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

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.

SUBMITTER: Tsumura Y

PROVIDER: S-EPMC8936481 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Tsumura Yoshinori Y Tsushima Yu Y Tamura Azusa A Kato Hirotsugu H Kobayashi Tsunefumi T

PloS one 20220321 3

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 activa ...[more]

PMID: 35312718

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Project description:Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

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

Publications

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

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