Impaired intracellular signal transduction in gastric smooth muscle of diabetic bb/w rats. Takahashi, Toku, Yuichiro Kojima, Yasuhiro Tsunoda, Lisa A. Beyer, Mikiko Kamijo, Anders A. Sima, and Chung Owyang. Department of Internal Medicine, Department of Pathology, Michigan Diabetic Research & Training Center, The University of Michigan Medical Center, Ann Arbor, Michigan 48109
APStracts 2:0185G, 1995.
The pathophysiologic mechanisms responsible for diabetic gastroparesis remain unclear. Diabetes mellitus occurs spontaneously in 90% of a partially inbred colony of BB/W rats. This animal model resembles human insulin dependent diabetes and is suitable for investigating the mechanism of diabetic gastroparesis. Diabetic BB/W rats were sacrificed 6 months after the onset of diabetes. Muscle contraction experiments and 3H-acetylcholine release studies were performed with muscle strips of gastric body. Biochemical measurements of inositol triphosphate (IP3) and protein kinase C (PKC) in gastric muscle were performed to characterize the abnormalities of the intracellular signal transduction system in gastric myocytes. Circular muscle contractions in response to direct myogenic stimulants, carbachol (10-7 -10-3 M) or substance P (10-7-10-5 M), were significantly impaired in diabetic BB/W rats compared to controls. Similarly, muscle contractions in response to NaF (10 mM), a direct stimulant of G proteins, were also impaired in diabetic BB/W rats. In contrast, muscle contractions in response to KC1 (25-75 mM) were similar between control and diabetic BB/W rats, indicating normal voltage dependent Ca2+ entry in muscle strips obtained from diabetic BB/W rats. 3H-acetylcholine release from gastric myenteric plexus in response to electrical transmural stimulation remained intact in diabetic BB/W rats. In separate studies, we demonstrated that carbachol (10-6 - 10-4 M)-induced IP3 responses were significantly reduced in diabetic rats compared to control. In addition, there was also impairment of translocation of PKC in diabetic BB/W rats. These observations indicate that myogenic impairment occurred in diabetic BB/W rats. This resulted from altered intracellular signal transduction involving abnormal IP3 production and PKC translocation. 

Received 3 April 1995; accepted in final form 30 August 1995.
APS Manuscript Number G135-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.