Category Archives: Dr. Ali’s Insulin-Smart Diabetes Reversal

Delicious Insulin Friendly Cheesecake!

INGREDIENTS:
1 1/4 cups Grounded Walnuts
tsp SPLENDA® No Calorie Sweetener, Granulated
1/4 cup butter, melted
4 packaged (8 oz each) philidelphia regular cream cheese softened
2/3 cup SPLENDA® No Calorie Sweetener, Granulated
4 large eggs
1 1/2 teaspoons vanilla
DIRECTIONS:
Preheat oven to 325 degrees F.
1.Make Crust: Mix crust ingredients together and press into a 9-inch pan.
  • Grounded walnuts
  • Melted butter
  • tsp Splenda

2.Make filling: Beat cream cheese, SPLENDA® Granulated Sweetener in a  medium bowl until well mixed and smooth. Add eggs and beat until smooth. Add vanilla. Mix until well blended. Pour filling over crust.

  1. Bake 55 minutes at 325 degrees F. or until center is almost set. Refrigerate for 4 hours and enjoy!

    images-2.jpg

    Walnut crust cheesecake

SEVEN QUESTIONS FOR INSULIN-BASED DIABETES REVERSAL

 

Dr. Ali’s Video Series

For Answers With Honest “Insulin Conversations”


Seven Questions That Matter

  1. What is diabetes? (It is excess insulin and insulin toxicity.)
  2. What is your chance of getting diabetes? (One in two now, seven in ten in 20 years.)
  3. Can you lose diabetes? (Only you can answer the question by learning what insulin and how insulin toxicity develops).
  4. How can you reverse diabetes? (With insulin-wise diet and insulin detox.)
  5. 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.)
  6. 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!

https://vimeo.com/114736194

 Who Does Not Want You to Be Insulin-Literate?

https://vimeo.com/98543658


Insulin Health and Free Insulin Course

https://vimeo.com/110630431

 Insulin Buddy

https://vimeo.com/117652624


Diabetes and insulin Majid Ali MD

https://vimeo.com/90230647

 Insulin Health and Free Insulin Course

https://vimeo.com/110630431

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

https://vimeo.com/91241758


What Is Your Diabetes Subtype?

https://vimeo.com/95706972

 Insulin Toxicity, and Fatty Liver With Normal Liver Blood Tests

https://vimeo.com/117652403

 Inflammation-Insulin Connections

https://vimeo.com/119093752


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

https://vimeo.com/132580419

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

https://vimeo.com/107155876

Seventy Percent of World Population Diabetic in 25 Years

 https://vimeo.com/117357611


 

Insulin Buddy and Fatty Liver

https://vimeo.com/117652486

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

https://vimeo.com/117702014

 Obesity Is Cellular Inflammation

https://vimeo.com/119094041


 

 Gestational Diabetes Is Insulin Toxicity of the Unborn – Part Two

https://vimeo.com/117703033

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

https://vimeo.com/118455458

 

 

SEVEN QUESTIONS FOR INSULIN-SMART WEIGHT LOSS

 

 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!

https://vimeo.com/114736194

 Who Does Not Want You to Be Insulin-Literate?

https://vimeo.com/98543658


Insulin Health and Free Insulin Course

https://vimeo.com/110630431

 Insulin Buddy

https://vimeo.com/117652624


Diabetes and insulin Majid Ali MD

https://vimeo.com/90230647

 Insulin Health and Free Insulin Course

https://vimeo.com/110630431

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

https://vimeo.com/91241758


What Is Your Diabetes Subtype?

https://vimeo.com/95706972

 Insulin Toxicity, and Fatty Liver With Normal Liver Blood Tests

https://vimeo.com/117652403

 Inflammation-Insulin Connections

https://vimeo.com/119093752


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

https://vimeo.com/132580419

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

https://vimeo.com/107155876

Seventy Percent of World Population Diabetic in 25 Years

 https://vimeo.com/117357611


 

Insulin Buddy and Fatty Liver

https://vimeo.com/117652486

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

https://vimeo.com/117702014

 Obesity Is Cellular Inflammation

https://vimeo.com/119094041


 

 Gestational Diabetes Is Insulin Toxicity of the Unborn – Part Two

https://vimeo.com/117703033

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

https://vimeo.com/118455458

 

 

Evidence of Oxygen Model of Insulin Toxicity


Majid Ali, M.D.

In this article in my library of articles on insulin toxicity and oxygen model of insulin toxicity, I present some compelling facts about insulin toxicity. To make my case with simple words, I invite you to consider a thought experiment. We will conduct two large trials to investigate the incidence of death caused by insulin used to treat diabetes. 


In the first randomized trial, we take 5,000 patients with a median A1c level of 8.1% and assign them to receive intensive therapy for a target A1c value below 6.0%.. Next, we take another 5,000 patients and give them standard therapy with a target A1c level from 7.0 to 7.9%.

Needless to point out, the first group will receive more diabetes drugs to lower A1c level with higher insulin activity, since all diabetes drugs increase insulin activity. Question: Which group will have a higher death rate, the more drugs/more insulin group or the less drugs/less insulin group?


For the second randomized trial, we take 6,000 patients admitted to ICUs in various countries. We treat 3,000 of these patients with insulin by intravenous infusions to lower the blood glucose level and reach a target of 81 to 108 mg /dL. We treat the remaining 3,000 patients without insulin drips and allow the blood glucose level to reach 180 mg/dL.


Question: Which group will have a higher death rate, the group with intravenous insulin infusion or the group without it?

If insulin in excess is toxic—I strongly assert it is—then there will be more deaths in patients given larger doses of insulin in both trials. That indeed is the case. Both insulin trials of my thought experiment have been done and published in The New England Journal of Medicine. The first was called the ACCORD trial and included 10,251 patients. The second, called the NICE-SUGAR Study, included 6,104 patients. Both trials proved that higher insulin activity was associated with higher death rates. 

Below are the conclusions (verbatum) of the two trials that speak for themselves:

As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes (N Eng J Med. 2008;358:2560-2572. June 12, 2008 ). 

In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. 
(N Eng J Med. 2009;360:1283-1297 March 26, 2009)

It is hard to teach old dogs new tricks. So, I was not surprised to find the following words in an editorial on the subject in The New England Journal of Medicine (360:1346-1349 March 26, 2009): 

Clinicians, particularly those involved in critical care, are now left in something of a quandary. Until further evidence becomes available, it would seem reasonable to continue our attempts to optimize the management of blood glucose in our hospitalized patients. 

The Journal has never shown interest in the problem of grease buildup on cell membranes caused by unhealthy foods, polluted environment, and chronic anger. None of the writers of the Journal seem to understand that grease on cell membrane—composed of rancid fats, sticky sugars, pulped proteins, metabolic waste, and debris—immobilizes and incapacitates insulin receptors. They are unable to learn that insulin receptor activity can be restored by grease-removing oxygen therapies. This is how the need for insulin can be reduced—even eliminated on many occasions—for superior clinical results. This is where the real potential of de-diabetization and better care of people with diabetes can be found. Of course, there are no drugs that remove cellular grease, hence theJournal’s disdain for nondrug oxystatic therapies.


My Oxygen Model of Insulin Toxicity Is the Flip-face of  my Oxygen Model of Diabetes

My Oxygen Model of Insulin Toxicity is an extension of my Oxygen Model of Health and Disease. It is a unifying model that explains all aspects of insulin toxicity—causes, clinical course, consequences, and control—on the basis of disturbed oxygen function. The most important among these compromised and/or blocked functions are: (1) oxygen signaling; (2) oxygen’s ATP energy generation; (3) oxygen’s detergent functions; (4) oxygen’s cellular detox functions; (5) oxygen-regulated cell membrane and matrix functions; (6) oxygen’s cellular repair roles.

The Oxygen Model of Insulin Toxicity provides a simple model that allows physicians to reduce complexities of diverse clinical syndromes into a workable simplicity.

This model predicts that ongoing research will reveal that components of acidosis (excess acidity), oxidosis (increased oxidative stress), and CUD (clotting-unclotting dysequilibrium) will be found to play important roles in the pathology and clinical features of insulin toxicity.

The crucial importance of the Unifying Oxygen Model of Disease is that it:

* Explains the scientific basis of primary aging processes in the body;

* Sheds light how health can be preserved by addressing all oxygen-related issues;

* Elucidates how toxicities of foods, environments, and thoughts cause tissue injury and disease;

* Reveals the mechanisms by which various detox therapies work (Oxygen is the primal detergent which removes cellular grease and allows cells to breathe freely).

* Allows the formulation of rational and effective designs for reversing chronic diseases; and

* Provides explanations of mechanisms by which time-honored natural remedies work.


 

Dr. Ali’s Insulin-Based Diabetes Reversal Plan  

The central goal of my Insulin-Based Diabetes Reversal Plan is to restore insulin functions by normalizing insulin receptor protein function.

 

 

Oxygen Model of Diabetes

Majid Ali, M.D.

Oxygen Model of Diabetes

Diabetes Type 2 is, first and foremost, an oxygen problem. This view of diabetes—The oxygen Model of Oxygen stated in simple words—has two primary strengths: (1) In understanding then nature of the disorder, it shifts the focus away from raised blood glucose levels and to the insulin receptor dysfunction caused by oxygen-blocking toxicities of foods, environment, and thoughts; and (2) It provides scientific sound treatment plan for de-diabetization. I present in detailed the various aspects of this view in various tutorials of the Insulin toxicity Series.


Insulin Receptor Protein Dysfunction

Here is the scientific fact that must be understood clearly for implementing Dr. Ali’s Insulin-Smart Diabetes Reversal:  Diabetes type 2 (the type that most people get) develops when cells become resistant to insulin due to insulin receptor protein dysfunction. Insulin receptor dysfunction is caused by “plasticized” (chemicalized) and hardened cell membranes that immobilize the insulin receptors embedded in them. In the Oxygen Model of Diabetes, the metabolic syndrome is visualized as a “gummed-up matrix state and prediabetes is 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.

                   

              


Oxygen Model of Diabetes

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 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

* Pperoxisome 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,

* Plasminogen activator inhibitor (PAI-1),

* Adipsin (complement D),

* Acylation-stimulating protein (ASP) 39-42

* Heat shock protein 60, voltage-dependent anion channel 1 (VDAC-1),

* Grp7543; and

* 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.

There is an essential relatedness of the above epidemiologic, genetic, biochemical, and clinical observations. I address by: 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 Mitochondrial Function 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 cytokines22-24

· 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 Disorder

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 Oxygen 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 http://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

Mid-afternoon 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.

Valuable Phytofactors 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.

Concluding Comments

This tutorial has 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 Oxygen 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