As scientists explore the connections between type 2 diabetes and obesity, they seem to have settled on one principle: The amount of fat doesn't matter so much as where it is in the body.
Extra pounds are considered a risk factor for the condition, but most obese people don't develop diabetes.
And some type 2 patients, fewer than 20 percent, are lean, said Dr. Judith Fradkin, director of the National Institute of Diabetes and Digestive and Kidney Diseases' diabetes, endocrinology and metabolic disease division.
"Although the obesity epidemic is driving the dramatic increases in type 2 diabetes, that's not the only thing going on," she said.
In April, an international team of researchers, primarily sponsored by NIDDK, announced in the journal Science that after combing the human genome, they had identified at least four new gene variants associated with elevated diabetes risk and confirmed the existence of another six.
More work must be done to figure out what the key genes actually do to influence diabetes development.
"Now that we know these genes are linked to diabetes, there's going to be a huge explosion to try to figure out the pathways through which these genes are acting," Dr. Fradkin said. "The importance of that is to develop new therapies."
The hallmark problem in type 2 diabetes and its precursor, pre-diabetes, is that muscle and liver cells are resistant to insulin, a hormone that regulates blood sugar levels and is produced by the beta cells of the pancreas.
For a while, the beta cells are able to boost insulin production sufficiently to overcome the problem. When they no longer can rise to the challenge, blood sugars go up and the patient is diagnosed with pre-diabetes or the full-blown condition.
"Insulin resistance is the best predictor for whether or not someone will develop diabetes," said Dr. Gerald Shulman, an investigator for the Howard Hughes Medical Institute and a professor of medicine and physiology at Yale University. "So the question is, what causes insulin resistance?"
Using a technique called MR spectroscopy, his team was able to track tagged glucose molecules and their metabolism in the body. In muscle, they determined there was a problem in converting glucose into glycogen, a storage form of the sugar, primarily because glucose was not being transported efficiently into the cell.
Dr. Shulman noted that insulin-resistant individuals had a greater amount of fat inside muscle cells. "It's not marbling," like in a steak, he said. "It's little droplets of fat inside the [muscle cell]."
More research indicated metabolites of the intracellular fat interfered with insulin activation and signaling, which led to decreased glucose transport.
In liver cells, intracellular fat metabolites appear to trigger a cascade of events that alter the organ's normal conversion of glucose into glycogen, giving type 2 patients unusually high sugars after eating, and causes the organ to needlessly make more glucose from amino acids and lactate, causing high fasting sugars as well, he said.
So "it's not so much how much fat we have, it's really how it's distributed that's responsible for insulin resistance," Dr. Shulman said. "When it builds up inside the liver cells and muscle cells, that's when it causes trouble."
His team did a study with overweight, poorly controlled type 2 patients and found that calorie restriction and a 14- to 16-pound weight loss led to liver fat reduction and normalization of fasting blood sugar, he said.
In another project, they found that regular exercise could reverse insulin resistance in lean, otherwise healthy 20-year-olds. Dr. Shulman said exercise decreases intracellular fat by increasing the cell's need for energy, so it brings in glucose by a mechanism that doesn't depend on insulin. Also, activity increases the function of mitochondria, the so-called powerhouse of the cell.
The researchers reported in a July issue of the Proceedings of the National Academy of Sciences that insulin resistance appears to play the critical role in metabolic syndrome: high body mass, high blood pressure, high levels of triglycerides and LDL, or "bad" cholesterol; and low levels of HDL, or "good" cholesterol.
Young, lean but insulin-resistant individuals tended to divert carbohydrates they had eaten into liver fat, while their insulin-sensitive peers converted them into muscle glycogen, Dr. Shulman said.
The muscle defect likely comes first, he said, and "if they don't change anything and they put on more weight ... they will be prone to fatty liver disease. And this fatty liver disease then causes insulin resistance in the liver."
"We're trying to now identify pharmacological targets to melt fat away inside the liver and muscle cells," he said. "I'm quite excited about it because we've identified half a dozen potential targets that are working in mouse models and we're keen to then translate these findings into humans."
While some researchers have suggested abdominal fat is a particular risk factor for diabetes, the Yale findings seem to say, "Don't blame the belly fat," as Dr. Shulman put it, because it could just be a marker for liver fat.
"From my perspective, it's all pretty simple," he said. "If we keep our eye really focused on melting away intracellular fat, I think that's going to make a huge difference in our patients."
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