We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Novel SGLT Inhibitors (SGL5083 and SGL5085), Acting on Both Suppressing Intestinal Glucose Absorption and Increasing Urinary Glucose Excretion, Improve Postprandial Hyperglycemia in Diabetic Model Rats.
- Authors
Yamamoto, Koji; Kumeda, Shin-Ichiro; Jo, Fusayo; Kitajima, Risa; Asami, Jun; Fukasawa, Yoshiki; Kakinuma, Hiroyuki; Nakazawa, Kioshi
- Abstract
Glucose digested from meal is absorbed via sodium-dependent glucose cotransporter (SGLT) 1 located in an apical site of small intestinal epithelia. Blood glucose in the circulation is filtered in the glomeruli of the kidney, and then reabsorbed on renal proximal tubules via SGLT1 and SGLT2. It is expected that SGLT1 and SGLT2 are attractive targets as anti-diabetic drugs. One approach is the suppression of intestinal glucose absorption via SGLT1 inhibition. And another is the urinary glucose excretion resulting from suppression of reabsorption on renal proximal tubules via SGLT2 inhibition. We discovered potent novel SGLT½ inhibitors. SGL5083 and SGL5085 potently inhibits human SGLT1 and SGLT2 activities (SGL5083; IC[sub 50]=27 and 17 nmol/L, SGL5085; IC[sub 50]=62 and 19 nmol/L, respectively). In rats orally administered SGL5085, the maximum plasma concentration of drug (Cmax) reached to 29ng/mL, and also the drug existed in intestinal luminal contents (50% of dose). Oral administrations of SGL5085 (1 mg/kg) increased the residue of glucose in the intestine in starch loaded rats and increased the urinary glucose excretion in glucose loaded Zucker fatty rats. In streptozotocin-induced diabetic rats, SGL5085 (0.1-1 mg/kg) dose-dependently reduced the hyperglycemia after glucose loading. SGL5083 and SGL5085 (1 mg/kg) effectively suppressed the hyperglycemia on OGTT in Zucker fatty rats. These results indicate that SGL5083 and SGL5085 exhibited the dual activities resulting from characteristic pharmacokinetic profiles, inhibitions of intestinal and renal SGLT½ activities. Their potent efficacy on improvement of postprandial hyperglycemia might be based on dual actions on both suppressing intestinal glucose absorption and increasing urinary glucose excretion. In conclusion, SGLT½ dual inhibitor shows an attractive activity as an orally active anti-diabetic agent.
- Subjects
HYPOGLYCEMIC agents; BLOOD sugar; HYPERGLYCEMIA; EXCRETION; KIDNEY tubules; DIABETES
- Publication
Diabetes, 2007, Vol 56, pA136
- ISSN
0012-1797
- Publication type
Article