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. 2018 Jan 5:279:171-176.
doi: 10.1016/j.cbi.2017.11.017. Epub 2017 Nov 26.

Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic β cells

Chien-Hsing Lee  1 , Chih-Sheng Chu  2 , Han-Jie Tsai  1 , Liang-Yin Ke  3 , Hsiang-Chun Lee  2 , Jwu-Lai Yeh  4 , Chu-Huang Chen  5 , Bin-Nan Wu  6
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Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic β cells

Chien-Hsing Lee et al. Chem Biol Interact. .

Abstract

Hyperglycemia-associated glucotoxicity induces β-cell dysfunction and a reduction in insulin secretion. Voltage-dependent K+ (Kv) channels in pancreatic β-cells play a key role in glucose-dependent insulin secretion. KMUP-1, a xanthine derivative, has been demonstrated to modulate Kv channel activity in smooth muscles; however, the role of KMUP-1 in glucotoxicity-activated Kv channels in pancreatic β-cells remains unclear. In this study we examined the mechanisms by which KMUP-1 could inhibit high glucose (25 mM) activated Kv currents (IKv) in pancreatic β-cells. Pancreatic β-cells were isolated from Wistar rats and IKv was monitored by perforated patch-clamp recording. The peak IKv in high glucose-treated β-cells was ∼1.4-fold greater than for normal glucose (5.6 mM). KMUP-1 (1, 10, 30 μM) prevented high glucose-stimulated IKv in a concentration-dependent manner. Reduction of high glucose-activated IKv was also found for protein kinase A (PKA) activator 8-Br-cAMP (100 μM). Additionally, KMUP-1 (30 μM) current inhibition was reversed by the PKA inhibitor H-89 (1 μM). Otherwise, pretreatment with the PKC activator or inhibitor had no effect on IKv in high glucose exposure. In conclusion, glucotoxicity-diminished insulin secretion was due to IKv activation. KMUP-1 attenuated high glucose-stimulated IKv via the PKA but not the PKC signaling pathway. This finding provides evidence that KMUP-1 might be a promising agent for treating hyperglycemia-induced insulin resistance.

Keywords: Glucotoxicity; Insulin; KMUP-1; Kv channels; Pancreatic β-cells; Protein kinase A.

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