Category Archives: Dr. Ali’s Course on Hyperinsulinism

Insulin Toxicity of the Unborn

Majid Ali, M.D.

The incidence of pregnancy-associated insulin resistance is rising worldwide, I think it is appropriately designated as insulin toxicity of the unborn.


The incidence of pregnancy-associated insulin resistance is rising worldwide, and is commonly associated with many physiological bioenergetic, biochemical, metabolic, physiological, hematological and immunological alterations.  Many of the factors involved with these alterations render cell membranes resistant to the action of insulin.  At the end of healthy pregnancy, these changes are  reversible after delivery [1]. Healthy women pregnancy can be associated with resistance to the action of insulin on glucose uptake and utilization.


 

Here is an important link for expecting moms and dads

https://wordpress.com/post/alidiabetes.org/2730

 

The Crank-Crank-Shaft Model

of Insulin Resistance Insulin Toxicity

Insulin resistance as the resistance of cells, most notably of the muscles, liver, and fatty tissue to the action of insulin. In 2000, I offered the analogy of a crank and crank-shaft to explain how insulin resistance develops. 

I proposed The Crank-Crank-Shaft Model of Insulin Toxicity to offer a simple and visual model to explain insulin resistance, excess insulin activity (hyperinsulinemia), and insulin toxicity. In simple words, the “crank of insulin” fails to turn the “crank-shaft of insulin receptor” protein embedded in the cell membrane. This happens when the cell membrane is covered with grease—the crank-shaft is rusted, turned, and twisted, so to speak—so rendering insulin ineffective. I point out that the insulin receptor crankshaft is roughly 70 times larger than the insulin crank.

To illustrate injury to the cell membrane, I proposed The Grease and Detergent Model in which the cell innards, the cell membrane, and the cement that holds the cells together (the matrix) accumulate “cellular grease” due to insufficient detergents in the body. Cellular grease is composed of cellular waste, molecular debris, rancid fats, sticky sugars, and pulped 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

In cellular grease, in scientific terms, rancid fats are oxidized and peroxidized lipids, sticky sugars are glycosylated proteins and lipids, and pulped proteins are cross-linked peptides (chains of amino acids that make up proteins). This is a vast subject which I address in several articles in my Insulin Toxicity Series. Here I point out that cellular grease buildup is caused by toxic foods, toxic environment, and toxic thoughts.

In The Crank-Crank-Shaft Model of Insulin Toxicity, the blood sugar level rises when insulin fails to drive sugar into the cells to be metabolized (“burned”) to produce energy. The pancreas senses the rising blood sugar levels and responds with overproduction of insulin hormone in order to overcome the resistance of cellular grease. This works for sometime. However, excess insulin is fattening, inflaming, and grease-building. So begins the vicious cycle of:

*  More grease,

*  More insulin resistance,

*  Higher blood sugar,

*  More insulin production,

*  Yet more grease,

*  Yet higher blood glucose level,

*  Yet more insulin production, and

*  Yet more grease.

Pregnant women require an additional energy of 300 kcal/day over routine energy intake [2] while the average glucose utilized by a growing fetus at the 3rd trimester reaches approximately to 33 μmol/kg/min [4]. Maternal IR leads to more use of fats than carbohydrates for energy by mother and spares carbohydrates for fetus. Thus, the development of IR serves as a physiological adaptation of the mother to ensure adequate carbohydrate supply for the rapidly growing fetus [4].

As the pregnancy advances to third trimester, insulin sensitivity may gradually decline to 50% of the normal expected value [5]. This decline is reported to be mediated by a number of factors such as increase in the levels of estrogen, progesterone, human placental lactogen (hPL), among other factors [6].

Normally, insulin binding to insulin receptor causes phosphorylation of β-subunit of receptor and it further leads to phosphorylation of Insulin Receptor Substrate-I (IRS-I) at tyrosine residue which act as docking site for further signal transduction molecules [7].

Progesterone suppresses the phosphoinositol 3-kinase-mediated pathway by reducing the expression of IRS-1. Gradually increasing progesterone concentration with advancement of normal pregnancy is associated with increased inhibition insulin-induced GLUT4 translocation and glucose uptake [8]. Estrogen concentration is also high in pregnancy. 17β-estradiol diminishes insulin sensitivity at high concentrations [9].

hPL has both insulin-like and anti-insulin effects. In vitro, it has been shown to increase lipolysis and free fatty acids (FFAs) in adipocytes. Increased hPL level in pregnancy is found to increase glucose uptake, oxidation, and incorporation of glucose into glycogen, which may favor glycogen storage in the mother [10].

Human placental growth hormone (hPGH), a product of the human growth hormone variant gene, is not regulated by growth hormone- releasing hormone (GH-RH) and is secreted tonically rather than in a pulsatile fashion. hPGH has the same affinity for the growth hormone receptor as pituitary GH. The hPGH may also have the same diabetogenic effects as pituitary growth hormone such as hyperinsulinemia, decreased insulin-stimulated glucose uptake and glycogen synthesis, and impairment of the ability of insulin to suppress hepatic gluconeogenesis [10].

Other factors such as increased levels of serum cortisol, Tumor necrosis factor α ( TNF α, ILs etc., can interrupt the insulin signaling pathway and can lead to IR during normal pregnancy [11].

Available literature [1214] suggests that there is a rise in IR in 3rd trimester of pregnancy. However literature is less on the 1st and 2nd trimester. So the present study was undertaken to evaluate the status of IR in different phases of normal pregnancy.

Restoring Insulin Homeostasis, Reversing Diabetes

Majid Ali, M.D.

The Work of True Physicians Does Not Belong to Them, just As Their Words Do Not Belong to Them.  

The Healing of True Physician’s Belongs to Their Patients, ,Just As the Words of True Writers Belong to Their Readers.


First Things First

I.  There are two true markers of real enduring health:

                                                         1. Oxygen health

                                                         2.  Insulin health

II. To understand health is to understand oxygen health and insulin health.  

III. To understand disease is to understand inflammation.

IV. No healing is possible without physiological healing.

V. No disease is possible without pathologic inflammation.

VI. Pathologic inflammation results from disrupted oxygen and insulin signaling.


Insulin Health

Dr. Ali’s Diabetes Library 

Dr. Ali’s Diabetes Course – Part 1: The Basics of Diabetes
https://alidiabetes.org/2016/06/27/dr-alis-diabetes…-part-one-basics/ ‎
 
Dr. Ali’s Diabetes Course – Part 2: Insulin Detox – Beyond Sugar Talk
https://alidiabetes.org/2016/07/11/dr-alis-diabetes-course-part-two-2/ ‎
 
Dr. Ali’s Diabetes Course – Part 3:
https://alidiabetes.org/2016/07/25/dr-alis-3-part-d…ourse-part-three/ 
 
Diabetes Recipes
 Reversing Diabetes – Lesson One
 Reversing Diabetes – Lesson Two
 Reversing Diabetes – Lesson Three
Reversing Diabetes – Lesson Four
Reversing Diabetes – Lesson Five
Reversing Diabetes – Lesson Six
 Diabetes Recipes

Dr. Ali’s Insulin Library

Spiritual Healing Course byMajid Ali, M.D.
 What Is Insulin? What Are Its Functions?
 
 Insulin Detox for Wight Loss and Diabetes Reversal
 
 I’m Hungery After Meals. Why?
 Insulin Buddy and Fatty Liver
 
 What is the Evidence That Neuropathy Is Caused by Insulin Toxicity?
 
Obesity Is Cellular Inflammation
 
Dr. Ali’s Best Anti-Insulin Toxicity Breakfast
 
 Gestational Diabetes Is Insulin Toxicity of the Unborn – Part Two
Your Child – Hyperactive or Hypoglycemic?
 
Why Do I Consider Blood Insulin Test to be the Most Important Test for Metabolism and Diabetes 
Insulin-Toxic Obesity
What Is the Most Important Question in Science, Health, and Healing
 
What Is the Second Most Important Question in Science, Health, and Healing
 
Insulin Videos
 
 
What is Diabetes
Insulin Toxicity De-mystifies Syndrome X
Don’t Trust A1c for Diabetes Diagnosis, Please!
 
 Recipes for Insulin Toxicity – Majid Ali, MD
 
 
Almond Butter Snack for Losing Weight and Reversing Diabetes, An Excellent Choice
 
 
Peanut Butter or Hemp Seed Butter Peanut Butter Snack for Weight Loss and Diabetes Reversal
  
 
 Dr. Ali’s Insulin Course, Basics
 
What Is the Problem With Calorie Counting?
Is a Calorie a Calorie a Calorie?
 
 
Is Insulin Excess Bad for the Heart?
 
 
 
What Is Diabetes? Majid Ali, M.D. With Ben Svoboda
 
Is Excess Insulin Toxic to Nerves
 
 
 
 
Majid Ali, M.D. – Is a Calorie a Calorie a Calorie?
 
I’m Hungry After Meals. Why?
 
 
Recipes for Insulin Toxicity – Majid Ali, MD
 
 
 
Almond Butter Snack for Losing Weight and Reversing Diabetes, An Excellent Choice
 
 
Peanut Butter or Hemp Seed Butter Peanut Butter Snack for Weight Loss and Diabetes Reversal
 
 
 
 Diabetes and insulin Majid Ali MD
Why Do I Consider Blood Insulin Test to be the Single Most Important Test
 
What Is Your Child’s Peak Insulin Level? Is She or He Insulin-Toxic?
 

Shifting Focus From Sugar to Insulin for Personal Health – Part One – Basics

     Majid Ali, M.D.

  • Shifting Focus From Sugar to Insulin for Personal Health Part One – Basics
  •  Shifting Focus From Sugar to Insulin for Personal Health Part Two – Advanced
  •  Shifting Focus From Sugar to Insulin for Personal Health Part Three – Detox
  • Shifting Focus From Sugar to Insulin for Personal Health Part Four – Citations

 


Why the Shift?

  1. Insulin toxicity (hyperinsulnism) precdes Type 2 diabetes by five, ten, or more years during which period blood glucose test hides much. The individual with excess insulin (insulin toxicity often suffers from weight gain, metabolic dysfunctions, immune and inflammatory diseases, cardiovascular disease, neurological disorders, and problems of the kidneys, eyes, and other body organs.
  2. Blood sugar test is a test for sugar metabolism only. By contrast, the  blood insulin tests is a test for total body metabolism.
  3. Blood sugar test is a test for just one carbohydrate (glucose). By contrast, blood insulin test is a test for carbohydrates of all types as well as proteins and fats.
  4. Blood sugar test is a test for glucose level just at one moment. By contrast, the  blood insulin test reveals the status of total body metabolism over months.
  5. Blood sugar test is interpreted as a single value (100 mg/mL is considered upper limit of normal for a fasting sample). By contrast, the  blood insulin test is interpreted in light of the expected value within an insulin curve.
  6. Blood sugar test done on parts of the same blood sample with a real level of 100 mg/mL is likely to be reported as 98, 99, 100, or 102 by different laboratories. Indeed, a laboratory may report values of 98, 99, or 102 for the same blood sample on the same day. This happens quite commonly. Small changes in the results of insulin test are not fraught with this danger of wrong interpretation. 
  7. Blood sugar test does not inform doctors about the immune status of the person tested. By contrast, an elevated blood insulin test values is a test for total body metabolism.
  8. During pregnancy, women with gestational diabetes are assured that diabetes will disappear after delivery. This is false reassurance. Hyperinsulinism of pregnancy always persists after delivery to varying degrees.
  9. I have seen many patients whose fasting blood glucose level was below the mark of 100 mg/dL but who proved to have Type 2 diabetes on three-hour test, even by the glucose standards.

 


Life Is An injury-Repair-Injury Cycle.

Every cell in the body is an energy being. Every injured cell needs an extra energy to repair itself -energy in the form of repair materials as well as energy for the process of replacing injured parts of a cell or rebuilding what is lost.
In the oxygen order of human life, insulin is assigned the primary responsibility of both generating and regulating utilization of energy in the cells. This, simply stated, is the scientific basis, of the title of this article.

Insulin Intelligence for Personal Health

Next to oxygen, insulin is the most clinically significant molecular Dr. Jekyll Mr. Hyde. In lower physiological concentrations, insulin acts as the “master energy hormone” of the body.
In higher concentration, in a condition called hyperinsulinism, insulin is toxic. Specifically, insulin in excess is:

 

  1. Inflaming

  2. Fermenting

  3. Fattening

  4. Endo-toxic (toxic to endothelial cells that line inside of blood vessels

  5. Brain-toxic

  6. Liver-toxic

  7. Heart- toxic, and eventually “every cell toxic” toxic


Diabetes Is An Insulin Problem Years Before It Becomes A Sugar Problem
  1. Diabetes can be detected with blood insulin tests years before with blood sugar (glucose) tests.
  2. Diabetes can be reversed for years only with focus on insulin.
  3. Diabetes (the common Type 2, T2D) can be reversed far more reliably when guided by insulin tests than when guided by glucose tests.

  1. with insulin  diagnos

ianot be diagnosed early


Insulin In Health and Disease

In health, insulin in needed in very small amounts to metabolize carbohydrates, fats, and proteins to generate energy to meet normal needs of healthy cells. Such levels of insulin also keep blood glucose levels in the physiological range. In chronic diseases, the pancreas gland located in the upper abdomen chronically releases insulin in larger amounts to meet increased demands of injured tissue for cellular repair. Unless, the chronic diseases are controlled by addressing their underlying causes, , eventually producing a state called hyperinsulinims. 


Master Energy Hormone of the Body

In the current medical practice, insulin is mentioned only in the context of diabetes. Insulin is not recognized as the “master energy hormone” of the body. Nor are the toxic effects of excess insulin (hyperinsulinism) are duly recognized and addressed. This is most regrettable since hyperinsulinism predates diabetes Type 2 by five, ten, fifteen, or more years. Toxic effects of excess insulin in various body organs go unrecognized. Patients pay an enormous price for this neglect.



Global Tides of Insulin Dysregulation and Diabetes Type 2

Type 2 Diabetes is rapidly eclipsing other chronic diseases in becoming the preeminent threat to human health worldwide. In 2013, prevalence rate of 50.1% for prediabetes and T2D among the Chinese adults was reported (ref. 1). The prevalence of the disease in India and some other countries exceed this rate.

Hyperinsulinism is the underlying molecular lesion of T2D since it predates the disease by five to ten or more years. Prior to its progression to T2D,  it exerts several well-established adverse metabolic, inflammatory, cardiovascular, and neurologic effects (ref. 4).  Earlier this year, my co-workers and I reported prevalence rate of 75.1% for hyperinsulinism in 684 subjects in the general population of New York Metropolitan area (see the full text of the article on this web site (use search box to access it). Hyperinsulinism in this study was established with fasting, 1-hour, 2-hour, and 3-hour post-glucose-challenge blood insulin concentrations.



Insulin Toxicity in Autism and Dysautonomia

In Notably, in a companion study, mild-to-moderate degrees of hyperinsulinism were encountered in the majority of 25 children with autism (12) and dysautonomia (13).

Effective hyperinsulinism modification strategy to prevent T2D requires a clear understanding of core aspects of optimal insulin homeostasis, for the clinician as well as the patient, including differential responses to carbohydrate and non-carbohydrate challenges in insulin-based care of metabolic disorders, such as prediabetes, T2D, and gestational diabetes (citations appear at the end of the full text of the article)


Dr. Ali’s Insulin Reduction Protocol

To reverse pre-diabetes and diabetes (completely or partially), my primary objective is to lower both blood sugar and insulin levels by making insulin work better. For individuals with pre-diabetes with insulin toxicity but without high blood sugar levels, my goal is to lower blood insulin levels by increasing insulin efficiency.

Dr. Ali’s Insulin Reduction Protocol

My Insulin Reduction Protocol has two components:

1. A plan of food choices to prevent sugar spikes that trigger insulin spikes, and

2. A plan to do daily gentle bowel and liver detox.

In the Table 2 below, I present a case study to show how blood glucose and insulin levels were lowered (by increasing insulin efficiency) with the clinical application of Dr. Ali’s Insulin Reduction Protocol. I follow this with some explanatory comments. In Table 1, I present the insulin and glucose values of an individual in good metabolic health.

Table 1. Insulin-conserving Profile of a 77-Yr-Old Metabolically Fit 5′ 5″ Man Weighing 133 Lbs. He Was Seen for Allergy Treatment.

6.23. 2010

Fasting

1 Hr

2 Hr

3 Hr

Insulin

<2

24

29

30

Glucose

78

96

75

71

Table 2. Concurrent Reduction of Blood Insulin and Blood Sugar Levels With Dr. Ali’s Insulin Reduction Protocol in a 58-Yr-Old Woman With Complete Loss of Hair (Alopecia), Chronic Fatigue, Memory Deficit, Underactive Thyroid Gland, Allergy, and Mood Swings.

10.28.10

Fasting

1 Hr

2 Hr

3 Hr

Insulin

9.7

184.4

35.3

24

Glucose

102

133

79

73

11.23.1202

Insulin

12.7

87.7

50.2

Glucose

96

117

77

Diabetes Reversal Requires a Philosophy of Healing

Diabetes Type 2 can be reversed neither with the denial of dieting nor with euphoria of eating. Diabetes can be reversed only with a philosophy of eating and living. It requires knowing the difference between being “diabetes-literate” and “healing-literate.” Diabetes is the number one cause of blindness, neuropathy, toe and limb amputations, kidney failure leading to dialysis, and increased risk of strokes, memory loss, and heart attacks. So reversing diabetes is an act of self-compassion. If these words pull you toward making an honest attempt to lose diabetes Type 2, please consider studying “Dr. Ali’s Course on Healing” (available at www.aliacademy.com).

Use search box to access a series of articles on the subject.



Article Published in the Journal Townsend Letters 2017;402:91-96.

Majid Ali, M.D., F.R.C.S. (Eng), F.A.C.P., Alfred O. Fayemi, M.D., MSc (Path), F.C.A.P.  Omar Ali, M.D., F.A.C.C, Sabitha Dasoju, M.B;B.S, Daawar Chaudhary,  Sophia Hameedi, Jai Amin, Benjamin Svoboda


ABSTRACT

 Objectives 

A retrospective survey of insulin responses to a 75-gram glucose challenge in 684 subjects in New York metropolitan area was conducted to determine: (1)  prevalence of hyperinsulinemia;  (2) characteristics of optimal insulin homeostasis; (3) stratification of  hyperinsulinism for optimal clinical use; and  (4) mechanisms of action of  risk factors of  hyperinsulinism  and Type 2 diabetes (T2D).

Methods

Post-glucose blood insulin and glucose levels were measured with fasting and  ½ hr, 1- hr, 2-hr, and 3-hr samples at university and large commercial laboratories. Guided by the initial 100  profiles,  a profile peak insulin concentration of 160 uIU/mL.

Results

The overall prevalence of hyperinsulinism in the general New York metropolitan population without Type 2 diabetes was 75.1%. The rates of optimal insulin homeostasis and the degrees of hyperinsulinism (mild, moderate, and severe in 506 subjects without T2D were 1.7%, 24.9%, 38.9%, 26.5%, and 9.7% respectively. The corresponding rates for three degrees of hyperinsulinism in 178 subjects with T2S were 29%, 24%, and 13.9%. The profile peak insulin concentrations ranged from 11 uIU/mL to 718 uIU/mL. The rates of optimal insulin homeostasis and hyperinsulinism of three degrees in 506 subjects without T2D were 36.5%, 25.7%, and 10.8% respectively; corresponding rates in 178  subjects with T2D were 29%, 24%, and 13.9% (with the overall rate of 66.9%), The remaining 33.1% in the atype 2 diabetes group showed insulin deficit of varying degrees. The profile peak insulin concentrations ranged from 11 uIU/mL to 718 uIU/mL.

Conclusions

Our findings call for further study of insulin homeostasis in other general populations. Viewing data in the broader context of mitochondrial dysfunction related to recognized dietary, environmental, and other risk factors of T2D, a need for a shift of focus from glycemic status to insulin homeostasis is recognized for stemming the global tides of hyperinsulinism/T2D continuum.

INTRODUCTION

Type 2 diabetes is a spreading pandemic. The high prevalence of the disease in China (50.1% of adults)1 is disturbing; the rates in India and some other countries may even exceed this number..2 Hyperinsulinism predates diabetes by five to ten or more years, and its adverse metabolic, inflammatory, immunologic, cardiovascular, and neurologic effects are well established.3-9 There is a clear need for an approach that focuses on: (1) a clear understanding of insulin homeostasis in health and a range of its disruptions in chronic diseases; (2) delineation of the hyperinsulinism-to-Type 2 diabetes progression; (3)  early detection and appropriate modification of hyperinsulinism; and (4) possibility of reversibility of Type 2 diabetes for individuals willing and able to undertake well-informed hyperinsulinism modification plans.

Clinicians will encounter some difficulties in implementing the Shift, most notably: (1) a lack of  consensus among clinical pathologists and laboratory professionals about how to interpret blood insulin concentrations; (2) absence of an insulin database that allows direct stratification of hyperinsulinism for patient education and assessment of the efficacy of therapeutic options; (3) disparate laboratory reference ranges for blood insulin concentrations in current use in the U.S. (Table 1)9; and (4) the initial real and imagined difficulties in implementing the Shift. This retrospective survey was conducted to address these concerns.


Study Subjects

Insulin and glucose profiles retrospectively gathered for this survey belonged to individuals (“survey subjects”) with digestive-absorptive, metabolic, inflammatory, cardiovascular, allergic, autoimmune, and degenerative disorders. Some of them consulted clinicians for wellness. Blood glucose and insulin tests were done as parts of complete laboratory evaluation of clinical issues, including the metabolic status. Specifically, glucose and insulin profiles comprised levels obtained with fasting blood samples and those drawn ½-hour, 1-hour, 2-hour, and 3-hour after an oral 75-gram glucose challenge. The ordering clinicians did not recognize any consent concerns in including insulin tests in their laboratory workup, and did not use the results to implement hyperinsulinism modification plans with any pharmacologic agents or specific commercial brands of nutrients. There were no financial relationships or conflicts among clinicians ordering the tests, laboratories performing the tests, and the authors.

Survey of Laboratory Insulin Ranges

Table 1 displays wide variations in the lower and upper limits in the reference ranges for fasting and post-glucose challenge blood insulin concentrations employed by six major laboratories in the New York City metropolitan area. Further details are presented in supplementary information.10   The insulin ranges of 0 to 121.9 uIU/mL for one-hour (Lab 2) and 40 to 300 uIU/mL (Lab 5) for two-hour values are most noteworthy in this context.

Table 1.  Insulin Reference Ranges  in uIU/mL of Six Laboratories in New York Metropolitan Area*
Laboratory Fasting 1 Hr 2 Hr 3 Hr
Laboratory 1 1.9 – 23 8  –  112 5 – 35 Not Reported
 Laboratory 2 2.6 – 24.9 0.0  – 121.9 0.0 – 163.5 Not Reported
Laboratory 3 2.6 – 24.9 8  –  112 5  –  55 3  –  20
Laboratory 4 6  – 27 20  –  120 18  –  56 8  –  22
Laboratory  5 00  – 30 30  –  200 40  – 300 50  – 150
Laboratory 6 Does not include insulin ranges in the report. Instead it includes the following note: Insulin analogues may demonstrate non-linear cross-reactivity in this essay. Interpret results accordingly.**

*Upper and lower limits of laboratory reference ranges for blood insulin concentration determined following a Standard 75-gram glucose challenge.

**Personal communications with clinicians revealed that they do not find this laboratory note to be satisfactory in their clinical decision-making.


Cut-off Points for Optimal Insulin Homeostasis and Degrees of Hyperinsulinism

The selection of the peak insulin value of 160 uIU/mL for mild, moderate, and severe hyperinsulinism) with two considerations: (1) might these cut-off points prove appropriate  for this study; and (2) provide a frame of reference for future investigations of diverse aspects of insulin homeostasis and hyperinsulinism-to-Type 2 diabetes progression?  There are four other issues in this context: (1) No opinions on what constitutes optimal insulin homeostasis and what the insulin cut-off point for it might be were found in English literature; (2) No adverse effects of low insulin levels when accompanied by unimpaired glucose tolerance have been reported; (3) Ten of twelve survey subjects with peak insulin concentration of 20 uIU/mL reported negative family history of diabetes (grandparents, parents, uncles, aunts, or siblings); and (4) Hyperinsulinism and the metabolic syndrome are commonly spoken in the same breath,  explicitly or implicitly considering them as the two faces of the same coin. However, there is a crucial difference between the two: the peak insulin level and other features of three-hour insulin and glucose profiles provide clinicians with  specific and quantitative cut-off  points for detecting and stratifying hyperinsulinism — no such criteria have been established for the metabolic syndrome. In addition, three-hour insulin and glucose profiles shed light on other aspects of glycemic status and insulin homeostasis, some of which are presented later in the report.


Selection of Peak Insulin Values

The selection of the peak insulin value of 160 uIU/mL for mild, moderate, and severe hyperinsulinism) with two considerations: (1) might these cut-off points prove appropriate  for this study; and (2) provide a frame of reference for future investigations of diverse aspects of insulin homeostasis and hyperinsulinism-to-Type 2 diabetes progression?  There are four other issues in this context: (1) No opinions on what constitutes optimal insulin homeostasis and what the insulin cut-off point for it might be were found in English literature; (2) No adverse effects of low insulin levels when accompanied by unimpaired glucose tolerance have been reported; (3) Ten of twelve survey subjects with peak insulin concentration of 20 uIU/mL reported negative family history of diabetes (grandparents, parents, uncles, aunts, or siblings); and (4) Hyperinsulinism and the metabolic syndrome are commonly spoken in the same breath,  explicitly or implicitly considering them as the two faces of the same coin. However, there is a crucial difference between the two: the peak insulin level and other features of three-hour insulin and glucose profiles provide clinicians with  specific and quantitative cut-off  points for detecting and stratifying hyperinsulinism — no such criteria have been established for the metabolic syndrome. In addition, three-hour insulin and glucose profiles shed light on other aspects of glycemic status and insulin homeostasis, some of which are presented later in the report.

Exceptional Insulin Homeostasis

A subgroup of twelve survey subjects was designated “exceptional insulin homeostasis” for two reasons: (1) It showed extremely low fasting insulin value of

Results

Table 2 shows the prevalence rates of the categories of exceptional insulin homeostasis, optimal insulin homeostasis and hyperinsulinism of mild, moderate, and severe degrees in 506 survey subjects without Type 2 diabetes. The rising means of peak glucose levels correlate with rising means of peak post-glucose insulin concentrations (r value, 0.84). It is noteworthy that moderate increases in glucose levels are accompanied with disproportionately large rises in insulin levels. Specifically,  24% and 9% differences in glucose values between the first and the third category and that between the third and the fifth category respectively are accompanied by 400% and 395% rises in the corresponding means of peak insulin concentrations.

Table 2. Insulin Homeostasis Categories in 506 Study Subjects Without Type 2 Diabetes
Insulin Category* Percentage of Subgroup Mean Peak Glucose mg/dL(mol/mL) Mean Peak Insulin (uIU/mL)
Exceptional Insulin Homeostasis N =  12** 1.7% 110.2    (6.12) 14.3
Optimal Insulin Homeostasis                N =  126 24.9 % 121.2    (6.73) 26.7
Hyperinsulinism, Mild                             N =  197 38.9 % 136.5   (7.58) 58.5
Hyperinsulinism, Moderate                  N =  134 26.5 % 147.0   (8.16) 109.1
Hyperinsulinism, Severe                        N =  49 9.7 % 150.0   (8.33) 231.0
#   Correlation coefficient, r value, for means of peak glucose and insulin levels in the five insulin categories is 0.84.

*Criteria for classification: (1) Exceptional insulin homeostasis, a subgroup of optimal insulin homeostasis with fasting insulin concentration of

Table 3 shows the prevalence rates of the categories of optimal insulin homeostasis, and hyperinsulinism of mild, moderate, and severe degrees in 178 survey subjects with Type 2 diabetes. By contrast to the group without Type 2 diabetes, the means of peak glucose levels in this group with Type 2 diabetes do not correlate with means of peak post-glucose insulin concentrations. The fourth category of diabetic insulin depletion in this group indicates varying degrees of pancreatic failure to produce sufficient insulin to override insulin receptor resistance, drive glucose into the cells, and keep glucose in the normal range. The significance of this finding is discussed in the Discussion section of this report.

Table 3. Insulin Homeostasis Categories in 178 Study Subjects With Type 2 Diabetes
Insulin Category Percentage of Subgroup Mean Peak Glucose, mg/dL(mmol/mL) Mean Peak Insulin (uIU/mL)
Hyperinsulinism, Mild              N =  53 29.0% 252.0   (14.00) 55.4
Hyperinsulinism, Moderate    N =  42 24.0% 242.1   (13.45) 112.4
Hyperinsulinism, Severe          N =  24 13.9% 224.6   (12.47) 298.0
Insulin Deficit             N =  59 33.1% 294.0    (16.33) 22.9

ILLUSTRATIVE CASE STUDIES OF INSULIN AND GLUCOSE RESPONSES

Tables 4 to 8 present five illustrative sets of insulin and glucose profiles with brief clinical notes. The insulin profiles in Tables 4 and 8  represent the two extremes of insulin peaks (18 uIU/mL and 718.2 uIU/mL) encountered in this survey. The first of the two profiles (Table 4) is reflective of ideal metabolic efficiency of insulin in a larger evolutionary perspective of energy economy in the body. Notable findings here are: (1) a very low fasting insulin level of

Table 4. Example of Insulin and Glucose Profiles In Exceptional Insulin Homeostasis Category*
  Fasting ½ Hr 1 Hr 2 Hr 3 Hr
Insulin uIU/mL <2 18 14 4 <2
Glucose mg/mL  (mmol/L) 77     (4.27) 168   (9.33) 109      (6.05) 74       (4.11) 59    (2.88)
*The Patient,  A  60-Yr-Old 5’ 7” Man Weighing 138 lbs. Presented for a Wellness Assessment. He Was Considered to be in Excellent Health By Clinical and Laboratory Evaluation Criteria.
Table 5.  Severe Hyperinsulinemia in A Subject With Previously Undiagnosed Type 2 Diabetes*
  Fasting ½ Hr 1 Hr 2 Hr 3 Hr
Insulin uIU/mL 23.8 19.3 36.9 114.7 75.2
Glucose mg/mL  (mmol/L) 112     (6.21) 158   (8.77) 214      (11.76) 241    (13.38) 129   (7.16)
* The Patient,  A 64-Yr-Old 5’ 4” Woman Weighing 164 lbs. Presented With Hypothyroidism, History of Coronary Artery Stent Insertions, Fatty Liver, Memory Concerns And Without Previous Diagnosis of Type 2 Diabetes.
Table 6. Hyperinsulinism 18 Years After the Diagnosis of Type 2 Diabetes*
Fasting ½ Hr 1Hr 2Hr 3Hr
Insulin uIU/mL   12.9 27.2 29.2 36.2 25.4
Glucose mg/mL  (mmol/L) 128      (7.10) 224   (12.43) 278    (15.42) 297    (16.48) 249     (13.81)
*The Patient,  A 74-Yr-Old 5’ 6” Woman Weighing 155 Lbs. Presented With Bronchiectasis, Rheumatoid Arthritis, Prehypertension, and Inhalant Allergy.
Table 7. Brisk Insulin Response With A “Flat” Glucose Tolerance Profile*
Fasting ½ Hr 1Hr 2Hr 3Hr
Insulin uIU/mL 3 23 22 8 <2
Glucose mg/mL  (mmol/L) 72      (3.39) 44     (2.44) 63    (3.49) 58     (3.21) 65   (3.90)
*The Patient,  A 47-Yr.Old  5’ 5” Woman Weighing 170 Lbs. Presented With Polyarthralgia, Recurrent Sinusitis, and Fatigue.
Table 8. Severe Hyperinsulinism In A 13-Yr-Old With Lupus Erythematosus*
Fasting ½  Hr 1Hr 2Hr 3Hr
Insulin uIU/mL 27.9 362.5 424.0 718.2 571.7
Glucose mg/mL  (mmol/L)       70   (3.88)   140     (7.77)    157     (8.71)    150    (8.33)    111   (6.16)
Insulin and Glucose Profiles Obtained After Four Months of Robust Integrative Therapies
Insulin uIU/mL 7.2 125.1 238.5 208.0 132.0
Glucose mg/mL  (mmol/L) 81     (4.49) 154   (8.54) 181     (10.04) 130     (7.21) 97      (5.38)
*The Patient,  A 13-Yr-Old Girl With a History of Three Hospitalizations In One Year for Systemic Lupus Erythematosus, Recurrent Pneumonia, Thrombocytopenia, and Severe Optic Neuritis Resulting In Complete Loss of Vision In Right Eye. The Peak Insulin Fell from 718 to 238.5 In Four Months of Robust Integrative Treatment.

The insulin and glucose profiles in Table 5 illustrate the pattern of hyperinsulinism seen in previously undiagnosed Type 2 diabetes. This pattern highlights the importance of insulin profiling in order to prevent adverse effects of unrecognized hyperinsulinism over extended periods of time, as well as that of delayed diagnosis of Type 2 diabetes.

Table 6 shows hyperinsulinism persisting 18 years after the diagnosis of Type 2 diabetes and further underscores the importance of insulin profiling and the state of insulin homeostasis in Type 2 diabetes. The contrast between insulin and glucose profiles in Tables 4 and 6 is noteworthy; in Table 4, a very low (4 uIU/mL) 2-hour insulin level keeps the glucose level at 74mg/mL while in Table 6 a nine times higher (36.2 uIU/mL) 2-hour insulin level is accompanied by a glucose value of 297 mg/mL.

The glucose profile in Table 7 shows a paradoxical drop from the fasting value of 72 mg/dL to 44 mg/dL at thirty minutes and still lower-than-fasting values of 63, 58, and 65 mg/dL at one, two, and three hours respectively. Such “flat” glucose curves are considered enigmatic and indeed create doubt about whether the glucose challenge was administered. The accompanying insulin values (3, 23, 22, 8, and

The insulin and glucose profiles in Table 8 dramatically illustrate some aspects of the “inflammation-to-hyperinsulinism-to-more-inflammation-to-worsening-hyperinsulinism”    kaleidoscope,3-5 both in developing and healing phases of severe inflammatory immune disorders, such as  systemic lupus erythematosus. This subject is vast3-7,12-14 and its discussion is outside the scope of this report.

DISCUSSION

To provide a frame of reference for the merits of the proposed Shift for stemming the global tide of Type 2 diabetes, in 2004 one author reported evidence of impaired Krebs Cycle dynamics in patients with chronic immune-inflammatory and metabolic disorders.11His findings were subsequently validated by others12 as well as by his own additional work.13 Based on those findings, in 2007 he put forth oxygen models of hyperinsulinism and Type 2 diabetes with focus on insulin receptor dysfunction related to Krebs cycle disruptions.14 Two analogies were offered to explain the core tenets of these models: (1) a crank and crank-shaft analogy – insulin as the crank and its receptor as the crank-shaft – to provide a visual for the development of insulin resistance; and (2) a grease-detergent analogy in which oxygen and oxyradicals serve as the detergent to free up the jammed insulin receptor.13 In the first analogy, nutritional deficits,  environmental toxicants, gut microbial toxins, products of inflammatory-immune reactions, impaired hepatic detox pathways, chronic stress, and negative socioeconomic factors disrupt oxygen homeostasis, and cause mitochondrial dysfunction. The result of all of this is accumulation in cell membranes of oxidized lipids, cross-linked and misfolded proteins, glucose adducts, and excess molecular and cellular debris—“gumming up” the crank-shaft of the insulin receptor, so to speak, to create receptor resistance to the hormone.

To overcome the insulin receptor resistance, the pancreas overproduces the hormone, resulting in hyperinsulinism.  In obesity, hyperinsulinism and Type 2 diabetes (T2D), there is  release in excess of compounds such as non-esterified fatty acids, glycerol, and proinflammatory cytokines from the adipose tissue, and free DNA.3,5,6,15 These findings also support the notion of the primacy of insulin receptor dysfunction over beta cell dysfunction. Constructs for targeting glucose-sensing neurons in the ventrimedial hypothalamus have been employed for non-invasive, in-vivo activation and inhibition of neuronal activity to study the regulatory influences of central nervous system over glucose and insulin homeostasis.16 The Krebs cycle impairment that lead to insulin receptor dysfunction in peripheral cell populations is also expected to adversely affect glucose-sensing hypothalamic neurons as well.

In the second analogy, the collection of substances that gum up the insulin receptor is visualized as “cellular grease” and oxygen and oxyradicals are seen as the “cellular detergents.” The grease-detergent model, then, provides the rationale for therapeutic interventions which address all relevant threats to oxygen homeostasis and mitochondrial function in order to restore insulin homeostasis. This model also draws attention to the matter of subtyping Type 2 diabetes into: (1) subtype  A with insulin excess; and (2) subtype B with insulin depletion.17 In the treatment of the disease, the primary goal in both subtypes is the same regarding the glycemic status: optimal glycemic control. As for insulin homeostasis during treatment, however, the goals in two subtypes are divergent. Specifically, in subtype A, adverse effects of excess insulin need to be controlled or prevented by lowering insulin levels; in subtype B, by contrast, insulin levels need to be raised for superior long-term glycemic control.

To summarize, in the oxygen models of hyperinsulinism and Type 2 diabetes, insulin resistance begins with disruptions of oxygen homeostasis and mitochondrial functions which render insulin receptors unresponsive to the action of insulin. The pancreas responds to resistance of insulin receptors by increasing its production of insulin, so causing hyperinsulinism.


The oxygen model of hyperinsulinism and Type 2 diabetes also links digestive-absorptive disorders and changes in gut microbiota to mitochondrial dysfunction. Noteworthy in this context are the following: 1) anoxia leads to increased activity of inflammatory markers of diabetes.18 (2) changes in gut microbiota impair immunity and inflammatory responses in general19; and (3) specific diabetes-associated alteration in gut microbiota have been reported.20 In the studies organized by the Centre for Altitude Space and Extreme Environment Medicine at University College London, high-altitude anoxia was linked with rises in blood levels of inflammatory markers and heightened risk of Type 2 diabetes.19The subjects of how changes in gut microbiota influence immunity and the inflammatory responses is vast and has  been recently reviewed.20 Recent delineation of diabetes-associated changes in gut microbiota21 underscore the role of altered states of bowel ecology and changes in gut microbiota, in the pathogenesis of hyperinsulinism, as stipulated in the oxygen model of hyperinsulinism and Type 2 diabetes.22

The scope of this retrospective survey does not permit any firm inferences to be drawn concerning the beta cell dysfunction that may develop concurrently with hyperinsulinism due to mitochondrial dysfunction leading to insulin receptor dysfunction. In this context, four aspects of the survey findings are noteworthy: First, the relationships observed between incremental mean blood glucose levels and corresponding rises in the insulin concentrations in the five insulin categories are concordant with the prediction of the oxygen models of hyperinsulinism and Type 2 diabetes.  Second, large increases in insulin concentrations are accompanied with small increments in blood glucose levels, and  point to the primacy of insulin receptor dysfunction over beta cell alterations in the pathogenesis of hyperinsulinism. Third, the survey findings are concordant with the observations made in studies of insulin responses to carbohydrate and non-carbohydrate challenges.23

Fourth, high blood levels of insulin in the 3-hour sample (Table 5 and 8) may be seen as pointing to the result of beta cell dysfunction –  “beta cell gas pedal failure”, so to speak. However, such high levels in 3-hr samples were uncommon in this survey, the highest 3-hr level of 571.7 uIU/mL  being preceded by 718 uIU/mL (Table 8).

Some cost concerns are anticipated in any discourse on the proposed shift from focus on glycemic status to insulin homeostasis. Results of this survey clearly define the magnitude of the human suffering, including that of the unborn in the case of gestational diabetes, and the expected financial burdens of undetected and untreated hyperinsulinism and diabetes Type 2. However, no data are available on the exact cost of neglected issues of insulin homeostasis.  One aspect of this problem was highlighted by The New York Times on February 27, 2016 with the following words: “Ads for the condition [diabetes Type 2] have increased 200 percent in the last three years… though older, cheaper drugs are effective for most people — the ads have promoted an array of new injections and pills, including Toujeo (insulin glargine), Farxiga (dapagliflozin), and Victoza (liraglutide)  (each of which costs between $500 and $700 per month).” Not unexpectedly, none of the drug ads included any reference to the crucial underlying issues of disturbed insulin homeostasis.

We recognize one limitation of this study: multiplicity of clinico-pathologic entities among many survey subjects and the coexistence of multiple entities in the same individuals is wide, and precludes delineation of relationships between specific diseases and varying degrees of hyperinsulinism.


SUMMARY

 From an analysis of 684 pairs of fasting post-glucose-challenge three-hour insulin and glucose profiles in diverse clinical settings, the following conclusions are drawn: (1) Since hyperinsulinism predates Type 2 diabetes, direct insulin profiling for individual patients is necessary since tests for glycemic status (blood sugar levels and A1c)  allow assessment of insulin homeostasis only indirectly; (2) stratification of hyperinsulinism provides precise and modifiable markers for hyperinsulinism modification and for preventing Type 2 diabetes; (3) laboratory reference ranges of insulin levels in use presently at New York metropolitan laboratories are far too wide and variable to be clinically useful for the detection and management of hyperinsulinism; (4) insulin profiling can be suitably modified for specific patient populations, if necessary, for hyperinsulinism modification and reversal of hyperinsulinism and Type 2 diabetes24; and (5) the tabular format of insulin profiles offers the advantages of simplicity and clarity for patient education and  improved patient compliance.

The view of hyperinsulinism as a definable and modifiable entity presented here needs to be seen within the broader context of: (1) disturbing prevalence of prediabetes and diabetes in most populous countries of the world; (2) increasing urbanization and access to energy-dense foods that are driving a global dietary transition from traditional diets to diets with abundance of packaged foods, processed grains, sugars, modified fats, and meats;25 (3) incremental pollution (80% of water of Chinese flatlands was reported to be unfit for drinking by the New York Times on April 12, 2016), for example); and (4) the expected consequences of this transition which are fueling globalization of diabetes.26 

References

  1. Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310: 948-59.
  2. International Diabetes Federation. Diabetes Atlas. 2016. Seventh edition. www.diabetesatlas.org.
  3. Kahn SE, 1, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444, 840-846.
  4. Pascual G, Fong A, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-y. Nature. 2005;437:759–763.
  5. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116 :1793B1801.
  6. Shulman G. Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease. N Engl J Med. 2014; 371:1131‑1141.
  7. Ali M. Epidemic of Dysoxygenosis and the Metabolic Syndrome. In: The Principles and Practice of Integrative Medicine. Volume 5. Pp 246-256. Canary 21 Press. New York. 2005.
  8. Quan Yi. Current understanding of KATP channel s in neonatal disease. Focus on insulin secretion disorders. Acta Pharmacologica Sinico.2011. 32:765-7780.
  9. Ali M. Insulin Laboratory Ranges. https://alidiabetes.org/2016/02/25/insulin-laboratory-ranges/
  10. Ali. M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004;253:64-65.
  11. Chouchani ET, Victoria R. Pell VR, Edoardo Gaude E, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014; 515:431–435.
  12. Ali M. Succinate Retention. In: Chouchani ET, Victoria R. Pell VR, Edoardo Gaude E, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515:431–435. Data after references).
  13. Ali M. Dr. Ali’s Dysox Model of Diabetes and De-Diabetization Potential. Townsend Letter-The examiner of Alternative Medicine. 2007; 286:137-145.
  14. Ali M. Oxygen, Insulin Toxicity, Inflammation, And  the Clinical Benefits of Chelation. Part I. Townsend Letter-The examiner of Alternative Medicine. 2009;315:105-109. October, 2009.
  15. Nishimoto S, Fukuda D, Higashikuni Y, et al.  Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance. Sci Adv. 2016;25:2.
  16. Ali M.Importance of Subtyping Diabetes Type 2 Into Diabetes Type 2A and Diabetes Type 2B. Townsend Letter-The Examiner of Alternative Medicine. 2014; 369:56-58.
  17. Stanley SA, Kelly L, Kaasmashri N, et al. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Nature 531, 647–650.
  18. Ali M. Importance of Subtyping Diabetes Type 2 Into Diabetes Type 2A and Diabetes Type 2B. Townsend Letter-The Examiner of Alternative Medicine. 2014; 369:56-58.
  19. Grocott M, Richardson A, Montgomery H, et a. Caudwell Xtreme Everest: a field study of human adaptation to hypoxia. Critical care 2007;11:151.
  20. Kamada N, Seo S-U, Zhiming C, et al. Role of the gut microbiota in immunity and inflammatory disease. Nature Reviews Immunology. 2013;12:321-335.
  21. Qin J, Li Y, Zhiming C, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012; 490:55-60.
  22. Ali M. Dr. Ali’s Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.
  23. Ali M. Dasoju S, Karim N, Amin J, Chaudary D. Study of Responses to Carbohydrates and Non-carbohydrate Challenges In Insulin-Based Care of Metabolic Disorders.Townsend Letter-The Examiner of Alternative Medicine. 2016; 391:48-51.
  24. Ali M. Dr. Ali’s Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.
  25. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very-Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiologic Changes in Responders and Nonresponders. Diabetes Care. 2016 Mar 21. pii: dc151942.
  26. Tilman D, Clark M. Global diets link environmental sustainability and human health. Nature. 2014;515, 518B522.
  27. Hu, F. B. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 2011; 34:1249B1257.

 

END


Do You Know Your Diabetes 2 Subtypes?

Majid Ali, M.D.

Diabetes Type 2A and Diabetes Type 2B Are Two Different Problems and Need to be Managed Differently. 


 

Importance of Subtyping Diabetes Type 2

Into Diabetes Type 2A and Diabetes Type 2 B

(First published in Townsend Letter in April 2014)


 

In a previous column, I presented The Oxygen Model of Diabetes and the Crank-Crankshaft Model of Insulin Dysfunction.1 In my book entitled “Dr. Ali’s Plan for Reversing Diabetes,”I presented several insulin profiles and illustrated two subtypes of diabetes Type 2: diabetes Type 2A and diabetes Type 2B. Simply stated, diabetes Type 2A is a state of insulin toxicity created by insulin resistance and hyperinsulinism whereas diabetes Type 2B is an insulin-depletion state. In this article, I focus on the importance of subtyping diabetes type 2 and offer seven reasons for doing so, underscoring the profound clinical significance of the differences between the two subtypes.

In Tables 1-3, I present insulin and glucose profiles of three patients: (1) an individual in physiological insulin-glucose homeostasis; (2) a patient with diabetes Type 2A; and (3) a patient with diabetes Type 2B. Comparison of insulin profiles in Tables 2 and 3 illustrate the essential difference between the two subtypes. Later in this article, I present additional insulin and glucose profiles (Tables 4 and 5) to illustrate how diabetes Type 2A and Type 2B can be expected to respond to effective integrative de-diabetization management plans (outlined in a previous column and described at length in my book cited above).

Table 1. Insulin and Glucose Profiles of a 77-Yr-Old Metabolically Fit 5′ 5″ Man Weighing 133 Lbs. He Was Seen for Allergy Treatment.

6.23.2010

Fasting

1 Hr

2 Hr

3 Hr

Insulin

<2

24

29

30

Glucose

78

96

75

71

Table 2. Diabetes Type 2A. Insulin and Glucose Profiles of a 50-Yr-Old Man With Neuropathy and Prehypertension.

11.26.2012

Fasting

1 Hr

2 Hr

3 Hr

Insulin

13.2

73.0

178.7

56.4

Glucose

137

246

275

191

Table 3. Diabetes Type 2B. Insulin and Glucose Profiles of a 60-year-old 5′ 10″ Man Weighing 146 lbs With Hypertension, GERD, Recurrent Sinusitis

3.29.2010

Fasting

1 Hr

2 Hr

3 Hr

4 Hr

Insulin

<2

4

10

3

2

Glucose

104

300

166

62

69

Reasons for Subtyping Diabetes Type2

Diabetes Type 2A with insulin excess and diabetes Type 2B with insulin-depletion arequite different in their:

1. Basic natures of the disorder

2. Treatment goals of the disorder

3. Explanations of the disorder for the patient

4. Laboratory Tests for assessing treatment effectiveness

5, Expected duration of treatment for de-diabetization

6. Consequences of making exceptions in the dietary plans

7. Re-thinking insulin-dependent diabetes


1. Basic Nature of the Disorder

All clinical and pathological features in diabetes Type 2A are caused by the two primary lesions of insulin resistance and hyperinsulinemia. By contrast, metabolic derangements in diabetes Type 2B are caused by insulin deficit.

2. Treatment Goals for Diabetes Subtypes A and B

The primary treatment goal in diabetes Subtypes A and B is fundamentally different. The goal in subtype A is to restore insulin’s metabolic and energetic roles, and consequently lower its blood level. The primary treatment goal in diabetes Subtype B is exactly opposite of that: create islet cell conditions so insulin production can be resumed, as has been documented in experimental animal studies.

3. Explanations of the Disorder for the Patient

A core requirement for success in integrative medicine is to recruit the patient in her/his treatment plan for assuring strong compliance. This, of course, mandates that the patient not only be very well-informed but clear-eyed about the management plan. In my clinical work, I take time to explain that diabetes cannot be reversed, nor its complications prevented by focusing on blood sugar levels. These goals are only possible by focusing on insulin dynamics and precise insulin measurements.

4. Laboratory Tests for Assessing Treatment Effectiveness

I assess the effectiveness of my integrative plan with the following “Three-Step-Insulin-Testing” approach:

A. A 3-hour insulin and glucose profile following a standard glucose load before beginning the program

B. Fasting and one-hour post protein and fat food load insulin and glucose profile (a protein powder, lecithin, ground flaxseed, and organic vegetable juice are used for this purpose). Please Google “Dr. Ali’s Breakfast” for details.

C. A 3-hour insulin and glucose profile following a standard glucose load one year after beginning the program.

The profiles obtained in step provides the patient the best indication of how her/his insulin response changes with an all protein and fat food load . The comparative study of the profiles in A and C categories provides a clear indication of the degree of “insulin optimizing” over a period of one year.

5. Expected Duration of Treatment for De-diabetization

Creating microecologic conditions for pancreatic regeneration in diabetes 2B requires a strong commitment both for the patient and the physician. A high level of patient compliance is needed long periods of time (several months or longer) for the reasons given above. The required program for addressing toxicities of foods, environment, and thoughts is much more demanding in diabetes 2B than in diabetes 2A. Lowering blood insulin levels by improving insulin receptor function (by “de-greasing the cell membrane”) using dietary and detox measures can be achieved in most patients with diabetes 2A within some months.

6. Consequences of Making Exceptions in the Dietary Plans

Individuals on integrative de-debiatizing plans cannot always avoid making exceptions in their dietary and detox program. It follows from points made in item 5 that such exceptions (wrong food choices, missed supplements, neglected detox measures, and others) will exact a larger toll from patients with in diabetes 2B than on those with diabetes 2A. So this crucial aspect of recovery must be clearly understood by them.

7. Re-thinking Insulin-dependent Diabetes

The prevailing opinion among diabetologists and endocrinologists worldwide is that individuals with so-called insulin-dependent diabetes require insulin treatment for rest of their lives. This is unfortunate. In many such cases the use of insulin can be safely discontinued. In Table 5, I present data that supports my position.


Normalizing Insulin Homeostasis By Freeing Up Insulin Receptor

In my book on reversing diabetes,2 I established that hyperinsulinemia is the result of insulin receptor dysfunction. The insulin receptor is a protein that criss-crosses the cell membrane like a cord, with one end protruding to the exterior and the other to the interior of the cell. In a previous publications 1-3, I offered the analogy of a crank and a crank-shaft to explain insulin resistance and hyperinsulinemia. In this analogy, insulin is visualized as a cranka device that transmits rotary motionand the insulin receptor protein as a crank-shaft embedded in the cell membrane. The cell membranes become resistant to insulin action when they become greased and chemicalizedplasticized, so to speakand hardened, immobilizing the insulin receptors embedded in the membranes. I introduced the term cellular grease for accumulation of oxidized lipids, misfolded proteins, altered sugars, molecular debris, and cellular waste caused by toxicities of foods, environment, and thought. One of the consequences of grease buildup on cell membranes is that insulin receptor becomes turned and twisted, literally and figuratively. The crank/crank-shaft model of insulin receptor dysfunction is based on my Oxygen Model of Inflammation and is supported by a large number of studies linking inflammation with peripheral insulin resistance.5-9

The goal in my de-diabetization plan is to de-grease the cell membranes, free up the insulin receptors, restore insulin function, and so correct hyperinsulinemia.

Case Study 1

A 55-year-old 5’5″ woman weighing 234 lbs. consulted me for fibromyalgia, hypothyroidism, allergy, and Pruritis. Her previous doctors had neither performed tests for glucose intolerance nor for hyperinsulinemia. Table 4 shows her insulin and glucose profiles at the time of initial evaluation.

I implemented my previously described1,3 integrative program for restoring insulin and glucose homeostasis (for more details, please consider my three-part video seminar entitled ” Reversing Diabetes” downloadable from http://www.aliacademy.org). The follow-up insulin and glucose profiles performed after 20 months of implementing the program showed a lowering of one-hour blood insulin level from 107 to 44 uIU and a fall in the one-hour glucose value from 198 mg/dL to 171 mg/dL. So, where a pretreatment insulin level of 107 uIU was needed to keep blood glucose level to 198, after the treatment only 44 uIU were required to drop the glucose level to 171 mg/dL, a clear evidence of much improved insulin efficiency.

Table 4. Normalizing Insulin Homeostasis By Freeing Up Insulin Receptor of 55-year-old 5’5″ Woman Weighing 234 lbs. (Case Study 1).

3.11.2010

Fasting

1 Hr

2 Hr

3 Hr

Insulin

13

107

85

17

Glucose

110

198

137

56

12.21.2011

Insulin

10

44

Not done

Not done

Glucose

109

171

Not done

Not done

Beta Cell Regeneration and Increased Insulin Production in Diabetes Type 2B

Type 1 diabetes results from destruction of the pancreatic ß cells by ß cell–specific autoimmune responses.5-10 In experimental models of diabetes Type 1, in-vivo expansion of the ß-cell mass and consequent restoration of normoglycemia has been reported. Betacellulin is one beta-specific growth factors which induces ß-cell growth and differentiation.11-13 Application of this knowledge to human diabetes Type 1 is problematic for three main reasons: (1) it is difficult to produce and sustain sufficient numbers of ß cells for sustained normoglycemia; (2) newly formed ß cells are vulnerable to autoimmune attack which cause the disease in the first place; and (3) compliance to the pancreas regeneration program is not as big an issues in mice as it is for men (and women) .

Case Study 2

A 51-yr-old 5’9″ man weighing 167 lbs. was treated with Metformin for one year before consulting me. He discontinued Metformin within six months of our program. His subsequent A1c values ranged between 5.5% and 5.8%, indicating healthful insulin and glucose homeostasis. Table 5 shows increased insulin production in his case. His subsequent A1c values ranged between 5.5% and 5.8%, indicating healthful insulin and glucose homeostasis.

Table 5. Increased Insulin Production Due to Beta Cell Regeneration In Diabetes Type 2B. The subject Is a 51-yr-old Man Who Received Metformin for About Two Years Before Implementing the De-diabetization Plan. After Discontinuing Metformin Within 6 Months, His A1c Values Ranged Between 5.5% and 5.8%.

9.17..2011

Fasting

1 Hr

2 Hr

3 Hr

A1c

Insulin uIU

3

13

23

8

7.9

Glucose

130

246

229

125

 

4.7.2012

Insulin

8.8

24.2

38.2

 

6.5%

Glucose

137

241

182

   

9.26.2012

Insulin

10.9

29.6

42.6

19.4

6.6

Glucose

92

162

131

62

76

I anticipate the question: Doesn’t his April 7, 2012 glucose profile show that he is still diabetic? The issue of the differences in blood sugar responses to the sudden and large glucose load (glucola for testing) and “insulin-friendly” meals14,15 is important. His low A1c values (between 5.5% and 5.8% point to improved glucose tolerance. It can be reasonably expect that response to glucola-like load will also improve with time as insulin homeostasis improves further.

References

1. Ali M.The Dysox Model of Diabetes and De-Diabetization Potential. Townsend Letter-The examiner of Alternative Medicine. 2007; 286:137-145.

2. 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.

3. Ali M. Oxygen, Darwin’s Drones, and Diabetes. Volume 1—Dr. Ali’s Plan for Reversing Diabetes. 2011. New York, Canary 21 Press.

4Ali M. Oxygen governs the inflammatory response and adjudicates the man-microbe conflicts. Townsend Letter for Doctors and Patients. 2005;262:98-103.

5 1.Rabinovitch, A (2004). Roles of cell-mediated immunity and cytokines in the pathogenesis of type 1 diabetes mellitus. In:LeRoith, D, Olefsky, JM and Taylor, SI (eds.). Diabetes Mellitus: A Fundamental and Clinical Text,Lippincott Williams & Wilkins: Philadelphia, PA. pp. 519–538.

6. Nakayama M, Norio Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005; 435, 220-223.

7 Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature. 2005;435:224-228.

8. von Herrath M. Insulin trigger for diabetes. Nature. 2005;435:151-152.

9. Eisenbarth, G. S. et al. Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes. Autoimmun. Rev. 2002;1:139-145.

10. Eisenbarth, G. S. et al. Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes. Autoimmun. Rev. 2002;1:139-145.

11. Shin S, Na Li1, Kobayashi N, et al. Remission of Diabetes by ß-Cell Regeneration in Diabetic Mice Treated With a Recombinant Adenovirus Expressing Betacellulin. Jun1,3 Molecular Therapy (2008); 16 5 854–861.

12. Chen S, Ding, J, Yu, C, et al. Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1. Gene Therapy. 2007;14:1102–1110.

13. Liu M, Shin S, Li N, et al. Prolonged Remission of Diabetes by Regeneration of ß Cells in Diabetic Mice Treated with Recombinant Adenoviral Vector Expressing Glucagon-like Peptide-1 free. Molecular Therapy15, 86-93 .

14. Dr. Ali’s Insulin Diet. http://majidalimd.wordpress.com/2012/11/17/dr-alis-insulin-diet/

15. Oxygen, Insulin Waste, and Insulin Depletion/

http://www.ethicsinmedicine.us/oxygen,_insulin_waste,_and_insulin_depletion.htm

 

Primacy of Insulin Homeostasis Over Glycemic Status

https://wordpress.com/post/alidiabetes.org/711Majid Ali, M.D.

Supplemental Information for a Shift From Glyemic Status to Insulin Homeostasis


 

  1. Evidence for Oxygen Models of Hyperinsulinism and Diabetes Type 2
  2. Inappropropriate Laboratory Insulin References
  3. Pregnancy-Related Insulin Toxicity
  4. Importance of Subtyping Diabetes Type 2 Into Diabetes Type 2 Subtype A and Diabetes Type 2 Subtype B

 

 

 

The Oxygen Model of Insulin Toxicity

Majid Ali, M.D.

A Course on Hyperinsulinism


Hyperinsulinism is a state of excess insulin activity in the body as determined by raised blood insulin levels (hyperinsulinemia). measured by in which cells are resistant to actions of insulin. The blood insulin levels rise when the pancreas gland releases increasing amounts of insulin to overcome the resistance of cells to the action of insulin hormone. To explain the primary metabolic role of insulin hormone on cells, in 2000 I proposed a crank-crank-shaft analogy in insulin is visualized as a crank—a device that transmits rotary motion—and the insulin receptor protein as a crank-shaft embedded in the cell membrane.

The cell membranes become resistant to insulin when they become chemicalized—plasticized, so to speak, by toxicities of foods, environment, and thoughts (disappointments, chronic anger, and mental health issues) —and hardened. Cell membrane plasticization immobilizes insulin receptors embedded in the membranes. The insulin receptor is a protein that criss-crosses the cell membrane like a cord. One of the consequences of grease buildup on cell membranes is that insulin receptor becomes turned and twisted, literally and figuratively. In a previous paper, I offered the analogy of a crank and a crank-shaft to explain insulin resistance. I visualize insulin as a crank—a device that transmits rotary motion—and the insulin receptor protein as a crank-shaft embedded in the cell membrane.


The insulin resistance can then be seen as a “rusted” crank-shaft of insulin receptor which is impacted in a hardened cell membrane, and so cannot turn the insulin crank. Insulin cannot function well when cell membranes are greased, matrix is gummed, and mitochondria are gutted—conditions created by disturbances in oxygen function. The pancreas tries to compensate for it by over-producing insulin. The greater the production of insulin, the thicker the grease buildup and deeper the problem of insulin resistance.


My Oxygen Model of Hyperinsulinism is an extension of my Oxygen Model of Health and Disease. It is a unifying model that explains all aspects of insulin resistance—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 Hyperinsulinism 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 hyperinsulinism .

  • The crucial importance of the Unifying Oxygen Model of Hyperinsulinism is that it:
  • Explains the scientific basis of hyperinsulinism in the body;
  • Sheds light how altered insulin functions can be restored by addressing all oxygen-related issues;
  • Elucidates how toxicities of foods, environments, and thoughts cause buildup of cellular grease on cell membrane and lead to insulin resistance; and
  • Reveals the mechanisms by which various detox therapies work in freeing up insulin receptors and restoring insulin function.

Since hyperinsulinism and insulin resistance are essentially two terms for the same insulin disorder, my Oxygen Models of Hyperinsulinism and Insulin Resistance are the same.

It is important to recognize in this context that oxygen is the primal detergent which removes cellular grease and allows cells to breathe freely.

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