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Editor,
The Journal of Integrative Medicine
Formerly, Associate Professor of Pathology (adj.), College
of Physicians
and Surgeons of Columbia University, NY
Formerly, President of Staff and Chief Pathologist,
Holy Name Hospital, Teaneck, NJ
Fellow, Royal
College of Surgeons of England -
Diplomate,
American Board of Anatomic and Clinical Pathology
Diplomate, American Boards of Environmental Medicine
Past President Capital University of Integrative
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From The Journal of Capital University of
Integrative Medicine
J Capital University of Integrative Medicine 2001;1:101-141
BEYOND INSULIN RESISTANCE AND SYNDROME X:
The Oxidative-Dysoxygenative Insulin Dysfunction (ODID) Model
MAJID ALI, M.D.
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,19allergic 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.
Full article coming soon.
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