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Objectives: A retrospective survey of insulin responses to a 75-gram glucose challenge in 684 subjects in New York metropolitan area was conducted to investigate: (1) prevalence of hyperinsulinemia in New York metropolitan area; (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 <40 uIU/mL accompanied by unimpaired glucose tolerance was defined as the cut-off point for optimal insulin homeostasis. Hyperinsulinism was stratified into three categories based on the doubling of peak insulin values as follows: (1) mild, 40 to <80 uIU/mL; (2) moderate, 80 to <160 uIU/mL; and (3) severe, >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, severe) in 506 subjects without T2D were 24.9%, 38.9%, 26.5%, and 9.7% respectively. The corresponding rates for three degrees of hyperinsulinism in 178 subjects with T2D were 29%, 24%, and 13.9% (with the overall rate of 66.9%). The remaining 33.1% in the type 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 in the United States. In addition, we recommend viewing data in the broader context of mitochondrial dysfunction related to recognized dietary, environmental, and other risk factors of hyperinsulinism-to-T2D continuum; a need for a shift of focus from glycemic status to insulin homeostasis for stemming the global tides of hyperinsulinism and T2D is recognized.
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.3-8 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 of focus, 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 US (Table 1); and (4) the initial real and imagined difficulties in implementing the shift. This retrospective survey was conducted to address these concerns.
Tables 1 to 4 .pdf
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. 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. Photographs of some lab reports are posted at http://alidiabetes.org/2016/02/25/insulin-laboratory-ranges/ to underscore the importance of this crucial point.9
Cut-off Points for Optimal Insulin Homeostasis and Degrees of Hyperinsulinism
The selection of the peak insulin value of <40 mIU/mL as the cut-off point for optimal insulin homeostasis was arbitrary, albeit based on a preliminary review of the first 50 sets of insulin and glucose profiles. 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: Might these cut-off points prove appropriate (1) 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.
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 and peak insulin concentrations <20 uIU/mL (mean 14.3 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). The mother of the eleventh subject developed diabetes type 2 in the closing months of her life at age 74, and 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.
Grease buildup in a kitchen sink increases the rate of further grease accumulation in the sink unless grease is removed. The same holds for grease buildup on the cell membrane which houses the insulin receptor protein. The larger the amount of cellular grease buildup on the cell membrane (and the insulin receptor protein embedded in it), the greater the receptor dysfunction and its resistance to insulin hormone.
Tables 1 to 4 .pdf
The data in Table 2 offers a revealing look at the self-propagating nature of hyperinsulinism. Specifically, it is noteworthy that a 24% difference between the mean peak glucose values of 110.2 mg/dL of the first category (exceptional homeostasis) and 136.5 mg/dL value of the third category (mild hyperinsulinism) is accompanied by a 400% increase in the corresponding values for mean peak insulin concentrations (14.3 uIU/mL rising to 58.5 uIU/mL). By contrast, a much smaller difference of 9% between the mean peak glucose value of 136.5 of the third category (mild hyperinsulinism) and the mean peak glucose value of 150 of the fifth category (severe hyperinsulinism) is accompanied by nearly just as large (395%) difference between the corresponding mean peak insulin levels. The enormous clinical significance of these findings is explained by the grease-and-detergent analogy in the Discussion section of the paper.
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 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.
Tables 1 to 4 .pdf
Tables 5 to 8 .pdf
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 5 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 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) reflecting optimal beta cell response to glucose level falling below the fasting level.
The insulin and glucose profiles in Table 5 dramatically illustrate potent pro-inflammatory effects of incremental degrees of hyperinsulinism,3-5 both in developing and healing phases of severe inflammatory immune disorders such as systemic lupus erythematosus. This subject is vast3-7 and its discussion is outside the scope of this report.
The insulin and glucose profiles in Table 6 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 7 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 7 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 8 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 serum insulin concentrations (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.
Tables 1 to 4 .pdf
Tables 5 to 8 .pdf
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.10 His findings were subsequently validated by others11 as well as by his own additional work.12 Based on those findings, in 2007, he put forth the oxygen model of type 2 diabetes with focus on insulin receptor dysfunction related to Krebs cycle disruptions.13 In 2011, this model and the related oxygen model of hyperinsulinism were expounded in a book,14 in which 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. 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.
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