Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy
Crystal C. Watkins, … , Solomon H. Snyder, Christopher D. Ferris
Crystal C. Watkins, … , Solomon H. Snyder, Christopher D. Ferris
Published August 1, 2000
Citation Information: J Clin Invest. 2000;106(3):373-384. https://doi.org/10.1172/JCI8273.
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Article

Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy

Abstract

Gastrointestinal dysfunction is common in diabetic patients. In genetic (nonobese diabetic) and toxin-elicited (streptozotocin) models of diabetes in mice, we demonstrate defects in gastric emptying and nonadrenergic, noncholinergic relaxation of pyloric muscle, which resemble defects in mice harboring a deletion of the neuronal nitric oxide synthase gene (nNOS). The diabetic mice manifest pronounced reduction in pyloric nNOS protein and mRNA. The decline of nNOS in diabetic mice does not result from loss of myenteric neurons. nNOS expression and pyloric function are restored to normal levels by insulin treatment. Thus diabetic gastropathy in mice reflects an insulin-sensitive reversible loss of nNOS. In diabetic animals, delayed gastric emptying can be reversed with a phosphodiesterase inhibitor, sildenafil. These findings have implications for novel therapeutic approaches and may clarify the etiology of diabetic gastropathy.

Authors

Crystal C. Watkins, Akira Sawa, Samie Jaffrey, Seth Blackshaw, Roxanne K. Barrow, Solomon H. Snyder, Christopher D. Ferris

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nNOS protein expression in the pyloric myenteric neurons is depleted in ...
nNOS protein expression in the pyloric myenteric neurons is depleted in diabetic mice: reversal by insulin treatment. (a) Immunohistochemical analysis of nNOS protein expression. nNOS is present in wild-type but not nNOS–/– pyloric myenteric neurons, whereas nNOS expression is lost in both NOD-diabetic and STZ-diabetic mice. Insulin treatment (1 week) of NOD-diabetic and STZ-diabetic animals reverses the loss of nNOS expression. (b) Quantification of nNOS protein expression. The number of nNOS-expressing neurons per hpf (×40) was determined, for ten microscopic fields, for each group of animals, with SEM as shown by the error bars. These results have been obtained in two separate experiments with four to six mice per group. AP < 0.01 for nNOS–/– and STZ-diabetic samples compared with wild-type samples, for NOD-diabetic compared with NOD-prediabetic samples, for insulin-treated NOD-diabetic compared with NOD-diabetic samples, and for insulin-treated STZ-diabetic compared with STZ-diabetic specimens.