Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction.

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity.NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.

Technical description and feasibility of laparoscopic adrenal contouring using fluorescence imaging.

BACKGROUND: Identification of adrenal glands from the surrounding structures during laparoscopic surgery can be challenging especially in obese individuals. This can increase the chances for hemorrhage and conversion to open surgery. We present the first report of fluorescent infrared visualization of the adrenal glands in a large animal model. METHODS: Five adult Yorkshire pigs were utilized for the study, in compliance with the animal study regulations. After an intravenous bolus administration of 3 mL of indocyanine green (ICG), visualization was performed with a xenon/infrared light source and a laparoscope with a charge-coupled filter device. Activation of the device was done with a foot pedal. Images were analyzed using histogram software and the difference of enhancement was statistically analyzed using unpaired two-tailed t test. RESULTS: The right adrenal glands were visualized in all five animals immediately after administering ICG. Fluorescence facilitated demarcation of adrenal gland tissue from surrounding adipose tissue. Peritoneum and fat was visualized in black color. Adrenal enhancement lasted for 4 h in all cases. The mean value for adrenal fluorescence using histogram count was 71.75 pixels, and for adrenal xenon was 168.87 pixels (p = 0.0002; 95 % CI -130.93 to -0.63). The mean value for fat fluorescence using histogram count was 5.54 pixels and fat xenon was 187.15 pixels (p = 0.0001; 95 % CI -199.39 to -163.82). Although there was no significant difference between adrenal and fat enhancement with xenon light (p = 0.24; 95 % CI -15.53 to 52.09), the difference became significant between adrenal and fat fluorescence (p = 0.0001; 95 % CI 48.51-83.9). CONCLUSION: Fluorescence imaging appears to be a feasible and easy method to differentiate adrenal glands from the surrounding tissue in a large animal model. Further studies are necessary to investigate the real application of this method during laparoscopic adrenalectomy in humans.