Two Dimensions of Insulin Dysregulation

Majid Ali, M.D., FRCS (Eng), FCAP (Path)

Type 2 Diabetes (TD2) Is Rooted In the First Dimension of Insulin Dysregulation. Type 2 diabetes does not occur when the first dimension of insulin dysregulation is detected and reversed.


SPECIAL NOTES

Treatment plans for reversing prediabetes (hyperinsulinism) and diabetes are presented at this site under the titles of

Reversing Prediabetes and Diabetes With 3D Plan 

 Links to important related articles are included at the end of this article.


Two Dimensions of Insulin Dysregulation

The author recognizes two primary dimensions of insulin dysregulation: (1) the first dimension is of excess insulin accompanied by a multitude of adverse effects of hyperinsulinism without associated glycemic disruptions characteristic of Type 2 diabetes; and (2) the second dimension of excess insulin accompanied by glycemic disruptions that meet the numerical criteria of Type 2 diabetes (T2D). The first dimension is rooted in the toxicities of food, environment and thought, while the second dimension is rooted in the first dimension. The first dimension is optimally detected by measuring timed blood insulin concentrations following an oral glucose load as shown in Tables used for case studies. The core message of this short article is this: If the first dimension of insulin dysregulation can be reversed, the problem of the second dimension (T2D) simply does not arise.


The Oxygen-Insulin View of Insulin Dysfunction, Diabetes Type 2, and Reversing Diabetes 3D

Oxygen is the organizing principal of biology and governs the aging process. The author began his book Oxygen and Aging (2000) with those words. This simple statement was the essence of his interest and study of molecular biology of oxygen for twenty years.1-4 His interest in molecular biology of insulin5-8 arose from his work in oxygen. The “oxygen-insulin perspective” of the two dimensions of insulin dysfunction and its scientific underpinnings was comprehensively discussed in his book entitled Dr. Ali’s Plan for Reversing Diabetes (2011)9 as well as in a series of follow-up publications.10-18

Life is an injury-repair-injury cycle. Cellular injury is intertwined with cellular repair by diverse mechanisms. Patterns of repair change with varying types of injury and the prevailing tissue condition. The constant in all this is expanded energy requirement of cells in the repair processes. Whether cellular repair is in acne or psoriasis, in polycystic ovarian syndrome in young women or recurrent prostatitis in young men, in chronic GERD-gastritis complex or Crohn’s colitis, inflammatory arthritis or pulmonary interstitial fibrosis, steatosis of the liver or chronic renal failure, systemic lupus erythematosus (see illustrative case study in Table 4) or scleroderma, the core requisite of cellular repair is the same: increased energy demands. Hyperinsulinism, in this context, is pancreatic response to increased energy needs for repair of injured tissues. The author has documented the presence of the first dimension of insulin dysregulation in all of the above-mentioned pathologic entities.


 

Three Crucial Aspects of Two Dimensions of Insuloin Dysregulation

From a clinical standpoint, three other aspects of the two dimensions of insulin dysfunction are:

  1. Epigenetics play greater roles than genetics in both dimensions;
  2. Understanding the pathophysiology, clinical courses, and optimal management of both dimensions of insulin dysregulation calls for a shift of focus from glycemic status to insulin homeostasis;
  3. Since first dimension is not accompanied by glycemic disruptions, the lab tests for glycemic status (fasting and 2-hour postprandial blood sugar levels, and A1c test) are not suitable in the detection and reversal of the first dimension.

 

Neglect of the First Dimension Deepens the Suffering of the Second Dimension

The data in Tables 1 and 2 summarizes the core statistical relationships between the two dimensions of insulin dysfunction. The two columns presenting mean peaks of blood glucose and post-glucose-load insulin concentrations in Table 1 dramatically document how far the prevailing practices of neglecting the first dimension go to deepening the problems caused by the second dimension.

Table 1. Insulin Homeostasis Categories in 506 Study Subjects Without Type 2 Diabetes

Insulin Category* Percentage of Subgroup Mean Peak Glucose mg/dL(mmol/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, with fasting insulin concentration of <2 uIU/mL and mean peak insulin concentration of <20; (2) optimal insulin homeostasis, peak insulin <40 accompanied by unimpaired glucose tolerance; (3) mild hyperinsulinism, peak insulin <80 accompanied by unimpaired glucose tolerance; (4) moderate hyperinsulinism, peak insulin <160 accompanied by unimpaired glucose tolerance; (5) severe hyperinsulinism, peak insulin <160 accompanied by unimpaired glucose tolerance.

** Exceptional insulin homeostasis, a subgroup of optimal insulin homeostasis.


 

Table 2 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)
Diabetic Hyperinsulinism, Mild       N =   53
29.0% 252.0   (14.00) 55.4
Diabetic Hyperinsulinism, Moderat N = 42
24.0% 242.1   (13.45) 112.4
Diabetic Hyperinsulinism, Seve       N =   24
13.9% 224.6   (12.47) 298.0
Diabetic Insulin Deficit                     N = 59
33.1% 294.0   (16.33) 22.9

 

Neglect of the First Dimension By Laboratory Professionals

 The neglect of first dimension by the laboratory professionals is one of the most disturbing aspects of the sordid story of the two dimensions of insulin dysregulation. For instance, the reference range for the 2-hr post challenge blood insulin concentration of laboratory 2 (Table 3) is an astonishingly and utterly clinically unusable 0.0 to 163.5.

Table 3. 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 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.


 

Mechanisms of Insulin Regulation and Two Dimensions of Insulin Dysregulation

 The following is text on the subject from the author’s comments e-published in June, 2017 by the journal Nature. “The work of Zhang and colleagues is important for physicians who treat diabetes because class B G- protein-coupled receptors (GPCRs) are important therapeutic targets. Beyond that, this work invites all physicians to a deeper study of the inner mechanisms of insulin homeostasis, a subject that is seldom duly considered in clinical medicine. Specifically, insulin dysregulation has two distinct dimensions: (1) the first dimension of pathophysiology of hyperinsulinism which predates Type 2 diabetes (T2D) and is not accompanied by glycemic abnormalities detectable by the laboratory tests in current use; and (2) the dimension of T2D accompanied by hyperglycemia and its biochemical consequences. This author has long recognized the need for a shift of clinical focus from glycemic status to insulin homeostasis for detecting and optimally managing adverse metabolic, proinflammatory, endothelial, developmental, and neurologic effects of hyperinsulinism (ref. 2-6).”

Table 4. Severe Hyperinsulinism In A 13-Yr-Old With SLE, ITP, Recurrent Pneumonia, and Optic Neuritis With Right Eye Blindness.

The Peak Insulin Fell from 718 to 238.5 In Four Months of Robust Integrative Treatment.

Fasting ½ Hr 1Hr 2Hr 3Hr
Insulin uIU/mL
27.9 362.5 424.0 718.2 571.7
Glucose mg/mL
      70 140 157 150 111
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
81 154 181 130 97
 

Table 5. Control of Hyperinsulinism With Reversal of Type 2 Diabetes In A 75-Yr-Old 5’ 2” Female Weighing 162 Lbs. With Hypertension and Chronic Sinusitis.

4.30.2013 Fasting ½ hr 1 hr 2 Hr 3 Hr
Insulin uIU/mL
16 37 59 113 152
Glucose mg/mL (mmol/L)
112 158 214 241 155
10.17.2014*
Insulin uIU/mL
23.8 19.3 36.9 114.7 75.2
Glucose mg/mL (mmol/L)
116 167 253 297 172
4.14.2015**
Insulin uIU/mL
6.2 22.1 42.9 51.2 39.7
Glucose mg/mL /L)
96 130 193 112 105

* A1c, 6.3%; ** A1c, 5.9%

 

Reversing Prediabetes (Hyperinsulinism) and Diabetes With 3D Plan

The insulin homeostasis protocol (the “Protocol”) evolved as a three-prong approach comprising: (1) diet; (2) detox; and (3) dysoxic comorbidities (oxygen-related coexisting pathologic entities) including disrupted hypothalamic and related neural pathways which regulate the energy economy of the body. The three “diabetes 3D” subjects are vast and clearly beyond the scope of this brief outline. A comprehensive discussion of all above subjects is presented at free access www.alidiabetes.org. Google search words are: majid ali, shifting focus from glycemic status to insulin homeostasis.


 

References

1.   Ali. M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit Disorders. Townsend Letter for Doctors and Patients. 2004.

2.   Ali M. Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine. 1999;3:11-16.

3.   Darwin, Dysox, and Disease. Volume 11. The Principles and Practice of Integrative Medicine 11. New York: Canary 21 Press; 2002.

4.   Ali M. The Principles and Practice of Integrative Medicine Volume I: Nature’s Preoccupation With Complementarity and Contrariety. New York. Canary 21 Press. 1998. 2nd edition 2005.

5.   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.

6.   Ali M. Insulin Toxicity, Inflammation, And  the Clinical Benefits of Chelation. Part I. Townsend Letter-The examiner of Alternative Medicine. 2009;315:105-109. October, 2009.

7.   Ali M. Hypothesis: obesity is adipomyocytic dysoxygenosis. J Integrative Medicine. 2004;9:19-38.

8.   Kahn SE, 1, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444, 840-846.

9.   Shoelson, SE, Lee J. Goldfine AB. Inflammation and insulin resistance. J. Clin. Invest. 2006;116: 1793–1801.
2

10.                  Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854-859.

11.                 .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.

12.                 International Diabetes Federation. Diabetes Atlas. 2016. Seventh edition. www.diabetesatlas.org.

13.                 Shulman G. Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease. N Engl J Med. 2014; 371:1131‑1141.

14.                 Bahi-Buisson N, Roze E, Dionisi C, et al. Neurological aspects of hyperinsulinism-hyperammonaemia syndrome. Dev Med Child Neurol. 2008;50:945-9.

15.                Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependant diabetes mellitus: Prospective studies of Pima Indians. N Engl J Med. 1993;329:1988-1992.

16.                Ali M. Oxygen and Aging. (Ist ed.) New York, Canary 21 Press. Aging Healthfully Book 2000.

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

18.                Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J. Clin. Invest. 2005;115:1111–1119.

19.                 Ali M. Fayemy AO, Ali O. Dasoju S, et al. Shifting Focus From Glycemic Status to Insulin Homeostasis. .  Townsend Letter-The Examiner of Alternative Medicine. 2017;402:91-96.

20.                 Ali M. The Principles and Practice of Integrative Medicine Volume X: Darwin, Oxygen Homeostasis, and Oxystatic Therapies. 3 rd. Edi. (2009) New York. Institute of Integrative Medicine Press.

21.                 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.

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

23. Ali M. The Philosophy and Science of Healing. APPNA Journal. 2015;25:18-19.

24.                Nath D, Heemels M-T, Lesley Anson L Obesity and diabetes. Nature. 2006;444, 839.

25.                Das S. Identity of Lean-NIDDM: Clinical, metabolic and hormonal status. In: Kochupillai N, ed. Advances in Endocrinology, Metabolism, and Diabetes. Vol. 2. Delhi, India: Macmillian; 1994:42-53.

26.                 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J. Clin. Invest. 2005;115:1111–1119.

27.                Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466-8471.

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

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

30.                Xu H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 2003;112:1821–1830.

31.                 Stanley SA, Kelly L, Kaasmashri N, et al. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism. Nature. 2016  531:647–650.

32.                Ali M. Autism. Nature

33.                Ali M. Ali M. Molecular basis of autism and dysautonomia. Townsend Letter-The examiner of Alternative Medicine. 2017 (in press).

34.                Ali M. Lab ranges www.alidiabetes.org

35.                 Kaveeshwar SA, Cornwell J. The current state of diabetes mellitus in India. Australas Med J. 2014;7:45-48.

36.                 Lesley J, Manning LA, Ogle GD. A survey of diabetes services in hospitals in Ali Papua New Guinea. P N G Med J. 2001: 44:88-95.))

37.                 Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA. 2013; 310: 948-59.

38.                 Ali M.  Oxygen model of hyperinsulinism.  xxxx

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

40.                 Ali M. Plan for Reversing Diabetes. New York, Canary 21 Press. Aging Healthfully Book 2011.

41.                 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.

42.                 Chouchani ET, Victoria R. Pell VR, Edoardo Gaude E, et. al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435.

43.                 Ali M. Succinate Retention. In: Chouchani ET. Pel VR,  Gaude E, et al.Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature;2014;515:431. (commentary after references).

44.                 185. Ali M. Succinate Retention: The Core Krebs Dysfunction in Immune-Inflammatory Disorders. Townsend Letter. 2015;388:84-85.  

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s