes blindness, kidney failure, stroke, heart attacks, and neuropathy? No. The abnormalities of blood vessels are the consequences of oxidizing and deoxygenizing influences in diabetes.

In this column, I marshal evidence for my view that the state of insulin resistance should be regarded as a “hardened cell membrane state.” The so-called metabolic syndrome should be visualized as a “gummed-up matrix state.” Prediabetes should be seen as a “mitochondrial dysfunction state.” The strategies for the prevention and reversal of diabetes yield better long-term clinical results if diabetes is recognized as a “dysfunction oxygen signaling,” or dysox, state.

In type 1 diabetes, insulin itself becomes a potent autoantigen and initiates autoimmune injury to pancreatic islet cells.1-3 I will show how this recently documented role of insulin in the pathogenesis of diabetes fits in the dysox model of diabetes presented here. In type 2 diabetes, insulin cannot function – insulin resistance, in the common jargon – and hyperinsulinemia develops, which triggers and amplifies the inflammatory response.4-6 In all types of diabetes, the endothelial cells produce nitric oxide and other bioactive factors in abnormal quantities and proportions.7,8 Diabetes causes neuropathy, retinopathy, nephropathy, dementia, stroke, and heart attacks. I will describe how those complications of diabetes can be better understood when the problems are seen through the prism of oxygen signaling.


Clinical, Epidemiologic, and Experimental Evidence Links Obesity With Insulin Toxicity

The link is supported by known metabolic roles of nonesterified fatty acids (NEFAs) and altered paracrine and endocrine functions of fat cells (adipocytes) in the energy economy of the body. For example, in a healthy state, NEFAs serve as substrates for adenosine triphosphate (ATP) generation. In obesity, these fatty acids are retained in excess in biomembranes of all cell populations of the body and within adipocytes. NEFAs, along with trans fats and oxidized lipids, then “harden” the cell membranes to clamp down on insulin receptors – rusting and impacting the crank, so to speak – to cause insulin resistance.12 Those lipids also “gum up” the matrix, blocking molecular cross-talk there. Eventually, those elements, along with other toxins, uncouple respiration from oxidative phosphorylation and impede mitochondrial electron transfer events.


In obesity, output of fattening hormones in adipocytes (fat cells) is chaotic in the ways in which it further increases cellular fat build-up and sets the stage for the development of diabetes.13,14 However, the obesity/diabetes link does not prevail in all populations of the world. For instance, in India, there is also an epidemic of low body-weight (LBW) diabetes15 – a phenomenon that clearly points to the existence of environmental factors unrelated to obesity that are involved in the pathogenicity of diabetes, and supports the dysox model of diabetes.

A growing number of free radicals, transcription factors, enzymes, and proteins has been – and continues to be – implicated in the pathogenesis of diabetes, including:
· nitric oxide16,17
· inducible nitric oxide synthase (iNOS)18
· mitochondrial uncoupling proteins (UCPs)19-21
· proinflammatory cytokines22-24
· resistin25,26
· leptin27,28
· adipokines29
· adiponectin30
· tumor necrosis factor-alpha (TNF-a)31
· peroxisome proliferator-activated receptor gamma (PPARgamma)32-34
· nuclear respiratory factor-1 (NRF-1)35
· suppression of cytokine signaling (SOCS) proteins36
· retinol-binding protein-4 (RBP4)37
· antibodies against glutamic acid decarboxylase38
· prothrombotic species, including fibrinogen, von Willebrand factor, and plasminogen activator inhibitor (PAI-1), adipsin (complement D), and acylation-stimulating protein (ASP) 39-42
· heat shock protein 60, voltage-dependent anion channel 1 (VDAC-1), and Grp7543
· hypercoagulable platelets44

Oxygen, Diabetes, Insulin References 

1.Nakayama M, Norio Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.
Nature. 2005;435,220-223.
2.Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.
Nature. 2005;435:224-228.
3.von Herrath M. Insulin trigger for diabetes.
Nature. 2005;435:151-152.
4.Eisenbarth GS, et al. Insulin autoimmunity: Prediction/precipitation/prevention type 1A diabetes.
Autoimmun. Rev. 2002;1:139-145.
5.Todd JA, Bell JI, McDevitt HO. HLA antigens and insulin-dependent diabetes.
Nature. 1988;333,710-712.
6.Ali M. Hypothesis: obesity is adipomyocytic dysoxygenosis.
J Integrative Medicine. 2004;9:19-38.
7.Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes.
J. Clin. Invest. 2005;115:1111–1119.
8.Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance.
J. Clin. Invest. 2006;116:1793–1801.
9.World Health Organization Consultation on Obesity 1–253 (World Health Organization, Geneva, 2000).
10.Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030.
Diabetes Care. 2004;27:1047–1053.
11.Hedley AA. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002.
JAMA. 2004;291:2847–2850.
12.Leung, et al. Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men.
Diabetologia. 2004;247:204–213.
13.Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis.
Nature. 2006;444:847-853.
14.Nath D, Heemels M-T, Lesley Anson L Obesity and diabetes.
Nature. 2006;444, 839.
15.Das S. Identity of Lean-NIDDM: Clinical, metabolic and hormonal status. In: Kochupillai N, ed.
Advances in Endocrinology, Metabolism, and Diabetes. Vol. 2. Delhi, India: Macmillian; 1994:42-53.
16.Farmer SR. Transcriptional control of adipocyte formation.
Cell Metab. 2006;4:263–273.
17.Trayhurn P. Endocrine and signalling role of adipose tissue: New perspectives on fat.
Acta Physiol. Scand. 2005;184: 285–293.
18.Perreault M, Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle.
Nature Med. 2001;7:1138–1143.
19.Suh YH, Kim SY, Lee H, et al. Overexpression of short heterodimer partner recovers impaired glucose-stimulated insulin secretion of pancreatic beta-cells overexpressing UCP2.
J Endocrinol. 2004;183:133-44.
20.Ceddia1 RB, William WN, FB, et al. Leptin stimulates uncoupling protein-2 mRNA expression and Krebs cycle activity and inhibits lipid synthesis in isolated rat white adipocytes.
Eur. J. Biochem. 2000;267:5952-5958.
21.Enerback S et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.
Nature. 1997;387:90–94.
22.Xu H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
J. Clin. Invest. 2003;112:1821–1830.
23.Shoelson, SE, Lee J. Goldfine AB. Inflammation and insulin resistance.
J. Clin. Invest. 2006;116: 1793–1801.
24.Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis.
Nature. 2006;444:854-859.
25.Stepphan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes.
Nature. 2001:409;307-312.
26.Berti L, Kellerer M, Capp E, et al. Leptin stimulates glucose transport and glycogen synthesis is in C2C12 myotubes: Evidence for a P3-kinase mediated effect.
27.Minokoshi Y et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.
Nature. 2002; 415: 339–343.
28.Farooqi IS, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.
J. Clin. Invest. 2002;110:1093–1103.
29.Shimomura I, Hammer RE, Ikemoto S, et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.
Nature. 1999;401:73–76.
30.Fain JN, Madan AK, Hiler ML, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans.
Endocrinology. 2004;145:2273–2282.
31.Scherer PE. Adipose tissue: From lipid storage compartment to endocrine organ.
Diabetes. 2006;55:1537–1545.
32.Atherton HJ, Bailey NJ, Zhang W, et al. A combined 1H-NMR spectroscopy- and mass spectrometry-based metabolomic study of the PPAR-alpha null mutant mouse defines profound systemic changes in metabolism linked to the metabolic syndrome.
Physiol Genomics. 2006;27:178-186.
33.Kadowaki T et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
J. Clin. Invest. 2006;116:1784–1792.
34.Farmer SR. Transcriptional control of adipocyte formation.
Cell Metab. 2006;4:263–273.
35.Yang Q, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
Nature. 2005;436:356–362.
36.Mooney RA, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance.
J. Biol. Chem. 2001;276:25889–25893.
37.Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.
Proc Natl Acad Sci U S A. 2003;100:8466-8471.
38.von Boehmer H, Sarukhan A. DAG, a single autoantigen for diabetes.
Science. 1999;284:1135-1136.
39. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease.
Nature. 2006;444:875-880.
40.Matsuzawa Y. The metabolic syndrome and adipocytokines.
FEBS Lett. 2006;580:2917–2921.
41.Konstantinides S, Schafer K, Koschnick S, et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity.
J. Clin. Invest. 2001;108:1533–1540.
42.Bernal-Mizrachi E, Wen W, Stahlhut S, et al. Islet cell expression of constitutively active Akt1/PKB induces striking hypertrophy, hyperplasia, and hyperinsulinemia.
J. Clin. Invest. 2001;108:1631–1638.
43.Turko IV, Murad F. Quantitative protein profiling in heart mitochondria from diabetic rats.
J Biol Chem. 2003;278(37):35844-35849.
44.Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependant diabetes mellitus: Prospective studies of Pima Indians.
N Engl J Med. 1993;329:1988-1992.
45.Sakaue M, Fuke Y, Katsuyama T, et al. Austronesian-speaking people in Papua New Guinea have susceptibility to obesity and type 2 diabetes.
Diabetes Care. 2003 26: 955-956.
46.Katulanda P, Sheriff MH, Matthews DR. The diabetes epidemic in Sri Lanka – a growing problem.
Ceylon Med J. 2006;51:26-28.
47.Landau BR, Chandramouli V, Schumann WC, et al. Estimates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients.
Diabetologia. 1995;38:831-838.
48.Tian J, Zekzer D, Lu Y, et. al. B cells are crucial for determinant spreading of T cell autoimmunity among b-cell antigens in diabetes-prone NOD mice.
Journal of Immunology. 2006; 176: 2654-2661.
49.Jaeckel E, Lipes MA, von Boehmer H. Antigen-specific foxp3-transduced t-cells can control established type 1 diabetes.
Nature Immunol. 2004;5:1028-1035.
50.Lieberman SM, Evans AM, Han B, et al. Identification of the beta cell antigen.
Proc Natl Acad Sci U S A. 2003; 100:8384-8388.
51.Arif S, Timothy I. Tree1 TI, , Thomas P. Astill TP, et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health.
J. Clin. Invest. 2004;113:451-463.
52.Kent SC, Chen Y, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.
Nature. 2005;435:224-228.
53.Rotimi CN, Chen G, Adeyemo AA. A genome-wide search for type 2 diabetes susceptibility genes in West Africans: the Africa America Diabetes Mellitus (AADM) study.
Diabetes. 2004:53:1404.
54.Memon RA, Bessman SP, Mohan C. Impaired mitochondrial metabolism and reduced amphibolic Krebs cycle activity in diabetic rat hepatocytes.
Biochem Mol Biol Int. 1995;6:1079-1089.
55.Hotta K et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys.
Diabetes. 2001;50:1126–1133.
56.Giroix MH, Rasschaert J, Sener A, et al. Study of hexose transport, glycerol phosphate shuttle and Krebs cycle in islets of adult rats injected with streptozotocin during the neonatal period.
Mol Cell Endocrinol. 1992;83:95-104.
57.Rosen, E. D. et al. PPAR is required for the differentiation of adipose tissue in vivo and in vitro.
Mol. Cell. 1999;4:611–617.
58.La Selva M, Beltramo E, Pagnozzi F, et al. Thiamine corrects delayed replication and decreases production of lactate and advanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions.
Diabetologia. 1997;40:741-742.
59.Sullivan KA, Feldman EL. New developments in diabetic neuropathy.
Curr Opin Neurol. 2005;18:586-590.
60.Xie XM, Yang ZW, Chen MF. Effects of advanced glycation endproducts on the activity of NF-kappaB and the expression of fibronectin mRNA in the endothelial cells in aged rats.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2006;31:883-887.
61.Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome.
Nature. 2006;444: 881-887.
62.Ali M. Integrative Cardiology and Chelation Therapies: The Oxidative-Dysoxygenative Model and Chelation Therapies.
Principles and Practice of Integrative Medicine 6. 2nd ed. New York: Canary 21 Press; 2006.
63.Ali M. Oxygen governs the inflammatory response and adjudicates the man-microbe conflicts.
Townsend Letter for Doctors and Patients. 2005;262:98-103.
64.Ali M. Under Darwin’s Glow [editorial].
J Integrative Medicine. 1999. 3:1
65. Ali M. Darwin, fatigue, and fibromyalgia.
J Integrative Medicine. 1999;3:5-10.
66.Ali M. Darwin, oxidosis, dysoxygenosis, and integration.
J Integrative Medicine. 1999;3:11-16.
67.Ali M.
The Ghoraa and Limbic Exercise. Denville, New Jersey: Life Span Books; 1993.
68.Turnbaugh.PJ, Ley RU, Mahowald MA, et al. An obesity-related gut microbiome with increased capacity for energy harvest.
Nature. 2006;444:1027-1031.
69.Ley RE, Turnbaugh PJ, Klein S, et al. Human gut microbes associated with obesity.
Nature. 2006;444:1022.
70.Bajzer M, Seeley RJ. Obesity and gut flora.
Nature. 2006;444:1009-1010.
71.Ali M. Hurt human habitat and energy deficit – healing through the restoration of krebs cycle chemistry.
Townsend Letter. October 2006:112-116.
72.Ali M. Integrative Nutritional Medicine: Nutrition Seen Through the Prism of Oxygen Homeostasis.
Principles and Practice of Integrative Medicine 5. 2nd ed. New York: Canary 21 Press; 2005.
73.Ali M. Darwin, Dysox, and Disease.
The Principles and Practice of Integrative Medicine 11. New York: Canary 21 Press; 2002.


Is Diabetes An Oxygen Problem?

Majid Ali, M.D.

At a Foundational Level,  Diabetes Is An Oxygen Problem. These simple words enlighten doctors who have not thought  deeply about the disease more than any other.

In invite serious students of healing traditions to consider this friendly challenge, seriously  study the evidence for this view, and then decide if I trivialize here an important subject.

Hypoxia Begets Hypoxia

(Oxygen deficit leads to more oxygen deficit)

Hypoxia is a term for deficiency of oxygen. Hypoxia begets hypoxia in the human body is a simple fact of biology that lamentably is seldom, if ever, duly considered in the prevailing medical thought, even though everyone knows life is not possible for some minutes if this essential nutrient is not available. 

Oxygen Model of Diabetes


Majid Ali, M.D.

Direct Evidence for the Oxygen Model of Diabetes


On April 14, 2014, the journal PLOS One published additional direct evidence for my Oxygen Model of Diabetes. The study was conducted to investigate the effects of hypoxia (lack of oxygen) at high altitudes on Mount Everest climbers. Its core finding is that hypoxia increased blood levels of markers of inflammation and oxidative stress known to lead to insulin resistance.

During the Everest expedition in 2007, 24 people traveled to the mountain and were checked for blood sugar control, body weight changes and signs of inflammation at base camp, which was at an altitude of 5,300 meters (about 17,388 feet).

Half of the participants remained at base camp while the other half climbed Everest to a maximum altitude of 8,848 meters (29,028 feet). Measurements were taken in each group at week six and week eight of the trek.

“These results have given us useful insight into the clinical problem of insulin resistance. Fat tissue in obese people is believed to exist in a chronic state of mild hypoxia because the small blood vessels are unable to supply sufficient oxygen to fat tissue,” study leader Mike Grocott, a professor of anesthesia and critical care at the University of Southampton, said in a university news release.

Molecular Biology of Insulin

For professional and general readers, I present diverse aspects of molecular biology of insulin in depth in my Free Diabetes and Insulin Courses, which are posted on

Oxygen Model of Diabetes

My Oxygen Model of Diabetes is a unifying model that explains all aspects of diabetes Types 1 and 2—causes, clinical course, consequences, and control—on the basis of impaired oxygen signaling, diminished oxygen’s detergent functions, and interrupted oxygen’s cellular detox and repair functions. I put forth this model first in a series of articles in 2000 and presented it at length it in my book “Dr. Ali’s Plan for Reversing Diabetes (2006)” (available for download at

In my book, I illustrated the insulin/insulin receptor dysfunction with a crank/crank-shaft analogy.Briefly, the cell membranes become resistant to insulin when they become chemicalized—plasticized, so to speak—and hardened, immobilizing the insulin receptors embedded in the membranes. The insulin receptor is a protein that criss-crosses the cell membrane like a cord. One of the consequences of grease buildup on cell membranes is that insulin receptor becomes turned and twisted, literally and figuratively. In a previous paper, I offered the analogy of a crank and a crank-shaft to explain insulin resistance. I visualize insulin as a crank—a device that transmits rotary motion—and the insulin receptor protein as a crank-shaft embedded in the cell membrane.

Suggestred Readings

For more info, please consider:

  1. Dr. Ali’s Diabetes Course
  2. Dr. Ali’s Insulin Course
  3. Dr. Ali’s Oxygen Course



Shift from Oxyphils to Oxyphobes






Vast, Pristine and Threatened .  Lake Baikal. Nov 15, 2016

What Can Blood Cells Teach About Diabetes?


Majid Ali, M.D.

This article is especially suitable for children’s school science projects.

Healthy Red Blood Cells Are Regular, Round, and Non-sticky When the Blood Sugar (Glucose) Levels Is In the  Healthy Range of 70 to 85 in the Morning and Rises to 110 to 130 After Breakfast, As Shown in the Upper Photograph Presented Below.

Red Blood Cells Become Irregular, Crinkled, and Sticky When the Blood Sugar Levels Rise Above 100, As Shown in Lower Photograph below. Blood Glucose Levels are expressed in milligram/dL).

 * look Irregoular fWhen They Are Unhealthy 

Healthy Red Blood Cells When Blood Glucose Level Is Healthy (Upper Frame)

Unhealthy Red Blood Cells When Blood Glucose Level Is Unhealthy (Lower Frame)

Micro-clot and Micro-plaque Formation Occurs In the Circulating Blood When Rising Blood Sugar (Glucose) Levels Blood Cells Are Damaged By Excess Acidity and Oxidative Stress of Excess Bklood Sugar, As Shown In Two Photomicrographs Shown Below. 

A Large Microcot In the Circulating Blood Is Seen in the Center Field (Upper Field)

Clot-Busting Enzymes In the Circulating Blood Have Broken Up the Blood Clot to Clear It.


What Fats and Foods Keep Blood Cells Healthy, Non-Sticky and Not Crooked?

1. Eggs, Olive oil, butter, coconut oil, sesame oil,flaxseed Oil  

2. Fish, poultry, Cheeses, lamb,

3. Almond Butter, Peanut butter, Sesame seed butter, soy nut butter, and other natural butters of nuts and seeds.

What Foods Make Blood Cells Unhealthy, Irregular, and sticky?

1. Sugars, candy, cakes, fruit juices, sweet fruits.

2. Breads, pasta, grains, potatoes, starches

3. Low-fat or skim milks and products made with them.

How Does Diabetes Cause Blockages in Arteries?

Very High Blood Glucose Level Create Microclots in the Circulating Blood Which Are Then Compressed to Form Micro-Plaques, As Shown below. Microclots and micro plaques in the blood stick to arterial walls and causes blockages. Higher the blood sugar values, more the clots and plaques that block blood vessels. 



Q: How Does Diabetes Increase the Risk of Heart Attacks and Strokes?

A: By creating microclots and microplaques as shown above which block heart arteries and brain arteries to cause heart attacks and strokes.


Would You Want Your Child to Win A Prize?

The Link below takes you to an Example of a Winning Essay which you can consider for your child.

For Advanced Readers

Below is text from my articles written for doctors and advanced readers.


Below we describe our high-resolution, phase-contrast morphologic observations that comprise AA oxidopathy and oxidative coagulopathy. The degree and extent of oxidative changes, of course, varies over a broad range depending on the number and the nature of oxidative stressors. During the early months of our work with AA oxidopathy, we were concerned with the issue of whether the changes we observed involving the erythrocytes, granulocytes, platelets and plasma occurred in the circulating blood or were they artifacts caused by the process of preparing peripheral blood smears. We carefully examined fresh smears of several hundreds of apparently healthy individuals who sought our preventive medicine services—as well as those of many healthy volunteers—to assess the range of such morphologic changes in health. Thus, we were able to confidently differentiate semiquantitatively rather limited morphologic changes sometimes seen in healthy subjects from the frequently observed and pronounced abnormalities involving erythrocytes, platelets and plasma encountered in AA oxidopathy in a host of cardiovascular and noncardiovascular clinicopathologic entities.
In the context of IHD, important oxidant stressors include hyperadrenergic state, smoking, hyperglycemia, excess oxidized plasma lipids, obesity and cardiac arrhythmias. We have microscopically microscopically coagulopathy within the circulating blood to generally progress in the following seven morphologic stages:

1. Erythrocyte and leukocyte membrane deformities
2. Diaphanous congealing of plasma
3. Platelet aggregation and lysis
4. Filamentous coagulum (fibrin needles)
5. Lumpy coagulum
6. Microclots
7. Microplaques

The patterns of oxidative coagulative injury described in this article were observed in extensive studies of blood morphology in a host of acute and chronic cardiovascular as well as non-cardiovascular disorders, including advanced IHD, unstable angina, congestive heart failure, cardiac arrhythmias, hypertensive crises, acute and chronic viral and bacterial infections, fungemia, acute and chronic atopic disorders, chemical sensitivity reactions, acute and chronic degenerative disorders and malignant diseases.

Erythrocyte Membrane Damage and Lysis in AA Oxidopathy
Erythrocytes, when observed with an ordinary bright-light microscope in stained smears of peripheral blood, appear as rigid, biconcave, disc-shaped corpuscles. When examined with a high-resolution, phase-contrast microscope in freshly prepared unstained smears, these cells are seen as pliable, round cells that readily change their shape to ovoid, triangular, dumbbell, or irregular outlines to squeeze past other erythrocytes in densely populated fields. Such cells resume their regular rounded contour as soon as they find open space.
Erythrocytes may be expected to show evidence of oxidative damage earlier than other blood corpuscles since these cells transport oxygen, the most important oxidizer in the body. Furthermore, unlike the leukocyte cell membrane which is sturdy and uniquely equipped with enzymatic antioxidant defenses against oxidative stresses of microbial invaders, the erythrocyte membrane is more permeable (to facilitate oxygen uptake and delivery) and, hence, may be deemed more vulnerable. Our microscopic findings provide some evidence for such theoretical considerations. The earliest and most common abnormalities we observed in AA oxidopathy are erythrocyte membrane irregularities and cell deformities. As oxidopathy progresses, an increasing number of red cells show morphologic abnormalities and some cells appear as ghost outlines. Many erythrocytes show surface wrinkling, teardrop deformity, sharp angulations and spike formations. Other changes include rouleaux formations and zones of plasma congealing around damaged erythrocytes.. Some zones of plasma congealing sometimes appear to form spontaneously (without a discernable cause) in close vicinity of damaged erythrocytes and leukocytes.
We established the oxidative nature of plasma and cellular abnormalities described above by demonstrating their reversibility with antioxidants such as vitamin E, taurine, vitamin A, and vitamin C, reported previously12 but not shown here. Parenthetically, we add that we have observed similar evidence of erythrocyte membrane injury in diverse clinical entities associated with accelerated molecular injury such as disabling chronic fatigue, fibromyalgia and a host of severe nutritional, ecologic and autoimmune disorders.

Erythrocyte Homogenate, Free Iron and AA Oxidopathy
In deliberations of atherogenesis, the issues of oxidative injury to erythrocytes and the presence in the plasma of free hemoglobin leached from damaged red cells—and the presence of excess iron in the plasma as a result of those factors—are seldom, if ever, addressed. Our morphologic findings lead us to propose that oxidative erythrocyte injury plays an important role in the genesis of AA oxidopathy and, hence, atherogenesis. We observed erythrocyte membrane damage and lysis with high frequency in many acute ischemic coronary syndromes and, less often, in patients with advanced IHD but without severe, acute coronary ischemia.
Iron, like oxygen, is a molecular Dr. Jekyll and Mr. Hyde. It is needed for molecular transport (in hemoglobin for oxygen), for storage (in myoglobin), for energy functions (in cytochrome oxidase and other cytochromes), for respiration (in non-heme-iron proteins), and for antioxidant defenses (in catalase). In its Mr. Hyde role, iron (in free form) is a potent oxidant and catalyzes the generation of many dangerous oxygen-derived radicals.175-182 In health, the Mr. Hyde roles of iron are minimized by transferrin, an iron-binding protein that rigidly limits the availability of free iron. In normal plasma, only 20 to 30 percent of transferrin occurs in a saturated state.
Free hemoglobin has been considered a dangerous protein—a biological Fenton catalyst.179 It rapidly quenches free radicals in a highly oxidizing environment and becomes oxidized, thus turning into a potent oxidant. It is readily degraded by H2O2 to release free iron, which initiates and propagates several free radical reactions.182-183Hemoglobin reacts with H2O2 to produce a protein-bound oxidizing species capable of causing lipid peroxidation.184Free hemoglobin also avidly binds with nitric oxide radicals and induces vasospasm, triggering yet other oxidizing events, which, in turn, feed the “oxidative fires” of AA oxidopathy.
Beyond ample evidence of the destructive oxidizing capacity of erythrocyte-derived factors discussed above, there is also direct evidence that red blood cells play a role in atherogenesis. Sambrano et al.185 and colleagues have shown that certain receptors on macrophages for oxidized LDL also bind to oxidatively-injured red cells prior to their internalization and lysis. Oxidatively-modified lipid, proteins, and carbohydrate moieties of erythrocyte membranes can be expected to play a host of roles in oxidative coagulopathy and AA oxidopathy, just as they do in attachment, endocytosis, membrane fusion, and viral hemagglutination in viral infections.186-189 We may point out in this context, as shown by Oda et al.189 that oxyradicals play the key pathogenetic roles in virus-induced illness. As we discuss in Part II of this article, a growing body of evidence points to the roles of strong inflammatory, infectious and autoimmune mechanisms in atherogenesis. It seems obvious to us that additional evidence for inflammatory and immunogenic roles of erythrocyte-derived factors in oxidative coagulopathy, AA oxidopathy, atherogenesis and IHD will be forthcoming as those areas are explored further in the future. Of considerable interest in this context is the matter of electrostatic interactions among oxidatively damaged erythrocyte membranes and other oxidized elements in the circulating blood ecosystem. Phospholipids and lipid components of LDL inhibit infectivity and hemagglutination of rhabdoviruses, probably because of structural similarity between such compounds and the receptors for viruses in cell membranes.190,191 In the case of vesicular stomatitis virus, phosphatidylinositol, phosphatidylserine and GM3 ganglioside show inhibitory activity.192 What are the mechanisms of action of such lipid moieties? Some light on this question is shed by studies of Mastromarino and colleagues193 in which removal of negatively charged molecules from membrane lipids by enzyme treatment significantly reduces their inhibitory activity, suggesting that electrostatic interactions play important roles in viral cell membrane dynamics. It seems highly likely that similar electrostatic roles involving platelets, monocytes and other elements in circulating blood ecology will also be discovered in the future.

Granulocyte Clumping, Membrane Damage, and Lysis in AA Oxidopathy
The granulocyte is usually dismissed as inconsequential in discussions of atherogenesis. This surprises us for two reason: 1) we observe morphologic evidence of oxidative damage to granulocytes in AA oxidopathy with high frequency in patients with IHD; 2) it is known that granulocytes produce toxic oxidative species that degrade other intracellular and extracellular molecular species, inflict peroxidative injury to cytoplasmic and organelle membranes, enhance polymorphonuclear leukocyte-endothelial adhesion, and increase microvascular permeability.194-200Evidently, all of those factors can initiate, perpetuate and intensify oxidative phenomena that cause oxidative coagulopathy and AA oxidopathy and may result in IHD. Some oxidizing molecular species elaborated by granulocytes increase capillary permeability and enhance granulocyte-endothelial adhesiveness.202 It seems odd to us that the cell known to play initial and critical roles in oxidative tissue injury is ignored in conditions characterized by oxidative injury to the circulating blood that results in atherogenesis. We recognized that granulocytes would be found to play a central role in atherogenesis when the molecular dynamics of this cell in atherogenesis are eventually investigated. This, indeed, is beginning to happen.
The granulocyte, like the erythrocyte, is a victim of the current infatuation of cholesterol enthusiasts with cholesterol. Our microscopic findings show that granulocytes play pivotal roles in initiating and perpetuating oxidative cascades in the circulating blood. In freshly prepared, unstained peripheral blood smears of healthy subjects, we observe granulocytes as hunter cells that move like crabs on the ocean floor, their locomotion provided by streaming of their granules into little protrusions of their cytoplasm. These cells continuously change their shapes as they explore their microenvironment. Not uncommonly, we visualize active phagocytosis of bacteria and cellular debris by such cells. In AA oxidopathy, the earliest change involving granulocytes is loss of locomotion—the cells lie limp in pools of plasma, with diminished or absent granular streaming. In later stages, granulocytes exhibit clumping. As in the case of erythrocytes, some granulocytes in more advanced cases of AA oxidopathy show blurring of membranes while others appear as ghost outlines of cells. Eventually, badly damaged granulocyte show disintegration of segments of their walls, degranulation and lysis.
The cytoplasmic granules of human granulocytes are rich in many enzymes including proteases, such as elastase, which are capable of degrading proteins in intracellular as well extracellular fluids.202 Oxidative cell membrane injury may be expected to result in escape of proteases from granulocytes into the circulating blood. The destructive capacity of granulocytes represents an exaggerated physiologic response in which bursts of potent oxidative molecular species are produced during inflammatory and repair responses. Specifically, hydroxyl radical (OH.) derived from superoxide radical (O2-) produced by granulocytes are a major cause of cellular injury. Granulocytic myeloperoxidase generates hypochlorite radicals when exposed to H2O2 following phagocytic activation.203Hypochlorite, in turn, oxidizes protease inhibitors, thus leading to increased proteolytic tissue damage.
Granulocytes play a central role in the generation and function of oxidative species that control cellular signaling, regulate mediators of inflammatory and repair responses, and influence migration and replication of inflammatory cells.204-207 A spate of recent gene-activation studies show evidence of the involvement of granulocytes in atherogenesis. Transcription of many atheroscleroses-related genes is augmented by oxidant-sensitive regulatory pathways involving nuclear factor kB (NF-kB).207 Specifically, exposure to superoxide radicals produced in granulocytes—and to lesser degrees in other cells—activates the NF-kB regulatory complex,206,207 which, in turn, triggers transcription of genes that encode for a variety of proteins including leukocyte adhesion molecules, chemotactic cytokines and enzymes that regulate cellular and matrix metabolism.207 Indirect evidence of the relevance of granulocytic factors in coronary artery disease has been shown by Tanaka et al.204 who documented activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Direct evidence for activation of NF-kB in experimental injury has recently been shown by Lindner et al.209 Recent findings of Tardif et al.90 that probucol reduces the incidence of restenosis after coronary angioplasty is consistent with such considerations, since the drug is a potent antioxidant and would be expected to protect coronary arteries traumatized by the angioplasty procedure from granulocytic oxidative bursts.

Platelet Aggregation and Lysis in AA Oxidopathy
The role of platelets in atherogenesis and coronary thrombosis has drawn much—and persistent—attention.210-222Yet, the atherogenic role of oxidatively damaged platelets in the circulating blood is ignored, just as the atherogenic consequences of oxidatively damaged circulating erythrocytes and granulocytes are neglected in deliberations of atherogenesis. In pathogenesis of atherosclerosis, the role of platelets is usually limited to the circumstances under which platelets adhere to endothelium or subendothelial stroma. This shifts the focus—to a great detriment to clear understanding of the pathogenesis of IHD—from initial molecular oxidative events taking place in the blood ecosystem to subsequent cellular oxidative events occurring in the vessel wall ecosystem.
In freshly prepared, unstained peripheral blood smears examined with a high-resolution, phase-contrast microscope, platelets appear as dark, round-to- ovoid, structureless bodies with poorly visualized granules, and without well-delineated plasma membranes. There is little or no tendency toward clumping and the plasma in their vicinity shows no evidence of congealing. Indeed even when smears are allowed to stand for 15 to 30 minutes, platelets remain discrete and do not cause congealing of fields of plasma that surround them in the central portions of the smears. (The peripheral portions of such smears often show early platelet clumping due to oxidative stress caused by exposure to the ambient oxygen.) Familiarity with the range of platelet morphology observed in health is essential before an observer can meaningfully interpret platelet changing seen in AA oxidopathy and oxidative coagulopathy.
In subjects with known atherogenic risk factors—especially in smokers, uncontrolled diabetics and those with chronic inflammatory conditions—we observe evidence of variable damage to platelet membranes and degranulation. The platelets in AA oxidopathy aggregate, change shape, degranulate and release various thrombogenic and atherogenic factors. Not unexpectedly, most platelet aggregates and clumps are surrounded zones of plasma congealing of variable widths. In more advanced stages of AA oxidopathy, platelet membranes become indistinct and lysis occurs. Parenthetically, we might add that we also observe similar damage in patients with disabling chronic fatigue, fibromyalgia, chemical sensitivity and a host of acute autoimmune disorders. Such changes are only rarely seen in apparently healthy subjects.
One of us (MA) established the oxidative redox nature of platelet aggregation and clot formation by addition of ascorbic acid and ethylenediaminetetraacetic acid (EDTA) to platelet aggregates induced by oxidizing agents such as collagen, epinephrine, ADP and ristocetin. We observed that both ascorbic acid and EDTA can readily break up platelet aggregates formed by addition of various aggregating agents.13 Those observations support our view that platelet aggregation and clot formation are oxidative phenomena and that antioxidants ascorbic acid and EDTA caused dispersal of platelet aggregates by protecting the platelet membranes from the oxidant stress. Interestingly, both ascorbic acid and EDTA failed to break up platelet aggregates caused by collagen, indicating a stronger—and perhaps irreversible—effect of collagen on platelet aggregation. From a teleologic perspective, it may be argued that collagen exerts a stronger aggregating influence than epinephrine because circulating platelets are exposed to collagen under more threatening conditions (bleeding from trauma to vessel walls) rather than to epinephrine (a common hyperadrenergic state created by lifestyle stressors).
Endothelial cells and platelets repel each other by their nonthrombogenic character—by their surface charges as well as their ability to generate antithrombotic molecules such as heparin and prostacyclin.220 Thus, adhesion of platelets to endothelial cells is prevented under ordinary conditions. Such electromagnetic and molecular conditions, however, are threatened continuously by the normal oxidative stress in healthy circulating blood. In states associated with accelerated oxidative injury, the normal nonthrombogenic capacity of platelets and endothelial cells is exceeded and platelets begin to agglutinate and adhere to endothelial cells. Examples of conditions of accelerated oxidative stress include catecholamine surges that accompany lifestyle stresses, hypercholesterolemia, denuding endothelial injury caused by intra-arterial catheters, and anastomotic sites of bypass surgery. Under such conditions, injury to platelets triggers chain reactions of oxidative coagulopathy, first in the blood and subsequently in the vascular wall affecting all four lines of cells involved in atherogenesis—endothelial cells, monocytes/macrophages, myocytes, and yet more platelets.221-226 Platelet degranulation releases several growth factors, including platelet-derived growth factor (PDGF),215-217 epidermal growth factor,227 nitric oxide,228 and transforming growth factor-beta.228 Some of these growth factors are powerful mitogens. But generation of all such growth factors is initiated by direct oxidative stress on platelets.
What is the common denominator in all platelet factors that are associated with IHD? Evidently, it is accelerated oxidative injury to elements in the circulating blood that leads to oxidative coagulopathy and AA oxidopathy. Again, as for erythrocytes and granulocytes, the patterns of oxidative damage to the components of the vascular wall that lead to plaque formation—and which have claimed enormous sums of research funds without significant benefit to those who suffer from IHD—clearly are consequences of changes in the circulating blood.

Ali M, Ali O. AA Oxidopathy:
the core pathogenetic mechanism of ischemic heart disease.
J Integrative Medicine 1997;1:1-112.

Erythrocyte Morphology in Health
and Early Stages of AA Oxidopathy

Figure 1 (top): All erythrocytes and two lymphocytes shown in the photomicrograph keep their distance from each other (due to negative electrostatic surface charges) and show regular outlines. Note that none of the well-preserved erythrocytes are discoid in shape. Figure 2 (bottom) shows early changes of AA oxidopathy with many damaged erythrocytes.

Severe Erythrocyte Damage and Leukocyte
Clumping in AA Oxidopathy

Figure 3 (top) shows a more advanced stage of erythrocyte damage in a 66-year old hypertensive female than in figure 2. Only a few cells show well-preserved, completely regular outlines. Some cells appear as ghost outlines of leached cells. Figure 4 (bottom) shows clumped leukocytes surrounded by some faded cells.

Zones of Congealed Plasma Surrounding
Platelets and a Damaged Leukocyte

Figure 5 (top): A spreading zone of congealed plasma representing initial changes of oxidative coagulopathy in a smoker is seen near the center of the field. Note rouleaux formation of erythrocytes. Figure 6 (bottom) shows a similar zone of congealed plasma surrounding a damaged leukocyte. We confirmed the spreading nature of these zones of congealing by observing these zones over time.

Erythrocyte-Induced and “Spontaneous”
Plasma Congealing

Figure 7 (top) illustrates severely damaged erythrocytes in a 52-year-old man with persistent atrial fibrillation. Close examination shows some zones of congealing surrounding many damaged red blood cells. Figure 8 (bottom) illustrates a zone of plasma congealing unaccompanied by any cellular elements of the blood (seemingly a “spontaneous” phenomenon) in a diabetic with IHD. In our view, such congealing represents accelerated oxidative stress on plasma.

Needle-like and Amorphous Microclots
And “Dirty” Field of AA Oxidopathy

Figure 9 (top) shows some needle-like and amorphous granular microclots in a patient with unstable angina. Figure 10 (bottom) shows a “dirty” blood smear of a man with severe peripheral vascular disease and extensive bilateral leg ulcerations, showing zones of plasma congealing and lumpiness, platelet clumping, and some other zones of plasma congealing unaccompanied by any blood corpuscular elements, representing diffuse changes of AA oxidopathy.

 A Large Platelet Clot And a Meshwork of Clots

Figure 11 (top) shows a microclot formed by a large aggregate of platelets and congealed plasma in a patient five days after angioplasty. Figure 12 (bottom) shows another field from the same smear and illustrates how microclots in oxidative coagulopathy grow in size when oxidative stress persists.

Microplaque Formation In AA Oxidopathy

Figure 13 (top) and figure 14 (bottom) show two microplaques in a patient who had received three unsuccessful angioplasties for advanced IHD. Photomicrographs were taken the day after a major nosebleed. Note the compaction of necrotic debris and blood elements in microplaques as contrasted with loose structure of microclots in figure 11.

Dissociation of Platelet Aggregates by Vitamin C

Figure 15 (top) shows patterns of aggregation of platelets induced by oxidative stress of epinephrine, collagen, ADP and ristocetin. Such aggregation is the in vitro counterpart of in-vivo platelet clumping seen in AA oxidopathy and shown in figure 11. Figure 16 (bottom) shows patterns of dissociation of platelet aggregates obtained with the four aggregating agents on addition (arrow) of a 0.5 percent solution of ascorbic acid. Note that ascorbic acid completely dissociates epinephrine-induced aggregates (top), while its effect on collagen-induced aggregation (bottom line) is minimal.13

Reversal of Early Changes of AA Oxidopathy

Figures 17 (top) and 18 (bottom) show abnormal erythrocyte morphology in a highly stressed 53-year-old man before and after addition of 1:50 dilution of mycelized vitamin E solution. Note how vitamin E normalizes red cell morphology and establishes the oxidative nature of erythrocyte injury.

Reversal of Early Changes of AA Oxidopathy with Taurine

Figures 19 (top) and 20 (bottom) illustrate AA oxidopathy changes involving erythrocytes before (top) and after (bottom) addition of taurine (1 mg/50 ml) in a 63-year-old man in congestive heart failure. Taurine is a powerful cell membrane stabilizer that is known for its cardio- and neuroprotective roles. This simple experiment establishes the oxidative nature of red cell abnormalities seen in congestive heart failure.

Diaphanous Congealing of Plasma
We observed diaphanous zones of plasma congealing surrounding platelets, fragments of leukocytes, and fungal organisms. In many cases we observed areas of plasma congealing without any involvement of platelets, leukocytes and fungal organisms. That some free radical activity exists in plasma in health must be accepted on teleologic grounds alone. Such oxidative stress is generated by normal metabolic activity of red and white blood corpuscles as well as of platelets, oxidation of catecholamines, enzymatic glucose breakdown, nonenzymatic autoxidation of blood glucose in hyperglycemic states, and mechanical shearing stress on endothelial cells. Furthermore, zones of plasma congealing and microclots produced by physiologic redox dynamics may be expected to be dissolved as soon as they form by normal plasma fibrinolytic activity. Notwithstanding such physiologic fibrinolytic activity, some free radical damage to the endothelium and subendothelial matrix would be expected to ensue. Indeed, the presence of fatty-streak lesions in children attests to the existence of such insidious and clinically silent oxidative coagulopathy.
It is to be expected that normal oxidative stresses on blood plasma are markedly increased during a host of pathologic states of the cardiovascular system, as well as of other body organ ecosystems, accompanied by accelerated oxidative injury. This includes advanced IHD, unstable angina, congestive heart failure, cardiac arrhythmias, hypertensive crises, hyperglycemia, and during smoking.

Lumpy Coagulum and Fibrin Needles
Intravascular coagulation has long been assumed to be an uncommon and potentially life-threatening state. Our high-resolution, phase-contrast microscopy observations of peripheral blood in a host of cardiovascular and non-cardiovascular entities challenge this assumption. In health, plasma in peripheral blood smears appears as clear liquid that bathes cells. In states of accelerated oxidative molecular injury, damaged plasma proteins begin to congeal, and such zones of clotted plasma spread as thin diaphanous films. As the oxidative process advances, cross-linked fibrin appears as filamentous and lumpy coagulum. Some platelets can usually be recognized trapped within filamentous and lumpy fibrin deposits, undoubtedly contributing oxidized phospholipids and glycolipids to the protein coagulum. Such needles and masses of oxidized, coagulated proteins and peroxidized lipids grow by triggering the chain reactions of plasma lipid peroxidation and protein coagulation. We have consistently documented the presence of fibrin needles and lumpy coagulum of protein in freshly prepared and unstained blood smears in states of accelerated oxidative damage. By comparing peripheral blood morphology before and after intravenous infusions of EDTA and ascorbic acid, both administered with magnesium, we have repeatedly observed dissolution of fibrin needles and lumpy protein after the infusions in cases in which such evidence of oxidative coagulopathy was clearly discerned.

The presence in circulating blood of microclots formed by oxidative stress of normal blood ecology, and an excess of such clots in states of accelerated oxidative stress, may be reasonably deduced from the foregoing discussion of redox dynamics of plasma components and blood corpuscles in health and disease. Congealing of plasma, erythrocyte and leukocyte membrane damage and platelet clumping may be expected to add to the oxidizing capacity of blood by triggering fibrinogenic and lipid peroxidation chain reactions. Furthermore, such changes may be expected to initiate oxidative chain reactions, thus increasing oxidative stress and enlarging zones of plasma congealing into microclots. We document such progressive changes of AA oxidopathy.

A natural consequence of oxidant microclots—oxidative coals, in our terminology—circulating in blood would be for them to grow in size as the plasma at their periphery continues to congeal and as an increasing number of platelets and other blood corpuscles are entrapped into or stick to them. With ongoing oxidative stress, such microclots coalesce to make yet larger and lumpier microclots. With time, such loosely bound microclots are compacted in form layered structures with dead and dying cells and other necrotic debris trapped between layers of fibrin that we call microplaques. Such microclots and microplaques float in the bloodstream as simmering oxidative coals, lighting up oxidative fires and inflicting further oxidative damage to blood corpuscles, endothelial cells and subendothelial collagen matrix wherever the lining cells of the vascular lumen have been denuded by the shearing mechanical stress of circulating blood. We have observed microclots grow into microplaques that measure as much as several hundred microns.
All oxidants in circulating blood trigger oxidative coagulative phenomena involving blood corpuscles and plasma contents. Our clinical and high-resolution microscopic observations lead us to consider the following groups of causes of accelerated oxidative stress on the circulating blood that lead to oxidative coagulopathy:

1. Adrenergic hypervigilence associated with lifestyle stressors
2. Rapid glucose-insulin and adrenergic shifts
3. Mycotoxicity and, to lesser degrees, toxins from other microbes
4. Increased oxidizability of blood associated with obesity
5. Diminished dietary intake of natural antioxidants
6. Increased body burden of prooxidants such as iron, copper and mercury
7. Inflammatory factors
8. Infectious agents
9. Excess of oxidized and denatured lipids
10. Autoimmune factors
11. Oxidative stress of cigarette smoking
12. Hyperhomocysteinemia
13. Mechanical shearing stress associated with hypertension.

Ali M, Ali O. AA Oxidopathy:
the core pathogenetic mechanism of ischemic heart disease.
J Integrative Medicine 1997;1:1-112.

Smoking and AA Oxidopathy

Figure 21 (top) before smoking and Figure 22 (bottom) after smoking show changes of AA oxidopathy observed in a volunteer who abstained from smoking overnight and then smoked three cigarettes in three minutes.

AA Oxidopathy and Fungemia

There are four important questions here:

1. How often are fungal organisms seen in the circulating blood of nonfebrile ambulatory persons?

2. What roles do such organisms play in the pathogenesis of oxidative coagulopathy and AA oxidopathy?

3. What are the possible mechanisms of action of mycotoxins and other fungal proteins?

4. What roles do fungal organisms play in the inflammatory and autoimmune processes that are known to be atherogenic and involved in other aspects of IHD?

As to the first question of how frequently fungal organisms may be observed in afebrile ambulatory patients, there is wide divergence of opinion among those who routinely use high-resolution (15,000 x) phase-contrast microscopy and those who never use such technology. We have documented the presence of fungal organisms in peripheral blood of severely immunocompromised individuals with high frequency (over 95%).229 As a part of our study of the phenomena of oxidative coagulopathy and AA oxidopathy, we also examined the peripheral blood smears of 50 consecutive patients with advanced IHD (including those recovering from angioplasty and coronary bypass operations) and detected the presence of fungal organisms in many microscopic fields in 19. Identification of specific fungal species cannot be done with such microscopy. However, employing anticandida antibodies labeled with horseradish peroxidase, we have documented the presence of Candida species in peripheral smears in some cases.230,231 We have previously published the specificity characteristics of the anti-candida antibodies we employed in such studies.232,233 Such observations may be challenged by those unfamiliar with high-resolution microscopy on the ground that if true fungemia did exist in such patients, they would be critically ill. This requires further comment.
The clinical distinction between benign bacteremia and potentially life-threatening septicemia is well recognized; the former occurs after tooth brushing and is clinically insignificant. It is noteworthy that no such clinical distinction is made in the prevailing medical thinking between insidious and clinically silent fungemia and potentially life-threatening fungal invasion of the bloodstream. Fungemia, the presence of fungi in circulating blood, is always considered a serious pathologic entity. This is clearly erroneous in view of the direct evidence to the contrary that we present here. Regrettably, many physicians who have not taken the time to learn the use of high-resolution microscopy—and hence are uninformed about the prevalence of fungal organisms in the peripheral blood of immunocompromised individuals—make irresponsible and derogatory statements about those who use such technology. Indeed, some licensing boards controlled by such uninformed physicians have taken serious disciplinary actions, including suspension of medical licenses, against holistic practitioners who diagnosed fungemia with high-resolution phase-contrast microscopy and treated clinical yeast syndromes.234

Fungemia, Mycelia Formation and Fungal Budding
In figures 27 through 30, we illustrate the replication, mycelia formation and fungal budding in peripheral blood smears observed over a period of five hours for two reasons: 1) to provide additional proof that the bodies we recognize as fungal organisms are indeed fungi (shown by their ability to form mycelia and the ability of the mycelia to show budding); and 2) to document the rapidity with which fungal organisms multiply as oxygen tension falls and acidity increases in their microenvironment—the two conditions under which fungi would be expected to grow luxuriantly.
As to the second question concerning the possible roles of fungal proteins and mycotoxins in the pathogenesis of oxidative coagulopathy and AA oxidopathy, we illustrate some of the observable phenomenon of zones of plasma congealing surrounding fungal organisms.. We observed this phenomenon to occur within ten to sixty minutes in almost all instances in which we studied the morphology of fungal organisms continuously in freshly prepared unstained peripheral blood smears. We also observed fungal spores to germinate within one to ten hours in most such cases. The zones of plasma congealing surrounding fungal organisms increase in area, trap platelets and cellular debris, and grow into microclots, and finally into micro-plaques. Such findings suggest that fungal organisms play a role in the pathogenesis of oxidative coagulopathy and AA oxidopathy. We return to this subject later in this article.
If fungemia occurs frequently in chronic immune disorders, why can’t the fungal organisms be cultured from blood in such cases? This is a valid question. We have addressed this issue at length elsewhere.235 It is noteworthy that negative blood cultures are frequently seen in patients with documented invasive tissue fungal infections. In one study of such patients, a Candida enzyme called enolase was detected in 42 percent of patients with proven tissue candidiasis.236
The third and fourth questions concern the possible molecular mechanisms by which fungi cause AA oxidopathy and might play etiologic roles in the pathogenesis of IHD. We return to this subject after discussing AA oxidopathy in relationship to the known molecular dynamics of IHD.

Fungemia and AA Oxidopathy Phase-Contrast and Darkfield Views

Figure 23 (top) shows clusters of round-to-ovoid white fungal bodies that contrast with dark erythrocytes in a high-resolution (15,000X) phase-contrast photomicrograph. Figure 24 (bottom) shows the same microscopic field in darkfield. Note that unlike erythrocyte lipid membranes that reflect light, fungal membranes contain disaccharides that absorb light and do not appear as bright as red cell membranes.

Immunostaining of Candida Organisms
in Peripheral Smears

Figure 25 (top) and figure 26 (bottom) show unstained and immunostained Candida organisms in phase-contrast and darkfield fields. In this procedure, human anti-candida IgG antibodies labeled with horseradish peroxidase were used to specifically stain Candida organisms. For procedural details and antibody specificity characteristics, see references #230 through 233.

In Vitro Fungal Growth

Figure 27 (top) is a photomicrograph of a freshly prepared peripheral blood smear of a diabetic with leg ulcers and severe fatigue and shows several fungal organisms. Figure 28 (bottom) represents the same smear photographed 37 minutes later showing a luxuriant growth of fungal organisms as the oxygen tension of the smear under a coverslip falls and acidosis develops due to continued glycolysis(the two conditions that are known to support rapid fungal replication.

Mycelia Formation and Building

Figures 29 (top) and 30 (bottom) are photomicrographs of the smear shown in figures 27 and 28 taken 3 1/2 and 4 hours later respectively. Note how yeast grow mycelia with profusion and how some mycelia grow buds.

Fungemia and Oxidative Coagulopathy Earliest Changes




The Gut-Diabetes Connections

Majid Ali, M.D.

Simply stated, the risk of all disorders of the alimentary tract increases in diabetes.

The Gut-Diabetes Connections

 The Gut-Diabetes Connections

  • Throat
  • Esophagus
  • Stomach
  • Small intestine
  • Large intestine

Digestion starts within the mouth by the action of the enzymes in saliva. It then takes full effect within the stomach and some nutrients are also absorbed into the bloodstream here. Partially digested food known as chyme then undergoes further digestion mainly in the first part of the small intestine known as the duodenum. The small intestine, or small bowel, is the longest part of the gut and gradually the food is completely digested and almost all the nutrients are absorbed into the bloodstream.

Mechanisms of gut-diabetes connections

Insulin toxicity which precedes Type 2 diabetes injures blood vessels, nerves, and the muscuature of the intestinal tract. In addition it causes dysfunction of brain centers involved in the digestive-absorptive functions of the gut.


Read more in the articles in Dr. Ali’s Diabetes Course





Part Two. Is Diabetes Really A Sugar Problem

Majid Ali, M.D.

Some readers have been dismayed by my statement that diabetes is not a sugar problem.

Below are some questions they have raised. My answers follow the questions.


  1. Ali’s is wrong. Everyone in the world knows that diabetes is a sugar problem,” one dissenter complained.
  2. How can Dr. Ali be wrong and all other doctors in the world be wrong on the sugar-diabetes question?” another asked.
  3. Doesn’t he know that blood sugar is high in diabetes? Why would doctors do blood testing if diabetes was not a sugar problem?
  4. Doctors do blood A1c test. Isn’t it a sugar test,” comes another challenge.


  1. Everyone in the world knows that diabetes is a sugar problem. This not true. Scientists and well-informed doctors know that excess insulin (insulin toxicity) predates diabetes by five, ten, or more years.
  2. All doctors in the world would be wrong on the sugar-diabetes question. No, all doctors would not be wrong. I have never met any doctor who denies the scientific facts that insulin toxicity (hyperinsulinism) predate Type 2 diabetes (the type of diabetes that affects more than 90% of diabetics in the world).
  3. Does Dr. Ali know that blood sugar is high in diabetes? Yes, I know that. But blood sugar begins to rise years after blood insulin levels rise and begin to injure various body organs. I explain my simple point below with a kitchen gas rang” analogy.
  4. Isn’t A1c test a test for blood sugar? Yes, it is, but this test is not a reliable test for screening for diagnosing diabetes. I have seen patients in which A1c is in the normal range and the patients has diabetes, and other patients whose A1c value is higher but a three-hour test for glucose does not sjows evidence of diabetes.


Let us suppose that the gas line in the basement of a house leaks for weeks and then one day there is a fire in the kitchen stove and the house burns down. What would we blame for the house fire, the leaking gas line in the basement or the kitchen stove?



 Dr. Ali’s Video Series

For Answers With Honest “Insulin Conversations”

Seven Questions That Matter

  1. What causes weight gain? (It is insulin toxicity.)
  2. What is diabetes? (It is insulin toxicity.)
  3. What is your chance of getting diabetes? (One in two now, seven in ten in 20 years.)
  4. How can you lose weight? (With insulin-smart eating.)
  5. How can you reverse diabetes? (With insulin-wise diet and insulin detox.)
  6. How can I know if I am hurting my heart, brain, liver, kidneys, ovaries, and testis? (If you have excess insulin and are insulin-toxic, you are hurting all these organs.)
  7. How Can I Begin Losing Weight and/or reversing diabetes? (Be honest with yourself and learn with intelligent insulin conversations.)

Honest Answers to the Seven Questions 

A mirror does not accept lies. One cannot lie to one’s own self. This how I suggest you begin honest and intelligent insulin conversations. I invite you to put my statement to a challenge with my library of Insulin-Diabetes Video Library. View the videos once, twice, thrice, or more often, and then be honest with yourself. Next read the seven quesions and try to answer them. Then look at the videos and see if my very short answers to the questions really make sense to you.

List of Videos

For articles on the subject, please consider my free course entitled “Dr. Ali’s Diabetes Course.”

 Be Insulin-Literate, Please!

 Who Does Not Want You to Be Insulin-Literate?

Insulin Health and Free Insulin Course

 Insulin Buddy

Diabetes and insulin Majid Ali MD

 Insulin Health and Free Insulin Course

 Think Sugar-Diabetes and Remain Ill-informed or Think Insulin and Be Well-informed

What Is Your Diabetes Subtype?

 Insulin Toxicity, and Fatty Liver With Normal Liver Blood Tests

 Inflammation-Insulin Connections

 Why Do I Consider Blood Insulin Test to be the Single Most Important Test

 What Is Your Child’s Peak Insulin Level? Is She or He Insulin-Toxic?

Seventy Percent of World Population Diabetic in 25 Years


Insulin Buddy and Fatty Liver

 Castor Oil Rubs for Insulin Detox for Weight Loss and Diabetes Reversal

 Obesity Is Cellular Inflammation


 Gestational Diabetes Is Insulin Toxicity of the Unborn – Part Two

What is the Evidence That Neuropathy Is Caused by Insulin Toxicity?



On Diabetes, the Times Betrays Readers, Again


Majid Ali, M.D.

The New York Times has a very long history of betraying its readers on the subjects of obesity and diabetes. On December 1, 2015, it did it again, and did it on the top of its front page with the following heading and beginning text:

“New Diabetes Cases – At Long Last, Begin to Fall in the United States – After decades of relentless rise, the number of new cases of diabetes in the United States has finally started to decline.”

Diabetes Is Caused by Toxic foods, Environment, and Thoughts

Since there is clear evidence that toxicities of foods environment, and thoughts in the U.S. are increasing, what might be the reason for the Times’ Lapdog Joes not questioning the validity of the report they publish on the front page?

A Prediction

The Times will reverse itself, unequivocally and soon. This is my simple prediction. I make all my predictions in writing and all my predictions to date proved correct, except one. The only exception so far was in my book entitled “September Eleven, 2005” (published in February of 2002 in which I predicted that the 9/11 monument will be completed in five years0. I learned my lesson not to ever make any predictions except in matters of food, environment, stress, anger, oxygen, and fermentation.

Diabetes Is Not a Problem of Sugar, But of Insulin Toxicity

This is the truth that The New York Times has kept from its readers for over half a century. Why? Because its medical journalists have not been watchdogs for the society but Lapdog Joes, too lazy to dig for the scientific truth. They blindly accepted nonsense spouted by by their medical experts on the payroll of merchants of money in medicine.

Am I Guilty of the Same Crime Which I Accuse the Times of?

I invite you to find the answer in the following quotes from the Journal of American Medical Association on the subjects of dietary fats, obesity, cardiovascular disease, and other conditions clearly related to diabetes type 2.

 Text From JAMA of June 23/30, 2015:

Below, I reproduce some text from the June 23/30 issue of Journal of American Medical Association (JAMA) to illustrate my point:

“In the new DGAC [Dietary Guidelines Advisory Committee] report, one widely noticed revision was the elimination of dietary cholesterol as a “nutrient of concern.” (ref 2)

I point out that the view of cholesterol being a dietary nutrient of concern was vigorously challenged (ref 3,4) but such challenges went unacknowledged. Here is some more text about cholesterol from the same issue of JAMA: “This surprised the public, but is concordant with more recent scientific evidence reporting no appreciable relationship between dietary cholesterol and serum cholesterol or clinical cardiovascular events in general public.”

Second specific example of unrecognized vulnerability to bias concerns the matter of health and total dietary fat. Consider the following text from the same issue of JAMA:

“With these quiet statements, the DGAC report reversed nearly four decades of nutrition policy that placed priority on reducing total fat consumption throughout the population.” Here is more on dietary fat from the same issue of JAMA: “Randomized trials confirm that diets higher in healthy fats, replacing carbohydrate or protein and exceeding the current 35% fat limit, reduce the risk of cardiovascular disease.”

I point out that this view of limiting total dietary fat was also vigorously challenged (ref 5,6), and went un-acknowledged. Elliott and colleagues end their article by underscoring the importance of rigorous and trustworthy methods to make sense of the data. This is crucial advice for public health policy makers as well as clinicians.


  1. Elliott JH,Grimshaw J, Altman R, et al. Make sense of health data. Nature. 2015;527:31-32.
  2. Mazaffarian D, Ludwig DS. The 2015 US Dietary Guidelines – Lifting the Ban on Dietary Fat. JAMA. 2015;313:2421-2.
  3. Ali M, Ali O. AA oxidopathy: the core pathogenic mechanism of ischemic heart disease. J Integrative Medicine 1997;1:6-112.
  4. Ali M. Oxygen and Aging. (2nd ed.) New York, Canary 21 Press. 2000.
  5. Ali M. The Principles and Practice of Integrative Medicine Volume V: Integrative Nutritional Medicine: Nutrition Seen Through the Prism of Oxygen Homeostasis. New York. Canary 21 Press.1999.
  6. Ali M, Fischer S, Juco J, et al. The dysox model of coronay artery disease. Townsend Letter for Doctors and Patients. 2006;270:110-112.


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