CTSI Clinical Research Center-Supported Project Receives Endocrine Society Award

A team of UCSF researchers received the Endocrine Society and Pfizer, Inc. International Award for Excellence in Published Clinical Research. They describe the effects of leptin, a hormone that is made by fat cells, in HIV-infected patients. The award recognized the four best clinical research papers that appeared in The Journal of Clinical Endocrinology & Metabolism (JCEM) in 2009.

One of the lead-authors, Dr. Kathy Mulligan, PhD, UCSF Associate Professor and Director of CRCs Body Composition, Exercise, Metabolism Core, says they were interested in the research subject because “the same therapies that are saving lives in people with HIV infection are putting them at risk for other chronic diseases”. Many HIV infected patients who are treated with otherwise effective highly active antiretroviral therapy experience a constellation of metabolic alterations that are commonly referred to as HIV lipodystrophy, which is characterized by a loss of subcutaneous fat. Those patients develop conditions that can contribute to an increased risk of cardiovascular disease, diabetes and increased visceral fat. 

In animal models and also in non HIV-infected humans with low leptin levels due to rare genetic or acquired lipodystrophies, leptin replacement has reversed many of these metabolic abnormalities.  Although it does not reverse the underlying defect of lipodystrophy it can improve the metabolic complications associated with the subcutaneous fat loss. 

Mulligan and colleagues pursued a proof-of-principle pilot study to investigate see whether leptin replacement for 6 months could produce the same improvements in people with HIV-associated lipodystrophy. But the conduct of the study presented some challenges. “We had to make sure to keep the participants motivated to give themselves subcutaneous injections twice daily for six months,” she says. “They also needed to take time from their schedules for three 5-day admissions to the Clinical Research Center (CRC) that included rather grueling metabolic assessments.”  Yet, all 8 of the participants enrolled in the study completed it. “That is a tribute to the CRC and nursing staff at San Francisco General Hospital, who make everyone feel special; and to our study team,” Mulligan says. 

At UCSF, the Clinical Research Center coordinated by the Clinical & Translational Science Institute (CTSI), integrates eight clinical sites across San Francisco and Oakland that provide an array of adult and pediatric services and translate promising clinical research ideas into successful protocols.

“We literally could not have done the study without the assistance of these services,” said Dr. Morris Schambelan, Professor Emeritus of Medicine, former Director of the CRCs and senior author on the paper. Participants spent 5 days in the Center at the beginning of the study and again after 3 and 6 months of treatment.  During those inpatient studies, the bionutrition group provided fixed metabolic diets. The research team performed glucose clamps, stable isotope infusions, and glucose tolerance testing, all of which required intense nursing assistance and generated many biochemical specimens for processing and storage.  In addition, they performed measurements of body composition and calorimetry using equipment that is now part of the Body Composition, Exercise, Metabolism Core provided through CTSI’s Clinical Research Services.

We were struck by the consistency and magnitude of some of the results,” Mulligan says. They yielded greater decrease in visceral fat than has been achieved with any other treatment.  Likewise, lipids improved in every participant, even though most participants were already being treated with lipid lowering agents. 

Now, larger studies are needed before any claims about the efficacy of leptin can be made. Mulligan hopes to be able to do a randomized, placebo-controlled study to learn more about how leptin acts. Should they be successful, leptin may be a potentially valuable therapy in those HIV-infected patients. “For me, the most rewarding part of the research is the opportunity to interact with our research subjects,” Mulligan says.  “They remain my touchstone.”

The award recognized all authors of the paper

Kathleen Mulligan, PhD; Hootan Khatami, MD; Jean-Marc Schwarz, PhD.  Giorgos K. Sakkas, PhD; Alex M. DePaoli, MD; Viva W. Tai, RD, MPH; Michael J. Wen, MS; Grace A. Lee, MD;  Carl Grunfeld, MD, PhD; Morris Schambelan, MD.

Access the paper: The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia at http://www.ncbi.nlm.nih.gov/pubmed/19174500