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Epidemiologists have long known that obesity contributes to type 2 diabetes. But how, exactly, does the extra fat set off insulin resistance, the chronic metabolic disorder that foreshadows diabetes? Umut Özcan, MD, from Children's Division of Endocrinology, has untangled the links.
In 2004, while still a medical student, Özcan discovered that obesity leads to perturbations and stress in a cell's endoplasmic reticulum (ER), where amino acids are assembled into proteins and dispatched to do jobs for the cell. Obesity forces the ER to process higher-than-normal numbers of fats and proteins. In fat cells, this excess traffic makes orderly ER operations break down. The resulting "ER stress" activates a cascade of events that suppress the body's response to insulin.
Özcan reasoned that helping the ER withstand the onslaught of fat might prevent the treacherous metabolic slide to diabetes. Using chemicals that relieve ER stress, he and colleagues have succeeded in restoring the insulin response and normalizing glucose levels in diabetic mice. Now, Özcan hopes to do the same in humans.
Since joining Children's, he and his group have also sought to understand the basis of appetite and feeding regulation in the brain. Aided by a Translational Research Grant from Children's, the new work could provide a novel path to weight loss.
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