Effects of mitemcinal (GM-611), an orally active erythromycin-derived prokinetic agent, on delayed gastric emptying and postprandial glucose in a new minipig model of diabetes.

Abstract

AIMS:

This study was conducted to evaluate the suitability of a new minipig model for investigating aspects of diabetes such as delayed gastric emptying and glucose metabolism abnormalities, and to test the effects of mitemcinal (GM-611), an orally active erythromycin-derived motilin receptor agonist, on gastric emptying and postprandial glucose in normal and diabetic minipigs.

METHODS AND RESULTS:

Intravenous injection of 300 mg/kg streptozotocin (STZ) to 5-week-old minipigs induced moderate hyperglycemia (about 200 mg/dl) for >80 weeks without insulin treatment. Decreased insulin production (P<.05), increased area under the glucose curve (P<.05), and slower glucose disappearance (P<.05) were demonstrated, and there was no severe inhibition of body weight gain, liver failure, or renal failure. Gastric emptying was significantly delayed in diabetic minipigs (P<.05) at 80 weeks, but not at 40 weeks, post-STZ. Oral administration of mitemcinal (5 mg/kg) at 80 weeks accelerated gastric emptying and induced a similar postprandial glucose profile in normal and diabetic minipigs with delayed gastric emptying.

CONCLUSIONS:

The new diabetic minipig model showed suitability for investigating diabetes, gastric emptying, and plasma glucose excursions. Since delayed gastric emptying and irregular plasma glucose excursions are characteristic of diabetic gastroparesis, the accelerating and regulating effects of mitemcinal on this model add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.

• Authors: Ken-ichi Ozaki, Makoto Monnai, Mitsu Onoma, Hiroyasu Muramatsu, Kenji Yogo, Toshihiko Watanabe, Yasuhiro Oda, Koichi Katagiri, Hitoshi Arakawa, Zen Itoh, Satoshi Omura, Hisanori Takanashi
• Journal: Journal of diabetes and its complications (J Diabetes Complications) 2008 Sep-Oct Vol. 22 Issue 5 Pg. 339-47 ISSN: 1873-460X [Electronic] United States
• PMID: 18413164 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Gastrointestinal Agents
• Streptozocin
• Erythromycin
• mitemcinal

Topics

• Administration, Oral
• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Experimental (chemically induced, complications, drug therapy, physiopathology)
• Drug Evaluation, Preclinical
• Erythromycin (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Gastric Emptying (drug effects, physiology)
• Gastrointestinal Agents (administration & dosage, pharmacology, therapeutic use)
• Gastroparesis (chemically induced, drug therapy, physiopathology)
• Islets of Langerhans (drug effects, physiopathology)
• Kidney (drug effects, physiopathology)
• Liver (drug effects, physiopathology)
• Male
• Postprandial Period (drug effects, physiology)
• Streptozocin
• Swine
• Swine, Miniature