The Oxidative-Dysoxygenative Insulin Dysfunction (ODID) Model

MAJID ALI, M.D.

From the Department of Integrative Medicine, Capital University of Integrative Medicine, Washington, DC, and the Institute of Integrative Medicine, New York, NY.

OUTLINE

I. Abstract

II.  Introduction

III. The Epidemic of Oxidative-Dysoxygenative Insulin Dysfunction

IV. Glucose Oxidation and Reactive Oxygen Species
V. The Too-Much/Too-Little Sugar Dilemma
VI. Glucose Toxicity and Hexosamine Pathways
VII. Insulin and Insulin Receptors
VIII. Insulin Regulates Its Own Receptors
IX. Clinicopathologic Entities Associated With ODID and Insulin Resistance
X. Glucose Transporters
XI. Glucose Supports Insulin, Glucose Opposes Insulin
XII. Insulin Cell Transplantation and Insulin Production by Stem Cells
XIII. Free Fatty Acids and ODID
XIV. Counterregulatory Hormones
XV. GAD and the GAD-Less
XVI. Exercise and ODID
XVII. Nitric Oxide Dynamics and ODID
XVIII. Tumor Necrosis Factor and ODID
XIX. NF- B, Endothelial Cells and ODID
XX. IGF-1, IGF-2, and ODID
XXI. PPAR and ODID
XXII. Resistin and ODID
XXIII. Leptin: An Integrative Model of Dual Actions
XXIV. Thyroid, Adrenals, and ODID
XXV. Sex Hormone Dynamics and ODID
XXVI. D-Chiro Inositol and Gonadal Dysfunction
XXVII. Genetic Syndromes of Insulin Dysfunction
XXVIII. Hypoglyemia and ODID
XXIX. Noninsulin-Glucoregulatory Dynamics of the Human Ecosystems
XXX. Oxidative-Dysoxygenative Cell Membrane Dysfunction
XXXI. Ecogenomics and Econeutrogenomics
XXXII. Mechanisms of Action Drugs for Diabetes
XXXIII. Darwin, Dysoxygenosis, and ODID
XXXIV. Prevention and Reversal of ODID
XXXV. Summary

I. ABSTRACT

Oxidative-dysoxygenative insulin dysfunction (ODID) is defined as impairment of any or all aspects of insulin production and metabolism caused by oxidative injury to any or all molecular pathways in which insulin serves any pathophysiologic roles. This definition reaches beyond the prevailing concepts of insulin resistance, syndrome X, and diabetes mellitus. Specifically, it integrates into a global view of insulin dysfunction myriad molecular interrelationships of insulin pathways to those of exercise, nitric oxide, NF- B, TNF , leptin, peroxisome proliferator-activated receptor- (PPAR ), resistin, IGF-1, IGF-2, and glutamic acid decarboxylase (GAD). Equally important are the diverse counterregulatory signaling pathways involving glucagon, adrenal hormones, hypothalamic factor(s) and related molecular species that contribute to glucose/lipid homeostasis in health and disruptions of that in pathophysiologic states. Beyond that, the ODID model covers many "non-insulin-glucoregulatory" phenomena in the bowel, blood, and liver ecosystems that significantly contribute to epidemics of insulin resistance, syndrome X, and diabetes mellitus and yet are seldom, if ever, included in discussions of those disorders. Furthermore, the ODID model addresses the core issues of epidemics of rapid hyperglycemic-hypoglycemic shifts and brisk glucose-insulin-adrenergic responses in persons with chronic disorders characterized by accelerated oxidative molecular injury, such as chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity syndrome, Gulf War syndrome, and related autoimmune disorders.

Dysoxygenosis (dysfunctional oxygen metabolism) is defined as a state of sustained impairment of cellular enzymatic functions involved with oxygen metabolism. The ODID model is based on the following fundamental aspects of glucose and insulin pathophysiology: (1) essential oxidative nature of glucose metabolism (oxidative phosphorylation and oxidation of hydrogen atoms released during glucose degradation); (2) incremental hyperglycemic oxidative stress (oxidosis) in the circulating blood caused by chronic and cumulative sugar overload, oxidative endproducts of glycation, and sensitivity of antioxidant enzyme systems to incremental oxidosis; (3) vulnerability to oxidosis of insulin receptors and other proteins involved in insulin signaling; (4) direct cellular glucose toxicity associated with cumulative intracellular glucose burden; (5) spreading epidemics of obesity-associated type 2 diabetes mellitus in the Western countries and low-body-weight-associated type 2 diabetes in the orient; (6) association of derangements of glucose and insulin metabolism in clinical states characterized by accelerated oxidative molecular injury; and (7) reversibility of ODID state with measures that control oxidosis and dysoxygenosis.

The ODID model offers a unifying concept for disparate biochemical, genetic, and clinical observations concerning hyperinsulinemia, rapid hyperglycemic-hypoglycemic shifts, insulin resistance, syndrome X, and diabetes mellitus. Beyond that, it encompasses myriad "non-glucoregulatory" aspects of insulin pathophysiology, such as overproduction of androgens in women with polycystic ovaries as well as interactions of insulin pathways with major mediators of the inflammatory and immune responses. This model also has a strong explanatory power for normalization of insulin functions with "non-insulin therapies" that primarily address issues of the bowel, blood, and liver ecosystems.

II. INTRODUCTION

In 1983, in a monograph entitled Spontaneity of Oxidation in Nature and Aging,1 I put forth a hypothesis that spontaneity of oxidation in nature provides the primary drive for all metabolic pathways in human biology and serves as the core mechanism for initiating, amplifying, and perpetuating molecular and cellular injury in all disease processes. In a series of follow-up publications,2-14 I described many clinical, biochemical, and morphologic observations to support that hypothesis including: (1) oxidative coagulopathy9,10; (2) oxidative lymphopathy11, (3) oxidative dysautonomia12, (4) oxidative regression to primordial cellular ecology13, (5) primacy of the erythrocyte in vascular ecology14; and (6) oxidative dynamics of apoptosis.15 My colleagues and I also firmly established the central role of those oxidative phenomena in a host of clinicopathologic entities including coronary heart disease,9, 16 chronic fatigue syndrome,17 fibromyalgia,18 environmental sensitivity syndrome,19 allergic diathesis,20 autoimmune disorders,21 asthma,22 cancer,23 oligomenorrhea and amenorrhea,24 arrested growth in children,25 and a host of other disorders.26-28

A large number of recent reports of oxidative phenomena involving reactive oxygen species, reactive nitrogen species, oxidant products of glycation, and other types of prooxidant molecules have elucidated the essential oxidative nature of myriad pathophysiologic changes involving carbohydrate and insulin metabolism.29-41 Those observations provide additional strong support for the oxidative insulin dysfunction. Specifically, antioxidant enzymes are proteins and, like other functional proteins, are vulnerable to oxidative injury or destruction leading to loss of their enzymatic functions.42

I presented the model of dysoxygenosis and marshalled extensive clinical and biochemical evidence for that model in a series of articles42-44 and in a book titled Oxygen and Aging.45 I marshall some additional evidence for that model in the forthcoming book titled The Principles and Practice of Integrative Medicine. Volume I: Nature's Preoccupation With Complementarity and Contrariety.46 In this article, a large body of clinical, biochemical, and genetic knowledge concerning the pathophysiology of carbohydrate and insulin metabolism is reviewed to propose a unifying model of oxidative-dysoxygenative insulin dysfunction.

III. THE EPIDEMIC OF OXIDATIVE-DYSOXYGENATIVE INSULIN DYSFUNCTION

There is a global epidemic of oxidative-dysoxygenative insulin dysfunction. Insulin resistance and type 2 diabetes mellitus are recognized as spreading epidemics by the medical communities in all countries.47-54 In the United States, 15.7 million people suffer from this type 2 diabetes and nearly 200,000 of them die every year of complications of diabetes. The disease affects over 250 million people worldwide and is the leading cause of blindness, kidney failure, and amputation among adults.55-63

The defining features of type 2 diabetes include defects in: (1) insulin-stimulated peripheral glucose uptake and disposal (insulin resistance); (2) suppression of hepatic glucose production; and (3) insulin secretion. Insulin resistance is target-tissue resistance to insulin—a state in which glucose homeostasis cannot be maintained by -cell hypersecretory response. Type 2 diabetes and insulin resistance put an individual's lifespan in serious jeopardy. Both are strongly associated with obesity and lead to well-recognized complications of coronary heart disease, stroke, renal failure, peripheral vascular disease with threat of limb amputation, blinding retinopathy, and disabling neuropathy. The relationship between insulin resistance and type 2 diabetes has been elucidated with: (1) longitudinal studies that show insulin resistance generally precedes the onset of the disease by 10 to 20 years64-66; (2) cross-sectional studies that document the consistent presence of insulin resistance in the disease67-69; and (3) prospective studies that establish insulin resistance as the best predictor of the disease.66-68,70,71

Type 2 diabetes and insulin resistance are thought to develop insidiously in older persons with a family history of diabetes and who have normal or high blood insulin levels. That is a common mistake, because the increases in diabetes prevalence rates are most pronounced in children and adolescents.47-49 Indeed, the presence of insulin resistance is seldom recognized and emphasized by pediatricians. In health, insulin is the primary hormone that facilitates entry of glucose into cells and its utilization there. Insulin resistance develops in younger individuals when the insulin receptors and signaling pathways on the cell membranes fail to respond to insulin and blood sugar level rises. The pancreas produces more insulin to overcome the resistant insulin receptors, but to no avail.

Parallel to the epidemic of type 2 diabetes is the epidemic of obesity in the industrialized world. The two epidemics are clearly related to each other, with obesity being present in 60 to 80% of diabetics in the West.72-74 However, the molecular links between the two are thought to be elusive. Obesity is associated with increased triglyceride storage in adipocytes. Triglyceride metabolism involves release of free acids from the fat cells to provide the energy needs of other cells. The blood levels of free fatty acids are higher in obese patients, and such acids are known to induce insulin resistance in adipose as well as other tissues.

Concurrent with the epidemic of obesity-associated type 2 diabetes in the West is the epidemic of low-body-weight-associated (LBW) type 2 diabetes in the Orient. Specifically, the incidence of this pattern of diabetes increased more than threefold in India during the last two decades.51-54 Studies of hepatic glucokinase and microsomal enzymes (cytochrome P-450) employing antipyrine and lidocaine in vivo probes showed hyperactivity with increased futile cycles of carbohydrate metabolism in LBW type 2 diabetes. The frequency and levels of islet cell antibodies and those with specificity for glutamic acid decarboxylase (GAD) in LBW type 2 diabetes are similar to that in the West.