Abstract
The glucose disposal effect of insulin is doubled in response to a meal. This meal-induced insulin sensitization results from insulin acting on the liver, in the presence of a permissive hepatic parasympathetic feeding signal and elevated hepatic glutathione (GSH), to release hepatic insulin-sensitizing substance (HISS), a hormone that acts selectively on skeletal muscle to stimulate insulin-mediated glucose uptake. Blockade of the parasympathetic feeding signal to the liver, either through surgical denervation or atropine-mediated antagonism of hepatic muscarinic receptors, eliminates the HISS response, resulting in HISS-dependent insulin resistance (HDIR) and decreasing the response to insulin by approximately 55% in the fed state. Insulin action in Sprague-Dawley rats, as determined with a rapidly sampled, transient euglycemic clamp in response to insulin (50 mU/kg), is decreased in a dose-dependent manner by atropine. In this study, we have used the ED75 atropine-induced model of HDIR. After a submaximal dose of atropine, potentiation of the remaining parasympathetic effect with the acetylcholinesterase antagonist neostigmine significantly restored postprandial insulin sensitization in a dose-dependent manner with peak effect at 0.1 μg/kg/min. Neostigmine reversed the insulin resistance induced by partial fasting and partial muscarinic inhibition (hepatic GSH levels are at fed levels), but not that induced by surgical hepatic denervation (GSH normal, no nerve signal) or 24-h fasting (low GSH). No potentiation of the response to insulin by neostigmine occurred in normal, fed rats. The data suggest the use of either direct or indirectly acting cholinergic agonists for the treatment of impaired postprandial insulin sensitization.
Footnotes
This work was supported by the Canadian Institutes for Health Research [Grant MOP68960] and DiaMedica, Inc.
Conflict of interest: The University of Manitoba has licensed a patent for the use of acetylcholinesterase inhibitors in the treatment of insulin resistance to DiaMedica, Inc. W.W.L. is an inventor and consultant to DiaMedica, D.J.L. has done contract work for DiaMedica, and J.S. is a research scientist for DiaMedica.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.164509.
-
ABBREVIATIONS:
- GSH
- glutathione
- HISS
- hepatic insulin-sensitizing substance
- HDIR
- HISS-dependent insulin resistance
- i.p.v
- intraportal venous
- MIS
- meal-induced insulin sensitization
- RIST
- rapid insulin sensitivity test
- ANOVA
- analysis of variance.
- Received December 8, 2009.
- Accepted February 3, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|