A proposed new paradigm for insulin resistance

The perspective presented here is a working hypothesis suggesting a new paradigm for insulin resistance where, analogous to the cause of type 1 diabetes being attributed to lack of insulin, type 2 diabetes is due to lack of action of a hepatic insulin sensitizing substance (HISS). In both cases, the major metabolic dysfunction is with post-meal nutrient processing. In the immediate postprandial state, insulin causes the release of the putative hormone, HISS, from the liver. HISS stimulates glucose uptake in skeletal muscle. The hepatic parasympathetic nerves determine, in a permissive manner, the ability of insulin to cause HISS release maximally in the postprandial state. HISS release in response to insulin is progressively reduced with fasting. The glucose disposal effect of insulin in the fed state is decreased by approximately 55% by blocking HISS release. HISS release is blocked by fasting, surgical parasympathetic denervation of the liver, blockade of hepatic cholinergic muscarinic receptors, blockade of hepatic nitric oxide production, or blockade of hepatic cyclooxygenase, and results in a condition referred to as HISS-dependent insulin resistance (HDIR). HDIR is physiologically and appropriately produced in the fasted state and, pathologically, in chronic liver disease, sucrose fed, fetal alcohol exposed, spontaneously hypertensive, and aging rats. Therapeutic approaches to correct the metabolic imbalance in processing the meal nutrients that occur in type 2 diabetes can be approached through this paradigm.