Weight Loss Promoted By Drug Combination In Polycystic Ovary Syndrome

Women with polycystic ovary syndrome, or PCOS, lost significantly more weight when they took two drugs that are traditionally used to treat diabetes, rather than either drug alone, a study from Slovenia demonstrates. The results were presented at The Endocrine Society's 95th Annual Meeting in San Francisco.

PCOS is the leading cause of infertility among women. In the United States, the disorder affects approximately 5 million women, according to the U.S. Department of Health and Human Services Office of Women's Health. This translates to 1 in 10 to 20 women, overall, who are affected. The disease probably is genetic, although the exact causes are still unknown.

In PCOS, the ovaries produce excessive amounts of male sex hormones, or androgens. The name of the disease derives from small cysts that form on the ovaries, which do not produce enough of the hormone that triggers ovulation. When this occurs, the ovarian follicles, which have filled with fluid in preparation for ovulation, remain as cysts when ovulation fails to take place. In addition to infertility, symptoms include excessive hair growth in areas that usually are relatively hairless; obesity; menstrual irregularity; thinning or balding hair on the scalp; prediabetes or diabetes; and anxiety or depression. Weight loss in these women leads to higher chances of conception, improved pregnancy outcomes and improved metabolic profile.

Treatment varies depending upon the severity of the disease, and includes lifestyle modifications and drug therapy. Some of the same medications that are used to treat diabetes also improve PCOS symptoms. One of these medications, metformin, works by regulating the hormone insulin and by suppressing androgen activity, which, in turn, helps control blood-sugar levels and has beneficial effects on ovarian function. The problem with metformin, however, is that it does not always aid with weight loss.

Because of this, investigators examined different drug combinations to see which ones caused the most weight loss. In addition to metformin, they administered another diabetes medication called liraglutide, both alone and in combination with metformin, to determine which approach led to the greatest amount of weight loss.

They found that patients who took the combined drugs lost 6.5 kilograms (kg), or about 14 pounds, on average, compared to about 4 kg, or almost 9 pounds, on liraglutide alone, and 1 kg, or about 2 pounds, on metformin alone. Furthermore, 22 percent of participants on the combined treatment lost a significant amount of weight, defined as 5 percent or more of their body weight, compared to 16 percent of those on liraglutide. No one in the metformin group achieved this amount of weight loss. In terms of body-mass index and waist circumference, the combined-treatment group saw greater improvements than either of the single-medication groups. For both of these measurements, liraglutide alone outperformed metformin alone.

"The effect of metformin on weight reduction in polycystic ovary syndrome is often unsatisfactory," said study author Mojca Jensterle Sever, MD, PhD, who served as lead author with Andrej Janez, MD, PhD, a fellow consultant at the University Medical Center in Ljubljana, Slovenia. "Short-term combined treatment with liraglutide and metformin appears better than either metformin or liraglutide alone on weight loss and decrease in waist circumference in obese women with PCOS who had been previously poor responders regarding weight reduction on metformin alone."

The main side effect was nausea, which occurred more often with liraglutide than with metformin. The nausea did improve with time, however, and was not associated with weight loss.

Study participants comprised 36 women with PCOS who had lost less than 5 percent of their body weight on a six-month course of metformin preceding the study. Their average age was 31 years. Investigators randomly assigned them to one of three treatment groups for the 12-week study, including metformin alone, liraglutide alone, and both medications.

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Research Links Two Genes To Obesity And Health Disorders

Family DNA may influence development of Metabolic Syndrome.

Two genes may be linked to obesity and health disorders according to new research by the TOPS Obesity and Metabolic Research Center at the Medical College of Wisconsin. The study of obese individuals from four generations of families shows that hereditary DNA may influence development of Metabolic Syndrome, a cluster of conditions effecting one in five Americans, which dramatically increases the risk for heart disease and diabetes. So far, the TOPS families' DNA samples have made it possible for researchers to query almost one million variations in genes that are associated with whether or not someone develops the Metabolic Syndrome and how the disease surfaces in different people.

Soon to be published in Obesity, the official journal of The Obesity Society, the report reveals evidence of two new genes that significantly impact weight gain. One gene affects the growth and development of newborn infants, as well as regulation of glucose/insulin response, lipid profiles, and body weight in adults. The other gene affects pro-inflammatory pathways, which are precursors of traits of Metabolic Syndrome.

"Our genome-wide survey could lead to the creation of early diagnostic tools for detecting risks for developing obesity, as well as the discovery of drugs targeted specifically to these genes," said Yi (Sherry) Zhang, Ph.D., instructor, Department of Medicine, Human & Molecular Genetics Center at the Medical College of Wisconsin. "This is the first published work of our genome-wide survey, and we expect a series of reports will soon follow to address other aspects of this complex disease," she added.

Zhang and her colleagues from the TOPS Obesity Center have been working to determine the full picture of the genetic makeup that encourages development of Metabolic Syndrome, including body composition, insulin resistance, and circulating blood levels of the hormone leptin, which is exclusively produced by fatty tissue.

"We've all heard such common expressions as, 'You have your mom's eyes,' or 'I developed high blood pressure in my '40s, just like my grandfather," notes Barbara Cady, TOPS President. "When we discuss 'inheritance' like this, we're relating to a question that scientists have been striving to answer for decades: how does our genetic makeup determine our traits? Knowing which genes are detrimental to our health may help researchers develop a strategic plan to treat or even prevent the symptoms that are caused by these genes."

This research is the latest in a series of papers based on the TOPS Obesity and Metabolic Research samples housed at the Medical College of Wisconsin as part of an ongoing partnership.

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Research Breakthrough Of Essential Molecule Reveals Important Targets In Diabetes And Obesity

Insulin is the most potent physiological anabolic agent for tissue-building and energy storage, promoting the storage and synthesis of lipids, protein and carbohydrates, and inhibiting their breakdown and release into the circulatory system. It also plays a major role in stimulating glucose entry into muscle tissue, where the glucose is metabolized and removed from the blood following meals. But gaps exist in understanding the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells.

A research team led by Assia Shisheva, Ph.D., professor of physiology in Wayne State University's School of Medicine, has made breakthrough advancements on a molecule that may provide more answers to this mystery.

The conserved phospholipid enzyme, PIKfyve, was discovered in Shisheva's lab in 1999. Based on studies in cultured cells, the lab has implicated PIKfyve in the insulin-regulated glucose transport activation, which led to the development of a unique mouse model with PIKfyve ablation, or removal, in muscle (MPlfKO), the tissue responsible for the majority of postprandial glucose disposal.

In Shisheva's recent paper, "Muscle-specific PIKfyve gene distribution causes glucose intolerance, insulin resistance, adiposity and hyperinsulinemia but not muscle fiber-type switching," published online in the American Journal of Physiology - Endocrinology and Metabolism, Shisheva and her research team characterize whether this new model exhibits metabolic defects.

"Our team found a striking metabolic phenotype in the MPIfKO mice consisting of glucose intolerance and insulin resistance at an early age and on a normal diet," said Shisheva, a resident of Royal Oak. "We also revealed that PIKfyve is essential for normal insulin signaling to GLUT4/glucose transport in muscle and provided the first in vivo evidence for the central role of PIKfyve in the mechanisms regulating healthy blood glucose levels, or glucose homeostasis."

In addition, the research team found that these metabolic disturbances were followed by increased animal fat (adiposity) and elevated levels of insulin (hyperinsulinemia), but not abnormal amounts of lipids or cholesterol in the blood (dyslipidemia).

"The combined phenotype manifested by the MPlfKO mouse closely recapitulates the cluster of typical features in human prediabetes including systemic glucose intolerance and insulin resistance, hyperinsulinemia and increased visceral obesity without dyslipidemia," said Shisheva.

"Therefore, our mouse model, in addition to providing novel mechanisms of insulin resistance, represents a valuable tool for exploring new preclinical strategies to improve treatments in individuals with prediabetes."

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Study Sheds Light On Molecular Basis For Metabolic Health And Disease

Inside each of us is our own internal timing device. It drives everything from sleep cycles to metabolism, but the inner-workings of this so-called "circadian clock" are complex, and the molecular processes behind it have long eluded scientists. But now, researchers at the Gladstone Institutes have discovered how one important protein falls under direct instructions from the body's circadian clock. Furthermore, they uncover how this protein regulates fundamental circadian processes - and how disrupting its normal function can throw this critical system out of sync.

In the latest issue of the Journal of Neuroscience, Gladstone Investigator Katerina Akassoglou, PhD, and her team reveal in animal models how the production of the p75 neurotrophin receptor (p75NTR) protein oscillates in time with the body's natural circadian clock - and how these rhythmic oscillations help regulate vital metabolic functions. This discovery underscores the widespread importance of p75NTR by offering insight into how the circadian clock helps maintain the body's overall metabolic health.

Virtually every organism on the planet - from bacteria to humans - has a circadian clock, a biological timing mechanism that oscillates with a period of about 24 hours and is coordinated with the cycle of day and night. And while it runs independent of external cues, it is influenced by the rhythms of light, temperature and food availability. Intriguingly, recent studies have also found a link between circadian clocks and metabolism.

"Important metabolic functions are also heavily influenced by circadian clocks, which is why activities such as chronic night-shift work - which can cause a misalignment of this clock - increase one's risk for metabolic and autoimmune diseases such as obesity, Type 2 diabetes, cancer and multiple sclerosis," said Dr. Akassoglou. Dr. Akassoglou is also a professor of neurology at the University of California, San Francisco, (UCSF) with which Gladstone is affiliated. "In this study, we pinpointed p75NTR as an important molecular 'link' between circadian clocks and metabolic health."

Originally, p75NTR was only thought to be active in the nervous system. Later studies found it to be active in many cell types throughout the body, suggesting that it impacts a variety of biological functions. Last year, Gladstone researchers discovered that p75NTR was present in the liver and in fat cells, and that it regulates glucose levels in the blood - an important metabolic process. Since these findings uncovered a link between p75NTR and metabolism, the research team tested - first in a petri dish and then in animal models - whether there was also a link between p75NTR and the circadian clock.

The team focused on two genes called Clock and Bmal1. These so-called "circadian regulator genes," and others like them, are found throughout the body. Their activity controls the body's circadian clock. The researchers wanted to see if there was a connection between these circadian genes and p75NTR.

"Our initial experiments revealed such a connection," recalls Gladstone Postdoctoral Fellow Bernat Baeza-Raja, PhD, the paper's lead author. "In individual cells, we saw that p75NTR production was controlled by Clock and Bmal1, which bind directly to the gene that codes for the p75NTR and start production of the protein."

But perhaps even more important than how p75NTR was produced was when. The team found that p75NTR production, like the circadian clock genes themselves, oscillated in a 24-hour cycle - in sync with the cells' natural circadian rhythm. Experiments in mouse models further supported these findings.

And when the team genetically modified a group of mice so that it lacked the circadian Clock gene, everything else fell out of sync. The circadian oscillation of p75NTR production was disrupted, and p75NTR levels dropped.

However, what was most fascinating, say the researchers, was how a drop in p75NTR levels then affected a variety of circadian clock systems. Specifically, the regular oscillations of other circadian genes in the brain and the liver became disrupted, as well as genes known to regulate glucose and lipid metabolism.

"The finding that a loss of p75NTR affected circadian and metabolic systems is strong evidence that this protein is intricately tied to both," said Life Sciences Institute Director Alan Saltiel, PhD, who is also a professor at the University of Michigan and was not involved in the study. "It will be fascinating to see what additional insight Dr. Akassoglou and her team will uncover as they continue to examine the role of p75NTR in circadian clocks and metabolic function."

"While these findings reveal p75NTR to be an important link between circadian clocks and metabolism, the system is complex, and there are likely other factors at play," said Dr. Akassoglou. "We are currently working to identify the relationship between the circadian clock, metabolism and the immune system, so that one day we could develop therapies to treat diseases influenced by circadian clock disruption - including not only obesity and diabetes, but also potentially multiple sclerosis and even Alzheimer's disease."

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