Practice and principles of pharmacodynamic determination of HISS‐dependent and HISS‐independent insulin action: Methods to quantitate mechanisms of insulin resistance

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Abstract
Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver in the fed state. HISS action accounts for 50–60% of the glucose disposal produced by a wide range of insulin doses (5–100 mU/kg). Although the chemical nature of HISS is unknown, precluding pharmacokinetic studies, the pharmacodynamics of HISS has advanced because of the use of the rapid insulin sensitivity test (RIST) which is a transient euglycemic clamp used following a bolus of insulin. HISS action can be blocked by hepatic denervation and restored by intraportal but not intravenous infusion of acetylcholine or a nitric oxide donor. HISS release is prevented by blockade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, aging, obesity, and fetal alcohol exposure. HISS acts on skeletal muscle but not liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24‐hr fasting in rats. Cats and dogs appear to require a longer period of fasting to prevent HISS action. Lack of HISS action is suggested to be the cause of post‐meal hyperglycemia and hyperlipidemia in type 2 diabetes and other disease states with similar metabolic dysfunction. The RIST can be carried out up to six times in the same animal, is not affected by pentobarbital anesthesia, and can readily differentiate HISS‐dependent and HISS‐independent insulin action. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 1–14, 2003; Published online in Wiley InterScience ( www.interscience.wiley.com). DOI 10.1002/med.10022