Potential Weight-Loss Drug May Be Linked To Adult Diabetes

November 15, 1996

REHOVOT, ISRAEL--November 14, 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 edition of Science (Vol. 274, pp. 1185-1188), 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 meat 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 ignificantly 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 attact to the protein). This failure caused several processes to take place, the net effect of which was that a much greater amount of glueoneogenesis took place.

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

The Weizmann Institute of Science, in Rehovot, Israel, is one of the world's foremost centers of scientific research and graduate study. Its 2,400 scientists, students, technicians, and engineers pursue basic research in the quest for knowledge and the enhancement of the human condition. New ways of fighting disease and hunger, protecting the environment, and harnessing alternative sources of energy are high priorities.

Prof. Rubinstein can be reached in Israel, seven hours ahead of New York, at:
011 972 8 934 2313 (lab)
011 972 35 324055 (home)
e-mail userid: LVRUB@weizmann.weizmann.ac.il


For press in the U.S., contact: Julie Osler (212) 779-2500
Director of Public Affairs
American Committee for the
Weizmann Institute of Science
(212) 779-2500
JULIE@ACWIS.ORG CompuServe: 76675,366

For foreign press, contact: Luba Vikhanski
Acting Head, Foreign Press and Publications
Weizmann Institute of Science
Rehovot, Israel
011 972 8 934 3855

American Committee for the Weizmann Institute of Science

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.