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(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) 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.

T-1095A and T-1095 are synthetic agents derived from phlorizin, a specific inhibitor of Na+-glucose cotransporters (SGLTs). Unlike phlorizin, T-1095 is absorbed into the circulation via oral administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney. Orally administered T-1095 increases urinary glucose excretion in diabetic animals, thereby decreasing blood glucose levels. Indeed, the postprandial hyperglycemia after a meal load was shown to be suppressed by this compound in streptozotocin (STZ)-induced diabetic rats. With long-term T-1095 treatment, both blood glucose and HbA1c levels were reduced in STZ-induced diabetic rats and yellow KK mice. In addition, there was amelioration of abnormal carbohydrate metabolism, i.e., hyperinsulinemia and hypertriglyceridemia, and of the development of microalbuminuria, in yellow KK mice. Thus, T-1095 may be a useful antidiabetic drug, providing a novel therapeutic approach for diabetes.

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.

Pellets of poly(ethylene terephthalate) (PET; 0.48-1.92 g) were heated in anhydrous ethylene glycol (EG; 5 mL) with 2-equivs of NaOH at 150ЊC for 80 min or 180ЊC for 15 min to convert them quantitatively to disodium terephthalate (Na 2 -TPA) and EG. The disodium salt was precipitated quantitatively in pure state from the EG solution and separated readily. The other product EG, being the same component to the solvent, remains in the solution and can be obtained after distillation as a part of the solvent. The rate of decomposition was significantly accelerated by the addition of ethereal solvents to EG, such as dioxane, tetrahydrofuran, and dimethoxyethane. The reaction system is simple; no water and no extra reagent other than NaOH and EG are used. A few recycling systems of PET can be designed on the basis of the present alkali decomposition reaction.

No abstract

In our studies of Na(+)-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivatives substituted on the B ring was prepared and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-beta-D-glucopyranoside (4) showed the most potent effect. To overcome hydrolysis of compound 4 by beta-glucosidase in the digestive tract, the OH groups on the glucose moiety of compound 4 were modified. Three prodrugs (5, 42, and 55) were more potent than the parent compound 4 by oral administration, and finally 3-(benzo¿bfuran-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-beta-D-glucopyranoside) (5) was selected as a new promising candidate. Compound 5 was metabolized mainly by liver esterase to the active form (4), which was about 10 times more potent than 5 in inhibiting SGLT. In oral glucose tolerance test in db/db mice, compound 5 dose-dependently suppressed the elevation of glucose levels. Single administration of 5 reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-A(y) mice. Furthermore, compound 5 suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-A(y) mice. Additionally, long-term treatment with 5 dose-dependently reduced hyperglycemia and HbA1c in KK-A(y) mice. These pharmacological data strongly suggest that compound 5 has a therapeutic potential in the treatment of NIDDM.

No abstract

To determine the contribution of hyperglycemia to the insulin resistance in various insulin-sensitive tissues of Zucker diabetic fatty (ZDF) rats, T-1095, an oral sodium-dependent glucose transporter (SGLT) inhibitor, was administered by being mixed into food. Long-term treatment with T-1095 lowered both fed and fasting blood glucose levels to near normal ranges. A hyperinsulinemic euglycemic clamp study that was performed after 4 wk of T-1095 treatment demonstrated partial recovery of the reduced glucose infusion rate (GIR) in the T-1095-treated group. In the livers of T-1095-treated ZDF rats, hepatic glucose production rate (HGP) and glucose utilization rate (GUR) showed marked recovery, with almost complete normalization of reduced glucokinase/glucose-6-phosphatase (G-6-Pase) activities ratio. In adipose tissues, decreased GUR was also shown to be significantly improved with a normalization of insulin-induced GLUT-4 translocation. In contrast, in skeletal muscles, the reduced GUR was not significantly improved in response to amelioration of hyperglycemia by T-1095 treatment. These results suggest that the contribution of hyperglycemia to insulin resistance in ZDF rats is very high in the liver and considerably elevated in adipose tissues, although it is very low in skeletal muscle.