Gain of function mutation in K(ATP) channels and resulting upregulation of coupling conductance are partners in crime in the impairment of Ca2+ oscillations in pancreatic ß-cells.

Gain of function mutations in the pore forming Kir6 subunits of the ATP sensitive K+ channels (K(ATP) channels) of pancreatic ß-cells are the major cause of neonatal diabetes in humans. In this study, we show that in insulin secreting mouse ß-cell lines, gain of function mutations in Kir6.1 result in a significant connexin36 (Cx36) overexpression, which form gap junctional connections and mediate electrical coupling between ß-cells within pancreatic islets. Using computational modeling, we show that upregulation in Cx36 might play a functional role in the impairment of glucose stimulated Ca2+ oscillations in a cluster of ß-cells with Kir6.1 gain of function mutations in their K(ATP) channels (GoF-K(ATP) channels). Our results show that without an increase in Cx36 expression, a gain of function mutation in Kir6.1 might not be sufficient to diminish glucose stimulated Ca2+ oscillations in a ß-cell cluster. We also show that a reduced Cx36 expression, which leads to loss of coordination in a wild-type ß-cell cluster, restores coordinated Ca2+ oscillations in a ß-cell cluster with GoF-K(ATP) channels. Our results indicate that in a heterogenous ß-cell cluster with GoF-K(ATP) channels, there is an inverted u-shaped nonmonotonic relation between the cluster activity and Cx36 expression. These results show that in a neonatal diabetic ß-cell model, gain of function mutations in the Kir6.1 cause Cx36 overexpression, which aggravates the impairment of glucose stimulated Ca2+ oscillations.

Should we reconsider high-risk features in thyroid ultrasonography?

SUMMARY OBJECTIVE: Round shape is generally considered to reduce the risk of malignancy according to recent guidelines. On the contrary, according to some reports, spherically shaped thyroid nodules are associated with a higher risk of malignancy. Thus, we aimed to evaluate the malignancy risk of solid round isoechoic nodules detected at thyroid ultrasonography and compare it with that of solid ovoid isoechoic nodules. METHODS: Between 2017 and 2022, solitary solid round isoechoic nodules with diameters ³10 and £25 mm at thyroid ultrasonography were retrospectively selected and enrolled in the study. Age, size, nodule volume, serum thyrotropin levels, thyroid antibody levels, and cytopathological and histopathological results were recorded. RESULTS: A total of 457 solitary solid isoechoechoic nodules from 457 patients (262 females and 195 males; median age, 59 [31-70] years) were selected, of which 203 were solid round isoechoic nodules, and 254 were solid ovoid isoechoic nodules. A total of 54 surgical operations were performed on 457 nodules, and 31 of them resulted in malignancy. From the 31 malignant results, 25 originated from solid round isoechoic nodules and the remaining 6 originated from solid ovoid isoechoic nodules (p<0.025). CONCLUSION: We found that round nodules have higher malignancy rates than ovoid nodules. We think that ultrasonographic risk stratification systems used to target the most suitable nodules for the necessary biopsies can be dynamically updated, and sphericity can be added as a parameter in patient-based decision-making.