The transient outward current (I to ), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural I to gradients and CHF-dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form I to , in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min −1 ventricular tachypacing. CHF decreased I to density in both epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the I to density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down-regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial-endocardial gradients in I to , and that I to down-regulation in human and canine CHF appears due primarily to changes in Kv4.3.

The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are responsible for >50% of nutrient-stimulated insulin secretion. After being released into the circulation, GIP and GLP-1 are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV (DP IV). The use of DP IV inhibitors to enhance these insulinotropic hormonal axes has proven effective on an acute scale in both animals and humans; however, the long-term effects of these compounds have yet to be determined. Therefore, we carried out the following study: two groups of fa/fa Zucker rats (n ‫؍‬ 6 each) were treated twice daily for 3 months with the DP IV inhibitor P32/98 (20 mg ⅐ kg ؊1 ⅐ day ؊1 , p.o.). Monthly oral glucose tolerance tests (OGTTs), performed after drug washout, revealed a progressive and sustained improvement in glucose tolerance in the treated animals. After 12 weeks of treatment, peak OGTT blood glucose values in the treated animals averaged 8.5 mmol/l less than in the controls (12.0 ؎ 0.7 vs. 20.5 ؎ 1.3 mmol/l, respectively). Concomitant insulin determinations showed an increased earlyphase insulin response in the treated group (43% increase). Furthermore, in response to an 8.8 mmol/l glucose perfusion, pancreata from controls showed no increase in insulin secretion, whereas pancreata from treated animals exhibited a 3.2-fold rise in insulin secretion, indicating enhanced ␤-cell glucose responsiveness. Also, both basal and insulin-stimulated glucose uptake were increased in soleus muscle strips from the treated group (by 20 and 50%, respectively), providing direct evidence for an improvement in peripheral insulin sensitivity. In summary, long-term DP IV inhibitor treatment was shown to cause sustained improvements in glucose tolerance, insulinemia, ␤-cell glucose responsiveness, and peripheral insulin sensitivity, novel effects that provide further support for the use of DP IV inhibitors in the treatment of diabetes. Diabetes 51: 943-950, 2002

Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and ␤-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg ⅐ kg -1 ⅐ day -1 for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU ⅐ kg -1 ⅐ min -1 and included a constant infusion of [ 3 H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction ϳ6 mol ⅐ kg -1 ⅐ min -1 ) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in ␤-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.

BackgroundThe CanMEDS Health Advocate role, one of seven roles mandated by the Royal College of Physicians and Surgeons Canada, pertains to a physician's responsibility to use their expertise and influence to advance the wellbeing of patients, communities, and populations. We conducted our study to examine resident attitudes and self-reported competencies related to health advocacy, due to limited information in the literature on this topic.MethodsWe conducted a pilot experience with seven internal medicine residents participating in a community health promotion event. The residents provided narrative feedback after the event and the information was used to generate items for a health advocacy survey. Face validity was established by having the same residents review the survey. Content validity was established by inviting an expert physician panel to review the survey. The refined survey was then distributed to a cohort of core Internal Medicine residents electronically after attendance at an academic retreat teaching residents about advocacy through didactic sessions.ResultsThe survey was completed by 76 residents with a response rate of 68%. The majority agreed to accept an advocacy role for societal health needs beyond caring for individual patients. Most confirmed their ability to identify health determinants and reaffirmed the inherent requirements for health advocacy. While involvement in health advocacy was common during high school and undergraduate studies, 76% of residents reported no current engagement in advocacy activity, and 36% were undecided if they would engage in advocacy during their remaining time as residents, fellows or staff. The common barriers reported were insufficient time, rest and stress.ConclusionsMedical residents endorsed the role of health advocate and reported proficiency in determining the medical and bio-psychosocial determinants of individuals and communities. Few residents, however, were actively involved in health advocacy beyond an individual level during residency due to multiple barriers. Further studies should address these barriers to advocacy and identify the reasons for the discordance we found between advocacy endorsement and lack of engagement.