The effects of intermittent use of the SGLT-2 inhibitor,dapagliflozin, in overweight patients with type 2 diabetes in Japan: a randomized,crossover, controlled clinical trial

Background: This study examined the effects of short-term administration of the sodium glucose cotransporter 2 (SGLT-2) inhibitor, dapagliflozin, on visceral fat area (VFA) in Japanese patients with type 2 diabetes.

Research design and methods: In this randomized, crossover, controlled clinical trial, overweight patients with type 2 diabetes were randomized to treatment with 5 mg dapagliflozin for the first (n = 27) or second 12-week study period (n = 29). The parameters evaluated at baseline and after 12 and 24 weeks included blood pressure, hemoglobin A1c (HbA1c), body composition, VFA, and subcutaneous fat area (SFA).

Results: In both groups, dapagliflozin administration improved the levels of HbA1c, body weight, blood pressure, total fat mass, and VFA. Cessation of dapagliflozin, however, reversed the improvements in HbA1c, blood pressure, body weight, and SFA levels, whereas reductions in VFA and total fat mass levels were somewhat maintained even after 12 weeks without treatment.

Conclusions: Dapagliflozin led to decreases in VFA and, consequently, body weight after a short treatment period. However, these effects were largely reversed by the cessation of dapagliflozin, suggesting that this agent should be administered continuously to maintain clinical usefulness in overweight patients with type 2 diabetes.     

Induction of tissue factor synthesis in human umbilical vein endothelial cells involves protein kinase C.

Incubation of human umbilical vein endothelial cells with one of the following compounds: endotoxin, recombinant interleukin-1 beta, recombinant tumor necrosis factor alpha, allogenic lymphocyte subpopulations or phorbol ester resulted in significant induction of tissue factor synthesis. Diacylglycerol had the same effect and also enhanced synergistically the induction caused by endotoxin and interleukin-1 beta. Two different inhibitors of protein kinase C, H7 and sphingosine, inhibited tissue factor synthesis at concentrations which did not depress protein synthesis in general, suggesting that protein kinase C is involved in the processes leading to tissue factor synthesis. Cells down-regulated for the tissue factor response to TPA responded essentially normally to endotoxin and interleukin-1 with regard to tissue factor synthesis.     

Immunosuppressive factor(s) present in crude preparations of human chorionic gonadotropin

The present study was undertaken to purify and characterize the immunosuppressive factor(s) present in commercially available crude human chorionic gonadotropin (crude hCG). Amberlite CG-50 column chromatography of crude hCG(2,680 IU/mg) produced hCG(7,130 IU/mg) and non hCG(130 IU/mg) fractions. The hCG fraction was further fractionated by Sephadex G-100 column chromatography and a highly purified fraction with a potency of 18,600 IU/mg was obtained. The non hCG fraction was separated into two fractions, F-1 and F-2, on Sephadex G-75. Each fraction was examined for its inhibitory effect on the incorporation of 3H-thymidine by normal human peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA test) or mixed lymphocyte reaction (MLR test). The original crude hCG showed considerable inhibition in both PHA and MLR tests, but the purified hCG showed no inhibition. F-1 fraction, having a molecular weight (M.W.) ranging from 75,000 to 100,000 daltons, was the most potent in the inhibition of all the other fractions. The inhibitory activity in the F-1 fraction was dose-dependent and relatively stable when exposed to heat and trypsin treatment, but completely inactivated by neuraminidase treatment. These results strongly suggest that the macromolecular substance(s), with a M.W. of 75,000 to 100,000, which is present in crude hCG but different from genuine hCG, has potent immunosuppressive effects and that sialic acid residues in the substance(s) are related to the manifestation of these effects.