Unraveling the Gordian knot of insulin resistance in type 2 diabetes mellitus

Abstract

β-cells play an important role in unraveling the Gordian knot of insulin resistance in type 2 diabetes. Firstly, a key feature of the etiology of type 2 diabetes, which appears in the prediabetic phase, is a reduction in the unsaturation index (number of cis carbon-carbon double bonds per 100 acyl chains of membrane phospholipids) compared to healthy controls, which leads to a lower rate of transmembrane glucose transport, and consequently causes reduced glucose effectiveness. Thus, the amount of glucose entering the β-cell via glucose transporter-2 reduces insulin production, leading to reduced insulin sensitivity. Secondly, after synthesis of monomer insulin, six monomer insulin molecules can join together in the presence of zinc ions. The mature hexamers are packed inside mature intracellular vesicles that are transported to the β-cell plasma membrane. Fusion of the intracellular vesicle membrane with the β-cell plasma membrane creates a fusion pore that allows expulsion of monomer insulin molecules into the blood circulation. The large dimensions of the monomer insulin molecule (30 Å wide and 35 Å high) require substantial flexibility of the vesicle membrane and the β-cell plasma membrane. Reduction in the unsaturation indexes leads to a lower rate of insulin transport into the blood circulation, which results in a further decrease in insulin sensitivity. That brings us to a crucial point. The conceit behind the term “insulin resistance” is wrong. It suggests that cells do not respond well to insulin, but the fact is that this term ignores the essential reduction, compared to the plasma glucose concentration, in the amount of glucose entering the β-cell via glucose transporter-2, resulting in reduced insulin production. We now know that an increase in glucose effectiveness, powered by an increased unsaturation index, reframes fundamentally the mechanisms that participate in the glucose homeostasis during type 2 diabetes mellitus.