Low glucose metabolizing capacity and not insulin resistance is primary etiology of type 2 Diabetes Mellitus: A hypothesis

Abstract

This paper puts forward the hypothesis that the etiology of type 2 Diabetes Mellitus (T2DM) is low cellular metabolizing capacity for glucose and insulin resistance develops as a protective mechanism when the intercellular glucose load overwhelms this capacity. Failure of intensive glycemic control to demonstrate better outcomes in macrovascular complications indicates that something is missing from our current understanding of pathogenesis of T2DM. This hypothesis is also able to give a simple explanation of multiple phenomena seen in T2DM like double diabetes, Insulin resistance (IR) preceding hyperglycemia, better than expected cardiovascular benefits from SGLT2 (sodium glucose transport protein 2) inhibitors, association of diet and physical activity and the increasing prevalence of the disease in the population. This hypothesis also implies that IR may be a wrong target in management of the disease. Drugs surpassing insulin resistance is likely to cause increased cardiovascular mortality and morbidity. There might be a need to rethink the role of insulin, insulin secretagogues and insulin sensitizing agent in management of T2DM. If the hypothesis is indeed true, it could reveal new drug targets and there is hope that T2DM might become curable in years to come.