Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement

Hot off the presses, a scientific statement by the Endocrine Society about the use of hormone replacement in Post-menopausal women. This may be the first statement to tackle the issue of HRT in women immediately after entering menopause. The authors also review data from the WHI and report "Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause."

Conclusions:
The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

BPA and Metabolic Syndrome

A recent study was just published revealing that there is no significant link between mice being exposed to BPA in the fetal and prenatal stage, and development of obesity as adults.

ABSTRACT:
Bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of plastic food and beverage containers, leading to ubiquitous low-dose human exposure. It has been suggested that exposure to even low doses of BPA during development may be associated with increased susceptibility to obesity and diabetes later in life. Despite growing public concern, the existing empirical data are equivocal, prompting The Endocrine Society, the National Institute of Environmental Health Sciences, and others to call for further research. In this study, we tested the hypothesis that perinatal exposure to an ecologically relevant dose of BPA (1 part per billion via the diet) results in increased susceptibility to high-fat diet-induced obesity and glucose intolerance in adult CD-1 mice. The data did not support this hypothesis. In agreement with previous reports, we find that weanling mice exposed to BPA during gestation and lactation are heavier compared with control mice. We also find that BPA mice are longer than controls at 4 wk of age, but these differences are no longer apparent when the mice reach adulthood, even when tested on a high-fat diet. We conclude that this larger size-for-age represents a faster rate of growth early in development rather than an obese, diabetic phenotype in adulthood.


Click here for Article.

Click here for accompanying editorial.

Go to GoodReader as well.

Long Term Bisphosphonate Use

This study by Nelson B. Watts and Dima L. Diab from University of Cincinnati is an excellent review of the pharmacodynamics and pharmacokinetics of bisphosphonates and the effect of their long term use. I thought what was striking about this particular article are the recommendations of a drug holiday. This is something many have discussed previously but has not be published significantly.

"Bisphosphonates are popular and effective for treatment of osteoporosis. Because they accumulate in bone and provide some residual antifracture reduction when treatment is stopped, we recommend a drug holiday after 5–10 yr of bisphosphonate treatment. The duration of treatment and length of the holiday are based on fracture risk and pharmacokinetics of the bisphosphonate used. Patients at mild risk might stop treatment after 5 yr and remain off as long as bone mineral density is stable and no fractures occur. Higher risk patients should be treated for 10 yr, have a holiday of no more than a year or two, and perhaps be on a nonbisphosphonate treatment during that time."

Read the full article in Goodreader...

Sleep Deprivation Leads to Insulin Resistance

A Single Night of Partial Sleep Deprivation Induces Insulin Resistance in Multiple Metabolic Pathways in Healthy Subjects

Esther Donga^*, Marieke van Dijk, J. Gert van Dijk, Nienke R. Biermasz, Gert-Jan Lammers, Klaas W. van Kralingen, Eleonara P. M. Corssmit, and Johannes A. Romijn

This study examined the effect of sleep deprivation on insulin resistance. The volunteers were allowed to sleep either normally (>8hrs) or sleep deprived ( less than 4hrs) and then underwent insulin clamp. The following results were found:

Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (226 ± 11 vs. 454 ± 9 min; P 0.0001). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids, insulin, or endogenous glucose production. Sleep restriction resulted in increased endogenous glucose production during the hyperinsulinemic clamp study compared to the unrestricted night (4.4 ± 0.3 vs. 3.6 ± 0.2 μmolxkg lean body mass^-1 · min^-1; P = 0.017), indicating hepatic insulin resistance. In addition, sleep restriction decreased the glucose disposal rate during the clamp (32.5 ± 3.6 vs. 40.7 ± 5.1 μmol · kg lean body mass^-1 · min^-1; P = 0009), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 25% (P = 0.001). Sleep restriction increased plasma nonesterified fatty acid levels during the clamp study (68 ± 5 vs. 57 ± 4 μmol/liter; P = 0.005).

What's fascinating is that previous studies have also shown that sleep restriction to only 4 h of sleep during two or more nights reduced glucose tolerance by 40% and reduced the acute insulin response to glucose in healthy subjects by 30%. In this study, there was a trend towards higher cortisol concentrations, but this was not statistically significant. There was a rise in fatty acid concentrations as well.

Great study...don't want to know the results of Q4 call on insulin resistance.

Possible Weight loss drug target...

Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phosphorylation of LKB1

Eijiro Yamada, Jeffrey E. Pessin, Irwin J. Kurland, Gary J. Schwartz, Claire C. Bastie

This is an article with a significant amount of biochemistry describing the effects of inhibition of Fyn-kinase in mice on weight loss. Without adding to much details here is a summary:

They recently reported that conventional Fyn knockout mice displayed increased energy expenditure and fatty acid oxida- tion due to increased activation of adipose tissue and skeletal muscle AMPK activity, resulting in reduced adipose tissue mass and enhanced insulin sensitivity.
This group then used an Fyn-kinase inhibitor and noted that the mice given the drug had lower R/Q indicating increased fatty acid utilization as well as higher oxygen consumption.
The SU6656-treated animals also dis- played decreased body weight 12 hr after the injection and the total weight loss was 40% greater than that of the vehicle-treated group.

Great Podcast on the topic of Osteoporosis

This is a great podcast to share with patients on the topic of osteoporosis by our very own Dr. Komal Patil-Sisodia...

http://www.hoaghospital.org/information/Podcast.aspx

Update in Male Osteoporosis

This is a great review article on everything new in male osteoporosis by Dr. Khosla. He does a great job of summarizing male osteoporosis by focusing on three main topics: epidemiology, pathogenesis, and management.

Context: Osteoporosis in men is becoming an increasingly important public health problem. One in five men over the age of 50 yr will suffer an osteoporotic fracture during their lifetime, and men who sustain fractures have an increased mortality risk.

Evidence Acquisition: Evidence was obtained by PubMed search and author’s knowledge of the field.

Evidence Synthesis: Studies using computed quantitative tomography and high-resolution peripheral computed quantitative tomography have provided new insights into the bone structural changes with aging in men, including the somewhat surprising demonstration of significant, ongoing trabecular bone loss starting in young adult life. In addition, there are now data demonstrating that serum estradiol levels are important predictors of fracture risk in men and that there is a threshold estradiol level below which not only bone loss but also fracture risk increases markedly. Criteria for diagnosing and managing osteoporosis in men are also evolving, including the application of the fracture risk assessment tool to derive 10-yr fracture risks in men. Three bisphosphonates (alendronate, risedronate, and zolendronic acid) and teriparatide are currently U.S. Food and Drug Administration approved for the treatment of osteoporosis in men, with a number of new compounds, including a monoclonal antibody against receptor activator of nuclear factor-B ligand, selective estrogen receptor modulators, and selective androgen receptor modulators in varying stages of development.

Conclusions: Despite significant advances, there remain a number of key unresolved issues regarding the pathogenesis and management of male osteoporosis, not the least of which is increasing public awareness of this important cause of morbidity and mortality in men.

Exercise Reverses Aging

Went to a very interesting grand rounds where Dr. Nair discussed some of the research from his lab. The focus of the lab is to assess the effects of aging and whether it is reversible. They found that most proteins seem to have different isoforms and they have developed a new technique (a 2D gel) to differentiate these. Using labeling techniques they showed that these isoforms are age related in that a protein changes with time. They felt these were post-translational changes and maybe due to oxidative damage resulting in poorer function.
They studied physically active individuals and when compared to sedentary subjects, noted that they had significantly less "damaged/aged" muscle.

OBJECTIVE— We determined whether reduced insulin sensitivity, mitochondrial dysfunction, and other age-related dysfunctions are inevitable consequences of aging or secondary to physical inactivity.

RESEARCH DESIGN AND METHODS— Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and ATP production in mitochondria isolated from vastus lateralis biopsies of 42 healthy sedentary and endurance-trained young (18–30 years old) and older (59–76 years old) subjects. Expression of proteins involved in fuel metabolism was measured by mass spectrometry. Citrate synthase activity, mitochondrial DNA (mtDNA) abundance, and expression of nuclear-encoded transcription factors for mitochondrial biogenesis were measured. SIRT3, a mitochondrial sirtuin linked to lifespan-enhancing effects of caloric restriction, was measured by immunoblot.

RESULTS— Insulin-induced glucose disposal and suppression of endogenous glucose production were higher in the trained young and older subjects, but no age effect was noted. Age-related decline in mitochondrial oxidative capacity was absent in endurance-trained individuals. Although endurance-trained individuals exhibited higher expression of mitochondrial proteins, mtDNA, and mitochondrial transcription factors, there were persisting effects of age. SIRT3 expression was lower with age in sedentary but equally elevated regardless of age in endurance-trained individuals.

CONCLUSIONS— The results demonstrate that reduced insulin sensitivity is likely related to changes in adiposity and to physical inactivity rather than being an inevitable consequence of aging. The results also show that regular endurance exercise partly normalizes age-related mitochondrial dysfunction, although there are persisting effects of age on mtDNA abundance and expression of nuclear transcription factors and mitochondrial protein. Furthermore, exercise may promote longevity through pathways common to effects of caloric restriction.

Does Size really Matter?

Body Fat Distribution, Adipocyte Size, and Metabolic Characteristics of Nondiabetic Adults

Manpreet S. Mundi, Maksym V. Karpyak, Christina Koutsari, Susanne B. Votruba, Peter C. O'Brien, and Michael D. Jensen^*

Mayo Clinic, Department of Endocrinology, Rochester, Minnesota 55905

^* To whom correspondence should be addressed. E-mail: jensen@mayo.edu.

Context: It is unclear whether adipocyte size or body fat distribution is most strongly linked to the metabolic complications of obesity.

Objective: Our objective was to test whether adipocyte size better predicts metabolic characteristics of obesity than body composition.

Design, Participants, and Setting: We analyzed the relationship between metabolic and anthropometric data collected from 432 largely Caucasian research volunteers (264 women) participating in studies conducted in the Mayo General Clinical Research Center between 1995 and 2008.

Main Outcome Measures: Metabolic variables included fasting plasma glucose, insulin, and triglyceride concentrations. Anthropometric variables included body composition, fat distribution, and sc abdominal and femoral adipocyte size.

Results: Using both univariate and multivariate regression analysis, fasting triglyceride in both men and women was best predicted by computed tomography of visceral fat area. Fasting insulin concentrations were best predicted by sc abdominal fat area in women (r² = 0.40; P <>2 = 0.53; P <> In men, fasting glucose concentrations were predicted by femoral adipocyte size (partial r² = 0.07; P = 0.002), body mass index (partial r² = 0.03; P = 0.07), and age (partial r² = 0.02; P = 0.06). In women, fasting glucose was predicted by abdominal sc fat area (partial r² = 0.12; P <> r² = 0.03; P = 0.01).

Conclusions: Our hypothesis that adipocyte size is the best predictor of metabolic characteristics was not supported in this population. The alternative explanation is that fat mass and body fat distribution have more influence on metabolic responses than adipocyte size.

Hypogonadism and Diabetes

I recently had to review a paper on the topic of hypogonadism an diabetes and came across an entire topic that I was not aware of. There has been extensive research done looking at the association between testosterone (free and total), SHBG, and the development of diabetes.

A number of things affect both SHBG as well as testosterone. Age, exercise, obesity just to name a few. However, insulin also affects SHBG levels. Hyperinsulinemia is associated with a reduction in SHBG concentration and SHBG concentration is positively associated with insulin sensitivity. SHBG concentration is also negatively correlated with insulin resistance, insulin levels and glucose concentration. Both insulin and insulin-like growth factor 1 have inhibitory effects on SHBG secretion by Hep G2 cells in vitro. Insulin also suppresses hepatic SHBG synthesis.

Because of this relationship, many papers are studying whether SHBG levels can be predictive of the development of diabetes. Because SHBG binds to its receptor and actually has some actions through g-protein/cAMP pathway, there are studies also looking at whether low levels of SHBG may actually lead to diabetes. If this pans out, perhaps SHBG may be a target in the future for something else we have to raise.

Further Reading:

1. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23(4):490-494.

This article shows that there is a Odds ratio of 1.89 of developing diabetes with a 1SD reduction in SHBG concentration.

2. Nair KS, Rizza RA, O'Brien P, et al. DHEA in Elderly Women and DHEA or Testosterone in Elderly Men. N Engl J Med. 2006;355(16):1647-1659.

From the WFMC...this article shows what little effect treating the elderly with DHEA in women or testosterone in men had on inuslin sensitivity.

3. Betancourt-Albrecht M, Cunningham GR. Hypogonadism and diabetes. Int. J. Impot. Res. 2003;15 Suppl 4:S14-20.

A pretty good review article on the topic.

Put down that soda...as we call it... pop

Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes?
Richard J. Johnson, Santos E. Perez-Pozo, Yuri Y. Sautin, Jacek Manitius, Laura Gabriela Sanchez-Lozada, Daniel I. Feig, Mohamed Shafiu, Mark Segal, Richard J. Glassock, Michiko Shimada, Carlos Roncal, and Takahiko Nakagawa
Endocr Rev published 16 January 2009, 10.1210/er.2008-0033


This is a really great article about the link between our consumption of fructose and the development of diabetes and an absolute must read. They present a lot of data (about 300 references) regarding the effects of fructose in the body. Most notably, fructose enters the cells through transporters different from glucose. It is also phosphorylated in a non-regulated mechanism once it enters the cell. This leads to a rapid depletion to ATP in the cell creating an pseudo-ischemic situation. This is especially prevalent in the liver and may be responsible for fatty liver.
The fructose also competes with glucose as a substrate in the Krebs cycle. The authors also note that fructose does not lead to hyper-insulinemia. This may have some good effects but also leads to a lack of activation of satiety centers in the brain leading us to eat more.
The article also has a great deal of epidemiologic evidence showing increased rates of diabetes in populations that consume the highest amounts of sugar.

To read the full article click here. I've also summarized the article on my website so you can click here for a summary (username/password is the same as my notes section).

Overall, a must read article. I just spent the entire day trying to avoid HFCS...it is impossible.

Fracture Risk during puberty and why?

Kirmani S, Christen D, van Lenthe GH, et al. Bone Structure at the Distal Radius During Adolescent Growth. J Bone Miner Res. 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19113916 [Accessed January 13, 2009].

In conference today Dr. Kirmani presented his data on the topic of increased fractures in puberty. He noted that in reviewing data gathered over the last 4-5 decades by the Mayo Clinic, there is an increase in fractures during puberty in both boys and girls. Overall, the frequency of fractures is also increasing over this time period.

In order to study this, the group looked at the distal radius (the most common site of fractures in this age group). They used a novel technique of high-res QCT to obtain images that were very close in detail to bone biopsy. By enrolling subjects in different age groups, they were able to gather data regarding the changes that take place in terms of bone.

As seen in the figure, the cortical portion of the bone becomes the weakest during puberty as bone growth occurs. This may be due a delay in the formation of cortical bone as opposed to trabecular bone as overall lengthening occurs. The reasons behind this are unknown but many in the audience suggested a local action of PTH in serving up cortical bone as a source of calcium (similar to that seen in breast feeding).

Regardless of the etiology, due to the lenghtening process without adequate thickening, the bone strength is approximately 1/8 that of the original bone thus leading to increase fractures.

BMI vs. Waist circumference

Despres J, Lemieux I, Bergeron J, et al. Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk. Arterioscler Thromb Vasc Biol. 2008;28(6):1039-1049.

This is a great review article about the issue of abdominal and more importantly visceral fat and its relationship to metabolic complications.
It is too difficult to summarize the review article since there are just too many great points and supporting studies listed, so I just wanted to give a brief glimpse into the paper.
One of the points made in the article is the proposed mechanisms for visceral tissue and its relationship/cause of insulin resistance:

• The hyperlipolytic state of the omental adipose tissue, which shows resistance to the action of insulin, contributes to expose (through the portal circulation) the liver to high concentrations of free fatty acids, impairing several hepatic metabolic processes leading to hyperinsulinemia (decreased insulin clearance), glucose intolerance (increased hepatic glucose production), and hypertriglyceridemia (increased VLDL-apolipoprotein B secretion).
• The adipose tissue is a remarkable endocrine organ which is a source of adipokines like adiponectin and inflammatory cytokines such as interleukin (IL)-6 (IL-6) and tumor necrosis factor (TNF)-{alpha} (to only name a few) which contribute to the insulin resistant, proinflammatory, -thrombotic, and -hypertensive state of visceral obesity.
• Excess visceral adiposity is only (or partly) a marker of the relative inability of subcutaneous adipose tissue to act as a protective metabolic sink because of its inability to expand (lipodystrophy) or because it has become hypertrophied, dysfunctional and insulin resistant. Under this third scenario, sedentary individuals who cannot store their energy surplus in the subcutaneous adipose tissue would be characterized by accumulation of fat at undesired sites such as the liver, the heart, the skeletal muscle, and the pancreas. They list a study that showed men with a great deal of visceral fat remained hyper-triglyceridemic 8 hours after an oral fat load.

I thought that this last point of the inability to store energy properly was a great mechanism.
Another point the authors raise is whether we should measure loss of waist circumference instead of weight with the initiation of exercise regimen since people can gain muscle and lose fat resulting in no net weight loss.

Bisphosphonates INCREASE osteoclast number?

A new study published in NEJM questions the long-held belief that bisphosphonate use promotes osteoclast apoptosis.
This study examined 51 bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption among healthy postmenopausal women 40 through 59 years of age. The patients were assigned to one of five groups: those receiving placebo for 3 years; alendronate at a dose of 1, 5, or 10 mg per day for 3 years; or alendronate at a dose of 20 mg per day for 2 years, followed by placebo for 1 year. Formalin-fixed, undecalcified planar sections were assessed by bone histomorphometric methods.

The Results were startling:
The number of osteoclasts was increased by a factor of 2.6 in patients receiving 10 mg of alendronate per day for 3 years as compared with the placebo group (P<0.01).> the number of osteoclasts increased as the cumulative dose of the drug increased (r=0.50, P<0.001).> of these osteoclasts were giant cells with pyknotic nuclei that were adjacent to superficial resorption cavities. Furthermore, giant, hypernucleated, detached osteoclasts with 20 to 40 nuclei were found after alendronate treatment had been discontinued for 1 year. Of these large cells, 20 to 37% were apoptotic, according to both their morphologic features and positive findings from in situ end labeling.

The discussion also has a great explanation as to why this may be occurring. It is too long to add here but to paraphrase, it appears the signal for the osteoclasts to undergo apoptosis is from the calcium they have just absorbed. Since the bisphosphonates inhibit this bone resoption, they stop the signal to enter into apoptosis.

Can read further here...

NEW ADA Guidelines update

Recent article in diabetes care published an update to the ADA diabetes guidelines. Here are some of the updates (great source of board questions)...

• In patients with coronary heart failure (CHF), thiazolidinedione use is contraindicated. (C)
• For all patients with diabetes, perform an annual comprehensive foot examination to identify risk factors predictive of ulcers and amputations. The foot examination should include inspection, assessment of foot pulses, and testing for loss of protective sensation (10-g monofilament plus testing any one of: vibration using 128-Hz tuning fork, pinprick sensation, ankle reflexes, or vibration perception threshold). (B)

click here for a complete list of the updates...
A link to the complete guidelines...(click here)

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

In summary, the microvascular benefits were not promising

There were no significant differences between the two study groups in the number of new eye procedures.

1. The cumulative rates of events in all patients, including those who had undergone eye procedures at baseline, did not differ significantly.
   
2. Fundus photographs showed no significant differences in progression to proliferative diabetic retinopathy (P=0.27) or in progression to clinically important macular edema (P=0.31).
   
3. There was a nonsignificant trend toward a beneficial effect in the intensive-therapy group with respect to diabetic retinopathy, with an increased incidence of at least two steps in severity in the standard-therapy group (P=0.07).
   
4. The between-group difference in new onset of retinopathy was not significant (P=0.27)

The GFR declined to 76 ml per minute by year 6 (P<0.001) with no difference between the two study groups (P=0.36).

1. Severe renal changes were unaffected by treatment (P=0.35).
   
2. Any worsening of albumin excretion was greater in the standard-therapy group (P=0.05).

There was a nonsignificant increase in autonomic neuropathy in the intensive-therapy group (P=0.07). No other significant changes in neuropathy were seen.

Since Andy did such a great job of hitting all of the main points, I will just raise some questions I had when reading it...perhaps you guys can enlighten me about some of them:

• The study reports that a sample size of 1700 patients provided a power of 86% to detect a relative difference of 21% in primary outcome. --> is 86% sufficient or underpowered?
• Mean duration of diabetes was 11.5 years and 40% of subjects had already had a cardiovascular event. --> if almost half of the subjects already have a CV event, isn’t the study now have two additional groups, those with CV disease and those without. Should these groups be studied separately?
• The lack of difference in microvascular disease was also very surprising because of the amount of data available to show that tight control dramatically improves this.
• Overall, my big criticism is the inclusion of the subjects with and without CV disease into one large group. This really is an issue of primary prevention vs. secondary prevention and the groups don't belong together. Without this combined group the study is under-powered to detect a difference. They found a slight decrease in the primary outcome in intense therapy vs. standard and I really think with adequate power, this difference is statistically significant.
  

Click here to read further....

Pioglitazone and changes in body fat distribution.

This topic just came up in one a paper and I thought I might dig up some details about it. We all know that the TZDs tend to change fat distribution but may not have looked into the details of it. Dr. Jensen (my mentor) in 2003 published a paper on this topic in Diabetes Care. Here are the details: (its freely available from Diabetes Care) I've added in details that I thought were interesting and put them in italics.

Shadid S, Jensen MD. Effects of Pioglitazone Versus Diet and Exercise on Metabolic Health and Fat Distribution in Upper Body Obesity. Diabetes Care. 2003;26(11):3148-3152.

METHODS:
Thirty-nine upper body obese (BMI of 28-36 and waist to hip ratio >0.85 for women and >0.95 for men), insulin-resistant, nondiabetic men and premenopausal women were randomly assigned to receive either 30 mg/day pioglitazone or a diet (500kcal/day deficit) and exercise program for 20 weeks. The exercise regimen consisted of 15 mins of aerobic exercise 3x/week and increased gradually to 45 minutes of aerobic exercise 4 times a week. Before and after the intervention, insulin sensitivity, body composition, body fat distribution (waist-to-hip ratio [WHR], computed tomography abdomen, and dual-energy X-ray absorptiometry), and abdominal and femoral fat cell size were assessed.

RESULTS:
Diet and exercise resulted in an 11.8 ± 1.1 kg weight loss. Both diet and exercise and pioglitazone improved insulin sensitivity, but only diet and exercise were associated with loss of intra-abdominal fat. Pioglitazone increased total body fat, which preferentially accumulated in the lower body depot in both men and women. WHRs decreased in both groups although in the pioglitazone group, the waist circumference did not decrease. Abdominal fat cell size decreased (P = 0.06) after diet and exercise. No statistically significant changes in fat cell size were observed in pioglitazone-treated volunteers.
Another interesting change was in terms of the cholesterol. Only the diet/exercise group had a reduction in the total cholesterol while pio group did not.
BP reductions were also more significant for the diet/exercise group than pioglitazone group.

Dr. Jensen did not find a decrease in visceral fat area. In comparison to other publications, no change has been reported in the intra-abdominal adipose tissue area by 4 reports with pio. Three have reported a decrease and most have reported a decrease in the visceral to subcutaneous fat area ratio. Just note that some of the investigators reporting decreases in visceral fat area did combine TZD with diet.
The gain in insulin sensitivity may be due to the decrease in fat cell size and an increase in their numbers instead.

Post Etiquette!!

Please place a label in the lower hand corner:
1. of your name eg. *Ghaderi(place a star before your name)
2. of a subject title eg. lipids

Here are some post etiquettes:
Please do not just cut and paste information on the blog.
The blog is a space where you can start a conversation with people.
Please provide some analysis or comment.

Acceptable posts are:
1. Case presentations with a question.
2. Your interpretation of a study or article.
3. Endocrine comments on a problem.

For the Endocrine fellows:
Please provide one quality post every week.

Valvular Heart Disease and dopamine agonists

Recently the possible correlation between dopamine agonists and valvular heart disease has been raised in a few conferences. Originally brought on by a recent article in NEJM by Zanettini et al in 2007 that looked at 11, 417 subjects who were prescribed anti-parkinsonian drugs and matched each case of valvular disease to 25 controls. Noted 31 cases of valvular diease and out of these 6 were given cabergoline, 6 pergolide, and 19 were not exposed to dopamine agonists. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists.
Because of this higher incidence with cabergoline and pergolide as opposed to other dopamine agonists, the question is raised as to whether this is applicable to prolactinoma treatment in which we use much lower dosages of these agents.
To answer this Devin et al (Endocrine Practice Sept 2008) conducted a recent retrospective review of patients identified with hyperprolactinemia who underwent elective echocardiography. They noted valvular disease in 7% of cases (no different than the general population) and much less than close to 30% found in other studies.
Big differences were the mean dose of cabergoline was 0.91+/- 0.96mg per week, whereas the anti-parkinsonian doses may be as high as 3mg/d.

Novel apolipoprotein A-V discovered

Extreme biochem alert!!!

Just came back from recent fellows journal club and we discussed the discovery of a novel apolipoprotein V. I just wanted to add this to our Journal club because it may have some drug target implications.

Apolipoprotein V was discovered about six years ago and it appears that apoA-V may lead to increased plasma TG hydrolysis or mediate cellular uptake of remnant particles. It's over-expression leads to reduced levels of triglycerides.

It is still a novel apolipoprotein and its various isoforms have not been fully studied.

Click here for a good review article on the topic (if you have run out of Ambien).