Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid

The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu(8)/ Abu(2) (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu(8))GLP-1 was completely stable to human plasma (half-life > 12h), GLP-1, GIP, and (Abu(2))GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu(8))GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu(2))GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu(8))GLP-1 displayed substantial glucose-lowering and insulin -releasing activities, whereas (Abu(2))GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala(8)/Ala(2) substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu(8))GLP-1 represents a potential candidate for future therapeutic development. (C) 2004 Elsevier Inc. All rights reserved.

Novel nicotinamide adenine dinucleotide analogues as selective inhibitors of NAD-dependent enzymes

Three novel dinucleotide analogues of nicotinamide adenine dinucleotide (NAD+) have been synthesised from -ribonolactone. These compounds incorporate a thiophene moiety in place of nicotinamide and are hydrolytically stable. They have been evaluated as inhibitors of adenosine diphosphate ribosyl cyclase, glutamate dehydrogenase and Sir2 acyltransferase activities. Enzyme specificity and a high level of inhibition was observed for the dehydrogenase.

Do pigs form preferential associations?

This investigation examined whether pigs form long-term preferential associations or ‘friendships’ and factors that may influence the formation of these relationships. Thirty-three pigs from 16 litters were housed together from 4 weeks of age. At 10 weeks they were split into two groups of 16 and 17 pigs and each introduced into 3.05 m × 3.66 m observation pens (1st pen). At 17 weeks the two groups swapped pens (2nd pen). The lying patterns of each group were recorded over 3 weeks in both the 1st and 2nd pens. To identify dyads with preferential associations, association indices were calculated for each pair based on their lying patterns and analysed using SOCPROG1.3 and the permutation method [Whitehead, H., 1999. Programs for analysing social structure. SOCPROG 1.2, http://is.dal.cal/~whitelab/index.htm]. Dyads with high association indices for at least 2 out of 3 weeks in either pen, i.e. =0.10 (twice the mean), were classed as having preferential associations. Mantel tests were used to examine the relationship between the relative sex, weight, familiarity and relatedness of a dyad and their level of association and to examine consistency of associations between pens. The existence of preferential associations was identified in both groups, since the standard deviations for the observed half-weight association index means were significantly higher than for the randomly permuted half-weight association index means (P < 0.001). Of the 33 pigs observed, 32 formed preferential associations with one or more pigs in their group, resulting in 50 dyads. Only six dyads (12 pigs) formed preferential associations in both pens, suggesting that the remaining dyads either formed short-term associations only or were simply displaying a shared preference for the same lying location. Levels of association between pens showed no significant correlation. The relative sex, weight, familiarity and relatedness of dyad members also showed no significant correlation with their level of association. These findings suggest that unrelated pigs are capable of forming preferential associations. However, it is unclear whether such associations are widespread or important to pigs, since most dyads’ preferential associations were not consistent between pens.