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Diabetes research at Columbia University Health Sciences is grabbing attention with a trio of new grants for investigating the genetic basis of the disease. The results from the first two studies—designed to find diabetes genes in mice—will help direct the third study, which will investigate genes in families that have children with type 2 diabetes.

All three of the studies are led by Dr. Rudolph Leibel, professor of pediatrics and medicine, head of the Division of Molecular Genetics at P&S, co-director of the Naomi Berrie Diabetes Center, and deputy director of the New York Obesity Research Center.

Islets of Langerhans containing insulin-producing beta cells are shown above from 17-week-old obese mice of two different inbred strains. The diabetes-prone KsJ mouse, left, cannot compensate for the obesity-induced increase in demand for insulin: the beta cells are depleted and the islet atrophic. But the diabetes-resistant B6/J mouse, right, responds to insulin resistance by an increase in islet size and beta cell number. Using microarrays to examine gene expression in the islets of these strains before these changes are visible, Columbia researchers are trying to identify the specific genes responsible for the birth and death of these beta cells.

For the first study, the New York State Office of Science, Technology and Academic Research's (NYSTAR's) Faculty Development Program is providing a grant to study the molecular genetics of type 2 diabetes. The researchers will use molecular and computational genomics approaches to identify genes that predispose obese mice to diabetes. Mice are good for studying diabetes because the disease affects mice and humans in similar ways, and the genetics in mice can be simplified by use of inbred strains.

The NYSTAR grant was one of nine given to New York state universities to help the state attract and retain scientists who specialize in high technology and biotechnology research.

In the second study, the Foundation for Diabetes Research has awarded a two-year grant, renewable for a third year, to Dr. Leibel and his colleagues at the Berrie Center to better understand the molecular processes by which insulin-producing beta cells are generated and killed in type 2 diabetes. The research will be done primarily by Dr. Anne-Marie Brillantes, instructor in clinical medicine, working in the Berrie Center, with the help of Dr. Leibel, Dr. Domenico Accili, professor of medicine, and Dr. Argiris Efstratiadis, Higgins Professor of Genetics and Development. All are members of the Berrie Center.

Beta cells in the pancreas manufacture the body's insulin. In type 1, or juvenile diabetes, the body does not produce insulin due to immune-mediated killing of beta cells. In the much more common type 2 diabetes, the body produces too little insulin to meet increased metabolic demands imposed by resistance to the action of the hormone in muscle and other tissues. Once diabetes occurs, excess blood sugar kills beta cells. The investigators will study whether common molecular mechanisms account for some aspects of beta cell loss in both type 1 and type 2 diabetes. They will use inbred mouse strains with diabetes and employ gene chip analysis to study thousands of genes simultaneously.

The third effort is a one-year pilot study of the genetics of type 2 diabetes in adolescents at high risk for the disease. The study is funded by a grant from the HIP Health Plan of New York to the Academic Medicine Development Corporation (AMDeC). AMDeC, a 39-member consortium of New York state's major academic medical research institutions, including P&S, chose Dr. Leibel to lead the Berrie Center research team, which includes Dr. Robin Goland, Irving Associate Professor of Medicine and co-director of the diabetes center; Dr. Michael Rosenbaum, associate professor of clinical pediatrics; Dr. Wendy Chung, assistant professor of pediatrics; Dr. Barney Softness, assistant clinical professor of pediatrics; Dr. Holly Schachner, assistant professor of clinical pediatrics; and Dr. Accili.

The group expects to enroll 25 families with at least one child under age 18 who has type 2 diabetes. The first-degree relatives—siblings and parents—of these early-onset type 2 diabetics will be examined for early metabolic manifestations of predisposition to diabetes in a manner that will enable analysis of the genes responsible for such predisposition.

If the pilot study is successful, AMDeC intends to initiate a larger multi-site, multi-million dollar study of the genetics of type 2 diabetes and pre-diabetic traits. The expanded study would involve from 400 to 500 families in the New York City metropolitan area.

—Matthew Dougherty


The Irving Center for Clinical Research, which provides facilities and services for Columbia University Health Sciences faculty to conduct patient-oriented research, has received a new grant from the National Institutes of Health's National Center for Research Resources to fund young clinical investigators starting a research career.

The funding is a K-12 grant (K grants are career development grants). It will help postdoctoral fellows or a newly appointed junior faculty member make the transition to a fully independent investigator by providing funds and a mentor to support a focus on research, says Dr. Henry Ginsberg, Florence and Herbert Irving Professor of Medicine, director of the Irving Center, and the grant's principal investigator.

During the five-year grant, the Irving Center will provide funding for approximately eight researchers. The program will enroll three investigators each year for the first two years and two more researchers in the third year. Each researcher can be funded for two or three years. Yearly postdoctoral fellow funding consists of up to $50,000 in salary coverage and $25,000 in research support annually. Junior faculty chosen will receive up to $80,000 in salary coverage and $25,000 in research support each year.

Applicants must have either a doctor of medicine (M.D.) or a doctor of dental science degree (D.D.S) and either have or be working toward a master of science degree in epidemiology or biostatistics.

Dr. Ginsberg, Dr. Melissa Begg, associate professor of clinical biostatistics in the Mailman School of Public Health, and a Columbia advisory committee will select the investigators.

Dr. Begg is the principal investigator of another NIH grant, a 1999 award from the National Heart, Lung, and Blood Institute, that complements the new one. The older award, a K-30 grant, was given to Drs. Ginsberg and Begg and the Mailman School to start a patient-oriented research track in the master of science in biostatistics program. It is hoped graduates and current students in the K-30 program will apply for the K-12 funding.

"The overall goal, for both grants, is to enable young clinical researchers to compete more effectively with basic science researchers for NIH research dollars," Dr. Begg says.

—Matthew Dougherty


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