Obesity and type 2 diabetes mellitus (T2DM) are occurring at epidemic-like rates, and these epidemics appear to have emerged largely from changes in daily diet. In the present study, we compared effects of high-fat diet (HFD) and fructose-rich diet (FRD) in WBN/Kob-Leprfa (WBKDF) rats that spontaneously develop obesity, dyslipidemia and T2DM. After a 4-week feeding of each diet, WBKDF-HFD and WBKDF-FRD rats exhibited aggravated obesity and dyslipidemia compared with WBKDF rats fed standard diet (STD). In contrast, hyperglycemia developed in WBKDF-STD rats was significantly inhibited in WBKDF-FRD rats, but not in WBKDF-HFD rats. The present study demonstrated that the 4-week feeding of HFD and FRD caused diet-induced obesity with a distinct phenotype in the glucose metabolism in WBKDF rats.

An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S,24S)-2alpha-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50=7.4 pM) than 2 (IC50=6.3 nM).

A practical synthetic route to novel vitamin D antagonists of DLAM (1alpha,25-dihydroxyvitamin D(3)-26,23-lactam) was developed from vitamin D(2) via the 1,3-dipolar cycloaddition reaction as a key step. Six DLAM derivatives (24 compounds) with a variety of nitrogen substituents and stereochemistries at C23 and C25 were synthesized. Among these new derivatives, (23S,25S)-DLAM isomers bound effectively to VDRs and showed antagonistic activity in the HL-60 cell differentiation inhibition assay. The importance of the substituent on the nitrogen of DLAMs for antagonistic activity was also suggested by computational docking studies.

-Glucose has an important role in spermatogenesis. Nevertheless there are few reports in which the effects of long-lasting hypoglycemia on male reproductive organs have been evaluated. Therefore, insulin was administered subcutaneously at 100, 200, and 400 IU/kg to male rats twice a day for one month. This treatment regimen produced plasma glucose levels that rapidly decreased after treatment, with decreased glucose levels lasting for several hours after each administration on the first and final treatment days. During the treatment period, no abnormalities in clinical signs or body weight were observed. No statistically significant differences were noted in the weights of testes, epididymides, prostates and seminal vesicles, or pituitary glands. Histopathological examination revealed that the insulintreated animals exhibited degeneration of seminiferous tubules in the testes and exfoliation of germ cells in the lumens of epididymides as a secondary change related to the testicular lesions. The incidences of the histopathological findings were found to be proportional to insulin dose. Sperm analysis of the group receiving the highest dosage indicated that the sperm concentration tended to decrease and the incidences of sperm malformations tended to increase. Our results suggest that long-lasting hypoglycemia affects male reproductive organs in rats.