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

Controlling Diabetes May Reduce Cancer Risk and Death

There are myriad benefits from avoiding diabetes through exercise, diet and maintaining a healthy body weight. A new NIH-AARP Diet and Health Study has confirmed additional benefits in the form of reduced morbidity and mortality from certain cancers.

Diabetes is associated with lower risk of prostate cancer in men but with higher risk of other cancers in both men and women, and the results provide further evidence that abnormal insulin and glucose signaling may contribute to cancer initiation and development. Previous epidemiologic studies have also shown an association between diabetes and an increased risk for cancers including colorectal, liver and pancreas.

Diabetes Associated With Increased Cancer Risk

The 11-year prospective study followed more than 500,000 patients ‒ predominantly white, non-Hispanic men and women aged 50 to 71 years ‒ from 1995 to 1996. The results showed that diabetes was associated with an 8 percent increased risk for cancer among women and a 4 percent decreased risk for men.

In previous research, a decreased risk for prostate cancer was associated with diabetes, which researchers believe might be due to the lower testosterone levels associated with diabetes. After excluding prostate cancer from their evaluation, the researchers found that diabetes was associated with a 9 percent increased risk for cancer in men.

As for mortality, diabetes was associated with an 11 percent increased risk in women and a 17 percent increased risk in men. These risks appeared independent from other cancer risk factors, such as obesity and cigarette smoking.

After evaluating by cancer site, the researchers found diabetes was associated with a significant increase in risk for colon, rectal and liver cancers among men and women. In men, diabetes was associated with an increased risk for pancreatic and bladder cancers. In women, it was associated with an increased risk for stomach, anal and endometrial cancers. No association was found between diabetes and lung, skin or other cancers.

Earlier research has also linked obesity, diabetes and metabolism to cancer risk with the findings linking weight gain and diabetes to a variety of cancers affecting both men and women, including breast, prostate and colorectal cancer.

Colorectal Cancer & Type 2 Diabetes Share Common Factors

Women with diabetes are 1.5 times more likely to develop colorectal cancer than those who do not have the metabolic disorder. The findings add to the complex body of evidence linking diet and colorectal cancer and also provide new evidence that furthers our understanding of the role of insulin in cancer promotion.

It has been determined that colorectal cancer and type 2 diabetes share a number of common factors, including obesity, so it is interesting to see the direct line between these two conditions. In general, the idea is that if elevated insulin levels create a biochemical environment conducive to cancer growth, it provides one mechanism by which diet and lifestyle can really influence cancer risk.

Data from a massive screening study called the Breast Cancer Detection Demonstration Project, initiated at 29 centers throughout the United States in the 1970s involving more than 45,000 study participants with no history of colorectal cancer or self-reported diabetes for eight years (from 1987-1989 and from 1995-1998), was used to identify which of them subsequently developed colorectal cancer.

According to the findings, women with diabetes had a greatly increased risk of developing colorectal cancer. These results remained statistically significant even after controlling for all known and suspected confounding variables.

However, it is not exactly clear what aspect of diabetes is the underlying cause for this increased risk but one hypothesis centers on the elevated concentration of insulin typically seen in people with type 2 diabetes. In the early stages of the disease process, people become insulin resistant, meaning they must produce more and more insulin to regulate their blood sugar.

Pre-Diabetics Also at Increased Risk

Even after frank diabetes begins, insulin levels remain chronically elevated for extended periods before the pancreas can no longer supply the level of insulin the body demands. So, if the elevated insulin is the problem, then pre-diabetics, who are also hyper-insulinemic, should also be at increased risk for developing colorectal cancer.

To test that idea, the researchers re-analyzed the data, this time including women who were likely pre-diabetic at the beginning of the follow-up period. The idea was that these women were likely hyper-insulinemic at that stage. Surprisingly, the elevated risk, while still significant, had dropped slightly in comparison with that of known diabetics.

This suggests that either the pre-diabetic women had not had elevated insulin long enough or intensely enough to increase risk as they observed in the diabetic women, or alternatively, something other than or in addition to hyper-insulinemia could explain the significant, increased risk for colorectal cancer observed in people with diabetes.

Don’t Take Diabetes Lightly ‒ It Can Even Lead To Suicide

There is a general attitude that diabetes is a treatable disease, that’s it’s no big deal, that you just take medicine and you have a normal life.

The truth is diabetics have a 2.5 increased rate of death, meaning people with diabetes are 80 percent more likely to die prematurely than those without the disease.

A new British analysis ‒ published in the March 3 issue of the New England Journal of Medicine ‒ confirms that diabetes is associated with higher mortality.

And it’s not just diabetes that’s killing them. Besides dying from vascular problems caused by diabetes, people with the blood sugar disease are also more likely to die prematurely from many other causes, including cancer, infections, falls, liver disease, mental disorders and even suicide.

Although all the reasons that result in the greater risk of death among diabetics aren’t known, high blood sugar and inflammation are key players. These can decrease the body’s ability to fight off infections and even cancer.

A team lead by John Danesh, a professor of epidemiology and medicine at the University of Cambridge in the UK analyzed deaths among 820,900 people who took part in 97 studies. Among those in these studies, 123,205 died.

The risk of premature death was closely associated with blood sugar levels, with an excess risk of death at blood glucose fasting levels exceeding 100 milligrams per deciliter. There was no excess risk of death at fasting levels of 70 to 100 mg per dL, the researchers found.

The risk of dying from vascular disease, not surprisingly, was much higher in people with diabetes. But people with diabetes were also at increased risk for death from liver and kidney disease, pneumonia, other infectious diseases and chronic obstructive pulmonary disease, among other ills.

Danesh’s team also found that people with diabetes were 25 percent more likely to die from cancer, with scientists finding a moderate association between the disease and death from liver cancer, pancreatic cancer, ovarian cancer, colorectal cancer, and lung, bladder or breast cancer. They were also 70 percent more likely to die from falls than people without diabetes.

In addition, diabetics were 64 percent more likely to die from mental disorders and 58 percent more likely to die from suicide, mostly because they were more likely to be depressed. Indeed, another study showed that management of diabetes can cause chronic stress and strain, which in the long run, may increase risk of depression – the two are linked not only behaviorally but biologically. (See my post ‘Diabetes, Depression Can be a Two-Way Street’ here.)

Broken down, the hazard ratios for people with diabetes vs. people without diabetes were:

• 2.32 for death from vascular causes
• 1.80 for death from any cause
• 1.73 for death from other causes
• 1.25 for death from cancer

Summing up, the study authors write: “These findings highlight the need to better understand and prevent the multi-system consequences of diabetes.”

The challenge before researchers therefore is to continue to find a cure and to prevent diabetes ‒ it cannot just be managed with drugs.

Women With Diabetes Are 50% More Likely To Die If They Have Breast Cancer

Here is some alarming news: A new analysis from Johns Hopkins University shows that women with diabetes are 50 percent more likely to die if they have breast cancer. Why? The challenges of diabetes management play a role, as well as women’s overall health.

According to Kimberly Peairs, an assistant professor of medicine at Johns Hopkins University School of Medicine and the study’s lead author, “When patients are faced with a diagnosis of breast cancer, which they see as an imminent threat to their lives, diabetes care often goes on the back burner.”

The study, published in last month’s issue of the Journal of Clinical Oncology, showed that diabetic women faced multiple problems. They were more likely to be diagnosed with an advanced form of breast cancer. And because of their pre-existing illness, they were more likely to be treated with less effective drugs or suffer from toxic side effects of chemotherapy.

But that’s not all. As is often the case with diabetes, an array of risk factors are par for the course.

Type 2s are more likely to suffer from a constellation of health problems, including obesity and high blood pressure, research shows, along with a higher breast cancer risk. That overall health picture could contribute to their increased death rate, Peairs said.

“This research suggests we may need to proactively treat the diabetes as well as the cancer,” she said.

Where do researchers go from here? They may look at how insulin levels affect tumor growth. They’re also interested in seeing if improvements in diabetic control can also improve cancer outcomes.

The study was a meta-analysis of previously published studies that collected data about patients dealing with cancer and diabetes, and the outcomes of those illnesses. It was funded by the National Institutes of Health and the American Cancer Society, among others.

New-Onset Diabetes May Help Guide Pancreatic Cancer Screening

A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally “dismal” survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

“Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population,” she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify “the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk,” she explained. “So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening.”

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

“It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference,” she explained. “But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure.”

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

“We can make guesses, whether it is socioeconomic or cultural or there is something else in play.” For example, some patients may “tell the doctor about all their symptoms and get worked up early and get their doctors concerned more,” she said. “But if they never come to the physician or they never mention what’s going on, they get diagnosed late.”

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. “I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late,” she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. “Stay tuned for that,” she advised.

“Screening for pancreatic cancer will be a great future tool,” Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

By: SUSAN LONDON, Internal Medicine News Digital Network