INTEGRATED INSULIN AND TOXIC
METAL REDUCTIONS FOR CORONARY HEART DISEASE
Majid Ali, M.D.
Insulin excess (hyperinsulinemia)
has long been recognized as a major risk factor for
coronary heart disease. Then why do we not make
serious attempts to lower insulin levels to prevent
and/or reverse coronary heart disease? Mercury,
lead, cadmium, and other heavy metals are
established risk factors for coronary heart disease.
Then why do we not chelate such metals out of the
body to prevent and/or reverse coronary heart
disease? Lowering blood insulin levels and the
reduction of total body burden are complementary
approaches for preventing and/or reversing coronary
heart disease. Then why do we not employ these two
effective approaches to maximize the benefits for
the prevention and/or reversal of coronary heart
disease? I address these questions by presenting
previously published personal data and to make my
case for an integrated use of these approaches.
In 1923, the German physician, E.
Kylin published a paper entitled "Studies of the
clearly linking derangements of glucose metabolism
to cardiovascular disorders. In 1931, Professor
Wilhelm Falta of Vienna, Austria published a paper
in which he proposed that diabetes develops when
tissues fail to respond to insulin. Five years
later, Sir Harold Percival Himsworth of the
University College Hospital Medical Centre in London
confirmed Professor Falta's theory in a paper
published in Lancet entitled "Diabetes
mellitus: its differentiation into insulin-sensitive
and insulin-insensitive types". Professors Falta and
Himsworth did not offer specific insights into how
cells might become resistant to insulin.
Since the work of Kylin, Falta,
and Himsworth, the link between hyperinsulinemia and
cardiovascular disease (CVD) has been explored with
an enormous number of experimental and clinical
studies. However, doubts concerning the link
persisted. For example, a 1984 article published in
the journal Diabetologia was entitled "Type 2
(non–insulin-dependent) diabetes mellitus and
coronary heart disease—chicken, egg or neither?" In
1980s, Reaven and colleagues established the
relationships between insulin resistance, obesity,
hypertension, and cardiovascular disease (including
the so-called syndrome X and the metabolic syndrome.
Beginning in 1989, Barker, Hales, and colleagues
presented evidence indicating that low birth weight
and low weight gain during the first year of life
are associated with increased incidences of Type 2
diabetes and cardiovascular disease decades later.
They postulated that inadequate nutrition during
fetal and early life might lead to inadequate
development of pancreatic islet cells and decreased
insulin production. They appeared not to consider
the more important issue of maternal toxicities of
foods and environment.
Since then, the
link between hyperinsulinemia and cardiovascular
disease (CVD) has been explored with an enormous
number of experimental and clinical studies.2-8
The prevailing view attributes this
association to combined pro-inflammatory effect of
glucose and anti-inflammatory effect of insulin.
This is a serious error. Consider the following from
a 2006 review article published in Seminars in
Thoracic and Cardiovascular Surgery9:
In this article we
discuss data demonstrating an
anti-inflammatory effect of insulin and a
pro-inflammatory effect of glucose and free
fatty acids and provide a mechanistic
justification for the benefits of
maintaining euglycemia with insulin
infusions in the hospitalized patient.
The above quote summarizes well
the prevailing—grievously erroneous, in my view,
notion of the glucose/insulin dynamics. Two recent
large trials published in The New England Journal
of Medicine.10,11—the ACCORD trial
(10,251 patients) and the NICE-SUGAR trial (6,104
patients) —clearly showed that the greater use of
insulin and insulin-increasing drugs was associated
with higher morbidity and mortality. The
investigators failed to recognize clear evidence of
insulin toxicity. Indeed, the editorial accompanying
one of the articles considered the
more-insulin-higher-mortality association as a
In 1968 as a pathology resident,
I learned about three types of lesions, the crucial
significance of each escaped me. The first was fatty
change of the liver in Type 2 diabetes which is
characterized by hyperinsulinemia. I did not see
this abnormality in Type 1 diabetes in which there
is an absence or severe deficiency of insulin.
Neither my professors nor pathology texts explained
that fatty change was due to persistently elevated
levels of insulin. The second histopathologic
abnormality was fat necrosis in soft tissues of
diabetics. Again, hyperinsulinemia was not
identified as the cause of the lesion. The third
type of lesion was ground-glass appearance of the
nuclei of liver cells as evidence of gluconeogenesis
seen in Type 2 diabetes. My professors and books did
not link it with adverse effects of excess insulin.
In Part I of this column, I
documented cases of normalization of blood pressure
in some cases of hypertension when blood insulin
levels were reduced. In cases of prostate cancer
coexisting with hepatitis and hyperinsulinemia,
reduction of blood insulin levels is associated with
significant drops in liver enzymes and PSA values
(unpublished personal observations).
Insulin influences the behavior
of several vasoactive moieties in the endothelial
cells, as well as within the circulating blood. For
example, it stimulates
endothelial release of endothelin-1 and nitric
oxide.12 Hyperinsulinemia and not
glucose level is the predisposing factor to
The plasma levels of cell adhesion molecules
change in hyperinsulinemia and modulate some
Hyperinsulinemia induces overactivity of some
cytokines in in-vitro cell studies.15
Toxicities of Hyperglycemia and Hyperinsulinemia
In a previous article, I
presented the Dysox Model of Diabetes16
and demonstrated that all known biochemical,
histopathologic, and clinical aspects of diabetes
are rooted in the primary disruptions of oxygen
homeostasis and the consequent derangements of
oxidosis, acidosis, and clotting-unclotting
dysequilibrium. Here, I bring that perspective to
bear on the present context of relative toxicities
of hyperglycemia and hyperinsulinemia. Mitochondrial
ATP generation drives all major events involving
cellular development, differentiation,
detoxification, and demise. At the level of
fundamental energetics, all reactions involve
electron transfer events. It is true that glucose
autooxidizes in biologic systems to initiate and
perpetuate electron transfer chains; however, the
rates of such oxidation, uninitiated and
uninfluenced by insulin, are minimal under
physiological conditions. By contrast,
insulin-driven electron transfer chains constitutes
the principal mode of glucose oxidation in Krebs
cycle. It follows that hyperinsulinemia inflicts
oxidative molecular and cellular injury to a far
greater degree that hyperglycemia.
Notwithstanding the above
clinical, histopathologic, and biochemical aspects
of insulin excess, the fundamentals of insulin
toxicity escape the notice of clinicians. Indeed, a
Google search of "insulin toxicity" did not include
a single paper from clinicians (other than those
posted by the author). This, in my view, is an
enormously important and neglected subject, which I
address in my forthcoming book entitled "Oxygen,
Gila Monster, and Insulin Toxicity."17
In a series of
publications, my colleagues and I have documented
the efficacy of EDTA chelation for reversal of
coronary artery disease.18-21 The Dysox
Model of Coronary Artery Disease22
requires that all elements that disrupt oxygen
homeostasis be effectively addressed, including
nutritional therapies. Hyperinsulinemia is common in
patients with cardiovascular disorders and our
protocols eliminate or decrease its degree. However,
in past studies we did not investigate insulin
metabolism. In Part I of this column, I presented
aspects of 122 four-hour insulin and glucose
profiles to document some unusual patterns of
insulin pathobiology and certain unanticipated
findings. Here, I review the clinical benefits of
EDTA chelation and normalization of insulin
homeostasis to shed light on the complementarity of
these two potently beneficial clinical approaches.
In Oxygen, Darwin’s Drones,
and Diabetes (2010),22 I marshal
evidence for my view that in metabolic and
cardiovascular disorders, insulin toxicity is the
primary event and hyperglycemia is secondary. The
evolutionary insulin design is perverted by the trio
of toxicities of foods, environment, and thoughts.
These disruptions set the stage for insulin- toxic
states—dysfunctional insulin receptor function,
insulin resistance, obesity, fatty change of the
liver, hyperinsulinemia, prediabetes, diabetes,
renal insufficiency—that culminate into
cardiovascular disorders. The metabolic,
inflammatory, and degenerative aspects of these
disruptions are presented at length in Darwin and
Dysox Trilogy (2009), the tenth, eleventh, and
twelfth volumes of my textbook entitled The
Principles and Practice of Integrative Medicine.23-25
Complementary Benefits of
Insulin Reduction and EDTA Chelation
trials provide incontrovertable evidence of insulin
toxicity for patients with cardiovascular disorders.
A close examination of the spectrum of
insulin toxicity —pathological inflammatory response
being the most evident aspect—not only sheds light
on the insulin-CVD link but also on the mechanisms
underlying the additive benefits of integrating
insulin homeostasis with EDTA chelation infusions.
1. Hyperinsulinemia induces
oxidative stress on the circulating blood plasma,
platelets, erythrocytes, and leukocytes—and causes
atherogenesis. EDTA infusions arrest oxidative
2. Hyperinsulinemia exerts
procoagulative effects by activating inflammatory
3. Some serpins—a super
family of clot-busters and inflammation
EDTA counters such procoagulative influences.26
4. Hyperinsulinemia increases
lipid peroxidation reactions.29
EDTA counters such reactions which mostly require
the participation of transitional metallic
ions—iron, copper, and others—by binding and
5. Hyperinsulinemia impairs
mitochondrial efficiency by creating local dysox
EDTA preserves mitochondrial enzymes (specifically,
EDTA completely or partially restores the
ischemia-induced mitochondrial defects).31
6. In states of systemic
inflammation, hyperglycemia impairs neutrophil
degranulation and potentiates coagulation, whereas
hyperinsulinemia inhibits fibrinolysis.32
EDTA inhibits pathologic inflammatory responses.26
Hyperinsulinemia affects the activities of many
vasoactive substances, including tumor necrosis
factor alpha, endothelin-1 and nitric oxide.33
Hyperinsulinism can be expected to disrupt
homeostasis of these crucial regulators of
endothelial function and vascular flow. EDTA
restores these functions.26
Hyperinsulinemia induces overactivity of some
cytokines in in-vitro cell studies.34
EDTA prevents such overactivity.26
Oxygen is the king of human
biology. It maintains law and order in the body by
organizing and coordinating its three "executive
branches: acid-alkali balance, oxidant and
antioxidant regulation, and clotting-unclotting
equilibrium (CUE).23-25 The oxygen’s
order of biology is threatened by the trio of
toxicities of environment, foods, and thoughts. The
failure of its executive branches lead to acidosis,
oxidosis, and clotting-unclotting dysequilibrium
(CUD) respectively. Notwithstanding the explosive
growth of literature on redox chemistry, it is
ironic that crucial issues of redox regulation are
not addressed by mainstream doctors. Such doctors
liberally prescribe aspirin and yet they are adamant
against measures for insulin reduction and EDTA
chelation, two approaches that can restore clotting-unclotting
dysequilibrium which is the hallmark of
On March 24, 20I0, I
saw Sherry L., a 94-year-old woman with a sharp mind
and a strong heart. Her lipid profiles included the
following: cholesterol, 318 mg/dL; HDL cholesterol,
102 mg/dL; and LDL cholesterol, 197. On March 30, a
68-year-old 5' 10" man weighing 268 lbs. Told me his
insurance company had denied coverage of a four-hour
insulin test I had ordered for him. On March 31, a
front page story in The New York Times
reported the government’s support for a statin drug
for healthy people with normal cholesterol levels.
Three days later, C-Span spent an hour promoting
statin drugs. It had the Executive Director of
Center for Science in Public Interest who talked
about cholesterol clogging coronary arteries over
and over. No, he didn’t once mention statins, but
the message to the viewers was not lost. That night
I had a dream about the cholesterol-statin
industrial complex which I posted on
Serpents, Serpins, and Statins
In addition to nitric oxide,
endothelins, and adhesion molecules mentioned
earlier, there are serpins, a super family of
protease-inhibitors. Thirty-six serpins are known to
exist in humans (including antithrombin, kinin, some
coagulation factors) among the over 1000 members
known, including those of fungi, bacteria, and
certain viruses.35,36 By some estimates,
ten percent of all plasma proteins belong to this
family. The acronym serpin—short for serine protease
inhibitors—was coined to underscore the importance
of the serine-protease nature of chymotrypsin and
antitrypsin, the original members of the family
identified for their key roles in controlling blood
coagulation and inflammation respectively. It seems
safe to predict that insulin in excess will be found
to affect most, if not all, serpins, adding to the
growing CUE-CUD complexity.
Not unexpectedly in light of
nature’s preoccupation with complementarity and
contrarity, serpins also perform diverse non-proteolytic
functions, including hormone carriage proteins (thyroxine-binding
globulin, cortisol-binding globulin), tumor
suppressor genes (maspin), and storage (ovalbumin,
in egg white). In this broader context, serpins
serve the Oxygen King as senior officials in its CUE
executive branch, commonly with overlapping roles.
Contrast this with the simple-minded—and
misguided—notion of preventing cardiovascular events
with statins, which block one specific enzyme and
carry a significant risk of liver injury,
rhabdomyolysis (muscle cell death), and fatigue.
Statins also increase the risk of cancer of cancer.37
The kaleidoscope of the CUE-CUD
dynamics is vast. Evolution perfected the CUE
homeostasis over hundreds of million years. This
equilibrium is remarkably resilient but still
vulnerable to a vast number of disruptive elements.
Mythological serpents killed their victims by
curdling their blood, as some snake venoms do. Other
venoms induce fatal systemic bleeding. Yet other
venoms kill by triggering concurrent thrombo-hemorrhagic
events. I see a parallel of that diversity in human
CUE-CUD dynamics, albeit not so dramatic in most
clinical states except in acute cases of
disseminated intravascular clotting. Evolutionary
considerations are humbling as they are
enlightening. They compel us to look beyond
one-enzyme-one-blocker-drug model of the statin
industry, and to learn from empirical experiences of
diligent and astute clinicians. I know that I only
have a partial understanding of the exact mechanisms
of clot-busting herbs (which have scores of
components) and nutrients which I use in my
integrative protocols to achieve insulin reduction
and EDTA chelation18,19; however, that
lack of knowledge does not invalidate their
empirical and clinical value.
In 1997, my colleague, Omar Ali,
and I marshaled thirteen lines of evidence to
support our assertion that cholesterol is a minor
player in atherogenesis.38 In 2007,
The Lancet published an analysis of published
data for over 40,000 women who were given statin
drugs for primary prevention of coronary heart
disease.38 Consider the following quote
from that review of the subject in Lancet
The last major revision
of the US guidelines, in 2001, increased the
number of Americans for whom statins are
recommended from 13 million to 36 million,
most of whom do not yet have but are
estimated to be at moderately elevated risk
of developing coronary heart disease. In
support of statin therapy for the primary
prevention of this disease in women and
people aged over 65 years, the guidelines
cite seven and nine randomized trials,
respectively. Yet not one of the studies
provides such evidence.
Yet not one of the studies
provides such evidence! This comment should
surprise only those who have never critically
examined the statin data published during the last
Protocols for Insulin Reduction
Hyperinsulinema, I explained in
Part I, is caused by dysoxygenosis resulting from
the trio of toxicities of foods, environment, and
thoughts. It follows that integrated protocols for a
life-long plan for insulin reduction must address
all relevant oxygen issues. Clinical benefits of
many natural remedies that improve insulin
function—cinnamon, bitter gourd (karela, bitter
lemon), Gymnemia sylvestre, chromium, and others—are
well recognized. However, in my view the issues of
chronic anger, excessive gut fermentation, leaky gut
state, impaired hepatic detox pathways, and other
non-pancreas-related pathologies are deep and
pervasive. Simple remedies, such as mentioned above,
rarely yield long-term satisfactory results. I refer
interested readers to "Dr. Ali’s Insulin Reduction
In closing, the questions
concerning the bioenergetic basis of the insulin-CVD
link are reviewed. are explored. Evidence is
marshaled to support a hypothesis that insulin
toxicity is a major, if not the primary mechanism,
of atherogenesis in individuals with hyperinsulinism.
The mechanisms underlying the added clinical
benefits of insulin-reducing and EDTA chelating
therapies are considered to support this combined
1. Kylin E. Studies of the
(German). Zentralbl Inn Med 1923;44: 105-27.
2. Reaven GM. Banting lecture
1988. Role of insulin resistance in human disease.
3. Phillips GB. Relationship
between serum sex hormones and glucose, insulin, and
lipid abnormalities in men with myocardial
infarction. Proc Natl Acad Sci U S A.
4. Richard Kahn. Metabolic
syndrome—what is the clinical usefulness? Lancet.
2008; 371: 1892–1893.
5 Jarrett RJ. Type 2
(non–insulin-dependent) diabetes mellitus and
coronary heart disease—chicken, egg or neither?
6 JarrettRJ, ShipleyMJ Type 2
(non–insulin-dependent) diabetes mellitus and
cardiovascular disease—putative association via
common antecedents; further evidence from the
7. Barker DJ, Winter PD, Osmond
C, et al. Weight in infancy and death from ischaemic
heart disease. Lancet. 1989; 2:577-80.
8. Barker DJ, Hales CN, Fall CH,
et al. Type 2 (non–insulin-dependent) diabetes
mellitus, hypertension and hyperlipidaemia (syndrome
X): relation to reduced fetal growth. Diabetologia.
9. Dandona P, Chaudhuri A, Ghanim
H, et al. Anti-inflammatory effects of insulin and
the pro-inflammatory effects of glucose. Semin
Thorac Cardiovasc Surg. 2006:18:293-301.
10. The Action to Control
Cardiovascular Risk in Diabetes Study Group. Effects
of Intensive Glucose Lowering in Type 2 Diabetes.
New Eng J Med. 2008;358:2545-2559.
11. The NICE-SUGAR Study
Investigators. Intensive versus Conventional Glucose
Control in Critically Ill Patients. New Eng J Med..
12 Cardillo C, Mettimano M, Mores
N, et al. Plasma levels of cell adhesion molecules
during hyperinsulinemia and modulation of vasoactive
mediators. Vascular Medicine. 2004;9: 185-188.
13. Delgado A. Hyperinsulinemia
and Not Glucose Level Is a Predisposing Factor to
Endothelial Dysfunction. The American Journal of
14. Cardillo C, Mettimano M,
Mores N, et al. Plasma levels of cell adhesion
molecules during hyperinsulinemia and modulation of
vasoactive mediators. Vascular Medicine. 2004;9:
15. Wang L, Brown JR, Varki A. et
al. Heparin’s anti-inflammatory effects require
glucosamine 6-O-sulfation and are mediated by
blockade of L- and P-selectins. J. Clin. Invest.
2002; 110: 127-136.
16. Ali M.The Dysox Model of
Diabetes and De-Diabetization Potential. Townsend
Letter-The examiner of Alternative Medicine. 2007;
17. Ali M. Oxygen, Gila
Monster, and Insulin Toxicity.
in press. New York.
Institute of Integrative Medicine Press.
18. Ali M, Ali O, Fayemi A, et
al: Improved myocardial perfusion in patients with
advanced ischemic heart disease with an integrative
management program including EDTA chelation therapy.
J Integrative Medicine 1997;1:113-145.
19. Ali M. Fischer S, Juco J, et
al. The dysox model of coronay artery disease.
Letter for Doctors and Patients.
20. Ali M. The Principles and
Practice of Integrative Medicine Volume VI:
Integrative Cardiology and Chelation Therapies: The
Oxidative-Dysoxygenative Model and Chelation
Therapies. 2006. New York. Institute of
Integrative Medicine Press.
21. Ali M. Beyond the cholesterol
and inflammatory theories of coronary artery
disease: The oxidative-dysoxygenative coronary
disease (ODCAD) model. J Integrative Medicine. 2002;
22. Ali M. Oxygen, Darwin’s
Drones, and Diabetes (2010)
New York. Institute
of Integrative Medicine Press.
23. Ali M. The Principles and
Practice of Integrative Medicine Volume III: Darwin,
Oxygen Homeostasis, and Oxystatic Therapies. 3
rd. Edi. (2009) New York. Institute of Integrative
24. Ali M. The Principles and
Practice of Integrative Medicine Volume XI: Darwin,
Dysox, and Disease. 2000. 3rd. Edi. 2008. New
York. (2009) Institute of Integrative Medicine
25. Ali M. The Principles and
Practice of Integrative Medicine Volume XI: Darwin,
Dysox, and Integrative Protocols. New York
(2009). Institute of Integrative Medicine Press.
26. Ali M, Ali O. AA Oxidopathy:
the core pathogenetic mechanism of ischemic heart
disease. J Integrative Medicine 1997;1:1-112.
27. Craft S. Insulin resistance
syndrome and Alzheimer’s disease: Age- and
obesity-related effects on memory, amyloid, and
inflammation. Neurobiology of Aging, 2009;26:65-69.
28. Wada J. Vaspin: a novel
serpin with insulin-sensitizing effects. Opin
Investig Drugs. 2008 Mar;17(3):327-33.
29. Morris RT, Laye MJ, Lees SJ,
et al. Exercise-induced attenuation of obesity,
hyperinsulinemia, and skeletal muscle lipid
peroxidation in the OLETF rat. J Appl Physiol.
30. Fleury C, Neverova M, Collins
S, et al. Uncoupling protein-2: a novel gene linked
to obesity and hyperinsulinemia. Nature Genetics.
Stegenga ME, van der Crabben SN, Blümer RM, et al.
Hyperglycemia enhances coagulation and reduces
neutrophil degranulation, whereas hyperinsulinemia
inhibits fibrinolysis during human endotoxemia.
Blood. 2008; 12:82-9.
32. Zhao CX, Xu X, Cui Y, et al.
Increased Endothelial Nitric-Oxide Synthase
Expression Reduces Hypertension and Hyperinsulinemia
in Fructose-Treated Rats. J Pharmacol Exp Ther.
33 Hotamisligil GS, Shargill NS,
Spiegelman BM: Adipose expression of tumor necrosis
factor-alpha: direct role in obesity-linked insulin
resistance. Science 259:87–91, 1993.
34. Ruotsalainen E, Stancáková A,
Vauhkonen I, Salmenniemi U, et al. Changes in
Cytokine Levels During Acute Hyperinsulinemia in
Offspring of Type 2 Diabetic Subjects.
Atherosclerosis. 2009 Dec 2. (http://www.ncbi.nlm.nih.gov/pubmed/20031127)
35. Hunt LT, Dayhoff MO (1980).
"A surprising new protein superfamily containing
ovalbumin, antithrombin-III, and a1-proteinase
inhibitor". Biochem Biophys Res Commun.
36. Schwarzenberg SJ, Yoon JB,
Seelig S, et al. Discoordinate hormonal and
ontogenetic regulation of four rat serpin genes. Am
J Physiol Cell Physiol. 1992; 262:C1144-C1148.
37. Alsheikh-Ali AA, Maddukuri
PV, Han H, Karas RH. Effect of the magnitude of
lipid lowering on risk of elevated liver enzymes,
rhabdomyolysis, and cancer: insights from large
randomized statin trials. J Am Coll Cardiol.
38. Ali M, Ali O: AA oxidopathy:
the core pathogenic mechanism of ischemic heart
disease. J Integrative Medicine 1997;1:6-112. Ali;
39. Abramson J, Wright J. Statins for primary
prevention of coronary artery disease. The Lancet.