Category Archives: Dr. Ali’s Basic Insulin Toxicity and Diabetes Course

Beyond insulin resistance and syndrome X:

Majid Ali, M.D.

Oxidative – Dysoxygenative Model

of Insulin Toxicity and DiabetesHomeostasis (2001)


 

Beyond insulin resistance and syndrome X: tThe oxidative-dysoxygenative insulin dysfunction (ODID) modelof Insulin Toxicity--Part II. 

Nitric Oxide Dynamics and ODID

Reactive oxygen species (ROS) induce production of reactive nitrogen species (RNS). RNS, in turn, stimulate the generation of reactive oxygen species. The feedback loops provided by ROS-RNS dynamics feed the oxidative fires and inflict oxidative cellular injury. Under physiologic conditions, superoxide dismutase, catalase, glutathione peroxidase, and a host of enzymes support the reduction arm of redox equilibrium. In hyperinsulinemic and hyperglycemic states, the ROS/RNS loops significantly add to cumulative oxidosis. (158-160)

Endothelium-derived nitric oxide exerts several homeostatic effects in the vascular ecology, including regulation of vasomotor tone, inhibition of platelet aggregation, and prevention of adhesion of leukocytes to the endothelial surface (Vane 1990). In animal models as well as in both type 1 and type 2 diabetes, nitric oxide-dependent vasodilation is impaired. (158) Ascorbic acid improved the vasodilatory response in both types of diabetes. (29,30) Endothelium-dependent vasodilation is impaired in healthy subjects after six hours of hyperglycemic clamp. (159) Studies with incremental brachial artery administration of methacholine chloride during euglycemia and hyperglycemia support one of the core tenets of oxidative insulin dysfunction in that hyperglycemia contributes to abnormal endothelial function through production of superoxide anion. (37)

Higher concentrations of insulin in the blood increase blood flow to the skeletal muscle. (164-170) Some of the increase in the cellular glucose uptake has been attributed to that effect of insulin on the blood flow. The precise mechanism of action of insulin in blood vessel musculature has not been elucidated, but the role of nitric oxide in it has been postulated. (167) Other data suggest that the vasodilatory effect in the skeletal muscle is dependent on hyperinsulinemia and not consequent upon changes in carbohydrate metabolism. There is also evidence there is a reduction in insulin-induced vasodilation in insulin resistance associated with obesity. (165,169,170) in other words, insulin facilitates its own delivery to the cell membrane and degradation.

Activation of endothelial NO-synthase in higher concentration is deemed necessary for initiation of the oxidative cascade in endothelial cells that leads to production of excess reactive oxygen species and induction of NF-[kappa]B.

Tumor Necrosis Factor (TNF-[alpha]) and ODID

The secretion of TNT-[alpha] by adipocytes is of special interest to me in the context of the proposed oxidative insulin dysfunction model

of insulin resistance and type 2 diabetes. This cytokine plays many well-established and crucial roles in the inflammatory and immune responses. (94,171-176) It is expressed in excess in adipocytes of obese patients and is known to cause insulin resistance through its effects on insulin-mediated cellular signaling pathways.

Tumor necrosis factor [alpha] (TNF-[alpha]) is a potent inhibitor of insulin signaling in myocytes and adipocytes. (174) Since serum concentrations of TNF-[alpha] are very low in lean as well as obese subjects, this cytokine produced in the muscle and fat cells appears to function in a paracrine fashion. TNT-[alpha] expression is high in the muscle and fat cells of obese and diabetic subjects. Furthermore, the administration of antibodies that neutralize TNF-[alpha] to genetically obese Zucker (fa/fa) rats reverses insulin resistance. (171) That creates another mechanism of insulin resistance in mice. Interestingly, administration of the same antibodies to diabetic patients did not reverse insulin resistance. (175)

All known inflammatory and immunologic responses are initially triggered as well as regulated by oxidative and oxygenative phenomena. (173-175) Blockade of TNF-[alpha] can ameliorate, albeit for limited periods of time, both experimental and clinical forms of antoimmune disorders, such as Crohn's colitis and rheumateid arthritis. (177-180) Hypersecretory TNF-[alpha] responses induced by oxidative stresses are likely to play a role in insulin homeostasis in states of oxidosis associated with hyperinsulinism.

NF-[kappa]B, Endothelial Cells, and ODID

NT-[kappa]B is a potent proinflammatory molecule. (181-133) Blockade of NF-[kappa]B decreases inflammatory responses in experimental and such as Crohn's colitis and rheumatoid arthritis. (184-186) All inflammatory responses create regional oxidosis and most also lead to systemic oxidosis. Such theoretical considerations strongly suggest that NF[kappa]B might play some roles in the pathogenesis of oxidative-dysoxygenative insulin dysfunction.

Thus, it comes as no surprise that high concentrations of glucose (10-30 mM) result in excess generation of reactive oxygen species which, in turn, activate NF-[kappa]B and induce endothelial cell apoptosis. (187) Studies with 3O-methyl-D-glucose (a glucose derivative which is taken up but not metabolized by cells) and L-glucose have shown that endothelial reactivity is mediated by glucose-specific pathways. This finding is of direct relevance to the pathogenesis of oxidative coagulopathy in uncontrolled diabetics. Endothelial apoptosis results in denudation of the nonthrombogenic inner lining of the vessel wall, resulting in the exposition of highly thrombogenic subendothelial matrix.

IGF-1, IGF-2, and ODID

Both insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) have insulin-like effects on glucose transport in the myocyte and adipocyte. (188-190) That is not unexpected in light of close sequence homologies between insulin and both IGF-1 and IGF-2. In addition, there is also a high degree of sequence homology between the insulin receptor and the IGF-1 receptor. Again, not surprisingly, intracellular signaling pathways activated by both receptors are similar. Like insulin, IGF-1 affects translocation of GLUT-4 to the myocyte surface in vitro (188) and exerts a potent hypoglycemic effect. (191)

In health, the glucoregulatory roles of IGF-1 and IGF-2 have been thought not to be significant since these factors arc sequestered by specific binding proteins and their serum concentrations in a free state are low. IGF-1 bypasses the insulin receptor and, under those conditions, exerts a significant glucoregulatory role by facilitating glucose uptake in the myocyte and adipocyte. (192) This has been shown in persons with type 1 and type 2 diabetes as well as in instances of mutations in the insulin receptor.

In the oxidative insulin dysfunction states, however, oxidatively induced alterations in the structure and function of those binding proteins are likely to occur. Indeed, there is some evidence that is so in patients with severe insulin resistance, hyperinsulinemia, and poorly controlled diabetes.

PPAR[gamma] and ODID

Adipocytes are rich in nuclear factor called peroxisome proliferation activator receptor-[gamma] (PPAR[gamma]). This receptor is an important determinant of adipogenesis and stimulates adipogenesis in fibroblasts. (193) Persons heterozygous for a dominant-negative PPAR[gamma] allele suffer from severe insulin resistance. (194) Mice heterozygous for a null PPAR[gamma] allele on a high-fat diet have increased insulin sensitivity and develop adipocyte hypertrophy. (195)

Ligands for PPAR[gamma] include thiazolidinediones (TZDs), a class of drugs for diabetes (discussed later). PPAR[gamma] binding in vitro correlates well with in vivo lowering of blood glucose levels. Non-TZD PPAR[gamma] ligands also increase insulin sensitivity. Furthermore, activators of the PPAR[gamma] heterodimer partner, retinoid X receptor, also increase insulin sensitivity and exert antidiabetic effects. (196)

The antidiabetic effects of some drugs, such as those in the thiazotidinedione class, are due to their ability to decrease insulin resistance. This effect is mediated by a nuclear receptor protein called peroxisome proliferator activated receptor-[gamma] (PPAR[gamma]). This protein is involved in the differentiation of adipocytes and is found in large quantities in those cells. PPAR[gamma] also affects insulin sensitivity by mechanisms that are presumed to involve altered gene dynamics in adipocytes. Specifically, it was thought that some factor like PPAR[gamma] might switch on and off some adipocyte-specific gene involved in insulin-mediated signaling pathways. …

Shifting Focus From Glycemic Status to Insulin Homeostasis for Stemming Global Tides of Hyperinsulin and Type 2 Diabetes

Majid Ali, M.D.

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  <2 uIU/mL (mean 14.3 uIU/mL) and peak insulin concentrations <20 uIU/mL accompanied by unimpaired glucose tolerance; and (2) ten of the twelve had no family history of diabetes (parents, siblings, grandparents, children, uncles or aunts); while the mother of the eleventh subject developed diabetes Type 2 in the closing months of her life at age 74. Both parents of the twelfth subject had Type 2 diabetes. This subgroup appears to reflect ideal metabolic efficiency of insulin in the larger evolutionary context.

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 <2 uIU/mL and mean peak insulin concentration of <20; (2) optimal insulin homeostasis, peak insulin <40 accompanied by unimpaired glucose tolerance; (3) mild

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 <2 uIU/mL reflecting efficient insulin conservation during the fasting state; (2) low insulin peak value (18 uIU/mL) indicating high insulin efficiency following a substantial glucose challenge; and (3) a very low insulin level in the 3-hour sample (<2 uIU/mL) reflects optimal beta cell response to glucose level falling below the fasting level.

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 <2 uIU/mL) remove the doubt and provide the answer: a brisk initial insulin response (more than seven-fold increase in thirty minutes) eliminates the expected initial and delayed glucose rises. The highest post challenge glucose level of 65 mg/mL is finally seen at three hours when the accompanying insulin level is <2 uIU/mL.

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.11 His 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.19 The 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

Dr. Ali’s Diabetes Course

 

Majid Ali, M.D.

My Free Diabetes Course Has Two Parts: (1) Part One – Dr. Ali’s Insulin Toxicity Course; and (2) Part Two: Dr. Ali’s Diabetes Reversal Course. The first part of the course concerns the problem and the second part the solution. 


Scientific Basis of Insulin-Based Diabetes Reversal 

Scientific Basis of Dr. Ali’s Diabetes Insulin Toxicity and Diabetes Reversal Courses

  1. Molecular Biology of Oxygen
  2. Insulin homeostasis

Five Threats to Humankind:

  1. Developmental Challenges of the Unborn
  2. Diabetes
  3. Dialysis
  4. Dementia
  5. Disability

All  five are rooted in insulin toxicity. I anticipate that some readers will roll their eyes on the first item listed above. That only means they are not aware of the frequency with which hyperinsulinism is encountered in children with autism, dysautonomia, OCD, POTS, and related neurodevelopmental challenges faced by children in prenatal and postnatal lives.


 

Oxygen Models of Insulin Toxicity and Diabetes Reversal Five Threats to Humankind:

Dr. Ali’s Insulin Toxicity Course and Dr. Ali’s Diabetes Reversal Course are based on Oxygen Models of Diabetes and Insulin Toxicity. Simply stated, these models explains all aspects of Type 2 diabetes—causes, clinical course, consequences, and control—on the basis of disturbed oxygen function. A full description of these models is included at the end of this article.


Body Organs of Special Interest in Oxygen Models of Diabetes and Insulin Toxicity

  1. Gut
  2. Liver
  3. Thalamus in the Brain
  4. Muscles
  5. Pancreas

Why Is the pancreas gland that produces insulin so low in the order of body organs?

I invite readers to keep this question in the mind as they consider my Course on Diabetes?


 

The Gut-Diabetes Connection

 The Gut-Diabetes Connections

  • Throat
  • Esophagus
  • Stomach
  • Small intestine
  • Large intestine

Digestion starts within the mouth by the action of the enzymes in saliva. It then takes full effect within the stomach and some nutrients are also absorbed into the bloodstream here. Partially digested food known as chyme then undergoes further digestion mainly in the first part of the small intestine known as the duodenum. The small intestine, or small bowel, is the longest part of the gut and gradually the food is completely digested and almost all the nutrients are absorbed into the bloodstream.


The Thalamus-Feeding-Weight-Diabetes Connections

Picture

The Quick Facts

Location: Part of the forebrain, below the corpus callosum
Function: Responsible for relaying information from the sensory receptors to proper areas of the brain where it can be processed
The thalamus in the brain has special centers for glucose and regulates some aspects of  sensory information that is being transmitted to the brain.
 

 

What Is More Important in Diabetes?

In Beta Cells of the pancreas where insulin is produced? 

Or in cell membranes where it moves receptor proteins?

muscleWhere Insulin Is Produced Or Where It Is Used? 


What Is Insulin? Where Does It Come From?

The pancreas is a long, slender organ, most of which is located posterior to the bottom half of the stomach.  Although it is primarily an exocrine gland, secreting a variety of digestive enzymes, the pancreas has an endocrine function. Its pancreatic islets—clusters of cells formerly known as the islets of Langerhans—secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).

Pancreas

This diagram shows the anatomy of the pancreas. The left, larger side of the pancreas is seated within the curve of the duodenum of the small intestine. The smaller, rightmost tip of the pancreas is located near the spleen. The splenic artery is seen travelling to the spleen, however, it has several branches connecting to the pancreas. An interior view of the pancreas shows that the pancreatic duct is a large tube running through the center of the pancreas. It branches throughout its length in to several horseshoe- shaped pockets of acinar cells. These cells secrete digestive enzymes, which travel down the bile duct and into the small intestine. There are also small pancreatic islets scattered throughout the pancreas. The pancreatic islets secrete the pancreatic hormones insulin and glucagon into the splenic artery. An inset micrograph shows that the pancreatic islets are small discs of tissue consisting of a thin, outer ring called the exocrine acinus, a thicker, inner ring of beta cells and a central circle of alpha cells.

The pancreatic exocrine function involves the acinar cells secreting digestive enzymes that are transported into the small intestine by the pancreatic duct. Its endocrine function involves the secretion of insulin (produced by beta cells) and glucagon 

Two Dimensions of Dr. Ali’s Diabetes Course for Reversing Type 2 Diabetes

          ☞ Insulin Toxicity Course (to Know the Problem Well

         ☞ Diabetes Reversal Course to Know then Solution Well for Reversing Diabetes?

 

I offer my course in two parts: (1) Dr. Ali’s insulin Toxicity Course; and (2) Dr. Ali’s Diabetes Reversal Course. I attribute the two parts of this course to myself for the simple reason that it makes it easier for people to find it on the internet.

Dr. Ali’s Diabetes Course and Insulin Toxicity Courses are free for everyone, and are posted at http://www.alidiabetes.org. For my free recipes, please go to http://www.alidiabetes.org. 

Should anyone or any institution wish to teach this course, please send me a note and I will send you written permission to do so without any cost.


Dt. Ali’s Basic, Intermediate, and Advanced Diabetes Courses

 My both Diabetes Course and Insulin Toxicity Course are subdivided into three levels as follows:

  1. Ali’s Basic Diabetes Course
  2. Ali’s Intermediate Diabetes Course
  3. Ali’s Advanced Diabetes Course
  4. Ali’s Basic Insulin Toxicity Course
  5. Ali’s Intermediate Insulin Toxicity Course
  6. Ali’s Advanced Insulin Toxicity Course

What Does the Basic Diabetes Course Cover?

A selected list of questions covered in the Diabetes Course:

  1. What is insulin?
  2. What is insulin toxicity?
  3. How do weight gain and obesity develop?
  4. What is Diabetes?
  5. Can insulin toxicity be reversed?
  6. Can diabetes be reversed?
  7. Is a biology degree necessary for taking Dr. Ali’s Insulin Course and Dr. Ali’s Diabetes Course? The answer: No.

 


Question: Who Should Consider Basic Insulin and Diabetes Courses?

  1. People interested in health and healing.
  2. Parents interested in the health of their children, especially obesity, diabetes, and healthy living.
  3. Teachers teaching school and college classes.
  4. Healthy study groups in communities, associations, at

 Answer: Teachers teaching school health classes.

 


 

Question: Who Should Consider Intermediate Insulin and Diabetes Courses?

Answer: Teachers who teach college-level nutrition and health classes

Anyone whose natural curiosity and interest about the subjects of health, healing, insulin toxicity, weight gain, obesity, and reversal of diabetes has been sharpened by the basic couse.


 Question: Who Should Consider Advanced Insulin and Diabetes Courses?

Doctors and professors who teach advanced health, nutrition, and diabetes classes.

Those and who are iinsulin toxic or has diabetes and who wishes to clear insulin toxicity or has Type 2 diabetes and wishes to reverse the disease.


 Learning and Teaching Materials

  1. Video Seminars: Dr. Ali’s Insulin Toxicity and Diabetes Courses 7 Video seminars (This is Seminar One).
  2. Books: Dr. Ali’s Diabetes Reversal Plan
  3. Courses Taught by Dr. Ali Himself (call 212-873-2444 for course info.

 

Oxygen Model of Diabetes

 

My Oxygen Model of Diabetes is an extension of my Oxygen Model of Health and Disease. It is a unifying model that explains all aspects of Type 2 diabetes ( the type that affects more than 95% of individuals afflicted by diabetest—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 Diabetes 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 Type 2 diabetes.


The crucial importance of  the Unifying Oxygen Model of Type diabetes is that it:

☞ Explains the scientific basis of Type 2 diabetes and its complications;

☞ Sheds light how Type 2 diabetes can be prevented and reversed by addressing all oxygen-related issues;

☞ Elucidates how toxicities of foods, environments, and thoughts cause tissue injury and lead to Type 2 diabetes;

☞ Reveals the mechanisms by which various detox therapies work (Oxygen is the primal detergent which removes cellular grease and allows cells to breathe freely); and

☞ Allows the formulation of rational and effective designs for reversing Type 2 diabetes; and

☞ Provides explanations of mechanisms by which  time-honored natural remedies work to control and prevent Type 2 diabetes.

☞ Provides explanations of mechanisms by which  time-honored natural