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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Pylori from diabetic mice lack NO-mediated NANC relaxation: reversal by ...
Pylori from diabetic mice lack NO-mediated NANC relaxation: reversal by insulin treatment. (a) EFS-evoked NO-mediated NANC relaxations are substantially reduced at 2, 5, and 10 Hz in nNOS–/– pylori compared with wild-type pylori. NOD-prediabetic pylori resembled the wild-type mice with maximal relaxation at 10 Hz. NOD-diabetic pylori have nearly absent NANC relaxation at 2, 5, and 10 Hz, resembling that of nNOS–/– pylori, whereas insulin treatment (1 week) of NOD-diabetic animals partially restores NANC relaxation. NANC relaxations in pylori from STZ-diabetic mice are significantly reduced, similar to pylori from nNOS–/– mice, and insulin treatment (1 week) of STZ-diabetic animals restores NANC relaxation. In control experiments, we compared responses of wild-type pylori to EFS stimulation as 2, 5, and 10 Hz or in the reverse order 10, 5, and 2 Hz, and we observed no apparent differences. The results shown are representative samples of five to ten pyloric preparations from different animals. (b) Quantification of NANC relaxation in response to EFS in diabetic pylori. Several pylori, representing the indicated groups of mice, were used to quantitatively analyze the degree of NANC relaxation in response to EFS. Data shown are the means (± SEM) of several determinations for each group of mice: n = 10 for wild-type; n = 8 for nNOS–/–; n = 5 for NOD-prediabetic; n = 5 for NOD-diabetic; n = 8 for STZ-diabetic; n = 5 for insulin-treated NOD-diabetic (NODi); and n = 8 for insulin-treated STZ-diabetic (STZi). AP < 0.01 for nNOS–/– and STZ-diabetic compared with wild-type specimens, for NOD-diabetic compared with NOD-prediabetic specimens, for insulin-treated NOD-diabetic specimens compared with NOD-diabetic specimens, and for insulin-treated STZ-diabetic specimens compared with STZ-diabetic samples.