Category Archives: Diabetes Reversal With Insulin Detox

Optimal and Inappropriate Laboratory Testing For Assessing Insulin Homeostasis

Majid Ali, M.D.

Grievous Errors in Insulin Testing


What Is Optimal Laboratory Insulin Testing?

What Are Commonly Made Grievous Insulun Testing Errors?

 Optimal laboratory testing for assessing insulin homeostasis is to use tests that directly and specifically assess various aspects of insulin homeostasis. Inappropriate laboratory testing for assessing insulin homeostasis is to use tests that do not directly and specifically assess various aspects of insulin homeostasis.
Examples of optimal laboratory tests for insulin homeostasis are measurement of blood insulin concentration with fasting blood samples and timed samples obtained after a standard glucose challenge. Examples of inappropriate insulin tests are fasting blood glucose level, two-hours post-prandial blood glucose level, and A1c since these tests are test for glycemic status and not for assessing insulin homeostasis. 

Grievous Errors In Insulin Laboratory Tests
I recognize the following commonly made grievous errors in laboratory assessment of insulin homeostasis. Regrettably, these errors are deemed optimal standards for many doctors. 
1.   Blood insulin tests are done on randomly drawn blood tests (Results of such tests                              simply cannot be interpreted).
2.   The epidemic prevalences of hyperinsulinism of varying degrees are near-completely                     ignored in clinical medicine and insulin tests are simply not done (Table 2). 
3.   Tests for blood  sugar levels are done as substitutes for insulin tests. Glucose tests                            and others for glycemic status simply are not insulin tests.
4.   Laboratories use wholly inappropriate references ranges for blood insulin concentrations (See Table 2 for specifics). 
5.   Cut-off points for blood insulin concentrations determined with timed, post-glucose-                   challenge are not based on real insulin testing data.
6.   Insulin is the primary pro-weight gain and pro-obesity hormone, and yet insulin tests                 are done in weight loss and obesity programs. 
7.  Gestational diabetes is an insulin disorder before it becomes a glucose (sugar)                                 disorder. Insulin tests are not done for gestational diabetes.
8.  Insulin in excess is a potent the primary pro-weight gain and pro-obesity hormone,                       and yet insulin tests are done in weight loss and obesity programs. 
9. Insulin in excess is proinflammatory, pro-infections, pro-cancer, pro-premature aging,                 and pro-degenerative disorders and yet insulin tests are seldom, if ever, done by                 most doctors. 
10. Indeed, insulin in excess increases the risk of and fans the fires of all nearly chronic                  diseases 

Two Subtypes of Type 2 Diabetes: T2D Subtype A and T2D Subtype B
In 2014, I recognized the need to subtype Type 2 diabetes (T2D) into two T2D subtypes:
                              T2D subtype A
                               T2D subtype B
Diabetes is a two-faced disease, one with insulin toxicity and the other with insulin depletion: this diabetes duality in itself is most revealing. Below we present five sets of illustrative insulin and glucose profile taken from our original communication to make and illustrate our main points, which are presented and its full clinical implications considered in a separate chapter For the first five, ten or more years, the disease is characterized by rising blood sugar levels accompanied by increasing blood concentrations of insulin (hyperinsulinism aptly designated insulin toxicity). In the later years, T2D is characterized by rising blood sugar levels accompanied by falling insulin levels, this is the stage of insulin depletion (see Tables 1.1 and 1.2 for details).
Table 1. Insulin Homeostasis Categories in 506 Study Subjects Without Type 2 Diabetes
Insulin Category*
Percentage of Subgroup
Mean Peak Glucose  mg/dL
Mean Peak Insulin (uIU/mL)
Exceptional Insulin Homeostasis.N 12**
110.2     (6.12)
Optimal Insulin Homeostasis N =126
24.9 %
121.2     (6.73)
Hyperinsulinism, Mild                N =197
38.9 %
136.5   (7.58)
Hyperinsulinism,  Moderate       N =134
26.5 %
147.0    (8.16)
Hyperinsulinism,  Severe             N =  49
9.7 %
150.0    (8.33)
(less than time and a half higher) 
(nearly 17 times higher)
#   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 2.  Insulin Reference Ranges  in uIU/mL of Six Laboratories in New York Metropolitan Area*
 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.

Grievous Errors in Insulin Testing

First Grievous Error: Believing That Diabetes (T2D) Is a Sugar (Glucose) Problem 
The first grievous error of considering insulin insufficiency as the cause of T2D has misled generations of doctors, leading to the mistreatment of hundreds of millions of people with prediabetes and T2D. In reality, hyperinsulinism predates T2D for five to ten or more years, although the study of insulin homeostasis is not deemed a standard of care for health preservation and disease prevention and/or control. Indeed, it is not taught in medical schools or on hospital wards, even where there are patients with suspected or diagnosed diabetes. The neglect of this core aspect of insulin dysregulation results in: (1) delayed diagnosis of T2D, and (2) as we document conclusively, the failure to detect and address long-established metabolic, inflammatory, immune, cardiovascular, and neurological consequences of insulin hyperinsulinism (Bahi-Buisson et al., 2008; Dandona, Aljada and Bandyopadhyay, 2004; IDFDA, 2016; Khan, Hull and Utzschneider, 2006; Shoelson, Lee and Goldfine, 2006; Shulman, 2014; Wellen and Hotamisligil, Shargill and Spiegelman,2005). Notable in this context is the recent documentation of hyperinsulinism in autism and pediatric dysautonomia (Ali, 2017a), which is discussed in chapter 6.
During the years of excess insulin – hyperinsulinism, or more appropriately insulin toxicity – widespread damage is inflicted in nearly all cell populations in the body. There is a profound irony here.  The very definitions of T1D and T2D lays bare the falsehood of the prevailing belief, the former being a state of near-complete absence of insulin in the blood while the latter for years is accompanied by raised blood insulin concentrations (as documented in Table 1.2). To add to the irony of this, consider the definition of insulin from the website of Merriam Webster Dictionary (March 15, 2017) reproduced verbatim here:
a protein pancreatic hormone secreted by the beta cells of the islets of Langerhans that is essential especially for the metabolism of carbohydrates and the regulation of glucose levels in the blood and that when insufficiently  produced results in diabetes mellitus …and that when insufficiently  produced [insulin] results in diabetes mellitus!
Consequently, it is not surprising that this utterly false notion of T2D caused by insulin insufficiency has become so deeply entrenched in public consciousness? The enduring belief of medical and nursing communities in this misleading dogma is of great concern. The key question is why has this definition not been previously challenged by the medical community?
To bring this grievous error into yet sharper focus, T1D is an acute-onset type disease usually occurring in children, characterized by near-complete absence of insulin-producing capacity of the pancreas gland. By contrast, T2D develops insidiously and, until recently, nearly always developed in adults. The blood insulin concentrations begin to fall after decades of insulin waste that occurs during the hyperinsulinism phase of the disease: this is what medical students learn in classrooms and on medical wards and  what nurses learn in nursing schools. Then the medical tragedy happens. Simple blood tests, for determining blood insulin concentrations to assess the state of insulin homeostasis of individual patients, is not considered a standard of care in any medical specialty or general practice. This disturbing notion of T2D being rooted in insulin insufficiency persists and so the hazards of insulin toxicity go unrecognized.

Second Grievous Error
Neglect of a Specific Quantitative and Modifier Marker
 The Third Grievous Error: Absurd Laboratory Insulin References Ranges
The third grievous error concerns laboratory reference ranges for blood insulin concentrations reported by most university hospital and nationwide commercial laboratories. Rather than guide clinicians interested in the study of insulin dysregulation in their patients, clinical pathologists and laboratory professionals have for decades compounded the problem of neglected hyperinsulinism. Table 1.3 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. The variation in insulin reference ranges invariable invites skepticism, with photographs of actual laboratory reports on the web ( Note that laboratory 1 reports a range of 5-35 for 2-hour blood insulin level while laboratory 5 reports of range of 40-300 for the sample blood sample: while laboratory 1 reports a range of 5-35 for 2-hour blood insulin level. Further, laboratory 5 reports of range of 40-300 for the sample blood sample, while laboratory 2 reports a range of 0.0 to 121.9 and laboratory 4 reports 20-120 for the same blood sample. It is difficult to imagine a parallel for this level of absurdity in the entire field of laboratory medicine.

Cut-off Points for Optimal Insulin Homeostasis and Degrees of Hyperinsulinism
Our selection of the peak insulin value of <40 mIU/mL as the cut-off point for optimal insulin homeostasis in our survey of prevalence of hyperinsulinism in New York (see Table 1.1), was based on a preliminary review of the first 50 sets of insulin and glucose profiles (Ali et al., 2017a). We opted for cut-off points for hyperinsulinism stratification based on doubling of the levels (to <80, <160, and >160 uIU/mL for mild, moderate, and severe hyperinsulinism) with two considerations: (1) are these cut-off points appropriate for this study, and (2) do they provide a frame of reference for future investigations of diverse aspects of insulin homeostasis and hyperinsulinism-to-T2D progression? There are a number of other issues that need to be considered in this context: (1) what constitutes optimal insulin homeostasis, (2) what should the insulin cut-off point be, as there is no agreement within the relevant literature, (3) no adverse effects of low insulin levels when accompanied by unimpaired glucose tolerance have been reported, and (4) Hyperinsulinism and the metabolic syndrome are commonly spoken in the same breath,  explicitly or implicitly referring to 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 but 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 this chapter.
A subgroup of twelve participants was designated ‘exceptional insulin homeostasis’ for two reasons: (1) they showed an 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 T2D in the closing months of her life at age 74 and both parents of the twelfth subject had T2D. This subgroup appears to reflect ideal metabolic efficiency of insulin in the larger evolutionary context.

Shifting Focus from Glucose Testing to Insulin Testing
As reported in the preface, the much higher rate of hyperinsulinism observed in New York’s general population compared to rates of T2D in India (Kaveeshwar and Cornwell, 2014) and China (Xu et al., 2013), provides strong support for the view that there is a need to shift focus from glucose testing to insulin testing for stemming global tides of hyperinsulinism and T2D. A crucial point in this context is that the data published in the Indian and Chinese studies was derived from glucose testing, whereas our insulin database was derived exclusively from direct insulin testing, with measurements of post-glucose challenge blood insulin concentrations with sequential and timed blood samples.
Here we point out that the insulin and glucose profiles presented in this and other chapters shed light on the full spectra of insulin homeostasis, hyperinsulinism and related patterns of insulin dysfunction, for example insulin spikes followed by hypoglycemic episodes which create hunger for foods that create yet more sugar spike. Therefore the insulin and glucose profiles presented in Tables 1.4-1.8 in this (and numerous in other chapters) require that the data be considered in light of the clinical context as well as looking through the kaleidoscopic prisms of molecular biology of oxygen Ali, 2000, 2002, 2004a, 005a, 2007, 2009a, 2011), oxygen model of hyperinsulinism (Ali, 2014a) and oxygen model of T2D (Ali, 2001). As for co-morbidities of the hyperinsulinism-T2D continuum (metabolic, inflammatory, immune, infectious, cardiovascular, neurological, developmental, gut-microbiota-related, differentiative, and degenerative), we do not recognize any  inconsistencies between our observations and inferences and those of earlier workers (Nath, Heemels and Anson, 2006; Nichols, 2012; Patti et al., 2003; Saltiel and Kahn, 2001; Scherer, 2005; Stanley, 2016; Turnbaugh, 20


Table 3. Insulin Homeostasis Categories in 178 Study Subjects With Type 2 Diabetes
Insulin Category
Percentage of Subgroup
Mean Peak Glucose, mg/dL
Mean Peak Insulin (uIU/mL)
Diabetic Hyperinsulinism, Mild              N =  53
252.0   (14.00)
Diabetic Hyperinsulinism, Moderate    N =  42
242.1   (13.45)
Diabetic Hyperinsulinism, Severe          N =  24
224.6   (12.47)
Diabetic  Insulin Deficit                             N =  59
294.0    (16.33)
Illustrative Case Studies of Insulin Responses to Glucose Challenge
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*
½ Hr
1 Hr
2 Hr
3 Hr
Insulin uIU/mL
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*
½ Hr
1 Hr
2 Hr
3 Hr
Insulin uIU/mL
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*
½ Hr
Insulin uIU/mL
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*
½ Hr
Insulin uIU/mL
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 Girl With Lupus Erythematosus*
½  Hr
Insulin uIU/mL
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
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.

Insulin Essentials

Majid Ali, M.D.

Very little of What I Learned About Diabetes In Medical School Has Been Validated by My Patients, My True Teachers.


Insulin Essentials

  1. Insulin is the master energy hormone of the body, for energy generation as well as energy expenditure.
  2. The energy demands of chronically-injured cells increase because repair of injured tissues needs more energy.
  3. Increased demands for cellular repair energy can be met only with increased supply of fuel (glucose) for producing more cellular energy.
  4. Higher demands for glucose require higher insulin activity.
  5. The validity of these statements can be tested only with direct blood insulin tests, not by doing blood tests for glucose (fasting blood glucose, A1c test, two-hour post-prandial blood sugar, or three-hour glucose tolerance test after a glucose load.
  6. other forms of sugar.
  7. Anyone can test the validity of the above statement with blood insulin tests.


What My Professors Did Not Tell Me About Insulin Essentials

  1. Newborn babies with birth weight larger than eight pounds are insulin toxic.
  2. Mothers of babies with birth weight larger than eight pounds are insulin toxic.
  3. Expecting moms with gestational diabetes are insulin-toxic and will remain so after delivering their babies for variable periods of time.
  4. Boys with widespread persistent acne are insulin-toxic.
  5.  Young girls with polycystic ovarian cystic syndrome are insulin-toxic.
  6. Nearly all obese children are insulin-toxic.
  7. Children and adults with fatty liver and steatosis are insulin-toxic.
  8. Most patients with pulmonary fibrosis, bronchiectasis, and active tuberculosis are insulin-toxic. 
  9. Most individuals with psoriasis and sarcoidosis are insulin-toxic.
  10. Most individuals with chronic autoimmune disorders (rheumatoid arthritis, lupus, scleroderma, and others) are insulin-toxic.
  11. Most patients with chronic renal failure are insulin-toxic.
  12. Most individuals with memory loss, dementia, Alzheimer’s disease, and diverse chronic diseases of the brain are insulin-toxic.
  13. Most individuals with cancer are insulin-toxic.
  14. Nearly all people become insulin-toxic after receiving chemotherapy.



  1. Individuals with psoriasis are insulin-toxic.
  2. babies with birth weight larger than eight pounds are insulin toxic.
  3. In


Dementia Is Rooted in Insulin Brain Toxicity

Majid Ali, M.D.

All Known risk factors of dementia are first known risk factors of hyperinsulinism (insulin toxicity and then of Dementia.

Dementia Is rooted in insulin toxicity. I support my view by showing here that all known risk factors of dementia are rooted in insulin toxicity excess – hyperinsulinism, by another name.


Insulin Toxicity Can Be Reliably Detected Only by Blood Insulin Tests

The only direct and reliable method of detecting insulin toxicity is timed measurements of blood insulin concentrations after a glucose challenge. Employing this insulin test, in 2017, my colleagues and I documented a prevalence rate of hyperinsulinism of 75.1% in the general population in New York metropolitan area.1 This was not surprising since four years earlier the Chinese, employing blood glucose tests had reported a combined prevalence rate of prediabetes and diabetes of 50.1%.2

The core message of this short article, I state at the beginning, is: find out if you are insulin-toxic with blood insulin tests, and if this be the case, and you and on the path to dementia, clear insulin toxicity. For this purpose, I suggest my 3D Insulin Protocol comprising diet, detox, and dysox plans, and are presented in detail at


Dementia Is rooted in insulin excess – hyperinsulinism, in the medical jargon is the term for it – which precedes Type 2 diabetes (T2D) by five, ten, or more years. This, succinctly stated, is the basic relationship between dementia, diabetes, insulin resistance and hyperinsulinism.


As for the cause of dementia, my assertion that insulin toxicity is the root cause of dementia was one of the prediction of both oxygen model of hyperinsulinism and the oxygen model of dementia. I put forth these models in 19951 as extensions of my oxygen model of aging proposed in 19802. These models were based on my studies of mitochondrial dysfunction and respiratory-to-fermentative shift in chronic immune-inflammatory and other disorders proposed on 1980.

Diabetes Is Rooted In Insulin Toxicity – Part Two

Majid Ali, M.D.

Diabetes Begins 15–20 years before it is diagnosed


Text Reproduced From An Important Published Paper
Article: Hulsegge G, Spijkerman AMW, van der Schouw, et al. Trajectories of metabolic risk factors and biochemical markers prior to the onset of type 2 diabetes: the population-based longitudinal Doetinchem study.  Nutrition & Diabetes (2017) 7, e270; doi:10.1038/nutd.2017.23

Risk factors often develop at young age and are maintained over time, but it is not fully understood how risk factors develop over time preceding type 2 diabetes. We examined how levels and trajectories of metabolic risk factors and biochemical markers prior to diagnosis differ between persons with and without type 2 diabetes over 15–20 years.
A total of 355 incident type 2 diabetes cases (285 self-reported, 70 with random glucose 11.1mmoll−1) and 2130 controls were identified in a prospective cohort between 1987–2012. Risk factors were measured at 5-year intervals. Trajectories preceding case ascertainment were analysed using generalised estimating equations.
Among participants with a 21-year follow-up period, those with type 2 diabetes had higher levels of metabolic risk factors and biochemical markers 15–20 years before case ascertainment. Subsequent trajectories were more unfavourable in participants with type 2 diabetes for body mass index (BMI), HDL cholesterol and glucose (P<0.01), and to a lesser extent for waist circumference, diastolic and systolic blood pressure, triglycerides, alanine aminotransferase, gamma glutamyltransferase, C-reactive protein, uric acid and estimated glomerular filtration rate compared with participants without type 2 diabetes. Among persons with type 2 diabetes, BMI increased by 5–8% over 15 years, whereas the increase among persons without type 2 diabetes was 0–2% (P<0.01). The observed differences in trajectories of metabolic risk factors and biochemical markers were largely attenuated after inclusion of BMI in the models. Results were similar for men and women.
Participants with diabetes had more unfavourable levels of metabolic risk factors and biochemical markers already 15–20 years before diagnosis and worse subsequent trajectories than others. Our results highlight the need, in particular, for maintenance of a healthy weight from young adulthood onwards for diabetes prevention.

Text continued
Although it has been well established that adverse levels of risk factors often develop early in life and are maintained over time,123456 it is not fully understood how they progress to type 2 diabetes (T2D). For example, T2D might be preceded by a gradual accumulation of the adverse effects of risk factors starting at a young age, or by a relatively sudden deterioration in risk factors before disease onset, or by a combination of both. The comparison of long-term trajectories of risk factors between those who do and those who do not develop T2D may help to identify at which time point these trajectories start to deviate before the development of overt disease. Such insight into the timing and the extent of pathophysiological changes before symptoms occur may provide indications for the optimal timing of preventive actions. Trajectories of BMI and waist circumference are of particular importance since these are strong modifiable risk factors of T2D.78 Other relevant factors associated with T2D include glucose levels,9 β-cell function,10 insulin resistance,10 blood pressure,8lipids,8 liver fat markers,1112 markers of chronic inflammation13 and kidney function.14
Several studies have described gradual changes in β-cell function, insulin resistance, fasting glucose and 2-h post-load glucose many years before diagnosis of T2D with steeper unfavourable changes 3–5 years before diagnosis.1516171819 Only a few studies, mainly among men, have examined progressive changes of other risk factors, such as BMI, but so far findings have been inconsistent. The Whitehall II study showed that adults who developed T2D had similar trajectories of BMI and C-reactive protein (CRP) but more unfavourable trajectories of systolic blood pressure and high-density lipoprotein (HDL) cholesterol compared with adults without T2D, over a period of ~14 years.2021 In contrast, a small study of 177 men observed larger changes in BMI, but no differences in blood pressure, HDL cholesterol and liver fat markers in men who developed impaired fasting glucose compared with men who did not, over a 9-year period.22 A short-term study (that is, over 1.5 years) observed differences in changes of alanine aminotransferase (ALT) and triglycerides but not in blood pressure, total cholesterol and HDL cholesterol between high-risk men with incident T2D and controls.17
A longer follow-up period in a population-based study and inclusion of other metabolic risk factors and biochemical markers is needed for more insight in the physiological changes preceding the onset of T2D. There is also a need to investigate differences between men and women since previous studies reported several sex-related differences in the associations of risk factors such as systolic blood pressure, HDL cholesterol and uric acid with T2D.2324 Therefore, we examined whether trajectories of metabolic risk factors and biochemical markers among initially healthy men and women differed for those who developed T2D and those who did not over a period of up to 15–20 years.

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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. …

Library of Articles On Insulin Homeostasis


Majid Ali, M.D.

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