Lessons from glucokinase activators: the problem of declining efficacy

Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis

“…The potential benefits of GK activators have been explored before, and several have entered clinical trials since 2008. This class of compounds has shown good efficacy in terms of insulinotrophic, anti‐hyperglycaemic effects and reductions in HbA1c, but none have progressed beyond phase II, mainly because of failure of the therapeutic effect to be maintained . It is possible that targeting GK activators to the arc could alleviate these problems.…”

Opposite effects of a glucokinase activator and metformin on glucose‐regulated gene expression in hepatocytes

“…However, despite very good initial efficacy in controlling blood glucose in T2D, this efficacy declined rather rapidly during clinical trials . Whether this loss of efficacy is explained by a rise in blood triglycerides is unsettled …”

“…[10][11][12] Whether this loss of efficacy is explained by a rise in blood triglycerides is unsettled. [10][11][12][13] High glucose concentration represses the glucokinase gene (Gck) in hepatocytes, concomitantly with induction of glucose 6phosphatase (G6pc) which catalyses the final reaction in hepatic glucose production. 14,15 This effect of glucose is often described as glucotoxicity because induction in G6pc and, thereby, hepatic glucose production by hyperglycaemia is counter-intuitive.…”

Glucokinase and the potential of glucokinase activation in type 2 diabetes

“…Among other GK activators studied, piragliatin led to dose‐dependent decreases in both fasting and in 2‐hour postprandial glucose, but with hypoglycemia, and AZD1656 reduced HbA1c at 4 months to a degree comparable to the effect of glipizide, with less hypoglycemia, but also with a suggestion that HbA1c lowering was not sustained . A suggested explanation for the loss of glucose‐lowering effect of GK activators over time in T2D is that abnormal circulating insulin and glucagon concentrations elevate phosphate ester intermediates of glucose metabolism distal to G‐6‐P, reducing the effect of GK …”

“…2 A suggested explanation for the loss of glucoselowering effect of GK activators over time in T2D is that abnormal circulating insulin and glucagon concentrations elevate phosphate ester intermediates of glucose metabolism distal to G-6-P, reducing the effect of GK. 5 The most recent study of a glucokinase activator is that of dorzagliatin, administered in increasing doses to 258 people with T2D over a 12-week period. 6 In that study, there was a significant placebo-adjusted reduction in HbA1c of 0.4% and 0.8% with 50-and 75-mg doses of dorzagliatin given twice daily, from baseline levels of 8.3% and 8.5%, respectively.…”