When Christina, a girl from Vineland, New Jersey, entered puberty a few years ago, her fat cells atrophied and disappeared. She grew extremely thin and obsessed with food. "I thought I was starving," she recalls. "My parents had to lock the kitchen cabinets, or I'd eat until I got sick."
Christina had a rare metabolic disorder called lipodystrophy. She also had type 2 diabetes, and her blood contained more than 50 times the normal concentration of triglycerides, a fat precursor. Lacking fat cells, she stored fat in her liver and in lesions under her skin. These pockets of fat were so painful that Christina could not dress or bathe herself.
Doctors at the National Institutes of Health (NIH) could not treat Christina's underlying disease, so they cleaned her blood of triglycerides weekly, in a procedure akin to kidney dialysis. "When I first went to NIH, they said there was nothing they could do," Christina says. "They said I would probably die from it. It was pretty extreme."
In 1995, about the time her symptoms began to appear, HHMI's Jeffrey Friedman discovered the hormone leptin. Although people with lipodystrophy are extremely skinny, their insatiable hunger resembles that of the obese mice Friedman studied. When Christina's doctors at nih found that her body was making no leptin, they decided to test leptin supplements. "The logic was that if you are deficient in the hormone, and we give you the hormone, you may very well respond," says Phillip Gorden, then director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
In July 2000, Elif Oral and her colleagues at NIDDK began a study of Christina and eight other girls and women with lipodystrophy. When they gave Christina leptin injections, the results were swift and dramatic. The compulsive eating, the blood cleansing, the horrid skin lesionseven the rude stares of classmatesbecame memories. "I'm not hungry all the time," says the 20-year-old sophomore at Rowan University in Glassboro, New Jersey. Her life is consumed by schoolwork and a job, ironically enough, making sandwiches in a deli. Sounding a bit awed by something that most people take for granted, she adds, "I can eat a little bit and be full."
Christina and the others in the lipodystrophy study also experienced another positive effect seen in Friedman's original animal experiments: a great reduction in what Gorden calls the "extreme form of insulin-resistant diabetes" that is typical of lipodystrophy. Leptin somehow increases sensitivity to insulin, perhaps by redistributing fat. As a result, most of the people in the lipodystrophy study were able to stop taking medicine to control the high concentrations of sugar in their blood. "I've been involved in insulin resistance for 35 years," says Gorden. "To treat patients with something that has such remarkable benefits was quite gratifying."
Christina now seems cured, but her body may some day stop responding to leptin. Or it may start making antibodies to leptin. Although resistance has occurred in some people who are receiving leptin supplements, their treatments continue to work, according to Stephen O'Rahilly of the University of Cambridge.
For three years, leptin has allowed Christina to attend college, hold a job and feel like a fairly normal young woman. "I consider myself cured," she says. "I'm still really skinny, but I don't have any symptoms that I can't live with."
Photo: David Graham
this story in Acrobat PDF format.
Reprinted from the HHMI Bulletin,
March 2003, pages 24-27.
©2003 Howard Hughes Medical Institute