1 The therapeutic e ects of an orally active inhibitor of Na + -glucose cotransporter (SGLT), T-1095 (a derivative of phlorizin; 3-(benzo [b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-b-D-glycopyranoside)) were examined in C57BL/KsJ-db/db (db/db) mice, a genetic animal model of obese type 2 diabetes. 2 The higher renal SGLT activity in db/db mice than normoglycaemic C57BL/KsJ-db/+m (db/ +m) mice may support the rationale for using an SGLT inhibitor in the treatment regimen for type 2 diabetes. Both T-1095 and its metabolite, T-1095A, which had approximately 10 times more potency, e ectively inhibited renal SGLT activity of these mice in vitro.3 Single oral administration of T-1095 (10, 30, 100 mg kg 71 , p.o.) to db/db mice caused a dosedependent reduction in blood glucose levels and a concomitant increase in glucose excretion into urine. In contrast, T-1095 only slightly a ected blood glucose levels in db/+m mice. 4 Chronic administration of T-1095 (0.1% w w 71 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A 1C levels, and improved glucose intolerance in db/db mice. The agerelated decrease in plasma insulin levels was markedly inhibited and there was a 2.5 fold increase of insulin content in the pancreas of T-1095-treated db/db mice. Food consumption was not changed, while impaired body weight gain was ameliorated by T-1095 treatment. 5 Both the development of albuminuria and the expansion of glomerular mesangial area in db/db mice were signi®cantly suppressed by chronic T-1095 treatment, indicating the prevention of the progression of diabetic nephropathy. 6 These results demonstrate that the SGLT inhibitor T-1095 is able to improve the metabolic abnormalities and inhibit the development of diabetic complications in db/db mice. Thus, T-1095 can be used for therapy of type 2 diabetic patients.

No abstract

Abstract-Hyperhomocyst(e)inemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as coronary artery disease, cerebral artery disease, and venous thrombosis. Recently, the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correlated with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the association between the V allele of the MTHFR gene and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of the brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control subjects, the frequencies of the V allele were 0.45 and 0.32, respectively. The odds ratios and 95% confidence intervals adjusted for the other risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV genotype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (Pϭ0.041 and PϽ0.001, respectively). In patients with multiple infarcts in particular, the allele frequency of the V mutation was 0.56, and the association between the V allele and stroke was highly significant. Plasma homocyst(e)ine levels were significantly higher in patients with the VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene was significantly associated with cerebral infarction in an elderly Japanese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased plasma homocyst(e)ine levels, and dietary folate supplementation may be of benefit, particularly to patients with this genotype.

We investigated the circadian rhythm of chromogranin A (CgA) concentrations in saliva and blood samples from 40 male college students collected at 7 : 00, 8 : 00, 10 : 30, 12 : 30, 17 : 30, and 22 : 30. CgA concentrations were determined by ELISA. Salivary CgA levels peaked upon awakening, and then quickly decreased to the nadir after 1 hour and maintained a low level throughout the day. On the other hand, plasma CgA did not show any obvious circadian rhythm. These findings suggest that salivary and plasma CgA has different routes of secretion.