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Endocrinology & Metabolism News

	Endocrine Discovery

Top Endocrine Discovery Endocrine Practice Endocrine Policy Milestones in Endocrinology In the Journal 25...

 
In a 2-year randomized trial of 322 moderately obese subjects assigned to either a low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, non–restricted-calorie diet, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively among the 272 participants who completed the trial. (N Engl J Med [July 17, 2008] 359 (3):229)

A steep decrease in moderate-to-vigorous physical activity was observed in U.S. children between the ages of 9 and 15 years. At 9 years, almost all children were well above the recommended 60 minutes on both weekdays and weekends, but by 15 years only 31% met the guidelines on weekdays and only 17% did on weekends. (JAMA [July 16, 2008] 300 (3):295)

Enhanced thrombin generation, platelet activation, and unfavorably altered clot lysis time was observed in 60 hyperglycemic patients with and without known diabetes who had acute coronary syndrome studied within 12 hours of the onset of chest pain. (Diabetes Care [August 2008] 31 (8):1590)

In a study of pulmonary function in 69 nonsmoking type 2 diabetic patients, DLCO, DLNO, and VC at exercise were 10–25% lower compared with those in control subjects, and these abnormalities were directly related to A1C level, retinopathy, neuropathy, and microalbuminuria. (Diabetes Care [August 2008] 31 (8):1596)

Use of the bile acid sequestrant colsevelam 3.75 gm/d was associated with a 0.41% decrease in glycohemoglobin compared to placebo in a 16 week, prospective, randomized, double-blind, placebo-controlled trial of 287 patients with Type 2 diabetes. (Arch Intern Med [July 28, 2008] 168 (14):1531)

In a meta analysis of acromegalic patients, those attaining a serum GH <2.5 µg/l following treatment had mortality close to expected levels (SMR 1.1, 95% confidence interval (CI) 0.9–1.4) compared with an SMR of 1.9 (95% CI 1.5–2.4) for those with final GH >2.5 µg/l. (Eur J Endocrinol [August 2008] 159 (2):89)

Colesevelam improved glycemic control and reduced low density lipoprotein (LDL) cholesterol levels in patients with type 2 diabetes receiving sulfonylurea-based therapy. Patients on both these drugs saw a mean hemoglobin A1c reduction of 0.54% and a mean LDL cholesterol reduction of 16.7%. (Diabetes Care [August 2008] 31(8):1479)

Low (<1.0 mIU/L) or high (>2.1 mIU/L) thyrotropin levels were associated with an increased risk of incident Alzheimer’s disease in women, but not men. (Arch Intern Med [July 28, 2008] 168 (14):1514)

A low-fat dietary intervention in generally healthy postmenopausal women showed no evidence of reducing diabetes risk after 8 years, suggesting that weight loss, rather than macronutrient composition, may better predict lowered diabetes risk. (Arch Intern Med [July 28, 2008] 168 (14):1500)

Higher intakes of soy foods and soy isoflavones were linked with lower sperm concentration, particularly in overweight or obese men. (Human Reproduction [published online July 24, 2008])

In a large, population-based sample of U.S. adults, baseline periodontal disease was found to be a clinically relevant and novel predictor of incident type 2 diabetes. (Diabetes Care [July 2008] 31 (7):1373)

Among middle-aged American women, consumption of fruit juices was positively associated with incidence of type 2 diabetes, whereas intake of whole fruits and vegetables were inversely associated. (Diabetes Care [July 2008] 31 (7):1311)

Measurements of retinal flavoprotein autofluorescence identifed diabetic metabolic tissue stress and disease severity rapidly and noninvasively. (Arch Opththalmol [July 2008] 126 (7):934)

Obesity-prone rats were found to have an attenuated central dopamine system, implying that lowered dopamine would reduce the hedonistic response associated with feeding and induce compensatory hyperphagia and weight gain. (FASEB J [August 2008] 22:2740)[CrossRef]

A neuronal network model showed that the milk-ejection reflex by hypothalamic neurons is due to the synchronized release of oxytocin. (PLoS Computational Biology [July 2008] 7 (4):e1000123)

The fasting-induced hormone, FGF21, elicited in mice the same spectrum of effects as fasting on the GH-signaling cascade, including elevated plasma GH concentrations and decreased circulating IGF-I levels and growth hormone, suggesting that FGF21 plays a central role in causing GH-resistance in response to starvation. (Cell Metab [July 2008] 8:77)[CrossRef]

Resveratrol-fed elderly mice showed marked reduction in aging, including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. In mid-life mice, however, resveratrol did not increase longevity, indicating that this substance partially mimics the ability of dietary restriction to delay age-related diseases. (Cell Metab [August 6, 2008] 8:1)[CrossRef]

At higher glucose levels, leptin excited the hypothalamic anorexigenic proopiomelancocortin neurons, but at lower levels, leptin suppressed these cells and simulated the orexigenic agouti-related protein neurons, suggesting that hypothalamic glucose sensing may not only influence physiological functions directly, but also indirectly through the modulation of other neuropeptides. (Proc Natl Acad Sci USA [July 15, 2008] 105 (28):9811)

Mice with moderate overexpression of Sirtuin 1 under control of its natural promoter exhibited fat mass gain, prevention of glucose intolerance, and nonalcoholic fatty liver disease similar to wild-type controls when exposed to a high-fat diet, providing direct proof of the protective potential of this protein against metabolic syndrome. (Proc Natl Acad Sci USA [July 15, 2008] 105 (28):9793)

Conserved T cell receptor -chain targeting insulin B:9–23 generated insulin autoantibodies when transgenically or retrogenically introduced into nonobese diabetic mice without its corresponding variable β-chain, suggesting that anti-insulin autoimmunity can be rendered solely by an -chain motif. (Proc Natl Acad Sci USA [July 22, 2008] 105 (29): 10090)

Liver Protein Linked to Type 2 Diabetes

Older people with high levels of a liver-secreted protein called fetuin-A have an elevated risk of developing type 2 diabetes, according to a recent article in the Journal of the American Medical Association.

"There’s been substantial recent research about adipocytokines that are produced by fat cells and that may regulate glucose metabolism, but very little about liver proteins that may have a similar function," said lead author Joachim Ix, M.D., MAS, assistant professor of medicine, division of nephrology, University of California, San Diego and the Veterans Affairs San Diego Healthcare System. "If fetuin-A can differentiate diabetes risk, it may give us an opportunity for targeted public health interventions to delay or prevent diabetes."

Dr. Ix’s group measured fetuin-A blood levels at baseline in 519 diabetes-free individuals aged 70 to 79 years, and followed the subjects for incident diabetes over six years. Of the 135 participants who had developed diabetes, the researchers found that those with the highest fetuin-A levels (>0.97 g/L) had twice the risk of diabetes compared to those with the lowest levels (0.76 g/L).

The association persisted when the data was adjusted for other known diabetes risk factors such as age, sex, race, physical activity levels, and body weight. Although abdominal fat slightly dampened the association, adipocytokine levels had no significant effect on this relationship.

"It’s actually one of the most pioneering works in the field," commented Suresh Mathews, Ph.D., assistant professor of nutrition at Auburn University, Auburn, Alabama, whose work with mice lacking this protein showed an improved insulin action and lower lipid levels.

A dichotomy may exist between fetuin-A’s relationship with diabetes and cardiovascular disease, stated Dr. Ix. "While fetuin-A knock-out mice are insulin-sensitive, they also have more soft tissue calcifications. Also, in patients with end-stage renal disease, a lower level is linked with more extensive vascular calcification, cardiovascular disease events, and mortality," he explained. "It brings up an interesting paradox whereby higher levels seem to be linked to diabetes, but lower levels might potentially identify people at greater risk of cardiovascular disease events."

Both researchers claimed that fetuin-A may make a good target for pharmaceutical interventions. (JAMA [July 9, 2008] 300 (2):182)

New Susceptibility Gene Identified for Cowden and Cowden-Like Syndromes

Researchers have found a new susceptibility gene for those with Cowden and Cowden-like syndromes, a finding which may lead to effective screening and management for patients with these conditions.

Previously linked to the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene through pedigree studies, Cowden Syndrome has now been found to be associated with the B and D subunits of succinate dehydrogenase (SDHB/SDHD).

"When we started 10 years ago, it looked like there should be no other gene," explained Charis Eng, M.D., Ph.D., FACP, Sondra and Stephen Hardis Chair and director of the Genomic Medicine Institute at the Cleveland Clinic and lead author of the study published in The American Journal of Human Genetics. However, patients who do not meet the full diagnostic criteria, but have the features of Cowden syndrome, and of individuals lacking the PTEN mutation, but presenting with the condition led her to search for other candidate genes.

When Dr. Eng looked at a pheochromocytoma population-based registry, she found that 1% to 5% of individuals with mutations in succinate dehydrogenase had papillary thyroid cancer or renal cell carcinoma, two malignancies associated with the syndrome.

She decided to look closely at 375 individuals with either Cowden or Cowden-like syndrome without PTEN mutations. Among these individuals, 74 (20%) had increased manganese superoxide dismutase expression, a manifestation of mitochondrial dysfunction; and among these 74, 10 (13.5%) had germline mutation variants in SDHB or SDHD. Compared to individuals with Cowden or Cowden-like syndrome carrying the PTEN gene, those with SDHB/SDHD mutations or variants had more carcinomas of the thyroid (5/10 versus 15/106), female breast (6/9 SDH versus 30/107 PTEN), and kidney (2/10 versus 4/230).

"Succinate dehydrogenase is a very strange gene. When altered in this context, the penetrance is low but if you have the mutation, the susceptibility for renal and thyroid cancers is really high," commented Dr. Eng.

Genetic tests to identify succinate dehydrogenase mutations are already available, although Dr. Eng cautions that this type of testing should be done only in the setting of genetic counseling.

Doctors should also exercise caution as to whom they decide to genetically test. "The positive rate is pretty low so the chance you get something is pretty low, but if your suspicion is very high, it’s probably worth looking," said Sherri Bale, Ph.D., President and Clinical Director of GeneDx.

The researchers’ discovery yields promising news also on the research front.

"This is very strong evidence that the succinate dehydrogenase enzyme and the mitochondrial oxidation pathway in general may be if not causative, may be participating in the tumorigenesis in a variety of organs and systems well beyond the known association with paragangliomas and pheochromocytomas," said Constantine A. Stratakis, M.D., D.Sc., Head of the Pediatric Genetics and Developmental Endocrinology Program at the National Institute of Child Health and Human Development, who also found succinate dehydrogenase gene mutations in gastrointestinal stromal tumors.

"It opens our eyes to a new pathway," he added. "Now researchers will start looking at this pathway more carefully and help design medications targeting this enzyme and mitochondrial oxidation in various types of cancer from gastric sarcomas to breast, thyroid, and kidney, and perhaps other tumors." (Am J of Hum Genet [August 8, 2008] 83:261)[CrossRef]

	Endocrine Practice

Top Endocrine Discovery Endocrine Practice Endocrine Policy Milestones in Endocrinology In the Journal 25...

 
The National Institute of Diabetes and Digestive and Kidney Diseases has produced a guidebook for women with type 1 or type 2 diabetes who are expecting. The booklet, "For Women with Diabetes: Your Guide to Pregnancy," includes information on the importance of planning for pregnancy and controlling blood glucose levels before pregnancy. Logs for recording daily blood glucose and ketone levels, food intake, and physical activity are also included. (To order a free copy, go to http://www.catalog.niddk.nih.gov)

The U.S. Food and Drug Administration ordered Johnson & Johnson to add a "black box" warning about the risk of cancer in patients treated with the company’s Regranex diabetic foot gel. A study showed that patients who used three or more tubes of Regranex Gel 0.01% (becaplermin) had a five-fold increased risk of cancer mortality than those who did not use the product. (For more info, see: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01845.html)

The U.S. Food and Drug Administration announced that EMD Serono will no longer manufacture Geref Diagnostic (sermorelin acetate for injection), a drug used to diagnose growth disorders, since the active ingredient in the drug is no longer being produced. The last day to order samples will be September 30, 2008. (For more info, see: http://www.fda.gov/cder/drug/shortages/default.htm#Geref)

	Endocrine Policy

Top Endocrine Discovery Endocrine Practice Endocrine Policy Milestones in Endocrinology In the Journal 25...

 
The American Cancer Society recently received $8.5 million from an anonymous donor, the largest individual contribution in the Society’s 95-year history, to establish the Multiple Endocrine Neoplasia type 2 (MEN2) Thyroid Cancer Consortium, a 5-year research collaboration among 12 junior investigators and one senior scientist, who will investigate the ret proto-oncogene gene and other genetic origins of this disorder.

	Milestones in Endocrinology

Top Endocrine Discovery Endocrine Practice Endocrine Policy Milestones in Endocrinology In the Journal 25...

 
Fifty years ago, A. B. Lerner and colleagues isolated melatonin from the pineal gland. They proposed the name melatonin because of its relationships to melanin and serotonin.

	In the Journal 25 Years Ago

Top Endocrine Discovery Endocrine Practice Endocrine Policy Milestones in Endocrinology In the Journal 25...

 
3’-Isopropyl-3,5-diiodo-L-Thyronine [DIIP]: a potent synthetic thyromimetic thyronine analog. Studies of its kinetics and biological potency in man and rats and its toxicology. Kaiser CA, Salomon-Montavon NA, Merkelbach U, Burger AG. J Clin Endocrinol Metab [July 1983] 57(1):44–49. "One may therefore speculate that the biological activity of the two hormones [T3 and DIIP] may differ in different organs. This possibility requires further investigation."

View larger version (97K): [in this window] [in a new window]   FIG. 1. "Fetuin-A ... may give us an opportunity for targeted public health interventions to delay or prevent diabetes," said Joachim Ix, M.D., MAS, on the possible association between elevated fetuin-A and type 2 diabetes.

View larger version (116K): [in this window] [in a new window]   FIG. 2. "When we started 10 years ago, it looked like there should be no other gene," explained Charis Eng, MD, Ph.D., FACP, on her discovery that in addition to PTEN, succinate dehydrogense is associated with Cowden and Cowden-like syndromes.

View larger version (100K): [in this window] [in a new window]   FIG. 3. Pierre D. Delmas Pierre D. Delmas, founding president of the International Osteoporosis Foundation, and Professor of Medicine and Rheumatology at the University of Lyon, France, died at age 58 after a long illness. Dr. Delmas was considered by his peers to be the "medical face" of osteoporosis worldwide. His many accomplishments helped in the understanding of the pathogenesis of osteoporosis, its risk factors and ultimately in the management of the disease globally.

	Footnotes

This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content