A new angle in diabetes drugs from Roche. Still preclinical but very interesting:
Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy
Joseph Grimsby,1 Ramakanth Sarabu,1 Wendy L. Corbett,1 Nancy-Ellen Haynes,1 Fred T. Bizzarro,1 John W. Coffey,1 Kevin R. Guertin,1 Darryl W. Hilliard,1* Robert F. Kester,1 Paige E. Mahaney,1 Linda Marcus,1 Lida Qi,1 Cheryl L. Spence,1 John Tengi,1 Mark A. Magnuson,2 Chang An Chu,1 Mark T. Dvorozniak,1 Franz M. Matschinsky,3 Joseph F. Grippo1
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic ß cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
1 Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. 2 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. 3 Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
* Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Present address: Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
To whom correspondence should be addressed. E-mail: joseph.grippo@roche.com
Here's the related editorial comment in Science:
MEDICINE:
Drug Deals Diabetes a One-Two Punch
Jennifer Couzin
Like a seesaw poised in midair, insulin and blood sugar normally balance each other out. But in type II diabetes, that equilibrium goes awry: People have ineffective insulin and too much glucose, a condition that damages blood vessels and other tissue. Drugs control the disease by enhancing insulin activity, but they don't work for everyone. Now a novel strategy has drastically reduced blood sugar levels in rodents, sparking hope that it could become a powerful tool for controlling diabetes.
Insulin is a hormone that shuttles glucose into cells. When the pancreas churns out too little insulin or the body doesn't respond to it properly, cells don't absorb enough glucose and blood sugar levels soar. There's no perfect therapy, but most drugs tackle the problem by increasing insulin production or enhancing cells' sensitivity to insulin. In severe cases, patients rely on insulin injections.
On page 370, molecular pharmacologists Joseph Grippo, Joseph Grimsby, and their colleagues at Hoffmann-La Roche in Nutley, New Jersey, describe how their gamble on a different strategy paid off. The group bet on an enzyme called glucokinase, which regulates two key functions that fail in diabetics: secretion of insulin by the pancreas and production of glucose by the liver. Boosting glucokinase activity, they believed, might normalize both--something no diabetes drug can do.
Researchers don't know whether glucokinase abnormalities play a part in diabetes. But they've long agreed that the enzyme is a critical cog in the faltering machinery behind the disease. Two rare mutations in the glucokinase gene illustrate its powers. When the enzyme is curtailed, patients have a mild form of diabetes called MODY2; when glucokinase is overactive, patients wind up with too much insulin and low blood sugar.
Activated. A glucokinase (above) enhancer tackles two major defects found in diabetes.
CREDIT: J. GRIMSBY ET AL.
Using a molecular screen, Grippo and his colleagues dug a glucokinase activator out of a haystack of 120,000 candidate molecules. Identifying an activator is "like getting a number out of a lottery," because the vast majority of drugs act by inhibiting proteins, says Luciano Rossetti, director of the diabetes center at Albert Einstein College of Medicine in New York City.
The researchers tested the activator on islet cells, the pancreatic cells that secrete insulin. The drug coaxed rat islet cells to release insulin even when glucose levels weren't that high--something that could help diabetics who produce too little hormone. Rat liver cells were responsive, too: When exposed to the drug, they released less glucose than usual, easing another major problem for diabetes patients. The drug's ability to target the pancreas and the liver simultaneously "is a potential big plus," says Alan Cherrington, a physiologist at Vanderbilt University in Nashville, Tennessee.
Diabetic mice given the activator responded dramatically. With a single oral dose of the drug, their blood sugar levels plummeted by half, and in some cases they dropped below normal. Injecting animals with an almost identical molecule that doesn't activate glucokinase had no effect. Further studies confirmed that the activator was targeting glucokinase in both islet cells and liver cells.
This drug is a departure from existing ones, which "all circle around what insulin does," says Robert Rizza, an endocrinologist at the Mayo Clinic in Rochester, New York. But, Rizza notes, the activator's novelty also demands cautious calibration of risks and benefits. The main worry, he and others say, is that the drug might push blood sugar levels dangerously low.
"If and when it gets to people, it's going to have to be used cautiously," agrees David Moller, who oversees preclinical diabetes and obesity research at Merck, a Roche competitor in nearby Rahway, New Jersey. He points out another potential problem: accumulation of fat in the liver, a process that can be accelerated when the organ takes in too much glucose. And there are some obvious limits on the drug's potential: For example, it probably wouldn't be useful against type I or severe type II diabetes, both of which cause patients to secrete little or no insulin.
Grippo agrees that the drug is not risk-free, but he's optimistic that the risks can be managed. He notes that his team detected no liver problems in animal studies. And he says careful dosing would enable users to steer clear of side effects.
As a pharma, Roche is starting to look more respectable (mainly, but not only, because of DNA).
Peter
Peter |
