This article originally appeared in the May 2007 issue of the Townsend Letter.
Published online May 2009.

Is diabetes mellitus 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.

Strong clinical, epidemiologic, and experimental evidence links the epidemics of obesity with those of diabetes in an ever-increasing number of countries.^9-11 That 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, the hormonal output of adipocytes 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 oxide^16,17
· inducible nitric oxide synthase (iNOS)¹⁸
· mitochondrial uncoupling proteins (UCPs)^19-21
· proinflammatory cytokines^22-24
· resistin^25,26
· leptin^27,28
· 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

These factors constitute an enormous network of molecular and cellular cross-talk, nearly all aspects of which are linked to oxygen signaling and provide support for the dysox model of diabetes. To cite some examples, overexpression of several antioxidant and oxystatic systems – including superoxide dismutase, catalase, and glutathione peroxidase – in various tissue-organ systems of diabetic animals and humans has been documented.⁴⁵ Later in this column, I furnish direct evidence for impaired bioenergetics – altered Krebs cycle chemistry, glycolytic pathways, and mitochondrial functions – in individuals with diabetes, by presenting personal data.

Angry Diabetes Genes – Getting Angrier by the Decade
Is diabetes a genetic problem? No. My answer is likely to surprise most readers. I recognize that diabetes runs in families. However, the story of genetics unravels rapidly when we consider the epidemics of diabetes all over the world. Consider the following: on January 9, 2006, the New York Times projected the rising incidence of diabetes with the following words: "If unchecked, it is expected to ensnare coming generations on an unheard-of scale: One in every three Americans born five years ago. One in two Latinos." One in two Latinos! That is likely to surprise only those unfamiliar with the sad story of the galloping incidence of diabetes among the Pima Indians of the Southwestern US. A single case of diabetes was recorded among the tribes by a traveling physician in 1908. Then Elliot Joslin (the founder of Joslin Clinic for diabetes in Boston) found 21 cases in the early 1930s. The number of individuals with diabetes among the tribes had increased to 283 cases in 1954 and to over 500 in 1965. By mid-1990s, the prevalence of diabetes among the Pima Indians had risen to over 60%.⁴⁴ As for diabetes among children and adolescents, consider another quote from the Times article cited above: "So-called type 2 diabetes, the predominant form and the focus of this series, is creeping into children, something almost never heard of two decades ago."

Much-needed light on the genetics of diabetes is also shed by newer data concerning the epidemics of diabetes in Papua New Guinea (PNG), Ceylon, Africa, and India. For example, some years ago, the prevalence of diabetes in PNG population was reported to be "virtually 0%," whereas recent surveys showed that type 2 diabetes has become a common disease.⁴⁵ In March 2006, the Ceylon Medical Journal reported that in 1990, the prevalence of type 2 diabetes was 2.5%, and it had risen to 14.2% among males and 13.5% among females by 2005.⁴⁶ Similar data concerning epidemics of diabetes are being reported from various African and Asian countries. Most notable in this context is the epidemic of low-body-weight diabetes in India. The core questions here are the following: (1) Why did the diabetes genes become angry during the last century? and (2) Why are those genes getting angrier by the decade? Genes – not unlike physicians – are not solo performers. Genes do not exist and function in a vacuum, nor do they serve their roles in the essential injury-healing-injury cycle of life as independent agents. Genes continuously recognize and respond to changes in their environment. A new field of "ecogenomics" is what is sorely needed, not only to understand the true nature of the disease processes we collectively designate as diabetes, but also for designing integrative therapies for the prevention of diabetes and the process that may be called "de-diabetization" – complete (see illustrative case study below) or partial – in clinical practice.

In this column, I demonstrate the essential relatedness of the above epidemiologic, genetic, biochemical, and clinical observations and offer answers to questions I raise by (1) presenting personal data showing impaired altered Krebs cycle chemistry and mitochondrial functions; (2) summarizing a large body of recent experimental and clinical data that shed light on the subjects of disrupted molecular bioenergetics and impaired detox mechanisms in diabetes; and (3) presenting some illustrative case studies to underscore the potential for de-diabetization.

Impaired Krebs Cycle and Glycolytic Pathways in Diabetes
Diabetes, first and foremost, is a disorder of impaired molecular bioenergetics and oxygen signaling. Mitochondrial electron transfer events form the foundation of human molecular energetics.⁴⁷ This is where respiration is coupled with oxidative phosphorylation for ATP generation, which serves as the energy currency of the body. If one were to accept that diabetes is primarily a molecular bioenergetic disorder, one would expect to find in it clear evidence of dysfunctional mitochondrial uncoupling proteins. That, indeed, is the case.

I draw evidence to support my view from a large body of clinical, biochemical, and experimental data. Clinically, it is noteworthy in this context, the initial clinical presentation of diabetes in poor countries is often unexplained fatigue. In Table 1, I present biochemical evidence of the existence of impaired Krebs cycle and glycolysis, as well as biotoxins (mycotoxins and others) in a series of 17 patients with type 2 diabetes. The average age of 11 males in the study was 65 years (range 36 to 80), while those of six females was 68 years (range 66 to 71). The data presented show increased urinary excretion of intermediates of Krebs cycle and glycolysis, which serve as direct evidence of defects in those pathways. The data concerning increased urinary excretion of biotoxins (mycotoxins and others) – which are known to uncouple respiration from oxidative phosphorylation, interfere with mitochondrial electron transfer, and so impede or block Krebs cycle – provide indirect evidence for the same.

The data in Table 1 validate my observations concerning the clinical management of diabetes made over a period of two decades. For three decades, on clinical grounds, I became convinced that altered bowel flora affect the energy homeostasis of the body and that obesity alters the nature of the bowel microbiota. Specifically, I recognized two sets of factors that play crucial roles both in the optimal control of blood sugar levels and the prevention of diabetic complications: (1) the issues of bowel ecology, which include untreated mold allergy and adverse food reactions, altered bowel flora, mycotoxicosis, increased bowel permeability, and digestive-absorptive dysfunction, essentially in that order of importance; and (2) impaired hepatic detoxification and metabolic pathways. Note that all diabetic individuals in the study showed clear evidence of bowel-related biotoxins that directly or indirectly uncouple respiration from oxidative phosphorylation. More than half of the patients (10 of 17) had increased urinary excretion of hippuric acid, indicating impaired hepatic enzymatic detoxification functions. I discuss the therapeutic implications of the data in Table 1 in the section "De-Diabetization Strategies."

Immunology of Beta Islet Cells and Insulin
Insulin is itself a potent autoantigen that initiates autoimmune (juvenile-onset, type 1) diabetes.^1-3 What are the conditions under which insulin, a hormone without which life is not possible for more than a few days, becomes an autoantigen that unleashes diabetes? This is one of the central issues to be addressed in the dysox model of diabetes. Before attempting to answer this question, I briefly review here the immunology of pancreatic beta cells and insulin.

In type 1 diabetes, lymphocytes react against and destroy the beta cells in the pancreas of genetically vulnerable individuals. The loss of insulin-producing cells leads to insulin deficit, which, in turn, causes hyperglycemia (diabetes in the prevailing sense of that disease). Lymphocytes are expected to recognize other autoantigenic targets as beta-cell destruction proceeds with a process that has been termed "antigenic spreading."⁴⁸ Specifically, it is known that reduced expression of some islet cell autoantigens, or elimination of the lymphocytes that recognize them, can reduce the degrees of glucose dysregulation. However, beta-cell-specific autoimmune attacks cannot be aborted by such interventions.^49,50 It is known that insulin-reactive lymphocytes from healthy individuals exert healthful regulatory functions by producing some needed signaling molecules. By contrast, insulin-reactive lymphocytes from diabetics assume destructive roles by releasing molecules that are harmful to beta cells.⁵¹

About 50% of the lymphocytes isolated from the pancreatic draining lymph node of diabetic patients recognized a segment of the insulin A chain. Healthy control subjects, by contrast, do not show a similar accumulation of insulin segment-recognizing lymphocytes.⁵² A type of immune cell called an antigen-presenting cell plays an important role in such immune-recognition processes. Specifically, it captures protein fragments from dying beta cells and "displays" it to the convening lymphocytes in the pancreatic-draining lymph nodes. In 2006, it was reported that the cell-surface protein that binds to and displays the insulin A fragment on the antigen-presenting cells is encoded by a gene known to confer genetic susceptibility to diabetes.⁵³

At the level of adipocytes and myocytes, insulin can be visualized as a crank – a device that transmits rotary motion – and the insulin receptor protein as a crankshaft embedded in the cell membrane. In the dysox model of diabetes, insulin resistance can then be seen as a rusted crankshaft of insulin receptor, which is impacted in a "hardened" cell membrane and so cannot be turned by the insulin crank.

Diabetes as a Dysfunction of Mitochondrial Uncoupling Proteins
Mitochondrial uncoupling proteins (UCPs) are a family of proteins that serve as "metabolic brakes" located within the cellular powerhouses.^19-21 These proteins uncouple respiration from oxidative phosphorylation and provide counterregulatory mechanisms operating at the very foundational levels of human bioenergetics – a cooling system, so to speak, in times of "overheated" electron transfer events. (What an elegant example of Nature's preoccupation with complementarity and contrariety in its management of energy economy!) If one were to accept that diabetes is first a bioenergetic dysfunction, one would expect to find in it clear evidence of dysfunctional mitochondrial uncoupling proteins. That, indeed, is the case.

The production of mitochondrial uncoupling protein 2 (UCP2) in beta cells is increased in obesity-related diabetes,¹⁹ indicating increased mitochondrial response to factors that accelerate the electron transfer reactions – an effect predicted by the dysox model of diabetes. Another dimension of the role of UCP in the pathogenesis of diabetes is revealed in experimental animals in which UCP2 overexpression is associated with impairment of glucose-stimulated insulin secretion (GSIS). I might add that a nuclear receptor called the short heterodimer partner (SHP) is also involved with GSIS, as well as with some key cell membrane channels. For example, SHP overexpression increases the glucose sensitivity of ATP-sensitive K+ (KATP) channels and increases the ATP/ADP ratio.⁵⁴ In healthy animals, overexpression of SHP enhances GSIS in normal islets and restores this function in animals with UCP2-overexpressing islets. This represents another mechanism by which overwrought molecular "braking systems" can be loosened up.

There are yet other noteworthy aspects of SHP. Methylpyruvate is an energy fuel that bypasses glycolysis and directly enters the Krebs cycle. SHP overexpression also corrects the impaired sensitivity of UCP2-overexpressing beta cells to methylpyruvate.

Diabetes as a Dysfunction of Paracrine and Endocrine Roles of Adipocytes
Adipose tissue governs the body's energy economy (homeostasis) in many important ways.⁵⁵ Specifically, it modulates all aspects of human metabolism by releasing a host of signaling, hormonal, appetite-modifying, and proinflammatory substances called cytokines, including:
· NEFAs
· glycerol
· leptin (generally an appetite-suppressing hormone)^27,28
· suppression of cytokine signaling (SOCS) proteins³⁶
· inducible nitric oxide synthase (iNOS)¹⁸
· proinflammatory cytokines^22-24
· retinol-binding protein-4 (RBP4), which induces insulin resistance through reduced phosphatidylinositol-3-OH kinase (PI[3]K) signaling³⁷
· over-expression in muscle of gluconeogenic enzyme phosphoenolpyruvate carboxykinase in a retinol-dependent mechanism⁵⁶
· adiponectin, an insulin sensitizer,³⁰ which stimulates fatty acid oxidation in an AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor- (PPAR-)-dependent manner.^32-34

In health, all the above molecular pathways play Dr. Jekyll roles and regulate the cellular energy economy with physiological limits. In obesity and diabetes, those Dr. Jekylls turn into molecular Mr. Hydes and set the stage for incremental accumulation of fats in adipocytes. For example, nonesterified fatty acids in excess induce insulin resistance and impair beta-cell function. Stated simply, fat becomes fattening.

Diabetes as a Dysfunction of Molecular Signaling
In diabetes, there is abnormal expression of several important signaling molecules. One of the best-studied of such molecules is the transcription factor peroxisome proliferator-activated receptor (PPAR-?).^32-34,57 Impaired activity of this factor disrupts molecular energetics in many ways, including diminished glycolysis, impaired citric acid cycle, and gluconeogenesis. In obesity and diabetes, PPAR-alpha is weakly expressed in adipose tissue and is associated with profound metabolic derangements across all tissues. There is an increase in lactate and a profound decrease in glucose and a number of amino acids, such as glutamine and alanine.⁵⁸ The SHP dynamics appear to be independent of the role of PPAR-gamma, since a PPAR-gamma antagonist did not block it. Another line of experimental evidence that supports the dysox model of diabetes concerns a protein called nuclear respiratory factor-1 (NRF-1).³⁵ Insulin resistance and diabetes are associated with reduced expression of multiple NRF-1-dependent genes, which encode several key enzymes involved with oxidative phosphorylation and some mitochondrial function.

Diabetes as a Disorder of Glycation
Sugars adduct to nearly all normal cellular constituents – proteins, enzymes, fats, redox-restorative, and oxystatic substances – and render them dysfunctional. Beyond a certain point, this process produces irreversible permutations of those molecules to produce the toxic advanced glycation end-products (AGEs).^59,60 The rate of such transformations – the "sugarization" of nonsugars of the body is useful for patient education – increases with rising intracellular levels of sugars. Glycosylation of hemoglobin (the basis of the HbA1C test for monitoring the results of diabetes treatment) is the best-known example of sugarization of a vitally important protein, which renders it functionally impaired. AGEs form by several chemical reactions, some of which are blocked by thiamine and nenfotiamine (via reactions facilitated by transketolase and related enzymes⁶¹), and inflict oxidative damage on endothelial, neural, and other cellular populations. I discuss this crucial process at length in Integrative Cardiology, the sixth volume of The Principles and Practice of Integrative Medicine.⁶² Here in the context of the dysox model of diabetes, the crucial point is this: all abnormalities of mitochondrial electron transfer reactions, the Krebs cycle, the glycolytic pathways, and critical detox mechanisms encountered in diabetes and presented above occur more in endothelial, neural, retinal, and renal tissues than in other tissues of the body. I draw support for this statement from the established facts of much higher susceptibility of those tissues to impaired molecular bioenergetics seen in diabetes.

Diabetes as an Inflammatory Dysfunction
Injury is inevitable in an organism's struggle for survival. Healing is the intrinsic capacity of the organism to repair damage inflicted by that injury. Inflammation is the energetic-molecular mosaic of that intrinsic capacity. This energetic view of inflammation extends far beyond the classical and wholly inadequate notion of it being a process characterized by edema, erythema, tenderness, pain, and infiltrate of inflammatory cells. In my May 2005 Townsend Letter column, I marshaled a large body of clinical and experimental data to show that all molecular and cellular components of the pathophysiology of inflammation are directly or indirectly governed by oxygen signalling.⁶³ In this column, I extend that concept of inflammation to the pathogenesis of both obesity and diabetes by pointing out that all information presented in the preceding sections supports the view. Specifically, in both obesity and diabetes, impaired oxygen signaling is a phenomenon common to all aspects of impeded Krebs cycle and glycolytic pathways, altered free radical dynamics, impaired molecular signaling, proinflammatory cytokines, AGEs, and the immunology of insulin presented above.

The crucial clinical significance of the above "inflammatory view" of obesity and diabetes is this: All elements that cause chronic inflammation must be recognized as "obesitizing" and "diabetizing" influences. Equally important is the recognition that no strategies for the prevention of diabetes and de-diabetization can be considered complete if they do not effectively address all proinflammatory influences, such as insidious subclinical infections, undiagnosed and untreated mold and allergies, toxic metal burden, xenobiotic load, and impaired hepatic detoxification pathways.

The Dysox Model of Diabetes
Simply stated, there are three primary sets of elements that create the complex conditions that are simplistically labeled as diabetes: (1) toxic environment; (2) toxic foods; and (3) toxic thoughts. This is the only way it is possible to make some sense of spreading diabetes epidemics in all countries of the world – the greater the degrees of toxicity produced by those elements in any given country, the wider the epidemic. The US has the lamentable distinction of being the front-runner in the world. From those toxicities arise all the known molecular and cellular disruptions of diabetes, which are shown schematically in Figure 1.

In 1998, I proposed the dysox model of disease as a unifying concept of dysfunctional molecular bioenergetics that are clinically expressed as diverse disease states on the basis of varying environmental, nutritional, stress-related, and genetic factors.^64-66 This model has two primary strengths: (1) It focuses on quantifiable abnormalities of molecular bioenergetics as the basis of cellular and tissue injury; and (2) It provides clear scientific basis and/or rationale for integrative plans for arresting and/or reversing chronic disease. In 2001, I published an extensive review of the epidemiological, clinical, bioenergetic, and experimental aspects of insulin resistance and diabetes in a three-part article titled "Beyond Insulin Resistance – The Oxidative-Dysoxygenative Model of Insulin Dysfunction (ODID)" published in Townsend Letter (available at www.jintmed.com). In that series, I discussed altered dynamics of nitric oxide, inducible nitric oxide synthase, resistin, leptin, TNF-a, PPAR-?, and some proinflammatory cytokines. Above, I reviewed some recent advances in the knowledge of the immunology of insulin and beta cells of the pancreas, mitochondrial uncoupling proteins (UCPs), altered paracrine and endocrine functions of adipocytes, and advanced glycation end products (AGEs) to shed additional light on the dysox model of diabetes.

De-Diabetization Strategies
In my view, the four crucial components of the de-diabetization regimens, for complete or partial success, are: (1) choices in the kitchen; (2) fat-burning exercises (presented at length in my book The Ghoraa and Limbic Exercise);⁶⁷ (3) restoration of bowel ecology; and (4) optimization of the hepatic metabolic and detoxification functions. Beyond that, it is important to investigate and address other coexisting endocrine and neurotransmission dysfunctions. As to the third element of restoring bowel ecology, in December 2006, Nature published two landmark reports and an accompanying commentary that documented the impact of gut microbiota on the body's energy balance in mice and humans.^68-70 Specifically, obese human and mice showed an increase in the gut population of Firmicute species, while those of Bacteroides species – normally accounting for more than 50% of microbial species of human microbiome – were decreased. These observations shed some light on the mechanisms that underlie the observed weight loss with therapies that restore the digestive-absorptive dysfunctions and restore the gut mictobiota.

In my Townsend Letter column of October 2006, "Hurt Human Habitat and Energy Deficit – Healing Through the Restoration of Krebs Cycle Chemistry,"⁷¹ I presented the regimens that I prescribe for effectively addressing the bowel- and liver-related issues in chronic disorders. I find the same regimens equally effective to address those issues for my patients with diabetes. In that article, I also briefly outlined my approach to addressing other existing hormonal issues (concerning the thyroid, adrenals, and neuroendocrine systems). I refer the readers interested in detailed discussion of those subject to Integrative Nutritional Medicine, the fifth volume of The Principles and Practice of Integrative Medicine (2002).⁷² My essential clinical priorities are: (1) very low-carbohydrate diet; (2) high-frequency, low-intensity, predominantly lipolytic, limbic exercise (described and discussed at length in Limbic Exercise); and (3) the restoration of bowel, blood, and liver ecosystems.

Guidelines for Nutritional and Herbal Support for De-Diabetization
In my October 2006 column, I presented my herbal, nutrient, and detox choices for: (1) herbal protocols for restoring the gut ecology; (2) castor oil packs and other measures for liver detoxification; (3) adrenal, thyroid, and gonadal support, when needed; (4) antioxidant and oxystatic vitamin and mineral supplementation; (5) slow, sustained limbic exercise; and (6) meditative approach for coping with lifestyle stressors. In the following paragraphs, I offer some menu suggestions and guidelines for specific herbal remedies that I have found to be especially valuable in achieving optimal glycemic control:

Optimal Breakfast Choices for Diabetes
Dr. Ali's breakfast on five to six days per week comprising:
· two tablespoons of a protein powder containing 85%–90% calories in proteins and peptides;
· two tablespoons of a granular lecithin;
· two tablespoons of freshly ground flaxseed (the use of a coffee grinder is recommended);
· 12 to 16 ounces of organic vegetable juice (avoiding or minimizing the use of carrots and red beets);
· 12 to 16 ounces of water. A few ounces of seltzer water or a few drops of lemon juice may be added to suit personal taste.

I personally consume this mixture in portions of 6 to 8 ounces with my nutrient and herbal protocols during the period of my morning exercise, meditation, and preparation for work. I have not yet encountered any negative impact of the protein content in this breakfast on renal function. Still, individuals with serum creatinine levels above the normal range need to be monitored for renal function.

Optimal Lunch Choices for Diabetes
· Large salad with goat cheese, chicken, or fish
· Uncooked, steamed, or lightly stir-fried vegetables

Midafternoon Snack
Use 4 to 6 ounces of Dr. Ali's breakfast mixture (prepared in the morning and carried to work).

Optimal Dinner Choices for Diabetes
First, take uncooked, steamed, or lightly stir-fried vegetables. Next add proteins (fish, poultry, turkey, lamb, organic game meats, or beef). Pasta, bread, rice, and other starches should be taken in minimal amounts (just for taste). I ask my patients with diabetes never to allow bread to appear on the table (for them) before vegetables and animal proteins. In my experience, de-diabetization plans with vegetarian diets generally yield poor results.

Phytofactors of Special Value for Diabetes
The use of herbs for optimizing blood sugar control and for de-diabetizing efforts requires considerable clinical experience. As in the case of phytofactor remedies for chronic disorders, it is my clinical practice to prescribe herbal remedies for my diabetic patients in rotation. My preferred phytofactors are these: neem tree bark or leaves, bitter lemon, Gymnema sylvestre, fenugreek, fennel seeds, licorice extract, green tea, and pau d'arco. The following are other options: aloe, banaba, bitter lemon, cinnamon herb powder, cayenne, licorice extract, guggul, huckleberry, juniper berries, yarrow, and yellow gentian. I also liberally prescribe vanadyl sulfate in my program.

An Illustrative Case History of De-Diabetization
A 70-year-old man presented to the Institute on June 5, 2003, with the following health issues: uncontrolled diabetes of 22-years duration; gastroesophageal reflux disorder; colonic diverticulitis; benign prostate hyperplasia; and chronic fatigue. His HbA1c level was 11.1 despite the use of Glucophage and Glucontrol. Table 2 displays the data for four-hour glucose tolerance and insulin profile.

Other pertinent laboratory values were as follows:
· Hb, 14.7 gm/dL; WBC, 5,200
· an abnormally low value of T3-Uptake (0.7 units)
· homocysteine value (11.4 umol/L)
· dysautonomia (sympathetic-overdrive and parasympathetic deficit) as determined by a power spectral scan of heart rate variability
· PSA, 0.66 ng/mL
· Lead, aluminum, arsenic, nickel, and tin overload (measured with DMSA provocation)
· insulin-like growth factor, 66 ng/mL
· cholesterol 177 mg/dL and HDL cholesterol 47 mg/dL
· Raised levels of allergen-specific IgE and IgG antibodies to Aspergillus, Penicillium, Alternaria, Candida, and other mold species.

He complied well to my de-diabetization regimen, but was unable to follow my recommended exercise program for reason of long-established work habits. Table 3 shows the data for a period of follow-up of 28 months.

Closing Comments
I want to underscore the two crucial messages of this column: first, a clear understanding of the energetic consequences of the respiratory-to-fermentative shift in the dysox state is crucial to a complete comprehension of the Dysox Model of diabetes. The primary biochemical evidence for that model presented here concerns increased urinary excretion of metabolites of the Krebs cycle and glycolytic pathways for generation of ATP. In essence, the respiratory-to-fermentative shift with waste of organic intermediates represents a costly metabolic error that eventually affects all cell populations in the body. That is the energetic basis of all known complications of diabetes involving all organ-systems of the body.

Second, and equally important, is the understanding that no interventional strategies for the prevention of diabetes and de-diabetization can be considered complete if they do not effectively address all elements that threaten oxygen homeostasis and feed the pathophysiology of diabetes, especially those related to spiritual disequilibrium, lack of exercise, and the bowel blood ecosystems. Thus, the mere prescriptions for oral hypoglycemic agents and insulin regimens along with carbohydrate restrictions cannot be accepted as optimal management of diabetes. In the context of the gut ecology, consider the following quote from the December 21, 2006 issue of Nature:70

Gordon and colleagues' results tempt consideration of how we might manipulate the microbiotic environment to treat or prevent obesity. ... The two papers nonetheless open up an intriguing line of scientific enquiry that will ally microbiologists with nutritionist, physiologists, and neuroscientists in the fight against obesity.

There is something profoundly ironic in the above statement. For centuries, holistic physicians have cared for the sick with a sharp focus on the bowel flora. In recent decades, I have published more than 50 articles describing my clinical, pathologic, and biochemical observations concerning the altered states of gut ecology and their adverse consequences. The readers can obtain a compendium of many of those articles in my book Darwin, Dysox, and Disease, the 11th volume of The Principles and Practice of Integrative Medicine (2002).73

Majid Ali, MD, is president of the Institute of Integrative Medicine in New York, NY, and Denville, NJ. He is the author of the 12-volume series The Principles and Practice of Integrative Medicine and editor of the Journal of Integrative Medicine. Dr. Ali was formerly associate professor of pathology at Columbia University College of Physicians & Surgeons, New York, NY; president and professor of medicine, Capital University of Integrative Medicine, Washington, DC, and president and chief pathologist at Holy Name Hospital, Teaneck, NJ.

Notes
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. Diabetologia.1997;40:606-609.
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.