The link between lack of sleep and obesity traced to brain cells

A possible link between lack of sleep (insomnia) and obesity has been traced to hypocretin/orexin cells in the hypothalamus region of the brain that are easily excited and sensitive to stress, Yale School of Medicine researchers report in the April 2005 issue of Cell Metabolism.

“If these neurons are over-activated by environmental or mental stress in daily situations, they may support sustained arousal, triggering sleeplessness, leading to overeating,” said lead author Tamas Horvath, associate professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences (Ob/Gyn) and Neurobiology at Yale School of Medicine. “The more stress you have, the lower the threshold becomes for exciting these hypocretin neurons.”

Horvath and co-author Xiao-Bing Gao, assistant professor in Ob/Gyn, studied hypocretin/orexin neurons in mice using electrophysiology and electron microscopy. They found a unique, previously un-described organization of inputs on hypocretin neurons in which excitatory nerve junctions outnumber inhibitory contacts by almost 10 fold. Stressors such as fasting further excite these neurons.

“This unique wiring and acute stress-induced plasticity of the hypocretin neurons correlates well with its involvement in the control of arousal and alertness, which are vital to survival,” said Horvath. “But it may also be an underlying cause of insomnia and associated metabolic disturbances, including obesity. In addition, insomnia is characteristic of perimenopause (early onset of menopause), which may lead to increased prevalence of obesity in postmenopausal women.”

Previous studies demonstrated the association between lack of sleep and obesity and suggested a good night’s sleep to help obesity. Horvath found that the neurological basis of the link between obesity and insomnia make them both independent and related products of the overactivated hypocretin system. Therefore, he said, “people with weight and sleep problems could benefit from cutting back on stressful aspects of their lives, rather than trying to specifically medicate either insomnia or obesity.”

Obesity and metabolic disorders are a major cause of death and illness in the United States, with one of the highest financial burdens on the health care system.

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Article adapted by MD Only Weblog from original press release.
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Contact: Karen N. Peart
Yale University

Citation: Cell Metabolism Vol. 1, Issue 4 (April 2005).

Lack of sleep linked to high blood pressure

If you’re middle age and sleep five or less hours a night, you may be increasing your risk of developing high blood pressure, according to a study released by Columbia University’s Mailman School of Public Health and the College of Physicians and Surgeons, and reported in Hypertension: Journal of the American Heart Association.”Sleep allows the heart to slow down and blood pressure to drop for a significant part of the day,” said James E. Gangwisch, PhD, lead author of the study and post-doctoral fellow in the psychiatric epidemiology training (PET) program at the Mailman School. “However, people who sleep for only short durations raise their average 24-hour blood pressure and heart rate. This may set up the cardiovascular system to operate at an elevated pressure.”

Dr. Gangwisch said that 24 percent of people ages 32 to 59 who slept for five or fewer hours a night developed hypertension versus 12 percent of those who got seven or eight hours of sleep. Subjects who slept five or fewer hours per night continued to be significantly more likely to be diagnosed with hypertension after controlling for factors such as obesity, diabetes, physical activity, salt and alcohol consumption, smoking, depression, age, education, gender, and ethnicity.

The researchers conducted a longitudinal analysis of data from the Epidemiologic Follow-up Studies of the first National Health and Nutrition Examination Study (NHANES I). The analysis is based on NHANES I data from 4,810 people ages 32 to 86 who did not have high blood pressure at baseline. The 1982-84 follow-up survey asked participants how many hours they slept at night. During eight to 10 years of follow-up, 647 of the 4,810 participants were diagnosed with hypertension. Compared to people who slept seven or eight hours a night, people who slept five or fewer hours a night also exercised less and were more likely to have a higher body mass index. (BMI is a measurement used to assess body fatness). They were also more likely to have diabetes and depression, and to report daytime sleepiness.

“We had hypothesized that both BMI and a history of diabetes would mediate the relationship between sleep and blood pressure, and the results were consistent with this,” Dr. Gangwisch said.

Sleep deprivation has been shown previously to increase appetite and compromise insulin sensitivity.

Short sleep duration was linked to a new diagnosis of high blood pressure among middle-aged participants, but the association was not observed among people age 60 or older, he said. Dr. Gangwisch said the differences between the younger and older subjects might be explained by the fact that advanced age is associated with difficulties falling and staying asleep. Another factor could be that subjects suffering from hypertension, diabetes, and obesity would be less likely to survive into their later years.

Among study limitations, researchers found that high blood pressure often goes undetected. An analysis of NHANES III data showed that over 30 percent of people who had high blood pressure didn’t know they had it.

Since the study is based on observational data, Dr. Gangwisch said more research is needed to confirm the association between short sleep duration and high blood pressure. “We need to investigate the biological mechanisms and, if confirmed, design interventions that will help people modify sleep behavior,” he said.

Dr. Gangwisch said the study’s main message is clear: “A good night’s sleep is very important for good health.”

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Article adapted by MD Only Weblog from original press release.
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Contact: Stephanie Berger
Columbia University’s Mailman School of Public Health

Low Testosterone found in one-third of diabetic men

Study is first to reveal hypogonadism as common complication of diabetes

BUFFALO, N.Y. — Low testosterone production appears to be a common complication of type 2 diabetes in men, affecting 1 out of 3 diabetic patients, a new study has shown.Moreover, results of the investigation show that this condition, known clinically as hypogonadism, is caused not by a defect in the testes, where testosterone is produced, but by improper functioning of the pituitary gland, which controls production of testosterone, or of the hypothalamus, the region of the brain that controls the pituitary.

“This starts a whole new story on the crucial complications of type 2 diabetes,” said Paresh Dandona, M.D., senior author on the study and director of the Division of Endocrinology, Diabetes and Metabolism at the University at Buffalo and Kaleida Health, where the study was conducted.

Results of the study appear in the November issue of Journal of Clinical Endocrinology and Metabolism.

Sandeep Dhindsa, M.D., UB assistant professor of medicine and first author on the study, said the findings are important because hypogonadism has not been recognized as a complication of type 2 diabetes, and the high prevalence of 30 percent was unexpected.

“The surprisingly high prevalence of low testosterone levels was associated with lower levels of pituitary hormones called gonadotrophins, suggesting that the primary defect in these patients was either in the pituitary or higher up in the hypothalamus,” he said. “Since gonadotrophins drive the testes to produce testosterone, this finding gives us an insight into the pathogenesis of this complication of type 2 diabetes.”

Earlier studies, including those conducted by this research group, found that diabetic subjects with erectile dysfunction and low testosterone levels often have low levels of pituitary hormones. However, conclusions from prior studies have been fraught with problems with testosterone assays, Dhindsa noted.

“A large portion of testosterone in the blood is bound to proteins, but a small portion is unbound and largely determines the amount of testosterone that is available to the tissues,” said Dhindsa. “This active portion is called free testosterone. Assays to accurately determine it are delicate, tedious and time-consuming.

“This investigation set out to determine, in a prospective fashion, the prevalence of low total testosterone, accurately measure free testosterone in male patients with type 2 diabetes and to attempt to determine the seat of the problem in those with low free testosterone.” The study involved 103 consecutive males with type 2 diabetes who were referred to the Diabetes-Endocrinology of Western New York for treatment. None of the men had been diagnosed previously with low testosterone levels.

The researchers collected fasting blood samples from the participants and analyzed them for testosterone levels and for hormones associated with testosterone production. They also measured cholesterol and glucose levels, and a blood marker for how well glucose was controlled during previous months, called hemoglobin A1c. Data on height, weight and diabetic complications, including erectile dysfunction, neuropathy, retinopathy and coronary artery disease, were recorded.

Results showed that nearly one-third of the men had hypogonadism. Although obesity is associated with hypogonadism and is prevalent among type 2 diabetics, only 10-15 percent of the variation in low free testosterone levels could be attributable to body mass index, Dhindsa said. More than 30 percent of lean patients also were hypogonadal.

“Equally important, most of the men who had low testosterone levels also had lower levels of gonadotrophins, as compared to men with normal testosterone levels,” he noted. “Furthermore, the gonadotrophin concentration in the blood correlated positively with free testosterone levels, supporting the notion that the cause of the defect is in the pituitary or hypothalamus.”

The high prevalence of low testosterone in diabetic men is concerning, said Dhindsa, because in addition to lowered libido and erectile dysfunction, the condition is associated with loss of muscle tone, increase in abdominal fat, loss of bone density, and can affect mood and cognition.

“Further studies will help us determine why type 2 diabetic patients are more prone to developing hypogonadism,” he said. “While obesity may explain part of the high prevalence of hypogonadism, it is likely that other factors associated with type 2 diabetes also contribute significantly. This area is clearly ripe for further investigation.”

Additional researchers on the study were Sathyavani Prabhakar, M.D., UB clinical assistant instructor of medicine, Manak Sethi, M.D., research assistant, Arindam Bandyopadhyay, M.D., UB clinical assistant professor of medicine, and Ajay Chaudhuri, M.D., UB assistant professor of medicine.

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Article adapted by MD Only Weblog from original press release.
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Contact: Lois Baker
University at Buffalo

Low Testosterone Video

Many older men have circulating levels of testosterone well below the usual range in healthy young men. Many older men also have conditions that might be related to low testosterone levels: e.g., muscle weakness, sexual dysfunction, and cognitive dysfunction. Though epidemiologic data and some small intervention studies indicate that testosterone treatment for older men with low testosterone levels might alleviate some of these conditions.

Some data from epidemiologic studies and small intervention studies also indicate that testosterone treatment for older and middle-aged men with low testosterone levels may also have favorable effects on risk for cardiovascular disease, fractures, and other age-related conditions.

Low Testosterone Video

Low Testosterone Video Summary Material

Low testosterone levels in men after 40 increase risk of death

Men who have a low testosterone level after age 40 may have a higher risk of death over a four-year period than those with normal levels of the hormone, according to a report in the August 14/28 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Unlike women undergoing menopause, middle-aged men generally do not experience a dramatic decrease in the production of sex hormones, according to background information in the article. Testosterone levels gradually decline as a man ages, decreasing approximately 1.5 percent per year after age 30. The effects of low testosterone levels include decreased muscle mass and bone density, insulin resistance, decreased sex drive, less energy, irritability and feelings of depression.

Molly M. Shores, M.D., and colleagues at the VA Puget Sound Health Care System and University of Washington, Seattle, studied the relationship between hormone levels and death in a total of 858 male veterans older than age 40 years. All participants received care in the VA Puget Sound Health Care System and had their testosterone levels checked at least twice between 1994 and 1999, with at least one week and no more than two years elapsing between tests. The men were followed for an average of 4.3 years and a maximum of eight years, through 2002.

About 19 percent (166) of the men had a low testosterone level; 28 percent (240) had an equivocal testosterone level, meaning that their tests revealed an equal number of low and normal levels; and 53 percent (452) had normal testosterone levels. One-fifth (20.1 percent) of the men with normal testosterone levels died during the course of the study, compared with 24.6 percent of men with equivocal levels and 34.9 percent of those with low levels. Men with low testosterone levels had an 88 percent increase in risk of death compared with those who had normal levels. When the researchers considered other variables that may influence risk of death, such as age, other illnesses and body mass index, the association between low testosterone levels and death persisted.

Previous studies have found that testosterone levels may dramatically decrease one to two days after surgery, trauma or critical illness–all factors that can increase the risk of death. To eliminate these effects, the authors reanalyzed the data excluding men who had died within the first year of follow-up. Men with low testosterone levels were still 68 percent more likely to have died. “The persistence of elevated mortality risk after excluding early deaths suggests that the association between low testosterone and mortality is not simply due to acute illness,” they write. “Large prospective studies are needed to clarify the association between low testosterone levels and mortality.” (Arch Intern Med. 2006;166:1660-1665. (http://www.jamamedia.org.)

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Article adapted by MD Only Weblog from original press release.
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Contact: Clare Hagerty
JAMA and Archives Journals

Editor’s Note: This study was supported by the Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System; the Royalty Research Fund of the University of Washington (Dr. Shores); and a VA merit review grant (Dr. Matsumoto). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Depression Decreases Testosterone Concentrations in Men

Sex hormones are secreted at different rates in men who are severely depressed than those who are not depressed, a team of eight medical doctors associated with the Max Planck Institute of Psychiatry in Munich has determined.

“Our data suggest that men who suffer from severe major depression have disturbance of gonadal function as reflected by decreased testosterone concentration,” said Dr. Ulrich Schweiger, head of the study.

Comparison of men with depression and those without showed:

• Lower testosterone concentrations during daytime and significantly lower concentrations at night and across the 24-hour period.
• Similar concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone in both groups, but the LH pulse was lower in depressed men.
• Cortisol concentration 68 percent higher in men with major depression than in the comparison group.
• A negative relationship between cortisol and testosterone, that is, the higher the cortisol, the lower the testosterone levels.

The major implication of this study is that low testosterone may be one of several mechanisms in which severe depressive disorders impair sexual function and increase the risk of myocardial infarction and osteoporosis.”Previous studies of sex hormone concentration in depressed individuals had yielded inconsistent and ambiguous results,” said Schweiger. “Possibly because some patients in those studies were only mildly depressed.” The new research is reported in the June issue of Psychosomatic Medicine.

Schweiger and colleagues analyzed scores of blood samples from 15 male inpatients with major depression who were 22 to 73 years old, and 22 healthy men aged 23 to 85 in a comparison group, taken across a 24-hour period. Blood was drawn every half-hour during the day, every 10 minutes from 6 p.m. to midnight, and every 30 minutes from midnight to 7:30 a.m.

A major objective of the study was to analyze the functioning of the hypothalamic-pituitary-gonadal system in patients with major depression, the scientists said.

The samples were analyzed for testosterone, gonadotropin (a hormone that stimulates growth of the gonads), cortisol (a major stress hormone), follicle stimulating hormone (which stimulates sperm production), and luteinizing hormone (which stimulates the production of testosterone).

Germany’s chain of Max Planck Institutes, funded by the German federal and state governments, support intramural research in a broad range of scientific disciplines.

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Article adapted by MD Only Weblog from original press release.
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Contact: Ulrich Schweiger, M.D.
schweiger.u@psychiatry.mu-luebeck.de
Center for the Advancement of Health

Low testosterone levels associated with depression in men

Men with low testosterone levels are more likely to be depressed, according to an article in the February issue of The Archives of General Psychiatry, one of the JAMA/Archives journals.According to information in the article, testosterone deficiency (hypogonadism) is a common condition in older men, occurring in 30 percent of men older than 55. Testosterone levels peak in early adulthood, and then decrease by approximately 1 percent per year after age 40. Symptoms of hypogonadism include decreased muscle mass and strength, decreased bone mineral density, diminished appetite, decreased libido, fatigue and irritability. Some symptoms overlap with those of depression, but the association between hypogonadism and depression is unclear.

Molly M. Shores, M.D., of Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues examined the clinical records of 278 men (45 years or older) without depression to examine the relationship between testosterone level and the incidence of diagnosed depression over a two-year period.

The researchers found that over the study period, 21.7 percent of the hypogonadal men were diagnosed with depression, vs. 7.1 percent of men with normal testosterone levels. When the researchers adjusted for age, alcohol use disorders, prostate cancer, and other medical conditions, they found that men with hypogonadism were 4.2 times more likely to be diagnosed with depression. “Hypogonadal men showed an increased incidence of depressive illness and a shorter time to diagnosis of depression,” the authors write. “Further prospective studies are needed to confirm these preliminary findings and to clarify the role of testosterone in the treatment of depressive illness in older men.”

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Article adapted by MD Only Weblog from original press release.
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Contact: Kris Connor (Arch Gen Psychiatry. 2004;61:162-167. Available at http://www.archgenpsychiatry.com)

Contact: Jeri Rowe
JAMA and Archives Journals