Genes point to varied diabetes subtypes

By LAURAN NEERGAARD
You've heard of Type 1 and Type 2 diabetes, but what about a kind called MODY? Diabetes is undergoing a genetics revolution that suggests there actually are many subtypes of the disease.
The discoveries already trigger important changes in treatment for a fraction of patients with some rare diabetes types caused by single genes gone awry — if they have a doctor aware of the findings.
"We've got a whole group of diabetologists who have never heard of this," laments Dr. Andrew Hattersley, a British physician-scientist who pioneered how to treat single-gene subtypes collectively known as MODY.
Yet the vast majority of diabetes is caused by complex interactions among numerous genes and modern lifestyles — and a flurry of genetic discoveries in the past year finally points to new ways of attacking the epidemic.
So this week, U.S. health officials are bringing 20 drug companies together with international gene specialists to jump-start the hunt for new therapies.
"We're trying to inspire some really creative thinking," says Dr. Francis Collins, gene chief at the National Institutes of Health, who organized the first-of-a-kind meeting.
Why does diabetes strike one person who's overweight but not another who's equally heavy? Why does one diabetic need dialysis while another has healthy kidneys despite decades of bad blood sugar? The newest gene work suggests there likely are even more subtypes that explain those differences, and that in turn may require personalized treatment just as MODY does.
Some 21 million Americans have diabetes, meaning their bodies cannot properly turn blood sugar into energy. Either they don't produce enough insulin or don't use it correctly.
With the Type 1 form, the body's immune system attacks insulin-producing pancreatic cells, so that patients require insulin injections to survive. It usually, but not always, strikes in childhood.
With the most common Type 2 form, the body gradually loses its ability to use insulin, so the confused pancreas churns out extra until eventually its cells wear out. Most at risk are the overweight.
Genetics research is showing diabetes is far more complicated than those simple demarcations:
_First there's MODY, shorthand for six different subtypes thought to account for 2 percent of all diabetes. Each is caused by a single, different gene. Suspicions arise when patients are extra hard to treat, especially skinny people diagnosed with Type 2 diabetes or young adults with diabetic relatives who abruptly seem to develop Type 1.
Consider Dan Humphries of Shawbury, England, who at age 16 was diagnosed with Type 1. His mother, a nurse with diet-controlled diabetes, questioned the diagnosis. But doctors insisted he was too skinny for other diabetes. They prescribed insulin that had Humphries passing out from low blood sugar even with small doses.
His mother sought out Britain's Peninsula Medical Center in Exeter, where Hattersley performed a gene test that showed Humphries' pancreas actually can make its own insulin. But a gene called HNF1-alpha was essentially putting that production to sleep.
Over a decade of research, Hattersley had found that old diabetes drugs called sulfonylureas neutralize that gene so insulim production resumes. Sure enough, Humphries, now 19, is fine with a quarter-tablet morning and night.
_That brings us to the 16 genes discovered so far to play a role in Type 2 diabetes, and at least 14 in Type 1.
Surprisingly, the Type 2 genes don't affect how the body uses insulin, thought to be the trigger. Instead, they alter how the pancreas makes insulin in the first place, explains Dr. David Altshuler of Harvard and the Massachusetts Institute of Technology.
So how healthy your pancreas starts out could determine how vulnerable you are to other diabetes triggers, like getting fat.
Collins points to one potential drug target: A gene with the sole job of getting zinc to insulin-creating cells. Zinc's a key part of the recipe; too little or too much, and insulin isn't secreted.
But randomly choosing a gene to target is "a shot in the dark," cautions Eric Schadt of Merck & Co., who will urge another approach at this week's meeting, hosted by the National Disease Research Interchange.
Monday in the journal Nature, Schadt reports finding how multiple genes work together in computer-like networks that suggest which will be master control switches — and thus good drug targets. Already, Merck has begun checking whether one network of obesity genes really might predict which overweight people get diabetes.