KP increases the b-cell redox potential, suggesting that KP may potentiate insulin secretion, at least in part, through an enhancement of metabolic signaling. This data is consistent with the central dogma of insulin secretion stating that an increase in glucose metabolism will shift the ATP/ADP ratio to favor the production of ATP, which inhibits the ATP-sensitive inward rectifying potassium channel. This depolarizes the cell and allows for activation of voltage-gated Ca2+ channels . Further, it has previously been shown that neither the Gbc inhibitor, gallein, nor the Gbc-activator, mSIRK, significantly effect NADH levels compared to untreated control, suggesting that Gbc activation can modulate insulin release through a pathway independent of glucose metabolism. The slight, but not statistically significant, increase in insulin secretion with KP treatment at low glucose PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19691102/ supports the independence of KP’s actions from glucose stimulation. Thus, it is also possible that KP increases insulin secretion through a metabolism-independent mechanism, perhaps by altering diacylglycerol effects on the secretory machinery or by activating protein kinase C through direct Gbc action; additional studies should be performed to further test this. In b-cells, insulin secretion is regulated by changes in i, so increased i elicits insulin release. Thus, we measured the Ca2+ response upon application of KP in both whole islets and dispersed b-cells, but Chebulinic acid detected no significant effect. Bowe, et al. performed similar experiments in dispersed bcells and found KP increases i. There are several possible reasons for the differences between our data and that previously described. Dispersed b-cells respond differently to glucose stimulation than those in intact islets. The Ca2+ response may be modulated by the loss of juxtacrine or paracrine signaling upon dispersion. Also, proteolytic damage to the cell GLP-1 and KP Signaling in b-Cells during dispersion may modify the expression of cell surface proteins responsible for detecting changes in the PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19692133 extracellular environment. The differences observed between the Bowe, et al. study and our findings with dispersed b-cells may be due to protocol differences. Because we do not observe a significant 
effect of KP on i oscillation frequency or the amplitude of the oscillating component, the data suggest that KP does not exert its stimulatory effect on b-cell exocytosis by extensively modulating ER Ca2+ release. Upon co-application of KP and gallein, an inhibitor of Gbc activity, or mSIRK, a Gbc-activating peptide, we also do not observe an effect on the Ca2+ response. Previously, our lab showed that mSIRK treatment increases the frequency of i oscillations. Therefore, KP corrects the mSIRKinduced increase in Ca2+ activity. Because no change was detected with KP alone, the data suggest that the KP signaling pathway is independent of Ca2+. Our insulin secretion data suggest that KP potentiates insulin release through a process that functions primarily through the Gbc 8 GLP-1 and KP Signaling in b-Cells complex. As shown in GLP-1 potentiates insulin release through a metabolism and Ca2+ independent Ga pathway GLP-1 potentiates GSIS through activation of a Gs-coupled receptor, putatively by stimulating adenylate cyclase and increasing cAMP. Here, we confirmed that GLP-1 stimulates insulin release from isolated murine islets, and similar to previously published data, we noted that GLP-1 does not alter insulin secretion at sub-st