The news that tighter control of blood sugar levels appears to increase deaths in a large clinical study hit like a bomb Wednesday, a stark reminder of just how much remains to be learned about the metabolic complexities of diabetes.

The National Heart, Lung, and Blood Institute stopped one treatment in a large, ongoing clinical trial of diabetes and cardiovascular disease 18 months early due to safety concerns after review of available data, although the study will continue. In the trial of adults with Type II diabetes at especially high risk for heart attack and stroke, the strategy of intensively lowering blood glucose below current recommendations actually increased the risk of death compared with a less-intensive standard treatment strategy.

Those metabolic complexities continue to be unraveled at the basic science level. In the Feb 8, 2008, issue of Cell, researchers from the Karolinska Institute in Sweden, the University of Kuopio in Finland and the University of Utah reported that high levels of blood sugar can lower levels of an enzyme that is involved in intracellular fat metabolism, setting off an intracellular cascade that contributes to Type II diabetes symptoms such as insulin resistance and obesity.

The authors focused on the enzyme, called diacylglycerol kinase, because in a pilot gene expression profiling study, they found that diacylglycerol kinase is downregulated in the muscles of Type II diabetics, but only if they have poor blood sugar control.

"That was an eye-opener for us," senior author Juleen Zierath told BioWorld Today.

The scientists studied diacylglycerol kinase expression in muscle biopsies from 10 diabetics and 11 controls, and found that skeletal muscle expression of the delta type was specifically reduced in the diabetics.

The authors next went to animal studies to work out the kinase's mechanism and its relationship to glucose and insulin in more detail. They first compared normal rats to those that have a form of Type II diabetes, and found that the diabetic animals had low levels of skeletal DGK delta, and that those levels increased when their diabetes was treated.

Liver levels of both treated and untreated diabetic rats were similar to each other and to normal controls. Zierath said that other types of the kinase may be important in the liver, and also that such specificity is typical for abnormalities that contribute to diabetes: "to regulate glucose . . . multiple organs play a role," Zierath explained. "All of these tissues work together like an orchestra - though no one really knows who the conductor is." But what is clear is that diabetics have trouble with glucose uptake.

Because there are no pharmacological inhibitors of diacylglycerol kinase that are specific to the delta isoform, the researchers next bred knockout mice that were missing one copy of the kinase, giving them half the normal level of the protein. At nearly 40 percent, diabetic patients had a similar reduction in DGK delta levels.

Since the symptoms of Type II diabetes tend to appear with age - though the age they appear at has been getting younger as exercise and nutritional habits have been getting poorer - the mice were tested at two different ages for their insulin levels, ability to metabolize glucose and their ability to transport glucose.

Nine-week old mice with low DGK delta levels were somewhat less sensitive to insulin, but still showed normal metabolism in many respects. Older mice had a wider variety of problems, including more abnormalities in insulin signaling and obesity.

The animals also had metabolic inflexibility, meaning they were impaired at switching between using glucose and fat for energy. Typically, glucose will be used for energy when it is available, while fat is used for energy when it's not. But animals with low levels of DGK delta were impaired at making that switch. "When they are fasted, they are not able to switch into the fat [metabolism] pathway," Zierath said. And that means the fat is not used, contributing to obesity.

At the molecular level, DGK delta is involved in metabolizing intracellular fats, and when its levels are low, those fats build up. The fats, in turn, activate protein kinase C, which decreases glucose uptake into the skeletal muscle.

Overall, the data suggested that increasing the activity of DGK delta could help ameliorate the consequences of Type II diabetes. Zierath said that the best way to do so would be the old-fashioned one: exercise.

But the findings also provided pharmacological attack points, though Zierath pointed out that any such approach would still need "serious biological validation" in further studies.

Still, the pathway could provide drug targets for those who can't or won't exercise. Zierath said that going downstream to the fats themselves or protein kinase C, whose levels are increased, would probably be a more promising strategy than targeting diacylglycerol kinase delta directly. "It's always harder to activate something - you want to find an inhibitor if you can."