Akira Oku

Inhibition of gastric inhibitory polypeptide signaling prevents obesity

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr−/−) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr−/−, Lepob/Lepob) generated by crossbreeding Gipr−/− and obese ob/ob (Lepob/Lepob) mice gained less weight and had lower adiposity than Lepob/Lepob mice. The Gipr−/− mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.

Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na+-glucose cotransporter inhibitor T-1095

The therapeutic effects 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‐β‐D‐glycopyranoside)) were examined in C57BL/KsJ‐db/db (db/db) mice, a genetic animal model of obese type 2 diabetes. 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, effectively inhibited renal SGLT activity of these mice in vitro. Single oral administration of T‐1095 (10, 30, 100 mg kg−1, p.o.) to db/db mice caused a dose‐dependent reduction in blood glucose levels and a concomitant increase in glucose excretion into urine. In contrast, T‐1095 only slightly affected blood glucose levels in db/+m mice. Chronic administration of T‐1095 (0.1% w w−1 pellet chow, for 12 weeks) decreased blood glucose and haemoglobin A1C levels, and improved glucose intolerance in db/db mice. The age‐related 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. Both the development of albuminuria and the expansion of glomerular mesangial area in db/db mice were significantly suppressed by chronic T‐1095 treatment, indicating the prevention of the progression of diabetic nephropathy. 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.

Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters, on metabolic index and insulin secretion in spontaneously diabetic GK rats

1. To investigate the pharmacological effects of T‐1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T‐1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight.

Effects of added protein (bovine serum albumin) on the rate and enantiotopic selectivity of oxidative O-demethylation of methoxychlor in rat liver microsomes

Abstract The addition of bovine serum albumin (BSA) to rat liver microsomal suspensions during the O-demethylation of methoxychlor (1,1-bis(4-methoxyphenyl)-2,2,2-trichloroethane) produced a good substrate concentration-reaction rate relationship, and allowed us to determine the rate parameters for this reaction. The apparent K m became larger when the albumin content was increased, whereas V max was not changed. The enantiotopic selectivity of the reaction dramatically changed when the substrate concentration was increased in the absence of BSA in phenobarbital-treated rat liver microsomes.

Small ring compounds—XVI: Solvolysis of α(p-substitutedphenyl)cycloprophylcarbinyl p-nitrobenzoate

Abstract α-( p -substitutedphenyl)cyclopropylcarbinyl p -nitrobenzoate (IV), α-( p -substitutedphenyl)isobutyl p -nitrobenzoate (VI) and α-methylcyclopropylcarbinyl p -nitrobenzoate (V) were synthesized and solvolyzed in 65% aqueous dioxan. The substituents studied were Me, Cl and OMe. A plot of the kinetic data obtained in thesolvolysis of IV vs. σ p+ was linear with slop -3.61 at 30°. The structure of the transition state in the solvolysis has been discussed.