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Archived Comments for: Hyperinsulinemia improves ischemic LV function in insulin resistant subjects

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  1. Carbohydrate-rich Diet Is The Likely Culprit For Insulin Resistance

    Robert Su, Virginia Pain Clinic

    28 November 2010

    I thoroughly enjoyed reading this excellent article, “Hyperinsulinemia improves ischemic LV function in insulin resistant subjects” by Patrick M. Heck et al. Furthermore, the use of hyperinsulinemic euglycemic clamp (HEC) in this study prompts me to share my thought on the possible cause of insulin resistance.

    Insulin resistance is a situation when the body, or more specifically, the cell, has built up resistance to the (endogenous) insulin produced by its pancreas, and cannot use the endogenous insulin for taking up and metabolizing the circulating glucose to produce energy, metabolites of glucose, glycogen, and fats. At the same time, the patient with insulin resistance continues to consume carbohydrates; his blood glucose level will rise accordingly. The more he consumes carbohydrates, the higher his blood glucose level will be. Despite that the unused insulin continues to accumulate in the circulation, more insulin is produced and released into the circulation by the pancreas in response to the rising blood glucose level. Thus, the patient suffers from hyperglycemia and hypeinsulinemia at the same time under this detrimental circumstance. [1, 2]

    Insulin resistance is often observed in the patient who is pre-diabetic or type 2 diabetic. It is also observed in the patient with metabolic syndrome along with several pathological biomarkers such as increases in inflammatory factors, blood glucose LDLs, and fibrinogen, and a decrease in HDLs. Because one of the prevalence of insulin resistance is obesity, studies have claimed factors(s) of the adipose (fatty) tissue as the cause(s) of insulin resistance. But, interestingly, the fact that improvement in the blood glucose level of the diabetics decreased in a few days after bariatric surgery or gastric bypass surgery, even before the obese diabetics began to lose weight, should contradict the claims. [3, 4, 5]

    While several situations have been brought up as the causes of insulin resistance, the consensus blames hyperinsulinemia for desensitizing the insulin receptors of the cells to insulin. In other words, hyperinsulinemia with unknown reason(s) is supposed to be the culprit. Therefore, discovering the cause(s) of hyperinsulinemia and confirming the causative role of hyperinsulinemia in insulin resistance should be the foci of future studies. [6]

    To make insulin help the cell take in and utilize glucose, the cellular membrane has insulin receptors, which take up insulin in coupling like the combination between a key and a lock. Logically, if the key does not fit the lock, insulin cannot be coupled with the cellular insulin receptors, As a result, both hyperinsulinemia and hyperglycemia are observed. Setting aside the blame on the insensitivity of the insulin receptors to the endogenous insulin, two possible issues should be considered in insulin resistance. One is with the insulin receptors, and the other is with the endogenous insulin.

    Despite the belief of the consensus that accumulation of insulin or hyperinsulinemia desensitizes the cellular insulin receptors to endogenous insulin, one of the treatments for insulin resistance (hyperinsulinemia and hyperglycemia) is to use a large amount of exogenous insulin. The same technique was observed in a recent study, in which a hyperinsulinemia euglycemia (keeping the blood glucose level within the normal range) clamp improved the left ventricular functions in the patients with insulin resistance and coronary artery disease. In this approach, the patients received more exogenous insulin along with glucose to improve the uptake of glucose by the cardiac muscle cells. [7] How could one situation with hyperinsulinemia cause insulin resistance, and the other with hyperinsulinemia improve insulin resistance?

    Based on the compatibility between the key and the lock, the ability of cells to couple with the exogenous insulin but to not couple with the endogenous, means the possible issue is not necessarily with the receptors. Rather, the issue should be with the difference between the exogenous and endogenous insulin. And, the difference may well be in the structures of the endogenous and the exogenous. In other words, the amino acid sequence of the insulin in the case of insulin resistance and of the insulin in the normal state may be different.

    Having realized the potential of mutations by hyperglycemia, mutation of the ß cells in the environment of hyperglycemia is a reality that has yet to be further explored. [8, 9] Studies have shown hyperglycemia is responsible for damage, death, and mutations of cells including ß cells. A study, “Chronic Exposure of ß-TC-6 Cells to Supraphysiologic Concentrations of Glucose by Poitout V, et al., demonstrated that exposing the ß cells to supraphysiological concentration of glucose solution (199.8 mg%) for up to 41 weeks could decrease the production of insulin by changing (decreasing) their genetic factors. [10] With the findings of mutations of the ß cells, gene or genes, which are normally responsible for keeping a normal sequence of amino acids of insulin produced by ß cells, could be mutated when the ß cells are exposed to hyperglycemia. If that indeed happens as thought, the sequence of amino acids of the insulin produced by the mutated ß cells could be different from that of the insulin produced by the normal ß cells. The defective insulin with an abnormal amino acid sequence, despite its accumulation in the circulation, cannot help the cellular insulin receptors take up and metabolize glucose in the circulation, thus, results in both hyperinsulinemia and hyperglycemia.

    Undoubtedly, consuming carbohydrates is positively linked to the blood glucose level. Consequently, excess carbohydrate intake results in hyperglycemia. Restricting carbohydrates is the best way for reversing hyperinsulinemia and hyperglycemia in insulin resistance, by returning the blood glucose level to normal, as no addition of glucose from the dietary carbohydrate; and allow the normal insulin from the normal ß cells to have the time help the cells take up and metabolize glucose, which has already in the circulation. When the blood glucose level stays within the normal range, the demand for insulin will decline and hyperinsulinemia will subside. [11, 12, 13, 14, 15]

    Hopefully, the future studies will focus on the sequence of amino acids of insulin in the cases of insulin resistance to substantiate the author’s claim that carbohydrate-rich diet is the likely culprit for insulin resistance.

    1. Reusch JE. “Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome.” The American Journal Of Cardiology. Volume 90, Issue 5, Supplement 1, Pages 19-26 (5 September 2002)

    2. National Diabetes Information Clearinghouse (NDIC) “Insulin Resistance and Pre-diabetes.”

    3. Gumbs AA, et al. “Changes in insulin resistance following bariatric surgery: role of caloric restriction and weight loss” Obes Surg. 2005 Apr;15(4):462-73.

    4. van Dielen FM, et al. “Insulin sensitivity during first months after restrictive bariatric surgery, inconsistency between HOMA-IR and steady-state plasma glucose levels.” Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2009 Dec 11.

    5. Kormer J. et al. “Bariatric Surgery in Diabetic Adults Improves Insulin Sensitivity Better than Diet.” The Endocrine Society. June 19, 2010.

    6. Shanik, MH, et al. “Insulin Resistance and Hyperinsulinemia Is hyperinsulinemia the cart or the horse?” Diabetes Care 31 (Suppl. 2):S262–S268, 2008.

    7. Heck, PM, et al. “Hyperinsulinemia improves ischemic LV function in insulin resistant subjects.” Cardiovascular Diabetology 2010, 9:27.

    8. Olson LK, et al. “Chronic Exposure of HIT Cells to High Glucose Concentrations Paradoxically Decreases Insulin Gene Transcription and Alters Binding of Insulin Gene Regulatory Protein.” Journal of Clinical Investigation. Volume 92, July 1993, 514-519.

    9. Lee, AT, et al. “Hyperglycemia-induced embryonic dysmorphogenesis correlates with genomic DNA mutation frequency in vitro and in vivo.” DIABETES, VOL. 48, FEBRUARY 1999.

    10. Poitout V, et al. “Chronic Exposure of ß-TC-6 Cells to Supraphysiologic Concentrations of Glucose Decreases Binding of the RIPE3b1 Insulin Gene Transcription Activator.” Journal of Clinical Investigation. Volume 97, Number 4, February 1996, 1041–1046

    11. Samaha FF, et al. “A Low-Carbohydrate as Compared with a Low-Fat Diet in Severe Obesity.” New England Journal of Medicine. Volume 348:2074-2081. May 22, 2003.

    12. Plodkowski R. “Cutting Carbs is More Effective than Low-Fat Diet for Insulin-Resistant Women.” The Endocrine Society’s 92nd Annual Meeting in San Diego. June 19, 2010.

    13. Gannon MC and Nuttal FQ. “Effect of a High-Protein, Low-Carbohydrate Diet on Blood Glucose Control in People With Type 2 Diabetes.” Diabetes, Volume 53, Number 9, Pages 2375-2382. 2004.

    14. Nuttall FQ and Gannon MC. “The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 iabetes mellitus.” Metabolism. Volume 55, Issue 2, Pages 243-251. February 2006.

    15. Gannon MC and Nuttal FQ. “Control of blood glucose in type 2 diabetes without weight loss by modification of diet composition.” Nutrition and Metabolism. Volume 3, Number 1, Pages 16. 2006.

    Competing interests