Lysosomal storage of glycogen as a sequel of alpha-glucosidase inhibition by the absorbed deoxynojirimycin derivative emiglitate (BAYo1248). A drug-induced pattern of hepatic glycogen storage mimicking Pompe's disease (glycogenosis type II)

Abstract

Effects of the two absorbable alpha-glucosidase inhibitors miglitol (BAYm1099) and emiglitate (BAYo1248) on hepatic and muscular glycogen concentrations were investigated in the rat after 3, 7, and 28 days. Both compounds were (orally) administered at very high doses (5-50-500 mg/kg b.wt.). In a second experiment, glycogen storage after oral administration of acarbose (1000 mg/kg b.wt.) was studied after 7 days. In a third protocol, hepatic glycogen concentrations were investigated in the fed rat after 7 days of either inhibitor at the respective highest dosage. In fasted rats, emiglitate induced a significant, dose-dependent increase of hepatic glycogen concentrations, which--at the dose of 500 mg/kg b.wt.--were present after 3, 7, and 28 days, but resulted in a significant increase of the liver weight after 28 days only. Light and electron microscopy proved that the increase in hepatic glycogen was due to lysosomal storage of glycogen only. Emiglitate in the amount of 5 mg/kg b.wt. did not induce significant changes either of glycogen concentrations or at the EM-level. While emiglitate also increased hepatic glycogen at a dosage of 50 mg/kg b.wt., miglitol led to significant storage of hepatic glycogen after 3, 7, or 28 days at the highest dose only. With miglitol (500 mg/kg b.wt.), only insignificant lysosomal storage of glycogen could be detected by electron and light microscopy, and liver weight was essentially unaffected. Both compounds displayed a dose-dependent tendency towards higher glycogen concentrations in the soleus muscle, which was significant with the highest dosage of either inhibitor. At an oral dose of o.i.d. 1000 mg/kg b.wt., the almost unabsorbable alpha-glucosidase inhibitor acarbose induced significantly increased glycogen concentrations both in the liver and in the soleus muscle after 7 days. With respect to an enormous enlargement of the lysosomes (EM) and in the absence of cytoplasmatic alpha-glycogen, this accumulation of glycogen must be attributed to lysosomal storage. In fed rats, all alpha-glucosidase inhibitors investigated significantly decreased postprandial hepatic glycogen concentrations (emiglitate greater than miglitol greater than acarbose), thereby reflecting the modulation of absorption. It is concluded that in the rat acarbose at approximately 1000 x ED50 may penetrate the intestinal mucosa at amounts significant enough to induce lysosomal storage of glycogen. Miglitol may cause some hepatocellular, lysosomal glycogen storage at a dose of 500 mg/kg b.wt., but no glycogen storage could be proven up to 100 x ED50 over 28 days.(ABSTRACT TRUNCATED AT 400 WORDS)