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

J Clin Invest. 2000 Aug;106(3):373-84. doi: 10.1172/JCI8273.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diabetes Complications
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / enzymology*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / enzymology
  • Gastric Emptying / drug effects
  • Gastric Emptying / physiology
  • Gene Expression / drug effects
  • Humans
  • Insulin / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / genetics*
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type I
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stomach Diseases / drug therapy*
  • Stomach Diseases / enzymology
  • Stomach Diseases / etiology


  • Insulin
  • RNA, Messenger
  • Nitric Oxide
  • NOS1 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse