Type 2 Diabetes: Problems In The Furnace

The research team said that insulinresistance — an impaired response to the presence of insulin — isdetectable as early as 20 years before the symptoms of diabetes becomeevident. In fact, insulin resistance is now seen as the best predictorthat type 2 diabetes will eventually develop, said the study's seniorauthor, Gerald I. Shulman, a Howard Hughes Medical Instituteinvestigator at the Yale University School of Medicine.

In thenew study examining how insulin interacts with the energy-producingmitochondria inside living cells, Shulman and his colleagues found thatthe rate of insulin-stimulated energy production by mitochondria issignificantly reduced in the muscles of lean, healthy young adults whohave already developed insulin resistance and who are at increased riskof developing diabetes later in life.

“This is further evidencethat people who are prone to develop diabetes have signs ofmitochondrial dysfunction,” Shulman said in an interview. This isimportant because mitochondria are the “energy factories” inside cellsand produce most of the chemical power needed to sustain life.

Thenew research, which is published in the September 2005 issue of theopen-access journal PLoS Medicine, indicates that a decreased abilityto burn sugars and fats efficiently is an early and central part of thediabetes problem. Their new data also suggest the basic defect lieswithin the mitochondria, which exist in almost every cell.

Theyoung adults studied by the research team are the offspring of parentswho have type 2 diabetes, adding support to the idea that the risk canbe inherited, and that the problem begins well before diabetes symptomsbecome evident. In an earlier research study published in the journalScience, Shulman and his colleagues had also found that healthy, leanolder individuals have a major reduction in mitochondrial energyproduction that leads to accumulation of fat inside muscle cellsresulting in insulin resistance. “These data may explain the increasedprevalence of type 2 diabetes that occurs with aging” Shulman said.

Inthe new studies, Shulman and his Yale colleagues — Kitt Falk Petersenand Sylvie Dufour — discovered that the mitochondria in muscle cellsrespond poorly to insulin stimulation. Normal mitochondria react toinsulin by boosting production of an energy-carrying molecule, ATP, by90 percent. But the mitochondria from the insulin-resistant people theytested only boosted ATP production by 5 percent.

“These datademonstrate that insulin-stimulated rates of ATP synthesis are reducedin the insulin-resistant offspring of parents with Type 2 diabetes,”the researchers wrote in their report. Their work offers new insightinto the early steps in the development of insulin resistance, andoffers important clues to where the problem lies.

Among theirfindings was also evidence for a severe reduction in the amount ofinsulin stimulated phosphorus transport into the muscle cells of theinsulin-resistant participants. This also points to a dramatic defectin insulin signaling and may explain the observed abnormalities ininsulin-stimulated power production in the insulin-resistant studysubjects, since phosphorus is a key element in the mitochondrion'scomplex energy-production process, the oxidative-phosphorylationpathway.

“Type 2 diabetes affects about 171 million peopleworldwide, and the number of people likely to be affected by diabetesis expected to double by 2030,” Shulman and his colleagues added. “Type2 Diabetes develops when resistance to insulin action is combined withimpaired insulin secretion,” resulting in a severe oversupply of sugarsand fats in the blood. “Studies have demonstrated the presence ofinsulin resistance in virtually all patients with type 2 diabetes,”Shulman added. Diabetes is the leading cause of blindness, end stagekidney disease and non-traumatic loss of limb, and has associatedhealth care costs that exceed $130 billion a year in the United States.

Suchfundamental research is important because the problem of diabetes isgrowing rapidly worldwide, and effective drugs are needed to halt oreven reverse the disease process. Understanding how the cell's internalenergy system is controlled by the hormone, insulin, and how themitochondria behave, may eventually lead to improved ways to overcomeor prevent diabetes.