Oxygen, Insulin Toxicity, and Inflammation – Part One: Clinical Benefits of Chelation

                                                                       Majid Ali, M.D.

I describe some aspects of a series of consecutive 125 four-hour insulin profiles to present what I consider to be “evolutionary insulin design.” This design is disrupted by the trio of toxicities of foods, environment, and thoughts that cause the trio of molecular states of acidosis, oxidosis, and clotting-unclotting dysequilibrium (CUD). The insulin design so disrupted leads to insulin resistance, hyperinsulinemia, and “insulin- toxic states”—obesity, fatty change of the liver, diabetes, cardiovascular disorders, and others—which, in turn, set the stage for diverse metabolic, inflammatory, and degenerative, including cardiovascular disorders. These subjects 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.1-3

Some of the data presented to underscore the crucial importance are likely to stretch the credibility of those who have not studied insulin well in clinical medicine. The profound relevance of this evolutionary design to the pathogenesis of “insulin- toxic states”—obesity, fatty change of the liver, diabetes, cardiovascular disorders, and others—is underscored. Four case studies are furnished, the first two illustrate the evolutionary insulin design, and the remaining two demonstrate serious consequences of the disruption of this design, as well as dramatic clinical benefits of insulin reduction.

The Crank-Crank-Shaft Model of Insulin Toxicity

In a previous publication, I proposed a crank-crank-shaft model of insulin resistance— hyperinsulinemia develops as the pancreas gears up hormone production to overcome developing resistance of the cell membrane to insulin.4 Succinctly stated, in this model the crank of insulin (5,808 daltons) fails to “move” (activate) the crank-shaft of insulin receptors in the “hardened” cell membranes—the crank-shaft is rusted, turned, and twisted, so to speak—so rendering insulin dysfunctional. The crankshaft of insulin receptor is roughly 70 times larger than the insulin crank, including two alpha sub-units 135 kD each and two beta subunits of 95 kD each.

To explain “hardening of cell membranes,” I proposed the Grease and Detergent Model in which biomembranes and matrix are covered with “cellular grease” due to insufficient detergent functions of the body.5 The grease is composed of cellular waste, molecular debris, rancid (oxidized) lipids, sticky sugars (glycosylated proteins and lipids), and pulped (misfolded) proteins. The primary detergent in the body is oxygen, with secondary “oxy-detergents,” such as hydrogen peroxide, nitric oxide, hydroxyl radicals, oxygen-activated enzymes, and grease-eating phagocytes.

Evolutionary Insulin Design

Evolution optimized insulin homeostasis and cellular bioenergetics with such economy that extremely small amounts are required to keep fasting blood glucose levels in the normal range of 70 to 85 mg/dL. Surprisingly, 24 patients (19.6%) in this series had fasting insulin levels of less than two uIU/mL, clear evidence that evolution designed the beta cells of the pancreas to “rest” during sleep (Table 1). Notably, another 27 patients (22.1%) showed insulin values between two and five, adding to the strength of my conclusion. The data in Table 2 show a surprise finding of considerable clinical significance: while only 19.6% of the subjects had a low fasting insulin level of less than 2 uIU/mL, 64.7% had the peak insulin level of over 50 uIU/mL (the peak insulin values of several optimal insulin profiles in the series were below 30 uIU/mL (examples shown in Tables 3 and 4). The main inference I draw from these data is that fasting insulin levels often hide delayed hyperinsulinemia.

Table 1. Distribution of Fasting Insulin Levels, Expressed in uIU/mL, in
Consecutive 122 Four-Hour Insulin Profiles

< 2 ul/mL

(N=24)

2-5 ul/mL

(N=27)

6-15 ul/mL

(N=49)

16-25 ul/mL

(N=13)

26-60 ul/mL

(N=9)

Females
(n=78)

15
(12.3$%)

16

(13.1%)

33

(27%)

8

(6,5%)

6

(5.3%)

Males
(n=44)

9

7.3%

11

9.0%

16

13.1

5

4.1%

3

2.4%

Table 2. Distribution of Peak Insulin Levels (in 50 ul/mL) of 122 Profiles in Six Categories:
A, <50; B, 51-100; C3, 151-200; D 201-250; E, 251-300; F >300

Insulin uIU/mL

< 50

51-100

101-150

151-200

201-300

“>300

Females

(n=78)

26

(21.3%)

33

(27%)

16

(13.1%)

1

(0.8%)

1

(0.8%)

1

(0.8%)

Males

(n=44)

14

(11.4%)

13

(10.6%)

15

(12.3%)

0

2

(12.3$%

0

Case 1: Optimal Insulin Profile

An 82-year-old 5’8″ woman weighing 185 lbs. was seen for severe fatigue developing after resection of an abdominal abscess associated with a ruptured colonic diverticulum. She had been treated for hypertension and atrial fibrillation for over 20 years. Her fasting insulin level of 6 units reveals, with stunning clarity, the evolutionary insulin design: the beta cells of the pancreas were designed to rest at night, even for an elderly markedly overweight woman.

Table 3. Optimal Insulin Profile (Peak Value, 29 uIU/mL) of An 82-year-old 5’8″ Woman Weighing 185 lbs. With Hypertension, Atrial Fibrillation, and Diverticulitis.

1.14.10

Fasting

1 Hr

2 Hr

3 Hr

4 Hr

Insulin uIU/mL

6

27

29

9

4

Glucose

87

97

111

65

79

Case 2: Optimal Insulin Profile

A 51-year-old 5’2″ woman weighing 120 lbs. consulted me for hypothyroidism, allergy, and sinusitis. She was disabled with chronic fatigue syndrome ten years earlier following divorce and working as a single mom. She became committed to her health and rigidly followed a low-glycemic-index diet. She said, “Life has been good. If I were not so devoted to my health, I think I would be very sick. Adversity, if it doesn’t kill you, liberates you.”

Table 4. Optimal Insulin Profile (Peak Value, 11.8 uIU/mL) of a 51-year-old 5’2″ Woman Weighing 120 lbs. Consulted Me for Hypothyroidism, Allergy, and Sinusitis.

Fasting

30 M

1 Hr

2 Hr

3 Hr

4 Hr

Insulin

3.2

11.8

2.4

1.9

1.5

Glucose

85

110

75

70

52

91

Pathology and Clinical Aspects of Insulin Toxicity

Insulin in excess is a potent toxin—fattening, pro-inflammatory, immunosuppressive, pro-stroke, pro-heart disease, pro-degenerative disorders, pro-cancer, and pro-premature aging. Not unexpectedly in this light, it impedes oxygen-driven mitochondrial energetics and myriad oxygen signaling pathways. Insulin toxicity is the unrecognized spreading pandemic of our time. Unfortunaely, most doctors rely on fasting blood sugar values within the reference range—a regrettable practice that often masks insulin derangements (personal unpublished data)—and the consequences of insulin toxicity go unrecognized. Notable among such consequences are:

.  Fatty change of the liver;

.  Insulin-induced fat necrosis (a type of tissue death);

.  Insulin dermatitis, including gray-yellow discoloration;

.  Neuropathy; and

.  Higher vulnerability and mortality from cardiovascular events.

Strong evidence for increased morbidity and mortality from the cardiovascular consequences of increased insulin activity is drawn from two recent and massive trials, the ACCORD trial that included 10,251 patients6 and the NICE-SUGAR Study, that included 6,104 patients.7

The Only Reliable Test for Insulin Toxicity

My analysis of 122 four-hour insulin profiles revealed that it is not safe to rely on the fasting or random blood insulin level determinations. As indicated earlier, 67% of the subjects in this series had hyperinsulinemia that was not suspected or proven by their previous doctors. Remarkably, six individuals without prior diagnosis of diabetes were found to be diabetic using the standard blood sugar criteria—insulin profiles included four-hour glucose profiles as well.

The reason why insulin toxicity is neglected in clinical medicine is that doctors do not look for it with a four-hour insulin profile performed after a 75 gram glucose load. Most of more than 10,000 patients I saw during the last thirty years had complex chronic problems and had seen multiple specialists. Not more than twenty of them had four-hour insulin profiles performed before I saw them. Notably, none of the previous doctors had undertaken robust bowel and liver detox procedures to address hyperinsulinemia. Indeed, some aspects of these data are likely to stretch the credibility of doctors who have not studied insulin well in their practices.

Insulin Toxicity Case # 3

A 67-year-old 5’7″ woman weighing 215 lbs. presented with hypertension, chronic fatigue syndrome, GERD, IBS, fatty change of the liver, and allergy. The highest recorded blood pressure in the past was 240/110. The results of four-hour insulin and glucose profiles are presented in Table 1. Other pertinent laboratory data included the following: AST, 95; ALT, 138; A1c, 6.1%; vitamin D, 21 IU; decreased values of multiple urinary steroid metabolites; and increased urinary excretion of cadmium, mercury, and lead. I prescribed my integrated insulin reduction protocol (described later). Note the fall of the pretreatment two-hour postprandial insulin value of 84.8 units to post-treatment value of 31.3 units, and the pretreatment blood pressure values of 166/100 and 150/96 to post-treatment value of 130/80 (Table 5).

Table 5. Reduction in Insulin Levels are Correlated With Changes in Liver Enzyme Activities, and Blood Pressure of a 67-year-old 5’7″ woman weighing 215 lbs. With Hypertension, Chronic Fatigue Syndrome, GERD, IBS, Fatty Change of the Liver, and Allergy.

8.6.2009

Fasting

30 Min

1 Hr

2 Hr

3 Hr

4 Hr

AST

IU/mL

ALT

IU/mL

BP

Insulin

51.4

61.9

115

84.8

30

25.6

95

138

166/100*

150/96**

Glucose

98

190

122

124

68

51.5

12. 1, 2009

Insulin

AST

ALT

BP

31.3

44

61

130/80

* Right arm. ** left arm

Insulin Toxicity Case # 4

A 63-year-old 5′ 11.5″ man weighing 211 lbs. presented with a history of hepatitis C, cirrhosis, hypertrophic cardiomyopathy, GERD, eczema, onychomycosis, and leg edema. He had received interferon therapy six years earlier, which was tolerated poorly and failed to reduce the viral load longterm. In January 2010, seven years later, it was planned to enter him in the trial of a caspase inhibitor drug at a New York University hospital. He responded so well to our integrative treatment plan that the trial team found him unsuitable for inclusion. He lost 24 pounds. His BP values changed from 145/90 to 125/80, and hepatitis C viral count fell from 9.7 million copies in September 2009 to to 3.6 million copies in January 2010. Changes in insulin profiles and liver enzymes are shown in Table 6.

Table 6. Reduction in Insulin Levels Are Correlated With Improvement in Liver Enzyme Activities, and Blood Pressure of a 63-year-old 5′ 11.5″ Man Weighing 211 lbs. With Hypertension, Hepatitis C, Cirrhosis, and Hypertrophic Cardiomyopathy.

9.4.09

Fasting

1 Hr

2 Hr

3 Hr

4 Hr

AST

IU/mL

ALT

IU/mL

Hep C Count

Insulin

15.8

57.2

132

20

51

42

73

9.7 million

Glucose

79

165

115

40

11.8

1. 12, 2010

Insulin

4

48.3

44.2

10.2

2.9

3.6 million

Glucose

61

148

99

50

409

41

37

To summarize, I describe aspects of a series of consecutive 125 four-hour insulin profiles to put forth evolutionary insulin design, and discuss the clinical significance of insulin toxicity which results when this design is thwarted. The risks of relying on fasting or random insulin levels are highlighted. I consider a four-hour insulin profile the single most important laboratory test for assessing not only the glucose metabolism but also for the early detection and quantification of the insulin-toxic states, such as obesity, fatty change of the liver, pre-diabetes, diabetes, pre-hypertension, hypertension, neuropathy, incipient renal failure, and cardiovascular events. In Part II, I discuss the EDTA-insulin dynamics and present the details of my insulin-reduction program.

Related Tutorial:

INTEGRATED INSULIN AND TOXIC METAL REDUCTIONS FOR CORONARY HEART DISEASE

References

1. 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 Medicine Press.

2. 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 Press.

3. Ali M. The Principles and Practice of Integrative Medicine Volume XI: Darwin, Dysox, and Integrative Protocols. New York (2009). Institute of Integrative Medicine Press.

4. Ali M. Beyond insulin resistance and syndrome X: The oxidative-dysoxygenative insulin dysfunction (ODID) model. J Capital University of Integrative Medicine. 2001;1:101-141.

5. Ali M. The unifying dysox model of hormone disorders and receptor restoration therapy. Townsend Letter-The examiner of Alternative Medicine. 2007; 291;145-151.

6. 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.

7. The NICE-SUGAR Study Investigators. Intensive versus Conventional Glucose Control in Critically Ill Patients. New Eng J Med.. 2009;360:1283-1297.

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