Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator.
In: PLoS ONE, Jg. 17 (2022-03-21), Heft 3, S. 1-11
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Zugriff:
Glucokinase activators are regarded as potent candidates for diabetes treatment, however, in clinical studies on patients with type 2 diabetes, a diminishing efficacy was observed after chronic treatment with them. The mechanism of this reduction has not been elucidated, and whether it is a class effect of glucokinase activators remains inconclusive. Here, we firstly identified a diabetic animal model that shows the diminished efficacy after long-term treatment with MK-0941, a glucokinase activator that exhibited diminished efficacy in a clinical study, and we analyzed the mechanism underlying its diminished efficacy. In addition, we evaluated the long-term efficacy of another glucokinase activator, TMG-123. Goto-Kakizaki rats were treated with MK-0941 and TMG-123 for 24 weeks. The results showed that glycated hemoglobin A1C levels and plasma glucose levels decreased transiently but increased over time with the continuation of treatment in the MK-0941-treated group, while decreased continuously in the TMG-123-treated group. Only in the TMG-123-treated group, higher plasma insulin levels were shown at the later stage of the treatment period. For the mechanism analysis, we conducted a hepatic enzyme assay and liver perfusion study in Goto-Kakizaki rats after chronic treatment with MK-0941 and TMG-123, and revealed that, only in the MK-0941-treated group, the activity of glucose-6-phosphatase was increased, and hepatic glucose utilization was decreased compared to the non-treated group. These data indicate that disruptions in hepatic glucose metabolism are involved in the diminished efficacy of glucokinase activators. [ABSTRACT FROM AUTHOR]
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Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator.
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Autor/in / Beteiligte Person: | Tsumura, Yoshinori ; Tsushima, Yu ; Tamura, Azusa ; Kato, Hirotsugu ; Kobayashi, Tsunefumi |
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Zeitschrift: | PLoS ONE, Jg. 17 (2022-03-21), Heft 3, S. 1-11 |
Veröffentlichung: | 2022 |
Medientyp: | academicJournal |
ISSN: | 1932-6203 (print) |
DOI: | 10.1371/journal.pone.0265761 |
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