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Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator

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 ef...

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Autores principales: Tsumura, Yoshinori, Tsushima, Yu, Tamura, Azusa, Kato, Hirotsugu, Kobayashi, Tsunefumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936481/
https://www.ncbi.nlm.nih.gov/pubmed/35312718
http://dx.doi.org/10.1371/journal.pone.0265761
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author Tsumura, Yoshinori
Tsushima, Yu
Tamura, Azusa
Kato, Hirotsugu
Kobayashi, Tsunefumi
author_facet Tsumura, Yoshinori
Tsushima, Yu
Tamura, Azusa
Kato, Hirotsugu
Kobayashi, Tsunefumi
author_sort Tsumura, Yoshinori
collection PubMed
description 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.
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spelling pubmed-89364812022-03-22 Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator Tsumura, Yoshinori Tsushima, Yu Tamura, Azusa Kato, Hirotsugu Kobayashi, Tsunefumi PLoS One Research Article 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. Public Library of Science 2022-03-21 /pmc/articles/PMC8936481/ /pubmed/35312718 http://dx.doi.org/10.1371/journal.pone.0265761 Text en © 2022 Tsumura et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tsumura, Yoshinori
Tsushima, Yu
Tamura, Azusa
Kato, Hirotsugu
Kobayashi, Tsunefumi
Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title_full Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title_fullStr Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title_full_unstemmed Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title_short Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
title_sort disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936481/
https://www.ncbi.nlm.nih.gov/pubmed/35312718
http://dx.doi.org/10.1371/journal.pone.0265761
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