A hormone from the skeleton, signals from the immune system, the brain and the gut, all these play critical roles in controlling glucose and lipid metabolism, say scientists.
(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 Centre published startling results showing that a hormone released from bone may help regulate blood glucose.
Lead researcher, Dr. Gerard Karsenty said that working with mice, they found that a previously known substance called osteocalcin, which was produced by bone, acted by signaling fat cells as well as the pancreas. The net effect was to improve how mice secrete and handle insulin, the hormone that helped the body move glucose from the bloodstream into cells of the muscle and liver, where it could be used for energy or stored for future use.
In Type 2 diabetes, patients' bodies no longer heed the hormone's directives. Their cells are insulin-resistant, and blood glucose levels surge. Eventually, production of insulin in the pancreas declines as well.
Dr. Karsenty found that in mice prone to Type 2 diabetes, an increase in osteocalcin addressed the twin problems of insulin resistance and low insulin production. That is, it made the mice more sensitive to insulin and it increased their insulin production, thus 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 "unique new treatment" for Type 2 diabetes.
A deficiency in osteocalcin could also turn out to be a cause of Type 2 diabetes, Dr. Karsenty said.
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.
Only in the past few years has research into the relationship of obesity, inflammation and insulin resistance become "really hot," 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 that that 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: "Why are these macrophages attracted to fat, liver and muscle in the first place? What are they doing? What are they secreting? What other immune cells are in there?"
New research also suggests that "not all macrophages are created equal," added Dr. Saltiel. There appear to be "good ones and bad ones" 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. Certain cellular anti-inflammatory proteins may now be important new targets for drug discovery for diabetes treatment.
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.
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.
Again recently researchers were able to show that mice without insulin receptors in the brain could not regulate glucose properly and went on to develop diabetes.
It has also been found 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.
"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," said Dr. Michael W. Schwartz, a professor at the University of Washington. But if the brain senses inadequate amounts, he continued, it will "activate responses that cause the liver to make more glucose, and new evidence suggests that this contributes to diabetes and impaired glucose metabolism."
The gut also seems to chime in. 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.
Numerous molecules that mimic incretins or prevent them from being degraded are in clinical trials. Two such drugs have been approved by the Food and Drug Administration - Byetta, an incretin mimic, from Amylin Pharmaceuticals and Eli Lilly; and Januvia, from Merck, which inhibits the destruction of the incretin GLP1.
Focusing on the cross-talk between more different organs, cells and molecules represents a "very important change in our paradigm" for understanding how the body handles glucose, said Dr. C. Ronald Kahn, a diabetes researcher and professor at Harvard Medical School.