Is Diabetes Type 2 Rooted in Beta Cell Dysfunction Or In Insulin ReceptorDysfunction?
Majid Ali, M.D.
140 West End Avenue, New York, NY 10021
Diabetes Type 2 (DT2) is essentially rooted in insulin receptor dysfunction. The beta cell dysfunction largely occurs a late consequence of insulin receptor dysfunction. I base my conclusion on the findings of over 1200 three-hour insulin and glucose profiles obtained after following a standardized glucose challenge, and published in a series of articles as well as in my book entitled Dr. Ali’s Diabetes Reversal Plan. Full bibliography of my publications appears in my CV at this site. I especially suggest one article in this series entitled “Shifting Focus from Glycemic Status to Insulin Homeostasis for Stemming Global Tides of Hyperinsulinism and Diabetes Type 2. This article was published in the journal Townsend Letter and its abstract was published online by the journal Nature.
The article by Peter Holleb reproduced by the author’s permission is recommended as an introduction to the subjects of insulin receptor dysfunction and beta cell dysfunction.
Type 2 diabetes is becoming a growing epidemic. “Its prevalence has been due to sedentary lifestyles, obesity, aging and cardiovascular disease” (Pratley et al. 2013). “From 2007 to 2012, the number of Americans affected with Type 2 diabetes has increased from 23.8 million to 25.8 million” (Pratley et al. 2013). “Based on the prevalence of this disease in the past twenty years, it is predicted that the number of affected individuals will increase to 552 million adults by 2030” (Pratley et al. 2013). “One of the main factors in the increase in diagnosis of Type 2 diabetes is the rise in overweight and obese individuals leading to insulin resistance” (Kahn et al. 2006). Insulin resistance has increased the need for understanding insulin homeostasis and how it can be used for reversing Type 2 diabetes” (Ali et al. 2017).
During normal conditions, beta-cells of the pancreas increase insulin release to maintain glucose homeostasis. For individuals with Type 2 diabetes, “dysfunction in beta-cells make them unable to compensate for the decrease in insulin sensitivity” (Kahn et al. 2006). “With the dysfunction of beta-cells, there will be decreased uptake of liver and muscle glucose” (Khan et al. 2006). “One factor contributing to the malfunction of beta-cells would be the release of Non-Esterified Fatty Acids (NEFA)” (Kahn et al. 2006). Studies have suggested that the release of these fatty acids contribute to insulin response. “Insulin resistance will develop within hours of the release of Non-Esterified Fatty Acids” (Kahn et al. 2006). “It has been hypothesized that the release of Non-Esterified Fatty Acids inhibits pyruvate dehydrogenase, phosphofructokinase and hexokinase II activity by competing with glucose for oxidation” (Kahn et al. 2006). “Even though Non-Esterified Fatty Acids are important for insulin release, chronic exposure can drastically decrease insulin synthesis thus inhibiting its function” (Khan et al. 2006).
Type 2 diabetes is a rapidly spreading epidemic in the United States. Insulin resistance is a common aspect for predicting the onset of diabetes. ‘Hyperinsulinism can be described in the oxidative stress model focusing on a dysfunction of the insulin receptor as well as the disruptions in the Krebs cycle” (Ali et al. 2017).” According to the model, Insulin resistance accumulates inflammatory immune products disrupting oxygen homeostasis causing mitochondrial dysfunction” (Ali et al. 2017). “Through disruption of oxygen homeostasis, changes in gut microbiota will increase the rise in inflammatory markers making insulin receptors unresponsive leading to increased insulin resistance” (Festi et al. 2014). “The specific markers interleukin-6 (IL-6) and C-reactive protein (CRP) have been positively associated with an increased risk for type 2 diabetes and serve as a common target for treatments” (Wang et al. 2013). When treating type 2 diabetes, further research into inflammatory markers needs to be done due to elevations of blood glucose during inflammation.
When treating diabetes, it is important to examine the role of gut microbiota. These gut microbiotas can affect lipid metabolism as well as glucose storage. “Gut microbiota contributes to immune system maturation as well as T-cell differentiation” (Festi et al. 2014). “Disruption of the function of these microbiotas can lead to inflammation leading to insulin resistance” (Festi et al. 2014). Typically in individuals with hyperinsulinism, “there is a release of glycerol, non-esterified fatty acids as well as proinflammatory cytokines” (Ali et al. 2017). In 2014, a similar theory was purposed when the author noticed gram negative gut bacteria increased absorption of lipopolysaccharides (LPS) leading to a condition known as bacterial endotoxemia (Festi et al. 2014). The end result will disrupt oxygen homeostasis by accumulating oxidized lipids creating excess debris to create insulin receptor resistance (Festi et al. 2014).
Another possible mechanism for treatment of diabetes are drugs that act on the G-protein coupled receptors. More specifically, the “GPR91 which acts as a ligand for α-ketoglutarate and succinate” (Peterdi et al. 2010). “Succinate and α-ketoglutarate have been recognized as important signaling molecules involved in the hypoxic and hyperglycemic response in diabetic kidneys” (Peterdi et al. 2010). “This response has been associated with lower oxygen tensions further reducing mitochondrial function” (Peterdi et al. 2010). Over the years, studies have shown a link in the hypoxic response of GPR91 in diabetic nephropathy.
“The distal collecting duct system conveys the highest level of GPR91 expression as well as a key activator in the RAS system in a diabetic state “(Peterdi et al. 2010). “A possible theory in early diabetes for RAS activation is GPR91 renin release at the juxtaglomerular apparatus” (Peterdi et al. 2010). “This type of paracrine signaling mechanism is usually found after succinate administration or periods of high glucose” (Peterdi et al. 2010). When GPR91 expression is increased to activate RAS, Prostaglandin E2 and Nitric Oxide production occur to vasodilate the afferent arterioles thus triggering the hyperfiltration in early diabetes. Due to GPR91’s role in diabetes, more treatments need to target this G protein for success.
Prately, Richard. The Early Treatment of Type 2 Diabetes. Am J Med. 2013 Sep;126(9 Suppl 1):S2-9. doi: 10.1016/j.amjmed.2013.06.007.
Khan, Steven. Mechanisms Linking Obesity to Insulin Resistance and Type 2 diabetes. Nature. 2006 Dec 14;444(7121):840-6.
Peti-Peterdi, Janos. High glucose and renin release: the role of succinate and GPR91. Kidney International (2010) 78, 1214–121.
Festi, Davide. Gut Microbiota and Metabolic Syndrome. World J Gastroenterol 2014 November 21; 20(43): 16079-16094.
Ali, Majid. Shifting Focus Glycemic Status to Insulin Homeostasis for stemming Global Tides of Hyperinsulinism and Type 2 Diabetes. Journal Townsend Letters 2017;402:91-96.
Wang, Xia. Inﬂammatory Markers and Risk of Type 2 Diabetes. Diabetes Care 2013; 36:166–175.
Corkey, Barbara. Hyperinsulinemia: Cause or Consequence?. Diabetes 2012; 61:4–13.
Glaser, Benjamin. Type 2 Diabetes: Hypoinsulinism, Hyperinsulinism, or Both? PLoS Med 2007; 4(4): e148. doi:10.1371/journal.pmed.0040148.
Hurrle, Samantha. The Etiology of Oxidative Stress in Insulin Resistance. Biomedical Journal 2017; 40: 257-262.
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