Tackling diabetes treatment from a different angle

November 13, 2013 § 6 Comments

Image from http://www.cdc.gov/diabetes/statistics/diabetes_slides.htm

Midway through National Diabetes Month, researchers report the discovery of two small molecules that could lead to new treatments for Type 2 diabetes.

About 25.8 million people in the United States have diabetes, according to the Centers of Disease Control and Prevention. An enzyme called glucokinase plays an important role in holding blood glucose levels steady. It converts glucose to glucose-6-phosphate in various organs, such as the pancreas and the liver.

Glucokinase is a compelling drug target to control blood glucose levels. Efforts have focused on drugs that work as glucokinase activators to keep glucokinase turned on. But, as David Lloyd of Amgen explains, a drawback with these drugs has been severe hypoglycemia (too little glucose in the blood).

Lloyd and colleagues decided to take the opposite approach and target a liver-based glucokinase inhibitor called glucokinase regulatory protein. “GKRP inhibitory control over glucokinase via its direct interaction has been well documented. Recent genomewide association studies have uncovered GKRP’s association with common Type 2 diabetes,” explains Lloyd. “The main hurdle we faced was that no small molecule has ever been identified that directly targeted glucokinase regulatory protein.”

As they describe in their Nature paper, the investigators screened for compounds that targeted the interactions between glucokinase and GKRP. They found two molecules, AMG-1694 and AMG-3969, that disrupted the interaction between glucokinase and GKRP. The disruption kept glucokinase active in only the liver. “The liver-specific mechanism may spare the pancreas from increased insulin secretion associated with current glucokinase activators in clinical trials,” says Lloyd.

The work is significant because GKRP “had previously been considered intractable,” says Lloyd. “We determine that GKRP now is a bona fide target for the potential treatment for Type 2 diabetes.”

He says an important step was that he and his colleagues solved the structure of GKRP bound to AMG-1694 and AMG-3969 and identified “a pocket occupied by our molecules.” Lloyd adds that the identification of the pocket allowed the investigators to tweak their compounds for a better fit to the pocket and make the compounds more potent.

But Lloyd cautions the compounds still need to be tested in humans. “In general, a rodent model is a crude representation of the human disease,” he says. “We tested our molecules in several distinct rodent models of diabetes to get a general picture of their effects” under different in genetic and nutritional conditions.

Lloyd adds by testing the molecules in several models allowed  “us to gain confidence in the efficacy of the molecules. However, we still cannot make conclusions on their translation to the human disease.”

§ 6 Responses to Tackling diabetes treatment from a different angle

  • Boris Tizenberg says:

    Dear Dr. Mukhopadhyay,

    After reading Dr. Lloyd’s et al, paper, “Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors,” I have something I would like clarified. The biochemical and biophysical data in the paper shows that AMG-1694 caused the dissociation of the preformed GK–GKRP complex. The authors also mention that GKRP stabilizes and protects GK from degradation. This suggests that an interaction between GK and GKRP is necessary for protection, yet reduced GK levels were not observed in AMG-1694-treated ZDF rats. Is it possible for GKRP to protect GK without forming a complex?

    Thank you,
    Boris Tizenberg

    UMBC 2014

    • Raj Mukhopadhyay says:

      I’ll pass along your question to Dr. Lloyd and see if I can get an answer. Thanks for reading!

    • Raj Mukhopadhyay says:

      Got a response to your question from David Lloyd at Amgen. He says:

      “Interesting question. Without the protein-protein interaction we would find it difficult to conceive a stabilizing effect of GKRP on GK. The author is correct in stating that AMG-1694 did not reduce GK levels however we believe this effect to be specific to the diabetic state of the rodents. The stabilizing effect may play distinct roles depending on the disease state.”

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