1. Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator.
- Author
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Tsumura Y, Tsushima Y, Tamura A, Kato H, and Kobayashi T
- Subjects
- Animals, Blood Glucose metabolism, Enzyme Activators pharmacology, Enzyme Activators therapeutic use, Glucose metabolism, Glycated Hemoglobin metabolism, Humans, Hypoglycemic Agents therapeutic use, Insulin metabolism, Liver metabolism, Rats, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 metabolism, Glucokinase metabolism
- Abstract
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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors were employees of Teijin Pharma Limited and Teijin Pharma Limited has provided all funding for this study. Teijin Pharma Limited is Japanese local pharmaceutical company which has about 1500 employees and develops pharmaceuticals and medical devices. These do not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2022
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