After Cracking Metformin Code, Scientist Makes Breakthrough Discovery That Points The Way To New Class Of Diabetes Drugs

HDAC inhibitors may provide a novel way to cut excessive blood glucose levels at the source

RESEARCHERS have uncovered a novel mechanism that turns up glucose production in the liver when blood sugar levels drop, pointing towards a new class of drugs for the treatment of metabolic disease, the Salk Institute for Biological Studies announced in a press statement on Tuesday.

Dr Reuben J. Shaw

In a uniquely collaborative study, the scientists have found evidence ‒ published in the May 13, 2011 issue of the journal Cell ‒ that a group of enzymes, or proteins, currently under investigation for the treatment of cancer could potentially also work as a treatment for type 2 diabetes. This is significant because it not only portends a new treatment for diabetes, but it also could mean that a new treatment has already gotten through the costly and lengthy early stages of drug development.

The Salk discovery revolves around enzymes called histone deacetylases, or HDACs, which help the liver produce sugars when blood glucose runs low after prolonged periods of fasting, particularly at night. After a meal, insulin “instructs” muscle cells to store this glucose and turns off sugar production in the liver. In patients with type 2 diabetes, however, the body effectively doesn’t “listen” to insulin, and the liver keeps producing sugar.

In liver cells, so called class II HDACs (shown in green) are usually sequestered in the cytoplasm.

“These exciting results show that drugs that inhibit the activity of class II HDACs may be worthwhile to be pursued as potential diabetes drugs,” said lead author Reuben Shaw, an assistant professor in Salk’s Molecular and Cell Biology Laboratory.

Up to this point, all experiments had been performed in cultured cells but the researchers were really interested in whether class II HDACs controlled blood glucose in mouse models of diabetes. Strikingly, suppression of all three HDACs simultaneously restored blood glucose levels to almost normal in four different models of type 2 diabetes.

In response to glucagon, HDACs quickly move into the nucleus, where they help turn on genes needed for the production of glucose in the liver

“The key will be to specifically block HDACs involved in glucose control,” said Shaw, “but the fact gluconeogenesis takes place in the liver makes this task easier as most drugs sooner or later travel to the liver once they hit the bloodstream.”

“Our results predict then that some of those drugs, probably not the same ones that work on cancer but some of the ones that are sitting on the shelf that maybe weren’t effective for cancer but in fact hit these enzymes, that they could be potential therapeutics for diabetes,” said Shaw. “That means that the time from this initial discovery until the time that this can be tested in the clinic is much shorter.”

Dr. Ronald Evans, a professor in Salk’s Gene Expression Laboratory, said that while this discovery is novel, scientists have long noticed a link between cancer and diabetes, particularly because the risks of both diseases are increased in obese patients. This discovery — that suppressing HDACs can treat diabetes as well as cancer — is a way of turning this theory into a potential treatment.

“We know that along with increased weight and obesity there is an increased risk of cancer. We also know that cancer cells undergo a profound metabolic change and so the cancer metabolism has become a very big area (of study),” Evans said.

“So for those of us who study metabolism and study cancer, the link between these two seemingly separate areas, actually at the level of the genome, happen to work with several common pathways,” he continued, “because they’re both dealing with either consuming energy, which is what happens with cancer, or storing energy, which is what happens with obesity.”

Does Periodic Fasting Lower Diabetes Risk?

Currently, metformin (Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet), an oral biguanide anti-diabetic drug, is the most widely prescribed agent for treatment of type 2 diabetes. The drug mainly works by lowering glucose production by the liver, and thus lowering fasting blood glucose. Although metformin – approved in the United States in 1994, and in Europe prior to that – has been used for many years, its mechanism of action is not well understood.

Galega officinalis (Goat's Rue)

“Metformin is originally derived from a plant found in Western Europe called ‘French lilac’ or ‘Goat’s Rue’ because goats didn’t like to eat it. They steered clear of the plant because it contains a compound that acts to naturally lower blood glucose in animals that eat it ‒ to prevent them from eating it again,” Shaw explained.

A few years ago, Shaw discovered how metformin helps insulin to control glucose levels:  It binds to a “metabolic master switch” known as AMPK that blocks glucose production in the liver. Trying to identify novel targets of AMPK that might be relevant to diabetes, Maria Mihaylova, a graduate student in the Shaw laboratory, focused her efforts on a family of HDACs known as class II HDACs. They function as negative regulators of gene activity by stabilizing the tightly coiled structure of DNA in chromosomes, making it inaccessible to proteins that transcribe DNA.

Working closely with Ronald M. Evans and his team, Mihaylova found that inhibiting class II HDACs shut down genes encoding enzymes needed to synthesize glucose in liver. “We identified class II HDACs as direct targets of AMPK in a bioinformatics-based screen, but we didn’t know which genes they might regulate in liver since they weren’t even known to be found there,” said Mihaylova.

In collaboration with her colleagues in Marc Montminy’s lab, a professor in the Clayton Foundation Laboratories for Peptide Biology, and like Shaw and Evans a member of the Center for Nutritional Genomics at the Salk Institute, Mihaylova discovered that HDACs themselves associated with the DNA regulatory elements controlling the expression of the glucose synthesizing enzymes, but they only flocked there after she had treated cells with the fasting hormone glucagon.

“In response to the glucagon, chemical modifications on class II HDACs are removed and they can translocate into the nucleus,” she explains. There, they bind to FOXO, a key metabolic regulator, which had been shown previously to be shut down by insulin.

“It came as a big surprise that FOXO is activated by glucagon,” explains Shaw. Further experiments confirmed that the genetic suppression of class II HDACs in liver cells led to an increase in acetylated FOXO, which now can neither bind DNA nor activate the genes encoding glucose-synthesizing enzymes.

A parallel study, led by Montminy and published in the same issue of Cell as Shaw’s paper, shows that in fruit flies, FOXO not only controls the expression of a fat-digesting enzyme but is activated by a glucagon-like hormone in a manner similar to human FOXO.

“The central circuitry of how animals regulate metabolism in response to fasting and feeding is conserved from fly all the way to man emphasizing the importance of class II HDACs in coordinating how different hormones direct the creation and use of glucose,” says Shaw, who is a co-author on Montminy’s paper.

Shaw next plans to test whether these glucose loving HDACs may also play roles in certain forms of cancer as well.

Source: Salk Institute for Biological Studies

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