HISS-dependent control of insulin sensitivity in health and disease

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Sadri, Parissa
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It has been previously demonstrated that the hepatic parasympathetic nerves have a permissive role regulating the ability of insulin to release a hepatic insulin sensitizing substance (HISS) from the liver (Xie et al. 1993; Me and Lautt 1995a, 1995b). This thesis work demonstrates the involvement of other permissive factors in the release of HISS from the liver in response to insulin in health and a pathological condition in rats. Furthermore, the glucose disposal effect of insulin and insulin-like growth factor-1 (IGF-1) were compared in health and a pathological condition. To measure insulin sensitivity, we have developed a new rapid insulin sensitivity test (RIST). The RIST is a reproducible test and requires a bolus infusion of insulin (50 mU/kg) over 5 minutes. The amount of glucose infused during the RIST to maintain euglycemia is referred to as the RIST index. The release of HISS was shown to be dependent on the production of nitric oxide (NO) and prostaglandins (PGs) in the liver. Intraportal, but not intravenous, administration of a NO synthase (NOS) antagonist and a cyclooxygenase antagonist produced significant HISS-dependent insulin resistance (HDIR). Administration of a NO donor after NOS antagonism or hepatic parasympathetic denervation reversed HDIR and restored insulin sensitivity. IGF-1 (200 [mu]g/kg) had a similar glucose disposal effect to insulin (50 mU/kg) but its effect did not involve the release of HISS from the liver. In an experimental model of fetal alcohol exposure (FAE), male rats were prenatally exposed to ethanol through the maternal water supply containing 0%, 5%, 10%, 15% and 20% ethanol and female rats were prenatally exposed to 0%, 15% and 20% ethanol. FAE caused a dose-dependent increase in HDIR in both males and females in young adulthood. However, FAE did not affect the IGF-1 sensitivity. In conclusion, the permissive role of the hepatic parasympathetic nerves to the action of insulin to release HISS from the liver is through NO and PGs production in the liver. The glucose disposal effect of IGF-1 does not involve the release of HISS from the liver. FAE causes dose-dependent HDIR in young adulthood but does not alter the glucose disposal effect of IGF-1.