Pharmaceutical reversal of insulin resistance.

Insulin action is approximately doubled following a meal. The mechanism of postprandial insulin sensitization is dependent on hepatic parasympathetic nerves regulated by the prandial status. The nerves provide a permissive signal to the liver that allows insulin to cause the release of a putative hepatic insulin sensitizing substance (HISS) that selectively stimulates glucose uptake into skeletal muscle but not liver or adipose tissue. The parasympathetic signal has several steps identified in the regulatory pathway; acetylcholine acts on muscarinic receptors leading to activation of nitric oxide synthase and generation of HISS. The meal-induced insulin (MIS) sensitization requires hepatic GSH, which decreases with fasting and several disease states. Interfering with the MIS process results in severe insulin resistance with the response to insulin being reduced by approximately 50% to levels seen in the fasted state. A wide range of conditions have been shown to be associated with insulin resistance attributed to lack of the MIS process including insulin resistance; in chronic liver disease produced by chemical damage or bile duct ligation, hepatic denervation, sucrose fed rats, aging, spontaneously hypertensive rats, fetal alcohol exposed adult offspring, spontaneously insulin resistant rats, animals with pharmacological blockade of hepatic muscarinic receptors, NO synthase, cyclooxygenase, hepatic cGMP, and hepatic GSH levels. Pharmaceutical reversal of insulin resistance has been shown in several models using a variety of approaches including mimicking or potentiating the parasympathetic signal using cholinergic agonists, NO donors, cholinesterase antagonists, phosphodiesterase antagonists, and replenishment of hepatic GSH levels. These compounds are being evaluated for therapeutic application by our international academic/industry collaborative team. The MIS process has now been demonstrated in mice, rats, guinea pigs, cats, dogs, and humans, and has been demonstrated by independent laboratories.