Tesofensine - initial trials of a potential weight-loss drug

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial
Original source: The Lancet Volume 372, Issue 9653
Authors: Arne Astrup (corresponding author), Prof Sten Madsbad, Leif Breum, Thomas J Jensen, Jens Peter Kroustrup, Thomas Meinert Larsen
Publication date: 29 November 2008
DOI (digital document ID): 10.1016/S0140-6736(08)61525-1
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The investigators are interested in producing a safe, more-effective weight loss drug than those already on the market. They looked at safety and effectiveness of tesofensine, which inhibits the uptake of several hormones. Current weight loss drugs only provide an average of 3-5 kg (7-12 lb) greater weight loss than diet and exercise alone.

The investigators conducted a double-blind, placebo-controlled survey of 203 obese patients over a six-month period, along with diet and exercise. Three strengths of tesofensine were used in the study. The patients who used tesofensine lost more weight than those who did not, and the larger the dose of tesofensine, the more weight they lost. The most common side effects reported in the abstract were relatively minor.

The investigators reported that the two lower strengths of tesofensine did not raise blood pressure or heart rate, and that the middle dosage raised heart rate by an average of 7.4 beats per minute.

Reliability:
This is a Phase II study, conducted by the drug manufacturer. This means it is one of the earlier human-based studies. Based on the small sample and limited time, the investigators believe the drug is safe and effective; however, more complete, Phase III studies are needed to prove this over larger populations, over longer amounts of time.

That the lower strengths of tesofensine "showed no significant increases in systolic or diastolic blood pressure compared with placebo" suggests that the drug does indeed raise blood pressure (they did not state this of the highest strength tested -- suggesting that the higher dosage might indeed cause a significant rise in blood pressure). The increase in heart rate may have other adverse implications.

Update:
Several comments to this article were posted in the 2009 February 28 issue of The Lancet. Concerns addressed included not just the rise in blood pressure -- which apparently was not considered in the context of predicted drops in blood pressure due to weight loss -- and adverse psychological effects of the drug. The authors' response to these concerns was to suggest that drops in blood pressure were due to dietary change rather than weight loss itself, and to note that there were no adverse psychological effects observed in their test population.

Again, this was a Phase II trial, which means that it is one of the earlier human-based trials before a drug can be marketed in the United States.


Practical Applications:
The search for a safe, effective weight loss pill is ongoing. Our understanding of the interrelationship between obesity, insulin resistance, hypertension, and cardiovascular disease is still imperfect, but observation suggests that reducing the degree to which one is obese can reduce or reverse the damage of metabolic syndrome.

Since it will often take more than a year for a determined obese person to lose sufficient weight to move out of the "obese" classification, weight-loss drugs should be proven to be safe and effective over a period of years. Since there is also a potential for impatient patients to want to increase the dose, they should be proven to be safe at greater doses than those intended for prescription.

This synopsis was based on the abstract only.

How does your body-fat distribution affect your risk of death?

General and Abdominal Adiposity and Risk of Death in Europe
Original source: New England Journal of Medicine Volume 359:2105-2120 November 13, 2008 Number 20
Authors: T. Pischon, H. Boeing, K. Hoffmann, M. Bergmann, M.B. Schulze, K. Overvad, Y.T. van der Schouw, E. Spencer, K.G.M. Moons, A. Tjønneland, J. Halkjaer, M.K. Jensen, J. Stegger, F. Clavel-Chapelon, M.-C. Boutron-Ruault, V. Chajes, J. Linseisen, R. Kaaks, A. Trichopoulou, D. Trichopoulos, C. Bamia, Ph.D., S. Sieri, D. Palli, R. Tumino, P. Vineis, S. Panico, P.H.M. Peeters, A.M. May, H.B. Bueno-de-Mesquita, F.J.B. van Duijnhoven, G. Hallmans, L. Weinehall, J. Manjer, B. Hedblad, E. Lund, A. Agudo, L. Arriola, A. Barricarte, C. Navarro, C. Martinez, J.R. Quirós, T. Key, D.Phil., S. Bingham, K.T. Khaw, P. Boffetta, M. Jenab, P. Ferrari, and E. Riboli
Publication date: November 13, 2008
DOI (digital document ID): (unavailable)
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
This article addresses the question of whether the risks of obesity are related to the distribution of body fat, rather than the existence of fat excess body weight alone.

The investigators examined Body Mass Index (BMI), waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries over a period of almost ten years. The results were analyzed based on age at recruitment into the study, location at which they were entered into the study, height, educational level, whether or not the subject smoked, how much alcohol the person drank, and how physically active the person was.

The 1% of respondents with the highest and lowest energy intakes relative to estimated energy requirements were excluded from the study, as were respondents with a history of cancer, heart disease, or stroke.

"Normal" weight was considered to range from BMI 18.5 to BMI 25.0

The lowest risks of death based on BMI were at 25.3 for men and 24.3 for women. (This corresponds to the borderline between "normal weight" and "overweight".) After adjusting for this, absolute waist size and large waist-to-hip ratio were associated with greater risk of death. These last two correlations were stronger for people with lower BMI than for those with higher BMI, and stronger for men than for women.

One possible reason for the gender-related difference may be that overweight men tend to carry more fat in their midsections (visceral-fat) than equally-overweight women. This is important because visceral-fat tissue secretes a number of chemicals (lipokines) that can cause or exacerbate a number of chronic diseases.

Interestingly, it was found that the reasons for increased risk of death changed depending on waist measurement: those people who died and who were simply overweight or obese had more deaths from circulatory issues than from other causes, whereas those who had more abdominal obesity tended to die from respiratory issues rather than from other causes. (This may be a confounding issue, related to the observation that smokers tend to have more abdominal fat than non-smokers of similar BMI, and that smokers have higher risk of dying from respiratory system issues. The authors note that there is a known association between abdominal adiposity and chronic bronchitis, but do not state if this is a smoking-related association or not.)

The researchers conclude that these data suggest that both high body weight and abdominal fat are associated with higher risk of death, and support the use of waist circumference and or waist-to-hip ratio in addition to BMI in assessing the risk of death.

Reliability:
This study followed a large number of people for a relatively long period of time, making the study population relatively reliable; however, high BMI is not always related to adiposity. Body-builders, as a noted example, can have BMI in the obese range, but body fat measurement by either bioelectrical measurement or water immersion will indicate extremely low body fat percentages. On the other hand, these people generally have waist measurements and waist-to-hip ratios that are significantly smaller than people of the same body mass index, but with greater percentages of body fat. They also tend to have higher metabolic rates, making them more likely to place in the highest caloric intake per kilogram of body mass; some people who fit in this category were probably excluded from the study for that reason.

Another consideration, noted briefly by the investigators, is that there are a number of chronic diseases that were not excluded from the study. Some of these (such as Type 2 diabetes) affect, or are affected by, body weight and weight distribution. These could also affect the relative risks of death of the population observed.

Practical Applications:
The use of waist measurements and waist-to-hip ratios, in conjunction with BMI, can assist doctors and public health professionals in assessing individual and community health risks.

The authors' Figure 2, representing relative risk based on waist circumference and waist-to-hip ratio, shows a standardized risk of 1.0 for men at approximately 93 cm (about 36"), 0.94 waist-to-hip ratio (36" waist corresponding to about 39" hip), and for women at approximately 77 cm (about 30") waist size, 0.79 waist-to-hip ratio (30" waist corresponding to about 38" the hip). These measurements are lower than the standards currently used for determination of risk (102 cm/40" for men, 88cm/35" for women). Interestingly, these measurements correspond to the largest "standard" reference clothing sizes (men's pants to jacket size 42, women to U.S. Misses size 16/European size 42) as expressed in the home-sewing pattern industry, or "true-to-size" in the ready-to-wear industry.

This suggests that an average person should be able to determine his or her risk based on off-the-rack clothing size.

For further reading:
Home-sewing pattern measurements:

• Simplicity Patterns (United States):
  
  • US measurements
  • European measurements


• Burda Patterns (Germany):
  
  • US and European measurements

This synopsis was based on the complete article.

Iron-rich blood and metabolic syndrome

Hyperferritinemia Is Associated with Insulin Resistance and Fatty Liver in Patients without Iron Overload
Original source: PLoS ONE 3(10): e3547
Authors: Robert Brudevold (corresponding author), Torstein Hole, Jens Hammerstrøm
Publication date: October 28, 2008
DOI (digital document ID): 10.1371/journal.pone.0003547
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Over the past ten years, the investigators have seen a rise in patients with hyperferritinemia (high blood ferritin) -- excess iron in the blood. A certain amount of this is to be expected given the increasing awareness of hereditary hemochromatosis -- a genetic condition in which the blood retains an overload of iron. High blood ferritin is also seen in cases of inflammation and in cancer. Over the same period, there has been an increase in patients whose high ferritin levels cannot be explained by these conditions. Most of these patients are overweight, middle-aged men.

Previous research suggested links between elevated ferritin levels and non-alcoholic fatty liver disease (NASH -- in technical terms, non-alcoholic steatohepatitis), and between high ferritin and insulin resistance. Both NASH and insulin resistance are often seen in patients with metabolic syndrome. The authors chose to examine this possible link in more detail.

They examined forty consecutive patients referred to them for hyperferritinemia. After examination, 34 patients remained with unexplained hyperferritinemia -- 1 woman and 33 men. Fasting blood samples were taken and analyzed for iron, liver enzymes, c-reactive protein (a marker for inflammation), and c-peptide (a marker for insulin production). Liver biopsies were obtained for 29 of the patients, and liver iron stores were assessed for 16 of them.

The majority of the patients had either markers for metabolic syndrome, or could be clinically diagnosed as having metabolic syndrome, showing increased body mass index, elevated diastolic blood pressure, and insulin resistance. Nineteen of the 29 patients biopsied had steatosis (fatty livers). Only four patients showed increased levels of iron in their livers -- of which two could be explained by alcohol consumption. Ferritin levels were higher in subjects with insulin resistance than in those without.

Fourteen of 16 patients normalized ferritin levels after phlebotomy (removal of an amount of blood -- a standard medical procedure for persons with hemochromatosis), but after a while, their ferritin levels rose again. Those who changed lifestyle (diet and exercise) -- first-line therapy for patients with metabolic syndrome -- had stabler ferritin levels. Since NASH is often seen in obese patients and in patients with metabolic syndrome, this evidence supports the theory associating NASH with increased ferritin levels.

These observations suggest that fatty livers and insulin resistance, but not increased iron storage in the liver, may be frequently seen in patients referred to specialists because of high ferritin levels. The authors conclude that ferritin levels seem to be higher in people with insulin resistance and suggest that high ferritin levels are markers of metabolic syndrome with NASH and insulin resistance, rather than iron overload.

Reliability:
There were very few subjects examined in this study, and no indication of how common this complaint is within the population affected by insulin resistance and/or metabolic syndrome. Because of this, there is a possibility of skewed data.

The tests support previous research, adding information to the existing body of knowledge and suggesting directions for further research.

The authors are associated with accredited medical institutions and the article is published in a peer-reviewed journal.

Practical Applications:
Understanding the entire extent of physiological changes associated with metabolic syndrome can help doctors and pharmacists better understand both metabolic syndrome in general and how best to treat the individual patients.

While the population studied is small, it supports our understanding that lifestyle management -- maintenance of a stable, healthy weight through diet and exercise -- is of vital importance for maintaining or improving our overall health.

Ethics note: All patients gave oral consent to the examination program and to the use of clinical data for research purposes.

This synopsis was based on the entire article.

Can fish oil counteract sleep deprivation?

Dietary fish oil did not prevent sleep deprived rats from a reduction in adipose tissue adiponectin gene expression
Original source: Lipids in Health and Disease 2008, 7:43
Authors: Ana BM Mattos, Monica JS Pinto, Cristiane Oliveira, Carolina Biz, Eliane B Ribeiro, Claudia M Oller do Nascimento, Monica L Andersen, Sergio Tufik, and Lila M Oyama (corresponding author)
Publication date: 5 November 2008
DOI (digital document ID): 10.1186/1476-511X-7-43
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Sleep deprivation has been one of the hallmarks of modern society. Where it was once limited to the elderly, now even youth are chronically sleep deprived. Sleep deprivation is linked to adverse metabolic effects, including insulin resistance. Omega-3 fatty acids found in fish oil have been seen to improve insulin sensitivity -- decrease insulin resistance. We don't yet know how this works, but researchers believe that adiponectin has a role.

The aim of this study is to assess the effects of diets high in fish oil on sleep-deprived subjects. The authors note that while in humans, sleep deprivation is associated with weight gain, sleep-deprived rats tend to lose weight. This suggests to them a method of measuring insulin resistance in such a way that it is not related to weight gain. Glucose tolerance, serum insulin, and adiponectin levels are examined in both sleep-deprived and non-sleep-deprived rats.

The rats were kept awake for 96 hours, which is when the most dramatic alterations in lipid and hormone concentrations occur. At that time, the rats were subjected to a glucose tolerance test, starting with blood drawn after a 12-hour fast, and then after the glucose was given, at time intervals of 4, 12, 20, 24, 28 and 32 minutes. The blood sampled was tested for glucose concentration, insulin, and adiponectin levels. The animals were then killed, weighed, and the fat and protein contents of their bodies separated and measured. Adiponectin and transfer-RNA were measured from the animals' adipose tissues.

Sleep deprivation caused the rats to lose weight whether or not they were on fish-oil-rich diets (this is normal for rats). Non-sleep-deprived rats did not lose weight. Sleep-deprived rats fed a normal diet lost fat; those fed a fish-oil-rich diet did not. No change was observed in protein content of any of the groups.

Following the glucose tolerance tests, glucose concentration was significantly higher in the rats allowed to sleep than those who were sleep-deprived -- and in the last measurement, the glucose level in the rats who were both sleep-deprived and fed a fish-oil-rich diet dropped even further relative to the other groups.

Serum insulin and adiponectin was similar across all groups; however, the gene expression of adiponectin in abdominal tissue was lower in the sleep-deprived rats than the non-sleep-deprived rats. Insulin levels were lower in sleep-deprived male rats, so there may have been unaccounted-for factors in the test.

The authors examine the findings of previous studies on lipid consumption, fish oil, sleep deprivation, and adiponectin expression in rats to put their study into context. They conclude that sleep deprivation does cause a stress-related drop in adiponectin gene expression, which negatively effects insulin sensitivity.


Reliability:
There were only 5-9 rats per group studied. This is a very small sample, in which results can be skewed. Rats may not be a good model for humans in this environment, as humans tend to gain weight when sleep-deprived and there are perceived correlations between weight gain and insulin sensitivity. The readings for the rats were taken at the point of peak change of a single episode of sleep deprivation, rather than after a long period of chronic sleep deprivation (e.g., 1 month at 2 hrs less sleep than normal mice get). This is the difference between students spending a couple of all-nighters cramming for an exam versus a young professional working sixteen-hour days for several years to establish himself in a competitive field.

Practical Applications:
If it could be proven that fish oil supplements (or a diet rich in fish) could protect humans against some of the adverse metabolic effects of sleep deprivation, then this could be an effective and inexpensive treatment against those medical risks.

This synopsis was based on the entire article.

Food in the home and obesity

The validation of a home food inventory
Original source: International Journal of Behavioral Nutrition and Physical Activity 2008, 5:55
Authors: Jayne A Fulkerson (corresponding author), Melissa C Nelson, Leslie Lytle, Stacey Moe, Carrie Heitzler, and Keryn E Pasch
Publication date: 4 November 2008
DOI (digital document ID): 10.1186/1479-5868-5-55
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
A validated home food inventory can be a useful tool to assess what foods are readily available to a person or family, and by consequence, what foods are frequently eaten. This differs from a self-reported food inventory, as it allows a trained professional to independently inventory both the items in general and their relative quantities, and for the results to be compared with the self-reported inventory. The authors of this study are looking to see if there is a relationship between the types of food available in the home and the likelihood that members of that household are obese.

The authors find that in many previous studies on home food inventories, the list of foods leaves out a lot of categories and specific foods, and there have been few attempts to see if the person doing the reporting is accurately including all the food and food types in the household. They note four previous studies that have had validation, each of which has focused only on a small group of food items, with a particular health goal in mind.

Their goal is to create a comprehensive food inventory, which can be completed by an average adult, and which takes into account both healthy and unhealthy foods, as well as "reduced fat" versions of foods often associated with obesity.

Using both trained volunteers and volunteers from the community, they developed a home food inventory form. They validated the inventories for 51 families and analyzed the results for accuracy of self-reporting. They then distributed the inventory survey to 349 families with adolescent children, measured the adults and the children and recorded their demographic characteristics, and then asked them what foods they ate over the previous 24 hours. They were given information on how to estimate portion sizes, and told to expect three phone calls over the next month asking them to recall their food intake for the past 24 hours. In addition, dietary health questionnaires were distributed; these are shown to be relatively accurate in assessing the usual food and nutrients that the participant consumes.

The final home food inventory included 190 items which were community-specific. Participants were instructed on key package words that might indicate a reduced-fat version of a dessert or snack food, since these were categorized separately from the original (full-fat/full-sugar) versions.

Foods were ranked according to their association with obesity, or the likelihood that eating a lot of those foods would cause a person to become obese over time.

The home food inventories filled out by the initial 51 families in the pilot project were compared with the identical inventory filled out by the trained volunteers to determine whether or not the consumers understood brands as being part of larger categories, and how well they understood the questionnaire overall. The results showed a high degree of correlation, which the researchers take to mean that an unvalidated inventory should be reasonably accurate.

The researchers note several limitations of the study, including some issues with correctly categorizing a number of prepared foods and frozen desserts, the limitation of specific food items and types, and the limitation of food items and categories to "yes-no" answers rather than measuring quantity and variety. The initial set of families had a greater number of educated Caucasian adults than was representative of the community at large, and may not accurately represent the responses of less-educated and/or non-white populations.

Reliability:
The authors are affiliated with the University of Minnesota, in the professional realms of nursing and community health. The study was published in a peer-reviewed journal.
The researchers note that there are several food categories that were not as well-correlated as others -- primarily, prepared and frozen desserts, and breads. Some of this is due to the large variety of products available in these categories.
There is some limitation in correlating food inventories with dietary intake, as about half of the the foods listed in the 24-hour recalls were not on the home food inventories. (This would suggest a fair amount of eating outside the home.)

Practical Applications:
A useful, friendly home food inventory is a basic tool that anybody can use in menu planning, grocery shopping, and disaster planning. It is also a tool that can provide your nutritionist, social worker, or Certified Diabetes Educator a better idea of what foods you have, and what you regularly eat. This information is helpful in showing you ways to improve your diet to lose weight, maintain healthy blood glucose levels, and reduce your risks of cardiovascular disease.

A validated home food inventory is also a useful basis from which to gather information for community health and public health studies regarding nutrition and health.

This synopsis was based on the entire article.

Mediterranean Diets: low-carb versus low glycemic load

Spanish Ketogenic Mediterranean diet: a healthy cardiovascular diet for weight loss
Original source: Nutrition Journal 2008, 7:30
Authors: Joaquin Perez-Guisado (corresponding author), Andres Munoz-Serrano, and Angeles Alonso-Moraga
Publication date: 26 October 2008
DOI (digital document ID): 10.1186/1475-2891-7-30
Requires subscription? No
Publicly-available abstract: Yes

Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in a randomized trial
Original source: Nutrition & Metabolism 2008, 5:29
Authors: Robert H Lerman (corresponding author), Deanna M Minich, Gary Darland, Joseph J Lamb, Barbara Schiltz, John G Babish, Jeffrey S Bland, and Matthew L Tripp
Publication date: 4 November 2008
DOI (digital document ID): 10.1186/1743-7075-5-29
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Both of these studies looked at variants of the Mediterranean Diet, followed over a period of 12 weeks (three months). The Spanish study emphasized the use of virgin olive oil as the primary source of dietary fat, green vegetables and salads as the primary source of carbohydrates, and fish as a primary source of protein. The US study is a follow-on to a previous study comparing a low-glycemic-load Mediterranean diet with added soy protein and phytosterols (plant-based fats) to the American Heart Association's diet plan. In this study, the diet is supplemented with plant-derived substances (phytochemicals) that they believe will improve insulin sensitivity and reduce cardiovascular and metabolic risk factors.

In the Spanish study, 31 obese people (BMI approximately 36) in their mid- to late-thirties were studied. They were not given caloric limits, but their diets included approximately 2 tablespoons of virgin olive oil (2 teaspoons per meal), 1-2 glasses wine daily (half at lunch and half at dinner),
green vegetables and salads to a maximum of 30 g carbohydrate per day, and unlimited protein. Non-nutritive sweeteners were allowed on this diet. Protein was divided into "fish" and "non-fish" (meat, fowl, eggs, shellfish and cheese), with "fish" and "non-fish" being consumed on separate days, and at least four "fish days" per week. In addition, subjects were allowed up to two cups of coffee or tea per day, and required to drink at least three liters of water per day. The subjects were given a standard multivitamin-and-mineral supplement and a calcium supplement; they were also asked to check their urine for ketones using ketostrips.

• Results: After 12 weeks, the subjects lost about 14 kg (30-35 lb), lowered their blood pressure (by about 15 points (millimeters mercury) systolic and 9 points diastolic), lowered their total cholesterol about 10%, significantly dropped their triglyceride levels (from about 218 down to 114 mg/dl), and reduced their fasting blood glucose level about 16 mg/dl. In addition, LDL ("bad") cholesterol levels dropped about 8%, and raised their HDL ("good") cholesterol about 9%. While the subjects were not heavy enough to have moved from "obese" to "overweight" in this time frame, the measured changes moved the patients' statuses from "prehypertension" to "normal blood pressure", from "prediabetic" to "normal", and from "high cholesterol" to "normal cholesterol". Based on the factors used to diagnose it, these subjects would be considered to no longer have metabolic syndrome. The researchers did not measure the beginning and ending percentages of body fat versus muscle mass, but their visual observation suggests that the weight lost was primarily fatty tissue.
• Limitations: The study had a number of limitations, including small size, short duration, highly-selected population, no measurement of total caloric intake, and the possibility that weight loss alone, as well as any of the factors of the program -- either by itself or in combination with others -- may have accounted for these changes. The authors suggest further study with a larger group of people, for a longer period of time, and also comparison with other low-carb diets.

The US researchers' initial viewpoint is that modern diets induce tissue inflammation, resulting in metabolic syndrome. They state that a number of active ingredients in medicinal plants target the pathways of this inflammation, and believe that the addition of these active agents to a low-glycemic-load adaptation of the Mediterranean diet can assist the body in repairing this damage. The US study included 49 patients with metabolic syndrome, average age 53 years, average BMI approximately 34. All subjects had high LDL cholesterol and triglycerides, and had at least two of the other signs used to diagnose metabolic syndrome (low HDL cholesterol, stage I hypertension or drug-treated hypertension, large waist size, and impaired fasting glucose. Half were put on a modified Mediterranean diet alone; the other half were put on the modified diet with the inclusion of phytochemical supplements. The two groups were split out in a way to minimize the initial differences between them.
In this version of the Mediterranean diet, wine was limited to 1 glass per day. Whole grains were allowed, but only one serving per day. Vegetables were mostly limited to very low glycemic load vegetables, with a maximum of one "occasional" serving of a small category of
phytochemical-rich vegetables with a moderate glycemic index (55-70). The only sweeteners allowed were stevia and low-glycemic agave nectar syrup.
The group receiving phytochemical supplementation received a nutritional supplement beverage (powdered) and supplement tablets. All subjects were required to engage in moderate aerobic exercise (at 70-75% target heart rate) for at least 2.5 hours per week. Food cravings, as well as food intake and satiety levels, were monitored (patient-generated logs and surveys). The results were analyzed, accounting for the effects of weight loss, consuming fewer calories, and consuming lower levels of carbohydrate.

• Results: At the end of 12 weeks, the diet-alone subjects lost about 5.7 kg (about 12.5 lb), and the supplemented group about an extra half-pound. While both groups showed lowered total cholesterol, LDL, and triglycerides, the group receiving the supplements saw greater reductions in these readings. Only the group with the supplements had increased HDL cholesterol. The group receiving the supplements were able to lower both systolic and diastolic blood pressure by about 6 points, while those receiving diet alone were only able to lower their systolic blood pressure, by about 4 points. Hemoglobin A1c (HbA1c), a measure of long-term blood glucose levels, went down in both groups, but fasting blood glucose did not drop in the group receiving supplements. Twice the number of subjects in the group receiving supplements were able to move from "having metabolic syndrome" to "normal".

Reliability:
The authors in the Spanish study are associated with the Genetics department of the University of Cordoba and do not report any conflicts of interest. Their bibliographic references are from peer-reviewed journals, mostly in the realm of nutrition.

The authors in the US study all work for the MetaProteomics, a research subsidiary of Metagenics, a company which produces and sells dietary plans, including a number of dietary supplements and meal replacement formulas, which it states will improve the health, weight,
and longevity of people with metabolic syndrome and cardiovascular disease. The MetaProteomics subsidiary is aimed at research into human proteins and how specific chemicals in foods are used by the human body. The bibliographic references are from peer-reviewed journals, and their source research is aimed more at finding the causes of cardiometabolic disease as well as specific chemicals that might lessen the probability of developing these diseases. As employees of a subsidiary of Metagenics, the authors' research is aimed at developing new products (both diets and supplements) for Metagenics to sell.

Both studies are limited in small sample size over short amounts of time; additionally, the Spanish study considers fewer variables.

There are significant differences in the two low-glycemic/low-carb "Mediterranean diets" studied: the Spanish study centers on healthy proteins and fats, while the US study aims more at trying to determine the effect of an anti-inflammatory diet and of the phytochemical
supplements the company sells.

Practical Applications:
Both versions of "Mediterranean diet", unsupplemented, showed favorable changes in cholesterol levels and blood glucose levels. The Spanish study showed greater changes in weight loss, blood pressure, triglycerides, and HDL cholesterol than the US study including supplements; however, the limitations of both studies does not indicate how effective either diet is at maintaining long-term health, or how safe they are over long periods of time.

Any highly-restrictive diet has its limitations, and even some less-restrictive diets may not be suitable for your personal medical conditions. Please consult your doctor and nutritionist before making any large-scale changes to your diet.

This synopsis and comparison was based on the full articles.

Are adverse effects of some diabetes drugs related to their suppression of sex hormones?

Are the adverse effects of glitazones linked to induced testosterone deficiency?
Original source: Cardiovascular Diabetology 2008, 7:30
Authors: M. Carruthers (corresponding author), T. R. Trinick, E. Jankowska, and A.M. Traish
Publication date: 15 October 2008
DOI (digital document ID): 10.1186/1475-2840-7-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors pose a theory that the various adverse effects of diabetes drugs in the class called "glitazones" -- including rosiglitazone (RGZ -- brand name Avandia) and pioglitazone (PGZ -- brand name Actos) -- may be related to a separate known action of these drugs -- their suppression of sex hormones. These side effects include heart disease, swelling, weight gain, and anemia.

Glitazones act on sex hormones by reducing the levels to which they are released and by making the body less sensitive to them. These sex hormones are responsible for directing new cell growth to become blood vessels, skin, muscle, and other types of structural cells, rather than fat cells. This might give further weight to an existing theory of how obesity might cause diabetes (called "Ungar's theory of the 'Lipocentric Pathway to Hyperglycemia'"(1)). The authors note evidence that low testosterone levels in men can cause a number of the same side effects that are being observed in diabetes patients treated with glitazones; furthermore, that diabetes and/or cardiovascular disease are often seen to develop where testosterone production has been suppressed in order to treat prostate cancer. Much of this can be tied to the abdominal weight gain related to low testosterone levels. Treatment with testosterone in these cases has been shown to reduce the side effects and lower the statistical occurrence of cardiovascular disease among patients showing a number of these metabolic symptoms.

The authors note a number of known effects of rosiglitazone and troglitazone (Resulin, which has been removed from the US market) on sex hormones and on the development and maturation of new body tissues.

The authors suggest that this hypothesis might be tested by double-blind, placebo-controlled clinical studies examining the endocrine profiles, and levels of sex hormones, in people with Type 2 diabetes both before and while/after being treated with a glitazone. Additionally, studies on treating diabetic men with testosterone might show us whether this might counteract (or at least lessen) the adverse effects of glitazones. They also suggest further research into exactly how glitazones inhibit sex hormones.

Reliability:
The authors are associated with a number of universities and medical research institutes throughout the world. The hypothesis was published in a peer-reviewed journal. The authors are posing a theory, rather than a statement of fact, and suggesting ways that others could determine whether or not their theory is correct.

Practical Applications:
If the theory is correct, and if administering testosterone to men can completely counteract the adverse effects of Avandia and similar medications, that would make Avandia a relatively safer choice to treat Type 2 diabetes than it is now.

For further reading:
(1) Roger H. Unger, MD Reinventing type 2 diabetes: pathogenesis, treatment, and prevention. Journal of the American Medical Association (JAMA), 2008;299(10):1185-1187.
Full text requires paide subscription.
First 150 words available free.

"Evidence-Based Medicine", Patient Pages, Journal of the American Medical Association (JAMA)

This synopsis was based on the entire article.

Does "dashboard dining" make you fat?

The joint impact on being overweight of self reported behaviours of eating quickly and eating until full : cross sectional survey
Original source: British Medical Journal BMJ 2008;337:a2002
Authors: Koutatsu Maruyama, Shinichi Sato, Tetsuya Ohira, Kenji Maeda, Hiroyuki Noda, Yoshimi Kubota, Setsuko Nishimura, Akihiko Kitamura, Masahiko Kiyama, Takeo Okada, Hironori Imano, Masakazu Nakamura, Yoshinori Ishikawa, Michinori Kurokawa, Satoshi Sasaki, Hiroyasu Iso (corresponding author)
Publication date: 21 October 2008
DOI (digital document ID): 10.1136/bmj.a2002
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Researchers in Japan surveyed over 3000 adults for one month, over a period of three years, to see if eating quickly, or eating until one is full, or both, makes people overweight. For the purpose of this research, "overweight" was considered to be having a body mass index (BMI) of greater than 25.
The adults, in one suburban and one rural community in Japan, were asked to rate themselves on how fast or slow they ate and on whether or not they routinely ate until they were full. The self-reporting was confirmed by the subjects' friends.

People with eating disorders such as binge eating disorder, gorging, and anorexia nervosa were excluded from the study, as were people with disordered eating, people with cardiovascular disease, and people who could not tell whether they ate quickly or slowly and/or who could not tell when they'd eaten until full.

The results were adjusted for several variables, including age, caloric intake, physical activity, smoking, and for possible effects of the specific community.
The results were also examined to find out if there was an additive interaction between eating quickly and eating until full (i.e., if one were more likely to be overweight if one both ate quickly and ate until full).

Just over half of the men, and about 58% of the women, said they ate until full. (These people consumed approximately 100 calories more per day, per person than the rest of the population.) Just under half of the men, and over a third of the women, said they ate quickly.

The results suggest that people who eat until full are twice as likely to be overweight as those who walk away from the table slightly hungry; also, that people who eat quickly are twice as likely to be overweight as those who eat slowly. People who eat until full and who eat quickly are over three times as likely to be overweight as those who do not eat quickly, and who leave the table slightly hungry.

The article contains an editorial sidebar that suggests that eating quickly, and/or eating until full, may be contributing factors to overweight and obesity independent of any other eating and exercising behaviors.


Reliability: Despite the large sample size and independent verification, the data were based on self-observation and therefore have the potential of being skewed. On the other hand, many or most of the factors that could give a false reading were accounted for and neutralized. Also, given that people who ate until full consumed 100-150 more calories per day than those who did not, one month may not be sufficient time to draw a theory of causality (that eating rapidly, or eating until full, causes overweight). The article itself does not draw any conclusions as to the reasons for the association between these eating behaviors and overweight, nor does it claim complete independence of factors beyond the ones adjusted for. Given that BMJ appears to posit a direct connection, more stringent research may be needed to test this theory.

Practical Applications: If direct connections can be made between eating quickly, and/or eating until full, and overweight, then it points to the need for education, and possibly abolishing the half-hour-or-shorter meal break, in favor of a longer one.

This synopsis was based on the entire article.

A possible reason for increased risk of infection of obese people and those with Type 2 diabetes

Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus
Original source: International Journal of Obesity (2008) Vol. 32, pp. 1407–1414
Authors: G R C Zilverschoon, C J Tack, L A B Joosten, B J Kullberg, J W M van der Meer and M G Netea (corresponding author)
Publication date: published online 22 July 2008
DOI (digital document ID): doi:10.1038/ijo.2008.109
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
Interleukin-18 (IL-18) is a signalling chemical (similar to hormones) that has a strong effect on stimulating interferon (IFN) release. It is produced by a number of different white blood cells and central nervous system cells. Interferon is an important chemical in fighting infections.

Higher levels of IL-18 have been shown to decrease abnormally large appetite and to improve insulin sensitivity. Interestingly, several studies have shown high levels of IL-18 in obese people with insulin resistance, and a recent study has demonstrated that a common version of the genes producing IL-18 is associated with a higher body mass index (weight) in people with type 2 diabetes or coronary heart disease. In addition, weight loss after bariatric surgery (such as gastric bypass or lapband) results in lowered blood concentrations of IL-18.

The investigators suspect that the cells of obese people and those with insulin resistant diabetes may have high levels of IL-18 because they do not respond as well to IL-18 as those of people of normal weight and who are not diabetic. To test this theory, they tested white blood cells of obese and Type 2 diabetes patients and compared them to those of lean, non-diabetic people, and measured their IFN production in relation to their IL-18 levels. They found that in the obese and the diabetic subjects, these cells respond poorly to IL-18 and produce less interferon. They also show impaired release of IFN after exposure to disease-carrying bacteria and fungi.

They conclude that the reduced response to IL-18 may be responsible for the increased susceptibility to infection among those who are obese or who have Type 2 diabetes.

Reliability:
The study was conducted with a small number of subjects: seventeen control subjects, eleven obese non-diabetic subjects, and fourteen subjects with Type 2/insulin-resistant diabetes. (The possibility of LADA or other autoimmune diseases was ruled out at the start of the study.) The smaller the number of subjects, the greater the possibility for skewed or atypical results. The research was published in a peer-reviewed journal, and the investigators are all associated with the a University Medical Center in the Netherlands. Based on the small number of subjects, the results should be considered to point in the direction of larger studies to confirm the investigators' results, as well as further research into why these cells have an impaired reaction to IL-18.

Practical Applications:
A confirmed pathway and reason for increased risk of infection among obese people and people with Type 2 diabetes could lead to therapy to reduce that risk and to better fight those infections that do occur. If insulin resistance and excessive appetite are also directly related to impaired IL-18 response, then improving that response could conceivably result in weight loss and improved insulin sensitivity as well.


This synopsis was based on the entire article.