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From the Townsend Letter
January 2017

Shifting Focus From Glycemic Status to Insulin Homeostasis for Stemming Global Tides of Hyperinsulinism and Type 2 Diabetes
by Majid Ali, MD, FRCS (Eng), FACP; Alfred O. Fayemi, MD, MSc (Path), FCAP; Omar Ali, MD, FACC; Sabitha Dasoju, MB, BS; Daawar Chaudhary; Sophia Hameedi; Jai Amin; Kadin Ali; Benjamin Svoboda
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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, 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.18 The subject of how changes in gut microbiota influence immunity and the inflammatory responses is vast and has been recently reviewed.19 Recent delineation of diabetes-associated changes in gut microbiota20 underscore the role of altered states of bowel ecology and changes in gut microbiota. The central roles of disruptions of gut ecology in the pathogenesis of hyperinsulinism and type 2 diabetes, as stipulated in the oxygen models of these entities, have been discussed at length.21,22

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

Tables 1 to 4 .pdf

Tables 5 to 8 .pdf

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). The subject of restoration of pancreatic beta cell function cannot be considered except within a broader context of essential ecologic relatedness between the gut, liver, pancreas, hypothalamus, and the immune organs.21,22

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. The coexistence of multiple entities in the same individuals is wide and precludes delineation of relationships between specific diseases and varying degrees of hyperinsulinism.

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 diabetes24,25; 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 In closing, we point out that the data presented here strongly supports the need for a shift of focus from glycemic status to insulin homeostasis.27

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References .pdf

Majid Ali MD

Majid Ali, MD, is author of the 12-volume series The Principles and Practice of Integrative Medicine. He is also the founder of the YouTube Science, Health, and Healing Encyclopedia, and producer and host of the program "Science, Health, and Healing" on MNN TV and WBAI radio (New York). In addition, Dr. Ali is president of the Institute of Integrative Medicine and was formerly associate professor of pathology at Columbia University.

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