Potential Weight-Loss Drug May Be Linked to Adult Diabetes


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REHOVOT, Israel -- November 15, 1996 -- Leptin, the protein that made headlines two years ago when it was found to reduce obesity in mice, may be a cause of adult-onset diabetes in humans, according to a new Weizmann Institute of Science study.

The study, to be published in the November 15, 1996, edition of Science, found that high levels of leptin disrupt some of the activities of insulin, the hormone that controls blood sugar levels. Since obese humans, unlike the genetically obese mice that received so much publicity, are known to have high leptin levels in their blood, this finding may explain why overweight people have a tendency to develop adult-onset, or Type II, diabetes. It may also point the way towards developing new treatments for Type II diabetes, which is the most common form of diabetes and mostly strikes overweight people over the age of 40.

Moreover, this research suggests that if leptin is developed into a weight-loss drug in the future, it should be used with caution because it may cause the user to develop diabetes-related symptoms.

"We know that overweight people have higher levels of leptin. We also know that these people have a tendency towards adult-onset diabetes, and that no one is sure exactly what causes this type of diabetes," said research head Prof. Menachem Rubinstein, of the Molecular Genetics Department.

"We have now shown that excessive leptin leads to reduced activity by insulin. All the evidence now points to the probability that excessive leptin may be one of the causes of Type II diabetes, although it is probably not the only cause. More studies are needed to examine the link between excess leptin and diabetes, and to determine whether anything can be done about it."

Leptin, a protein produced in fat cells, raises body temperature and lowers food intake. It was first identified in 1994 by scientists who found that it was absent in genetically obese mice, and that daily leptin injections caused the animals to eat less and to lose weight. This research generated great hopes for leptin's development as a weight-reduction drug for human consumption.

However, further studies introduced a cautionary note, finding that injecting leptin works mainly on obese mice with a genetic defect that results in an absence of leptin. Genetically normal obese mice, as well as obese humans, actually have excess leptin levels. (So far, no humans are known to have a genetically caused absence of leptin.)

Rubinstein's study now sounds a further warning, and points to a new avenue of research that will investigate the connection between leptin and adult-onset diabetes. In this form of diabetes, insulin production is usually normal but blood sugar levels are not under proper control.

Balancing Blood Sugar Levels

Insulin keeps blood sugar levels balanced in several ways: when glucose from a meal enters the bloodstream, insulin ensures it is converted into glycogen and fat, stored for later use. Insulin also ensures that the stored fat is not released and turned back into glucose, a process known as gluconeogenesis, until it is needed. This double-valve process is a finely tuned balancing act that goes on minute by minute, ensuring that cells get a constant amount of energy and that blood sugar levels are not subject to wild fluctuations.

Working with cells derived from human liver and using a quantity of leptin similar to that present in the blood of obese individuals, Rubinstein and colleagues Dr. Batya Cohen and Dr. Daniela Novick found that while leptin does not affect insulin's first function, it does significantly suppress its ability to slow down gluconeogenesis a process which, in the body, would cause raised blood sugar levels.

How Leptin Affects Insulin

Leptin, insulin and other "messenger" proteins act by binding with specific receptors on a cell's membrane, rather like a ship docking, setting off a cascade of processes inside the cell. Leptin's main receptor is in the brain's hypothalamus region, but there are also leptin receptors in the liver, heart, lungs and many other organs, and their workings had not been studied.

Rubinstein's team focused on the leptin receptor in the liver, and found that when leptin binds to liver cells, the resulting cascade affects a key protein involved in insulin's own cascade, the insulin receptor substrate 1 (IRS-1), stopping it from becoming phosphorylated (the process in which phosphate molecules attach to the protein). This failure caused several processes to take place, the net effect of which was that a much greater amount of gluconeogenesis took place.

Prof. Rubinstein holds the Maurice and Edna Weiss Chair of Cytokines Research.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.