BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice

Abstract

Impaired glucose-stimulated insulin secretion (GSIS) and increasing b-cell death are two typical dysfunctions of pancreatic b-cells in individuals that are destined to develop type 2 diabetes, and improvement of b-cell function through GSIS enhancement and/or inhibition of b-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting b-cells from cytokine-or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca 2C channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on b-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored b-cell functions as indicated by the increased plasma insulin level and decrease in the b-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.

SP6616 as a new Kv2.1 channel inhibitor efficiently promotes β-cell survival involving both PKC/Erk1/2 and CaM/PI3K/Akt signaling pathways

“…To investigate SP6616 regulation against Erk1/2 signaling, Erk1/2 phosphorylation (p-Erk1/2) levels under different concentrations of SP6616 were examined. As shown in Figures 3c–f , SP6616 did not affect p-Erk1/2 but reversed the STZ-induced decrease of the phosphorylation level, and such an effect was terminated by U0126 (MEK/Erk1/2 inhibitor) 13 treatment. These results thereby showed the regulation of SP6616 against Erk1/2.…”

“…Next, we investigated the potential protection of SP6616 against β -cell apoptosis by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with STZ (0.4 mM) as cell apoptosis stimulus. 13 As shown in Figure 2c , SP6616 had no effects on β -cell viability but counteracted the STZ-induced cell apoptosis in INS-832/13 cells. In addition, SP6616 also exhibited activity in antagonizing the STZ-induced increases in both the protein level of cleaved caspase 3 (pro-apoptosis protein) and the activity of caspase 3/7 (Promega, Madison, WI, USA) ( Figures 2d–f ), further confirming that SP6616 could protect β -cell from apoptosis.…”

Novel members of quinoline compound family enhance insulin secretion in RIN-5AH beta cells and in rat pancreatic islet microtissue

“…The calmodulin-dependent kinase II (CAMKII) is known to play a major role in mediating the effects of Ca 2+ in the cells and was described to take part in the regulation of insulin secretion as well. Its activation correlated with insulin secretion and proved to have an important role in the regulation of glucose dependent insulin secretion in beta cells252627. It is also known that treatments with various insulin secretagogue drugs (e.g.…”

DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway

“…(D) Primary hepatocytes were cultured with DMT (1, 10, 20 µM) for 3.5 h, followed by co-incubation with glucagon (10 nM) for another 0.5 h, and then collected for Western blot assay with antibodies against p- Ca 2+ /CaM axis is the upstream of DMT-regulated PI3K/AKT pathway. (A) Intracellular Ca 2+ level of primary hepatocytes was detected with FlexStation II 384 according to the previous report (Yao et al 2015). DMT (1, 10, 20 µM) increased intracellular Ca 2+ level in a dose-dependent manner.…”

“…Intracellular Ca 2+ level assay was performed as previously described with modification (Yao et al 2015). Primary hepatocytes were seeded onto 96-well plates at a density of 20,000 cells per well and incubated overnight.…”