August 2005 - The role of insulin resistance (IR) in type 2 diabetes, the most frequently encountered metabolic disorder in the world, has attracted much attention in recent years. Virtually all patients with type 2 diabetes have IR, which usually appears some 10-20 years before the disease itself. Although the link between IR and type 2 diabetes is well recognized, how IR develops and why it leads to diabetes is not well understood. A study by Kitt Petersen, Sylvie Dufour, and Gerald Shulman (of Yale University) published in the open access international medical journal PLoS Medicine now provides new information on the early steps in the development of IR and suggests why insulin-resistant people easily gain weight.
The researchers studied children of diabetic parents, some of whom are insulin-resistant while they are still young and lean. Because they have none of the confounding factors that are likely to be present in patients with type 2 diabetes, they are ideal for studying the earliest metabolic defects associated with IR. The researchers compared 7 such individuals with lean, healthy, non-smoking control participants who were matched for age and weight.
Specifically, they looked at energy generated in the muscles in response to insulin stimulation (insulin is normally released after a meal). They found that while insulin increases energy production in the muscles of the control participants by approximately 90%, it had very little effect in the insulin-resistant individuals. They also studied the amount of inorganic phosphate (an essential trace element and key regulator of energy generation) in muscle cells of both groups, and how it was affected by insulin. They found that in control individuals, insulin results in an increase of phosphate in muscle cells, and that this is also much reduced in insulin-resistant individuals.
These results provide more support for the notion that insulin resistance compromises proper functioning of energy generation in the mitochondria of muscle cells. It also suggests that impairment of phosphate transport into muscle cells might be one of the early events in the development of diabetes.
Anton Wagenmakers (of the University of Birmingham), who was not involved with the study, states that "the basal observation is clinically very relevant in that it might explain the weight maintenance problems that insulin-resistant and obese individuals experience". Because exposure to insulin (as normally happens after a meal) leads to increased energy production in the muscles of healthy individuals but not of insulin-resistant ones, insulin-resistant individuals appear to require less calories for basic body functions and will gain weight unless they eat less or exercise more.
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Citation: Petersen KF, Dufour S, Shulman GI (2005) Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med 2(9): e233.
Source: Public Library of Science