AO-128 is a potent and structurally novel inhibitor of the intestinal
disaccharidases, such as
maltase and
sucrase. Genetically obese-diabetic mice, KKA(y), were used to examine the acute or long-term effectiveness of this compound.
AO-128 decreased a postprandial rise in
blood glucose after
sucrose solution loading dose-dependently; the ED50 to reduce a delta increment of
blood glucose by 50% was 0.22 mg/kg. The intestinal
sucrase and
maltase activities were suppressed to 7 and 48% of the control levels, respectively, at a dose of 0.21 mg/kg. Four-week-old female KKA(y) mice were kept on a laboratory diet containing 10 or 50 ppm of
AO-128 for 12 weeks. The high dose of
AO-128 reduced food intake and
body weight gain throughout the experimental period. On the other hand, the low dose reduced
body weight gain for the first 4 weeks without any effect on food intake. Development of the
hyperglycemia and
hyperinsulinemia characteristic of KKA(y) mice was moderately prevented by the low dose, and completely by the high dose.
Hypertriglyceridemia tended to be suppressed by the
AO-128 treatment. The high dose decreased the
hemoglobin A1 level and parametrial adipose tissue weight.
Hepatomegaly and
fatty liver were ameliorated by
AO-128 dose-dependently. Nephropathy was ameliorated by the high dose. These findings indicate that
AO-128 may be useful for treating human
obesity and diabetes.