Novel SGLT Inhibitor (SGL5094) Improves Postprandial Hyperglycemia Through the Suppression of SGLT1-Mediated Glucose Transport Across the Small Intestine.

Kumeda, Shin-Ichiro; Io, Fusayo; Kitajima, Risa; Asami, Jun; Fukasawa, Yoshiki; Kakinuma, Hiroyuki; Yamamoto, Koji; Nakazawa, Kiyoshi

Carbohydrates are mostly digested to glucose, fructose and galactose before absorption by the small intestine. Absorption across the brush border and basolateral membranes of enterocytes is mediated by sodium-dependent and -independent membrane proteins. Glucose and galactose transport across the brush border occurs by a sodium-dependent glucose co-transporter 1 (SGLT1), whereas passive fructose transport is mediated by a uniporter (GLUT5). Therefore, inhibition of SGLT1 in the intestine could result in suppression of glucose absorption and cause therapeutically useful improvement of postprandial hyperglycemia. SGL5094 has been identified as a novel, potent SGLT inhibitor (SGLT1; IC[sub 50]=28 nmol/L, SGLT2; IC[sub 50]=23 nmol/L). In the pharmacokinetic studies in the Sprague Dawley (SD) rats, residues of SGL5094 in the intestinal contents and tisuues were 84% and 6.6% respectively 1 hour after oral dosing of 1 mg/kg, while concentrations of SGL5094 in plasma were very low (Cmax<1.5ng/mL). These data mean the minimal oral absorption of SGL5094. In the SD rats loaded starch (2g/kg) and SGL5094 (1mg/kg), SGL5094 significantly increased residual glucose (46% of dose) in the intestinal content at 1 hour after starch loading. In Type 1 diabetic rats subjected to an oral glucose tolerance test (OGTT), SGL5094 significantly reduced blood glucose excursion at the doses from 0.1 mg/kg (ΔGlucose AUC0-1h: 51% reduction) to 1 mg/kg (ΔGlucose AUC0-1h: 72% reduction). It also reduced blood glucose excursion following OGTT at the doses from 0.1 mg/kg (ΔGlucose AUC0-1h: 32% reduction) to 0.3 mg/kg (ΔGlucose AUC0-1h: 53% reduction) in Type2 diabetic Goto-Kakizaki rats. In conclusion, a novel potent SGLT inhibitor, SGL5094, suppressed SGLT1-mediated glucose transport across the small intestine in the diabetic rats. SGL5094 appears to have a therapeutic potential in the new class of antidiabetic agents.

HYPOGLYCEMIC agents; HYPERGLYCEMIA; BLOOD sugar; SMALL intestine; GLUCOSE tolerance tests; DIABETES

Diabetes, 2007, Vol 56, pA136

0012-1797

Academic Journal