The Physiology of Insulin Clearance.

Richard N Bergman,Morvarid Kabir,Marilyn Ader

doi:10.3390/ijms23031826

Richard N Bergman, Morvarid Kabir + Show 1 more

Open Access

https://doi.org/10.3390/ijms23031826

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Abstract

In the 1950’s, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable.

Highlights

Personal Note In 1965, I graduated in engineering from the Case Institute of Technology ( Case Western Reserve University) and realized that I did not want to sit in a large room with a slide rule, a T-square and a protractor and be an electrical engineer
It is a remarkable set of circumstances that have led our laboratory to return to insulin degradation as a possible pathogenic factor in type 2 diabetes
As discussed below, it is possible that this flow pattern developed because physiological changes in hepatic insulin degradation might be a mechanism involved in the ability of the intact organism to compensate for insulin resistance by delivering a larger fraction of secreted insulin into the systemic circulation

Summary

Introduction

Arthur Mirsky, a Professor in the Neuropsychiatric Institute. Professor Mirsky was a polymath, who did protein biochemistry in the morning, metabolic physiology in the afternoon, and practiced as a psychoanalyst in the evenings (he never asked me to enter his psychoanalytic program). Dr Mirsky was interested in insulin degradation [1,2,3,4,5]. It is a remarkable set of circumstances that have led our laboratory to return to insulin degradation as a possible pathogenic factor in type 2 diabetes. Arthur Mirsky was without question ahead of his time regarding the latter issue, and I only wish he were still around to enjoy the renewed interest in his work. Mirsky is to be remembered as a giant of the field

Insulin Sensitivity and Insulin Secretion

Possible Inadequacy of the Disposition Index Curve

Robert Turner’s Question

Characteristics of Insulin Degradation

Hypothesis