Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance

The frog skin host-defense peptide tigerinin-1R stimulates insulin release in vitro and improves glucose tolerance and insulin sensitivity in animal models of type 2 diabetes. This study extends these observation by investigating the molecular mechanisms of action underlying the beneficial metabolic effects of the analogue [Arg4]tigerinin-1R in mice with diet induced obesity, glucose intolerance and insulin resistance. The study also investigates the electrophysiological effects of the peptide on KATP and L-type Ca2+ channels in BRINBD11 clonal β cells. Non-fasting plasma glucose and glucagon concentrations were significantly (P<0.05) decreased and plasma insulin increased by twice daily treatment with [Arg4]tigerinin-1R (75 nmol.kg-1 body weight) for 28 days. Oral and intraperitoneal glucose tolerance were significantly (P < 0.05) improved accompanied by enhanced secretion and action of insulin. The peptide blocked KATP channels and, consistent with this, improved beta cell responses of isolated islets to a range of secretagogues. Peptide administration resulted in up-regulation of key functional genes in islets involved insulin secretion (Abcc8, Kcnj11, Cacna1c and Slc2a2) and in skeletal muscle involved with insulin action (Insr, Irs1, Pdk1, Pik3ca, and Slc2a4). These observations encourage further development of tigerinin-1R analogues for the treatment of patients with type 2 diabetes.

The duration compression effect is mediated by adaptation of both retinotopic and spatiotopic mechanisms

The duration compression effect is a phenomenon in which prior adaptation to a spatially circumscribed dynamic stimulus results in the duration of subsequent subsecond stimuli presented in the adapted region being underestimated. There is disagreement over the frame of reference within which the duration compression phenomenon occurs. One view holds that the effect is driven by retinotopic-tuned mechanisms located at early stages of visual processing, and an alternate position is that the mechanisms are spatiotopic and occur at later stages of visual processing (MT+). We addressed the retinotopic-spatiotopic question by using adapting stimuli – drifting plaids - that are known to activate global-motion mechanisms in area MT. If spatiotopic mechanisms contribute to the duration compression effect, drifting plaid adaptors should be well suited to revealing them. Following adaptation participants were tasked with estimating the duration of a 600ms random dot stimulus, whose direction was identical to the pattern direction of the adapting plaid, presented at either the same retinotopic or the same spatiotopic location as the adaptor. Our results reveal significant duration compression in both conditions, pointing to the involvement of both retinotopic-tuned and spatiotopic-tuned mechanisms in the duration compression effect.