Ssm Winter 2007 Biomed Diabetes

Diabetes

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biology + medicine

and

Calcineurin by Chelsea Young

A Single Protein May Treat The Symptoms of Diabetes

“The cause of diabetes continues to be a mystery,” states the American Diabetes Association (ADA) on its website. However, Stanford Medical School Professors Seung Kim and Gerald Crabtree, along with MD/PhD graduate student Jeremy Heit, are closer to solving this mystery. They recently singled out a specific protein that controls the disease’s symptoms -- a finding that could potentially lead to an effective cure for 20.8 million Americans - 7% of the U.S. population.

An Insulin Disease After eating a meal, a person’s blood sugar level rises. Beta cells, located in the pancreas, sense this increase in glucose and release insulin into the body. Insulin is a hormone that induces cells in the muscles and liver to absorb and store the glucose as the body’s energy source.

When insulin does not fulfill its function in diabetes, the body’s cells begin to starve from lack of glucose. In Type I diabetes, insulin production slows down or stops due to malfunctioning beta cells. In Type II diabetes, the beta cells still produce insulin, but the body’s cells develop a resistance

They recently singled out a specific protein that controls [diabetes] symptoms. to it. In both cases, continually high levels of sugar in the blood can lead to long-term problems such as blindness, kidney failure and nerve damage.

The molecular structure of the protein calcineurin.

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Photo Credit: Human Genome Program, U.S. Dept. of Energy, Human Genome News (v12n1-2)

Searching for the Cause Kim, winner of the ADA’s Career Development Award, and Heit decided to explore the mechanisms behind diabetes after noticing that up to thirty percent of patients taking the common immunosuppressant drugs tacrolimus and cyclosporin A, which inhibit calcineurin - a protein involved in immune response activation - also developed diabetes as a side-effect. Reducing the patients’ drug dosages tended to get rid of the disease. Based on their findings, the pair hypothesized that calcineurin is somehow inactivated in diabetes as well. With help from Crabtree, Kim and Heit’s team deleted the calcineurin gene in mice beta cells, and as expected, these mice quickly developed diabetes. Upon closer examination, the researchers deduced that calcineurin was necessary for beta cell proliferation, as well

biology

asthe production and secretion of insulin. Furthermore, they determined that these three functions were controlled by six genes, all of which had low levels of expression in the absence of calcineurin. However, further investigation revealed that calcineurin was not directly responsible for normal beta cell function. Instead, calcineurin activates a protein called Nfat (nuclear factor of activated T-cells), which in turn activates the six genes. When the team activated Nfat in the calcineurin-deficient mice, beta cell function was restored and the diabetes symptoms disappeared. “These data suggest that mutations in calcineurin or Nfat or other components of the signaling pathway they function in may be responsible for some forms of human diabetes, which is a new finding,” explained Heit. The researchers published their findings in the September 21st issue of Nature.

+ As always, even with such positive research medicine results, patients today may never experience the benefits of a drug based on these findings. Heit estimates that the development, testing and marketing of such a drug will take “probably ten to twenty years, but maybe faster if other people start to investigate this line of thought along with us.” While human studies and clinical trials will inevitably lead to some obstacles, Kim, Crabtree and Heit have taken a huge step toward making diabetes a problem of the past. S

“These data suggest that mutations in calcineurin or Nfat or other components of the signaling pathway they function in may be responsible for some forms of human diabetes, which is a new finding.” - Heit

CHELSEA YOUNG is a sophomore majoring in biological sciences. She also enjoys running, reading and eating chocolate.

Below: A woman tests her blood sugar level with a diabetes kit.

From Lab to Countertop

Photo Credit: ©sxc.hu/Dain Hubley

Photo Credit: ©sxc.hu/Karen Barefoot

If it can be proven that calcineurin acts in humans as it does in mice, its potential for therapeutic applications is tremendous. For instance, Kim also studies beta cell implantation for patients with Type I diabetes. After implantation, these patients must take immunosuppressant drugs that decrease calcineurin function. If Nfat activators could be introduced into the patients’ systems, via gene therapy prior to transplantation, then lifelong diabetes sufferers could experience a complete cure.

To Learn More: Visit the Kim Lab website: http://seungkimlab.stanford.edu/ Read ”Calcineurin/NFAT signaling regulates pancreatic ß-cell growth and function” in Nature: J.J. Heit, Å.A. Apelqvist, X. Gu, M.M. Winslow, J.R. Neilson, G.R. Crabtree and S.K. Kim. 2006.

Diabetics must carefully monitor their sugar intake to avoid dangerously high blood glucose levels.

layout design: Melanie Kanter

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