### A comparative study of the ionic events involved in stimulus-secretion coupling in pancreatic beta-cells of lean and obese mice.

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 Title: A comparative study of the ionic events involved in stimulus-secretion coupling in pancreatic beta-cells of lean and obese mice. Authors: Mealing, Linda A. Date: 1993 Abstract: The genetically obese mouse of the C57B1/6 strain displays hyperinsulinemia that is partly due to an exaggerated insulin-secretory responsiveness of its pancreatic $\beta$-cells. The cause of this exaggerated responsiveness is unknown. A comparative study of the behaviour of islets and cultured $\beta$-cells of lean and obese mice was undertaken to investigate the cause of the hyper-responsiveness of the $\beta$-cell of the obese mouse. Insulin secretion studies, electrophysiological studies and spectrofluorimetric studies using lean mouse islets and $\beta$-cells were conducted to study the regulation and modulation of the ionic events of the normal insulin secretory pathway. Such studies have never been conducted on lean mice of the C57B1/6 strain and hence provide a basis for comparison for work with the obese mouse and for future work on insulin secretion mechanisms in "normal" mouse $\beta$-cells. The results obtained in the lean mouse model were consistent with the currently accepted hypotheses for the role of K$\sp+$ and Ca$\sp{2+}$ channels in the control of insulin secretion. I hypothesized that the hypersecretion in the obese mouse $\beta$-cell was associated with an altered ionic channel. My research centered primarily on the ATP-sensitive K$\sp+$ channel and on voltage-dependent Ca$\sp{2+}$ influx, which depends on the activity of voltage-dependent Ca$\sp{2+}$ channels. Through the use of physiological and pharmacological agents, I found that the defect in the obese mouse $\beta$-cell could not be attributed to an alteration in the fundamental properties of the ATP-sensitive K$\sp+$ channel or in the regulation of voltage-dependent Ca$\sp{2+}$ influx. However, insulin secretion studies revealed that an apamin- and quinine-sensitive channel produced different secretory responses in lean and obese mouse islets. This type of inhibitor sensitivity could not be ascribed to any K$\sp+$ channel presently known to be involved in $\beta$-cell electrical activity. When modulatory mechanisms were compared in lean and obese mouse $\beta$-cells in spectrofluorimetric studies of (Ca$\rm\sp{2+}\rbrack\sb{i},$ it was found that there were differences in membrane repolarization involving a K$\sp+$ channel that also has a novel sensitivity to inhibitors (charybdotoxin, forskolin, TEA and tolbutamide). From the interpretation of the data the model proposed to explain hypersecretion in obese mouse $\beta$-cells is that in these $\beta$-cells there is the expression of an apamin-sensitive K$\sp+$ channel, which is not present in lean mouse $\beta$-cells, and that as a result of its altered structure or regulation, this apamin-sensitive K$\sp+$ channel is responsible for the altered behaviour of the obese mouse $\beta$-cell. URL: http://hdl.handle.net/10393/6927http://dx.doi.org/10.20381/ruor-15072 Collection Thèses, 1910 - 2010 // Theses, 1910 - 2010