New Paradigm for Insulin Resistance: the Hiss Story

  • W. WAYNE Lautt
Part of the Progress in Experimental Cardiology book series (PREC, volume 8)


There is increasing recognition that the insulin resistance state has its major path-ogenic consequences in the post-meal period when the nutrients from the meal are being processed and glucose storage, normally primarily into skeletal muscle, is impaired thus leading to hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. In this review I describe a recently discovered novel mechanism by which postprandial insulin action is potentiated and, when absent, results in severe postprandial insulin resistance. Injection of insulin causes release of HISS (hepatic insulin sensitizing substance) from the liver of fed rats. HISS actions account 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 a 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 intra-venous infusion of acetylcholine or nitric oxide donors. HISS release is prevented by block-ade of hepatic muscarinic receptors, nitric oxide synthase blockers, indomethacin, and animal models of insulin resistance, including chronic liver disease, sucrose feeding, hypertension, and fetal alcohol exposure. HISS acts on skeletal muscle but liver, gut, or adipose tissue. HISS is released by insulin in the fed state but decreases to insignificance after 24-hour fasting in rats. Lack of HISS action is suggested to be the cause of post-meal hyperglycemia and hyperlipi-demia in type 2 diabetes.

Key words

Insulin resistance HISS Hepatic nerves Skeletal muscle Nutrient partitioning RIST Obesity Feeding Postprandial Nitric oxide Cholinergic Parasympathetic nerves Glycogen Glucose uptake 


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Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • W. WAYNE Lautt
    • 1
  1. 1.Department of Pharmacology & Therapeutics, Faculty of MedicineUniversity of Manitoba, 753 McDermot AvenueWinnipegCanada

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