Abstract
Kv2.1 as a voltage-gated potassium (Kv) channel subunit has a pivotal role in the regulation of glucose-stimulated insulin secretion (GSIS) and pancreatic β-cell apoptosis, and is believed to be a promising target for anti-diabetic drug discovery, although the mechanism underlying the Kv2.1-mediated β-cell apoptosis is obscure. Here, the small molecular compound, ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2–a]pyrimidine-6-carboxylate (SP6616) was discovered to be a new Kv2.1 inhibitor. It was effective in both promoting GSIS and protecting β cells from apoptosis. Evaluation of SP6616 on either high-fat diet combined with streptozocin-induced type 2 diabetic mice or db/db mice further verified its efficacy in the amelioration of β-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored β-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on β-cell survival was tightly linked to its regulation against both protein kinases C (PKC)/extracellular-regulated protein kinases 1/2 (Erk1/2) and calmodulin(CaM)/phosphatidylinositol 3-kinase(PI3K)/serine/threonine-specific protein kinase (Akt) signaling pathways. To our knowledge, this may be the first report on the underlying pathway responsible for the Kv2.1-mediated β-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.
Highlights
Has become a serious global health problem bringing heavy burdens to societies.[1]
SP6616 is a Kv2.1 inhibitor SP6616 inhibited membrane potential in CHOKv2.1 cells: Given that the membrane potential-sensitive fluorescent dye is powerful for screening regulators of ion channels,[11] the membrane potential (FLIPR membrane potential assay kit) based platform by FlexStationII384 was at first applied to screen Kv2.1 inhibitor candidates against the lab compound library
The results indicated that SP6616 inhibited Kv2.1 channel by IC50 at 6.44 μM (Figures 1f and g), in which ScTx-1 (100 nM) was used as a positive control (Figure 1e)
Summary
Has become a serious global health problem bringing heavy burdens to societies.[1]. Currently, a series of anti-T2DM drugs are being clinically used, but their existing side effects are still triggering the urgent need for novel agents in the treatment of this disease.[1]. Accumulating evidence has revealed that pancreatic β-cell dysfunctions including glucose-stimulated insulin secretion (GSIS) defect and β-cell mass loss are major determinants for the progression from prediabetes with normoglycemia to diabetes with hyperglycemia, and the result that insulin resistance in prediabetes needs compensatory insulin hypersecretion likely leads to a progressive decline in islet β-cell function.[2] an ideal strategy for T2DM treatment is to improve pancreatic β-cell function.[1,2]. Kv2.1 overexpression activates the mitochondrial or ER stress-induced apoptosis[6] and elevates the sensitivity of cells to apoptotic factors,[7] whereas transient
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