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HERG Protein Plays a Role in Moxifloxacin-Induced Hypoglycemia.

Qiu HY, Yuan SS, Yang FY, Shi TT, Yang JK - J Diabetes Res (2015)

Bottom Line: The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents.In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice.Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China ; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.

ABSTRACT
The purpose of this study was to investigate the effect of moxifloxacin on HERG channel protein and glucose metabolism. HERG expression was investigated using immunohistochemistry. The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents. A glucose tolerance test was used to analyze the effects of moxifloxacin on blood glucose and insulin concentrations in mice. Results show that HERG protein was expressed in human pancreatic β-cells. Moxifloxacin inhibited HERG time-dependent and tail currents in HEK293 cells in a concentration-dependent manner. The IC50 of moxifloxacin inhibition was 36.65 μmol/L. Moxifloxacin (200 mg/kg) reduced blood glucose levels and increased insulin secretion in wild-type mice at 60 min after the start of the glucose tolerance test. In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice. Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice. The moxifloxacin-induced decrease in blood glucose and increase in insulin secretion occurred via the HERG protein; thus, HERG protein plays a role in insulin secretion.

No MeSH data available.


Related in: MedlinePlus

Moxifloxacin-induced inhibition of the HERG channel in HEK293 cells. (a) Cells were voltage-clamped at −80 mV for 1 s, were depolarized from −60 mV to +50 mV for 3 s, and were repolarized to −40 mV for 3 s. HERG currents were recorded in transfected HEK293 cells with and without 100 μmol/L of moxifloxacin. (b) The time-dependent current and peak tail current I-V curves were recorded before and after cell perfusion with 100 μmol/L of moxifloxacin. (c) Cells were depolarized to a voltage of +20 mV for 3 s using a stepped procedure. Peak tail currents were recorded at different moxifloxacin concentrations (10, 100, and 1000 μmol/L). (d) A moxifloxacin concentration-response curve was fitted to a Hill equation, y = [(A1 − A2)/(1 + (x/C)nH)] + A2, in which A1 represents 0 tail current inhibition, A2 represents 100% inhibition, C represents the IC50 concentration, and nH represents the Hill slope. ∗∗∗P < 0.001, n = 4.
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fig2: Moxifloxacin-induced inhibition of the HERG channel in HEK293 cells. (a) Cells were voltage-clamped at −80 mV for 1 s, were depolarized from −60 mV to +50 mV for 3 s, and were repolarized to −40 mV for 3 s. HERG currents were recorded in transfected HEK293 cells with and without 100 μmol/L of moxifloxacin. (b) The time-dependent current and peak tail current I-V curves were recorded before and after cell perfusion with 100 μmol/L of moxifloxacin. (c) Cells were depolarized to a voltage of +20 mV for 3 s using a stepped procedure. Peak tail currents were recorded at different moxifloxacin concentrations (10, 100, and 1000 μmol/L). (d) A moxifloxacin concentration-response curve was fitted to a Hill equation, y = [(A1 − A2)/(1 + (x/C)nH)] + A2, in which A1 represents 0 tail current inhibition, A2 represents 100% inhibition, C represents the IC50 concentration, and nH represents the Hill slope. ∗∗∗P < 0.001, n = 4.

Mentions: HEK293 cells were held at −80 mV for 1 s and then were depolarized for 3 s using 10 mV intervals from −60 mV to +50 mV. The current initially increased and then decreased, in a time-dependent manner, as the voltage increased. This reflected the inward rectification of the HERG channel. A tail current was elicited for 3 s at −40 mV and the peak tail current at each voltage represented the degree to which the HERG channel was open at that voltage. After perfusion of the transfected HEK293 cells with 100 μmol/L of moxifloxacin for 5 min, the current was reduced (Figure 2(a)).


HERG Protein Plays a Role in Moxifloxacin-Induced Hypoglycemia.

Qiu HY, Yuan SS, Yang FY, Shi TT, Yang JK - J Diabetes Res (2015)

Moxifloxacin-induced inhibition of the HERG channel in HEK293 cells. (a) Cells were voltage-clamped at −80 mV for 1 s, were depolarized from −60 mV to +50 mV for 3 s, and were repolarized to −40 mV for 3 s. HERG currents were recorded in transfected HEK293 cells with and without 100 μmol/L of moxifloxacin. (b) The time-dependent current and peak tail current I-V curves were recorded before and after cell perfusion with 100 μmol/L of moxifloxacin. (c) Cells were depolarized to a voltage of +20 mV for 3 s using a stepped procedure. Peak tail currents were recorded at different moxifloxacin concentrations (10, 100, and 1000 μmol/L). (d) A moxifloxacin concentration-response curve was fitted to a Hill equation, y = [(A1 − A2)/(1 + (x/C)nH)] + A2, in which A1 represents 0 tail current inhibition, A2 represents 100% inhibition, C represents the IC50 concentration, and nH represents the Hill slope. ∗∗∗P < 0.001, n = 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Moxifloxacin-induced inhibition of the HERG channel in HEK293 cells. (a) Cells were voltage-clamped at −80 mV for 1 s, were depolarized from −60 mV to +50 mV for 3 s, and were repolarized to −40 mV for 3 s. HERG currents were recorded in transfected HEK293 cells with and without 100 μmol/L of moxifloxacin. (b) The time-dependent current and peak tail current I-V curves were recorded before and after cell perfusion with 100 μmol/L of moxifloxacin. (c) Cells were depolarized to a voltage of +20 mV for 3 s using a stepped procedure. Peak tail currents were recorded at different moxifloxacin concentrations (10, 100, and 1000 μmol/L). (d) A moxifloxacin concentration-response curve was fitted to a Hill equation, y = [(A1 − A2)/(1 + (x/C)nH)] + A2, in which A1 represents 0 tail current inhibition, A2 represents 100% inhibition, C represents the IC50 concentration, and nH represents the Hill slope. ∗∗∗P < 0.001, n = 4.
Mentions: HEK293 cells were held at −80 mV for 1 s and then were depolarized for 3 s using 10 mV intervals from −60 mV to +50 mV. The current initially increased and then decreased, in a time-dependent manner, as the voltage increased. This reflected the inward rectification of the HERG channel. A tail current was elicited for 3 s at −40 mV and the peak tail current at each voltage represented the degree to which the HERG channel was open at that voltage. After perfusion of the transfected HEK293 cells with 100 μmol/L of moxifloxacin for 5 min, the current was reduced (Figure 2(a)).

Bottom Line: The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents.In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice.Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China ; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.

ABSTRACT
The purpose of this study was to investigate the effect of moxifloxacin on HERG channel protein and glucose metabolism. HERG expression was investigated using immunohistochemistry. The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents. A glucose tolerance test was used to analyze the effects of moxifloxacin on blood glucose and insulin concentrations in mice. Results show that HERG protein was expressed in human pancreatic β-cells. Moxifloxacin inhibited HERG time-dependent and tail currents in HEK293 cells in a concentration-dependent manner. The IC50 of moxifloxacin inhibition was 36.65 μmol/L. Moxifloxacin (200 mg/kg) reduced blood glucose levels and increased insulin secretion in wild-type mice at 60 min after the start of the glucose tolerance test. In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice. Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice. The moxifloxacin-induced decrease in blood glucose and increase in insulin secretion occurred via the HERG protein; thus, HERG protein plays a role in insulin secretion.

No MeSH data available.


Related in: MedlinePlus