Gastrointestinal Motility in Health and Disease

Alterations in coordinated gut motility are common in many systemic illnesses, including diabetes mellitus. The organ most commonly affected is the stomach. The resulting problems with delayed gastric emptying result in symptoms of nausea and vomiting. The control of gastric emptying is complex and involves gastric antral circular muscle contraction and pyloric sphincter relaxation. Antral smooth muscles contract in response to the release of neurotransmitters from the enteric nervous system, a plexus of nerves which lies between the circular and longitudinal muscle layers. Alterations in both the density of nerves and neurotransmitter release and in the smooth muscle response to these neurotransmitters have been described in diabetes mellitus.

Research in our laboratory explores the mechanism underlying changes in the neuronal and smooth muscle function in diabetes. Two models of diabetes, the streptozotocin-induced diabetic and the genetically diabetic BB rats, are used. We have shown that the response of the gastric antral smooth muscle to muscarinic and neurokinin agonists is impaired compared with age-matched non-diabetic controls. These agonists act directly at smooth muscle receptors and mediate their action via pertussis-toxin sensitive G-proteins and activation of L-type calcium channels to allow the influx of calcium. The increase in intracellular calcium causes activation of calcium dependent myosin light chain kinase. In the diabetic smooth muscle, an impaired response to non-specific G-protein activation and to high doses of potassium chloride are found. The current studies investigate the steps in the signal transduction pathway which are impaired in diabetes.

The second area of research examines the activity of the enteric nerves which are isolated and cultured. The effect of glucose and osmolality on neuronal responses to these agonists are under study using electrophysiologic and molecular biology techniques.

The third area of research is the investigation of the altered signal transduction pathway in the aged gut using similar physiologic and pharmacologic tools for the study of the changes in diabetes mellitus.