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Insulin Resistance and Hyperinsulinemia

Is hyperinsulinemia the cart or the horse?

Michael H. Shanik, MD¹, Yuping Xu, MD², Jan krha, MD, DSC³, Rachel Dankner, MD, MPH⁴, Yehiel Zick, PHD⁵ and Jesse Roth, MD^2,6

¹ Division of Endocrinology, North Shore–Long Island Jewish Health System, Lake Success, New York
² Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York
³ Department of Internal Medicine 3, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
⁴ Cardiovascular Epidemiology Unit, Gertner Institute for Epidemiology and Health Policy Research, Tel-Hashomer, Israel
⁵ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
⁶ Department of Internal Medicine, Albert Einstein College of Medicine, New York City, New York

Address correspondence and reprint requests to Jesse Roth, MD, 149-37 Powells Cove Blvd., Whitestone NY 11357. E-mail: jesserothmd{at}hotmail.com

Insulin resistance, recently recognized as a strong predictor of disease in adults, has become the leading element of the metabolic syndrome and renewed as a focus of research. The condition exists when insulin levels are higher than expected relative to the level of glucose. Thus, insulin resistance is by definition tethered to hyperinsulinemia. The rising prevalence of medical conditions where insulin resistance is common has energized research into the causes. Many causes and consequences have been identified, but the direct contributions of insulin itself in causing or sustaining insulin resistance have received little sustained attention. We examine situations where insulin itself appears to be a proximate and important quantitative contributor to insulin resistance. 1) Mice transfected with extra copies of the insulin gene produce basal and stimulated insulin levels that are two to four times elevated. The mice are of normal weight but show insulin resistance, hyperglycemia, and hypertriglyceridemia. 2) Somogyi described patients with unusually high doses of insulin and hyperglycemia. Episodes of hypoglycemia with release of glucose-raising hormones, postulated as the culprits in early studies, have largely been excluded by studies including continuous glucose monitoring. 3) Rats and humans treated with escalating doses of insulin show both hyperinsulinemia and insulin resistance. 4) The pulsatile administration of insulin (rather than continuous) results in reduced requirements for insulin. 5) Many patients with insulinoma who have elevated basal levels of insulin have reduced (but not absent) responsiveness to administered insulin. In summary, hyperinsulinemia is often both a result and a driver of insulin resistance.

Abbreviations: GnRH, gonadotropin-releasing hormone • IRS, insulin receptor substrate

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