Outfoxing Insulin Resistance
Authors: Leslie Mitch 
Published: August 2003

Cells of people with type II diabetes are hard of hearing. They don't respond normally to the hormone insulin, and consequently blood sugar concentrations can soar. A new study suggests that a single genetic flaw spurs many of diabetes' metabolic mishaps. Tweaking the guilty gene or its partners might sharpen cellular hearing and help rein in blood sugar quantities.

The communication breakdown in type II diabetes is called insulin resistance. The liver doesn't heed the message to stop releasing glucose; fat and muscle cells ignore insulin's edicts to sop up sugar from the blood. Simultaneously, insulin release by β cells in the pancreas falters. Diabetes experts have battled over whether insulin resistance and β-cell glitches have the same cause. A clue came in 1997, when two labs showed that mutations in the worm version of the gene
Foxo1
counteract mutations in
daf-2
, which resembles the mammalian insulin-receptor gene. Based on this observation, Nakae and colleagues guessed that
Foxo1
might regulate insulin sensitivity in humans. The Foxo1 protein is a forkhead transcription factor; other members of this family promote longevity in worms and might help mammals beat stress (see
"Stay Mellow, Stay Young"
). But these proteins hadn't previously been implicated in diabetes.

The researchers tested their hunch in mice whose physiology mimics human diabetes because they're genetically engineered to resist insulin. These insensitive beasts show above-normal blood concentrations of insulin and glucose, and about 10% of them become diabetic. Although obliterating both copies of
Foxo1
is lethal, disabling one copy of the gene slashed the animals' blood sugar and insulin values and protected them from diabetes, the researchers found. The team then cranked up
Foxo1
activity by inserting a version of the gene that never shuts off. In one group of altered mice, the pancreas released too little insulin, an indicator of malfunctioning β cells. In a second group that produced even more Foxo1, the liver poured too much glucose into the blood.

The findings, which suggest that a single defect causes insulin resistance and β-cell malfunction, could be a boon for diabetes treatment and early diagnosis, says study co-author and geneticist Domenico Accili of Columbia University in New York City. Inhibiting the gene might hike insulin sensitivity and trim blood sugar concentrations. What's more, it's possible that diabetics carry hyperactive versions of
Foxo1
. If so, genetic tests could detect people who are susceptible to the disease long before symptoms appear, he says.

The work shows that
Foxo1
is a big shot in the metabolic pathway that goes awry in diabetes, says Morris Birnbaum, a cell biologist at the University of Pennsylvania in Philadelphia. However, he says that Foxo1 is unlikely to make a good drug target. It controls gene activity, he notes, and compounds aimed at this type of protein usually flop. But the discovery of
Foxo1
's role will allow researchers to identify other genes in the pathway that might be easier to manipulate, he says. Such a breakthrough would be sweet news for diabetics.

--Mitch Leslie; suggested by Greg Liszt

J. Nakae, W. H. Biggs III, T. Kitamura, W. K. Cavanee, C. V. E. Wright, K. C. Arden, D. Accili, Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.
Nat. Genet.
, 3 September 2002 [e-pub ahead of print].
[Abstract/Full Text]