Spotlight on diabetes

Now, however, the party is proving to be much louder and more complex than anyone had shown before. Focusing on the cross-talk between more different organs, cells and molecules represents a 8220;very important change in our paradigm8221; for understanding how the body handles glucose, said Dr C Ronald Kahn, a diabetes researcher and professor at Harvard Medical School.

The defining feature of diabetes is elevated blood sugar. But the reasons for abnormal sugar seem to 8220;differ tremendously from person to person,8221; said Dr Robert A Rizza, a professor at the Mayo Clinic College of Medicine. Understanding exactly what signals are involved, he said, raises the hope of 8220;providing the right care for each person each day, rather than giving everyone the same drug.8221;

THE SKELETON

New research suggests that a hormone from the skeleton, of all places, may influence how the body handles sugar. Mounting evidence also demonstrates that signals from the immune system, the brain and the gut play critical roles in controlling glucose and lipid metabolism. The findings are mainly relevant to Type 2 diabetes, the more common kind, which comes on in adulthood.

Last summer, researchers at Columbia University Medical Center published startling results showing that a hormone released from bone may help regulate blood glucose.

When the lead researcher, Dr Gerard Karsenty, first described the findings at a conference, the assembled scientists 8220;were overwhelmed by the potential implications,8221; said Dr Saul Malozowski, senior adviser for endocrine physiology research at the National Institute of Diabetes and Digestive and Kidney Diseases. 8220;For the first time, we see that the skeleton is actually an endocrine organ,8221; producing hormones that act outside of bone.

In previous work, Dr Karsenty had shown that leptin, a hormone produced by fat, is an important regulator of bone metabolism. In this work, he tested the idea that the conversation was a two-way street. 8220;We hypothesised that if fat regulates bone, bone in essence must regulate fat,8221; he said.

Working with mice, he found that a substance called osteocalcin, which is produced by bone, controlled fat cells and pancreas. In mice prone to Type 2 diabetes, an increase in osteocalcin addressed both insulin resistance and low insulin production, bringing their blood sugar down. As a bonus, it also made obese mice less fat.

If osteocalcin works similarly in humans, it could turn out to be a 8220;unique new treatment8221; for Type 2 diabetes, Dr Malozowski said. Most current diabetes drugs either raise insulin production or improve insulin sensitivity, but not both. Drugs that increase production tend to make insulin resistance worse.

A deficiency in osteocalcin could also turn out to be a cause of Type 2 diabetes, Dr Karsenty said.

IMMUNE SYSTEM

Another recent suspect in glucose regulation is the immune system. In 2003, researchers from two laboratories found that fat tissue from obese mice contained an abnormally large number of macrophages, immune cells that contribute to inflammation.

Scientists have long suspected that inflammation was somehow related to insulin resistance, which precedes nearly all cases of Type 2 diabetes.

In the early 1900s, diabetics were sometimes given high doses of aspirin, which is an anti-inflammatory, said Dr Jerrold M Olefsky of the University of California, San Diego, School of Medicine. But only in the past few years has research into the relationship of obesity, inflammation and insulin resistance become 8220;really hot,8221; said Dr Alan R Saltiel, director of the Life Sciences Institute at the University of Michigan.

Many researchers agree that obesity is accompanied by a state of chronic, low-grade inflammation in which some immune cells are activated and it may be a primary cause of insulin resistance. They also agree that the main type of cell responsible for the inflammation is the macrophage, Dr Saltiel said. But major questions remain, he said: 8220;Why are these macrophages attracted to fat, liver and muscle in the first place? What are they doing? What are they secreting? 8221;

New research also suggests that 8220;not all macrophages are created equal,8221; added Dr. Saltiel. There appear to be 8220;good ones and bad ones8221; competing in fat tissue, with potentially large consequences for inflammation and diabetes.

Meanwhile, the promise of anti-inflammatory compounds as treatment continues to attract attention. 8220;Certain cellular anti-inflammatory proteins may now be important new targets for drug discovery for diabetes treatment,8221; Dr Olefsky said. But damping down the immune system is also potentially risky, he noted, 8220;If you8217;re inhibiting the macrophage inflammatory pathway, that8217;s good for diabetes. But it might not be so good for your susceptibility to infections.8221; A major goal is to develop a drug that quashes only the specific component of macrophage inflammation that leads to insulin resistance, without causing other side effects. One class of current medications, called thiazolidinediones, may work in part by reducing inflammation, which may in turn improve insulin sensitivity. But an example from this class, the drug Avandia, was also found to increase the risk of heart attacks.

THE BRAIN

Another participant in the glucose conversation is the brain.

Its role has long been suspected. More than a century ago, the French physiologist Claude Bernard suggested that the brain was important in blood sugar regulation. He punctured the brains of experimental animals in specific areas and managed to derange their blood sugar metabolism, making them diabetic.

But for years, virtually no one followed up on this finding, said Dr Kahn, of Harvard.

People thought glucose was a critical fuel for the brain, but did not explore the brain8217;s role in glucose regulation. Only recently, with more advanced laboratory techniques, has this role been definitively established and expanded upon.

Today8217;s genetic techniques, said Dr Rizza at the Mayo Clinic, are what have 8220;really driven the process.8221; For instance, once scientists developed the ability to manipulate mice so that they lacked particular receptors in specific tissues, they could show that mice without insulin receptors in the brain could not regulate glucose properly and went on to develop diabetes, said Dr Kahn, whose laboratory published this groundbreaking work in 2000.

Other researchers have shown that free fatty acids, as well as the hormone leptin, produced by fat tissue, signal directly to a part of the brain called the hypothalamus, which also regulates appetite, temperature and sex drive.

And several recent papers suggest that direct signaling by glucose itself to neurons in the hypothalamus is also crucial to normal blood sugar regulation in mice. 8220;If the brain is getting the message that you have adequate amounts of these hormones and nutrients, it will constrain glucose production by the liver and keep blood glucose relatively low,8221; said Dr Michael W Schwartz, a professor at the University of Washington. But if the brain senses inadequate amounts, he continued, it will 8220;activate responses that cause the liver to make more glucose, and new evidence suggests that this contributes to diabetes and impaired glucose metabolism.8221;

The brain, therefore, appears to be listening to 8212;and weighing and making sense of 8212; a chorus of signals from insulin, leptin, free fatty acids and glucose itself. In response, it appears to send signals to liver and muscle cells by way of several nerves, though additional mechanisms are probably involved.

AND THE INTESTINES

The gut also seems to chime in, said Dr Rizza, adding that for him, this aspect of sugar regulation came as 8220;the biggest gee whiz of all.8221; 8220;Food comes in through the gut, so of course you should look there8221; for molecules involved in glucose regulation, he said. 8220;But few people realised this until very recently.8221;

Hormones from the small intestine called incretins turn out to talk directly with the brain and pancreas in ways that help reduce blood sugar and cause animals and people to eat less and lose weight, Dr Rizza said. Numerous molecules that mimic incretins or prevent them from being degraded are in clinical trials.

8220;The picture is becoming more and more complicated,8221; Dr Saltiel said. 8220;And let8217;s face it, it was pretty complicated before.8221;