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.
OBJECTIVE
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.


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.
Ozaki
Ken-ichi
K
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka 412-8513, Japan.
Monnai
Makoto
M
Onoma
Mitsu
M
Muramatsu
Hiroyasu
H
Yogo
Kenji
K
Watanabe
Toshihiko
T
Oda
Yasuhiro
Y
Katagiri
Koichi
K
Arakawa
Hitoshi
H
Itoh
Zen
Z
Omura
Satoshi
S
Takanashi
Hisanori
H
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D004917:Erythromycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005746:Gastric Emptying / Q000187:drug effects* / Q000502:physiology; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018589:Gastroparesis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D019518:Postprandial Period / Q000187:drug effects* / Q000502:physiology; D013311:Streptozocin; D013552:Swine; D013556:Swine, Miniature
D001786:Blood Glucose; D005765:Gastrointestinal Agents; D013311:Streptozocin; D004917:Erythromycin; C103741:mitemcinal