Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents. Diabetes

Activation of ␤ 3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to upregulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with ␤ 3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus ␤ 3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a ␤ 3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for ␤ 3 agonists in the treatment of human obesity.

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The opsin shift, the difference in wavenumber between the absorption peak of a visual pigment and the protonated Schiff base of the chromophore, represents the influence of the opsin binding site on the chromophore. The opsin shift for the chicken cone pigment iodopsin is much larger than that for rhodopsin. To understand the origin of this opsin shift and the mechanism of wavelength regulation in iodopsin, a series of synthetic 9-cis and 11-cis dehydro- and dihydro-retinals was used to regenerate iodopsin-based pigments. The opsin shifts of these pigments are quite similar to those found in bacteriorhodopsin-based artificial pigments. On the basis of these studies, a tentative model of wavelength regulation in iodopsin is proposed.

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FK506 blocks T cell activation by preventing the transcription of lymphokine genes through binding to the intracellular protein FKBP12 and formation of complex that inhibits the phosphatase activity of calcineurin. Beside exerting potent suppressive activity on cellular and humoral immune responses, in vivo treatment with FK506 in rodent models induces thymic alterations characterized by a selective reduction of mature CD4+8- cells. The potential relationship between such thymic alterations and the immunosuppressive and calcineurin inhibitory activities of FK506 has not been defined. Here, we took advantage of the availability of FK506 analogs with different immunosuppressive potencies to address this question. Intravenous daily administration of FK506 in Sprague-Dawley rats for 4 days was found to be sufficient to cause a depletion of CD4+8- thymocytes with an ED50=0.06 mg/kg/day. Under the same conditions, L-683,590 which is 2-3-fold less potent than FK506 in inhibiting T cell activation and calcineurin function gave an ED50=0.17 mg/kg/day. In contrast, the nonimmunosuppressive, calcineurin noninhibitory antagonist L-685,818, failed to deplete the CD4+8- thymocyte subset but could reverse the reducing effect of FK506 on this subset. Another analog, L-688,617, which does not completely inhibit T cell activation in vitro, also behaved as a partial agonist of CD4+8- cell depletion. Therefore, the ability of FK506 analogs to deplete the CD4+8- thymocytes subset correlates with their immunosuppressive and calcineurin inhibitory potencies. This suggests that calcineurin is involved in the intra-thymic maturation processes of CD4+8- T cells. Moreover, the short-term treatment protocol described here provides a rapid and quantitative assay to determine the immunosuppressive potency of FK506-like compounds in vivo

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