Insulin inhalers don't prevent Type 1 diabetes in children with antibodies

Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial
Original source: The Lancet, Volume 372, Issue 9651
Authors: Kirsti Näntö-Salonen (corresponding author), Antti Kupila, Satu Simell, Heli Siljander, Tiina Salonsaari, Anne Hekkala, Sari Korhonen, Risto Erkkola, Jukka I Sipilä, Lotta Haavisto, Marja Siltala, Juhani Tuominen, Jari Hakalax, Heikki Hyöty, Jorma Ilonen, Riitta Veijola, Tuula Simell, Mikael Knip, Olli Simell
Publication date: 15 November 2008
DOI (digital document ID): 10.1016/S0140-6736(08)61309-4
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
In mice engineered to have risk of Type 1 diabetes, inhaled insulin has been shown to reduce their likelihood of developing diabetes. The authors wanted to know if this would work in humans. They screened a number of infants for a specific gene (the HLA-DQB1 susceptibility allele) linked to increased risk of developing Type 1 diabetes. The siblings of susceptible infants were also screened. Of these, over 11,000 infants and 1500 related siblings consented to having their children's blood screened for diabetes at 3-12 month intervals. [One would presume that for minors, their parents would have been the ones giving consent.] From these, 224 infants and 40 of their siblings (all of whom tested positive for two or more diabetes-specific antibodies) were entered into a trial in which some would be given short-acting human insulin (1 unit/kg) or placebo once a day intranasally (inhaled) until they developed Type 1 diabetes and needed traditional injectable insulin. The children were studied for an average length of 1.8 years (range lasted from 0-9.7 years). The study ended early because the insulin did not show any benefit -- as many children on insulin as on placebo developed diabetes, over similar ranges of time from the start of the trial.

Reliability:
Almost all of the authors are either medical doctors or professors of medicine. The number of children studied was not very large (only about 260), and they had already developed diabetes-related antibodies.

Would the results have been different if insulin had been administered before antibodies had developed, with the trial endpoint being the development of antibodies? Would the results have been different if a basal insulin had been used, or a different dosage?

As far as I know there is no inhaled insulin treatment for Type 1 diabetes in people. Does inhaled insulin work as primary treatment in those of that strain of mice who have developed diabetes? If it does, then the experiment is "comparing apples and oranges", and the analogous human experiment would require injected insulin.

Practical Applications:
Had there been a reduction in the number of children studied who developed Type 1 diabetes, or a significant delay in their development of Type 1 diabetes, then inhaled insulin therapy could have been used as a preventative (prophylactic) measure. The negative findings show that it cannot be.

Ethics Note:
The study was registered with ClinicalTrials.gov, number NCT00223613. Since the subjects were likely minors, their parents would have been required to provide the necessary consent.

This synopsis was based on the abstract only.

Vitamin D and Gestational Diabetes

Maternal Plasma 25-Hydroxyvitamin D Concentrations and the Risk for Gestational Diabetes Mellitus
Original source: PLoS ONE 3(11): e3753
Authors: Cuilin Zhang (corresponding author), Chunfang Qiu, Frank B. Hu, Robert M. David, Rob M. van Dam, Alexander Bralley, Michelle A. Williams
Publication date: November 18, 2008
DOI (digital document ID): 10.1371/journal.pone.0003753
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
There is increasing evidence that Vitamin D plays a role in maintaining stable blood glucose levels, but the studies directly examining circulating levels of 25-hydroxyvitamin D (25-[OH] D) are limited and inconsistent. This study aims to determine the association between levels of (25-[OH] D) earlier in pregnancy than previously examined, and the risk of the mother's developing gestational diabetes later on in the pregnancy.

A nested case-control study was conducted among 953 pregnant women. 57 had diabetes at the start of the study, and 114 women who were not diagnosed with GDM were selected as controls.

Blood samples were taken at 16 weeks gestation, with known time since last meal, and frozen at -80C until analysis. Per American Diabetes Association guidelines, participants were screened for gestational diabetes at 24-28 weeks gestation, using fasting blood glucose and an oral glucose tolerance test. The process used to measure 25-[OH] D levels produces a maximum 12% probability of error.

The results were categorized as sufficient, insufficient, or deficient.

The odds ratios were adjusted based on mother's age at conception, season of conception, diet, vitamin supplementation, mother's pre-conception body mass index, family history of Type 2 diabetes, physical activity, and whether or not the mother smoked.

The women who developed gestational diabetes tended to follow the known risk patterns: overweight, older, being non-white or Latino, and having a family history of diabetes. The heavier these women were, the lower their circulating levels of 25-[OH] D.

At 16 weeks' gestation, 25-[OH] D levels of the women who went on to develop gestational diabetes were, on average, 20% lower than those of the controls. This difference remained even when filtering out the known and suspected risk factors for diabetes. About one third of the women who developed diabetes, versus one seventh of the women who did not, had 25-[OH] D levels considered to be deficient.

Further analysis showed an inverse relationship between vitamin D levels and risk of developing gestational diabetes was observed and remained even after considering all the factors mentioned above.

Reliability:
The number of women studied was moderately large and restricted to women who sought prenatal care prior to the halfway mark in the pregnancy. The study was also limited to women who read and wrote English, and who planned to deliver at one of two study hospitals. This may or may not filter out less-affluent women in higher-risk populations.

A 12% error in the assay method may skew the results, despite statistical attempts to minimize them.

The authors submit that a single blood test for 25-[OH] D levels may not provide an accurate picture of the mother's levels of Vitamin D throughout the pregnancy; also, that some of the 25-[OH] D deficient women may have developed impaired glucose tolerance or gestational diabetes earlier in the pregnancy (but had not been screened for it). The authors would like to see a much larger study conducted to confirm (or refute) their findings.

Practical Applications:
If a firm relationship between 25-[OH] D and gestational diabetes (or diabetes in general) is confirmed, then lifestyle changes and dietary supplementation can be advised earlier in the pregnancy (or pre-pregnancy) to minimize the risks of developing gestational diabetes.

This study also contributes to the general body of research regarding Vitamin D metabolism and diabetes in general. There may be good reasons for people with diabetes, or at risk for developing diabetes, to screen for Vitamin D levels and to increase Vitamin D intake. [Please note that Vitamin D is a fat-soluble vitamin and that excess intake is not easily excreted from the body, so please consult your physician before adding additional vitamin D supplements to your diet.]


This synopsis was based on the entire article.

Diet planning as conversation, not monologue

Implementing shared decision making in nutrition clinical practice: A theory-based approach and feasibility study
Original source: Implementation Science 2008, 3:48
Authors: Sophie Desroches (corresponding author), Sylvie Tapp, Marie-Pierre Gagnon, and France Legare
Publication date: 5 November 2008
DOI (digital document ID): 10.1186/1748-5908-3-48
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Shared decision making is one of several methods that a health professional can use to help us change our eating habits to better control diabetes and other chronic illnesses. The investigators are looking primarily at dietary approaches to lower cholesterol levels.

The traditional low-fat/low-saturated fat strategy to lower cholesterol is perceived as restrictive, leading to a tendency for people to either "cheat" or to not follow the diet at all. Recently, a number of different dietary approaches have been shown effective in lowering cholesterol -- but the variety, added to the many diet systems discussed in the popular media, can leave the general public confused. Shared decision is a method in which the dietician works collaboratively with the patient, taking into account his cultural and financial perferences, to create a healthy diet that the patient is willing to follow. The process includes explaining the best evidence of the risks and benefits of different dietary models, and explicitly states that the method does include some uncertainties.

The authors of this investigation found no formal studies supporting the use and training of a shared decision making approach using evidence-based practice, and note that some dieticians have reported difficulty in suggesting and implementing this approach.

In this paper they propose a study to learn how shared decision-making is currently used in the field of nutritional consultation, to assess dieticians' intention to adopt two specific behaviors related to shared decision making using the Theory of Planned Behavior, and to learn what the obstacles are to dieticians adopting this approach. Their proposed protocol includes the education of dieticians, the introduction of the Theory of Planned Behavior, focus group discussions in which the dieticians' views and issues are discussed, and audiotaped observation of the dieticians' interactions with patients.

The proposed research project is expected to provide preliminary data about the adoption of shared decision making by dieticians and their patients, look at dieticians' beliefs regarding their intention to adopt shared decision making behaviors and comparing their actions to their intentions, and develop questionnaires to measure this information. The researchers hope that the results generated by the proposed research project will help improve the rate at which dieticians adopt a shared decision-making approach.

Reliability:
The initial study is intended to cover only 40 dieticians, but this is considered mostly as a focus group from which the parameters of a larger study can be planned.

Practical Applications:
The end goal of this research is to increase the adoption of shared decision making in the field of nutritional consulation. Having our dieticians engage us actively, and pay attention to our input, will help us find diets we can -- and will -- live with.

This synopsis was based on the entire article.

Heavy metal exposure and the human immune system

The role of interleukin-12 in the heavy metal-elicited immunomodulation: relevance of various evaluation methods
Original source: Journal of Occupational Medicine and Toxicology 2008, 3:25
Authors: Nasr YA Hemdan
Publication date: 6 November 2008
DOI (digital document ID): 10.1186/1745-6673-3-25
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Heavy metals are known to affect the actions of T-helper (Th) cells and thereby affect the development of illnesses and disease. Interleukin (IL)-12, a crucial one of these cells, is one of the Th cells affected by outside agents. IL-12 promotes systemic inflammation and affects the body's response to disease. The author is testing to see if IL-12 levels are affected by heavy metal exposure.

Tests were run using both cultured human immune tissues and live mice. The human cells were cultured without exposure to either cadmium (Cd) or mercury (Hg). The mice were continuously exposed to sublethal doses of Cd or Hg salts for 3 or 5 weeks. Several different methods were used to evaluate the IL-12 levels.

IL-12 levels were dependent on levels of exposure to Cd or Hg, and on interferon-gamma (IFN-gamma) levels. The various measurement approaches were considered equally valid. In the absence of heavy metals, the interaction between IL-12 and IFN-gamma was shown to depend on the disease microorganism to which the cells were exposed.

Reliability:
The author is associated with several accredited institutions and appears to specialize in immunology. The tests were run redundantly using several different methods and came out the same each way, suggesting accuracy in the results received. The study was published in a peer-reviewed journal. The number of subjects (both human and rodents) was not explicitly stated, so it is difficult to tell if the results may be skewed by small sample size.

Practical Applications:
We are increasingly exposed to heavy metals and other environmental toxins; these are now shown to depress our immune systems. One of the difficulties in living long-term with diabetes is that the immune system is compromised. (Type 1 diabetes is an autoimmune disease.) This suggests that people with diabetes may need to be more careful than non-diabetics in minimizing our exposure to heavy-metal toxins. (Certain fish are known dietary sources of these toxins.)

I was curious to find out if the author had made any correlation between heavy-metal exposure and the development or progression of autoimmune disease. (He did not.)

This synopsis was based on the entire article.

Can genetic risks accurately predict Type 2 diabetes?

Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes
Original source: New England Journal of Medicine Volume 359, Number 21
Authors: Valeriya Lyssenko, Anna Jonsson, Peter Almgren, Nicoló Pulizzi, Bo Isomaa, Tiinamaija Tuomi, Göran Berglund, David Altshuler, Peter Nilsson, and Leif Groop
Publication date: November 20, 2008
DOI (digital document ID): not available
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The aim of this paper is to determine whether environmental and clinical risk indicators, genetic factors, or both can be used to predict whether or not a person will develop Type 2 diabetes.

The authors singled out 16 specific gene markers that might be used to predict risk or development of diabetes. They tracked those, plus known environmental and clinical risk indicators, for over 16,000 Swedish patients and over 2500 Finnish patients, for a median period of 23.5 years. They studied the effect of variations of the gene markers on insulin secretion and insulin action over this period of time.

Over the observation period, approximately 11.7% of the subjects developed diabetes. Variations in 11 of the genes studied were associated with developing diabetes, independent of other risk indicators. Variants in eight of those genes were specifically associated with impaired beta cell function.

Adding the genetic risk to the clinical and environmental indicators slightly improved the long-term ability to predict whether or not an individual would develop Type 2 diabetes. This predictive ability increased with the duration of the follow-up.

Reliability:
While a large population was observed, and the medium observation time was over 20 years, the abstract does not provide insight into the distribution of follow-up duration, to let us know whether the median is a statistically-significant number. The improved prediction ability turns out to be about 1.5% better than the accuracy without the genetic information, which may not be cost-effective at the present time.

Practical Applications:
Known genetic risk is sometimes an incentive for making lifestyle changes to reduce the other risks for developing diabetes.

If the full paper shows direct correlations between insulin secretion, insulin resistance, and genetic variations, then initial pharmaceutical therapy can be better targeted to the individual's needs.

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.

Does Avapro help patients with heart failure?

Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction
Original source: New England Journal of Medicine Volume 359, Number 23
Authors: Barry M. Massie, M.D. (corresponding author), Peter E. Carson, M.D., John J. McMurray, M.D., Michel Komajda, M.D., Robert McKelvie, M.D., Michael R. Zile, M.D., Susan Anderson, M.S., Mark Donovan, Ph.D., Erik Iverson, M.S., Christoph Staiger, M.D., Agata Ptaszynska, M.D., for the I-PRESERVE Investigators
Publication date: online: November 11, 2008 print: December 4, 2008
DOI (digital document ID): 10.1056/NEJMoa0805450
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
There is a need to find a way of improving the outcome of patients with heart failure, whose left ventricles still function to some degree. The investigators wanted to know if irbesartan (brand names Avapro, Aprovel, Karvea) might serve that purpose.

Over 4000 patients, over the age of 60, and classified as having varying degrees of heart failure but at least 45% left ventricular evacuation fraction, were studied for just over 4 years. Some were given irbesartan and others were given a placebo. The investigators wanted to know how many of those patients had subsequent cardiovascular events requiring hospitalization, how many died from heart failure or cardiovascular causes, and how many died overall. The numbers of deaths were similar in both groups, though the number of hospitalizations for cardiovascular events were slightly lower in the group receiving the medication.

Because the numbers of deaths and cardiovascular events overall were not significantly different between the two groups, irbesartan is not considered to be effective for this application.

Reliability:
The study size is reasonable, and the subjects were followed for a reasonably-long period of time. Because of the ages of the subjects, the results may not be valid for younger patients.

The researchers are associated with accredited medical institutions in several countries. The article was published in peer-reviewed journal.

The research was sponsored by two pharmaceutical companies, Bristol Meyers Squibb (BMS) and Sanofi-Aventis. BMS and Sanofi-Aventis both manufacture and market Avapro and have a vested financial interest in its use for reasons in addition to the treatment high blood pressure.

Practical Applications:
Irbesartan has not been proven to be effective in preserving heart function among older patients with heart failure, but with preserved left ventricular function.

For further reading:
This is not the first time additional uses for Avapro have been considered. Avapro has also been studied as a drug with which to preserve kidney function in people with Type 2 diabetes. The following article is one of several published following that train of research:
The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

This synopsis was based on the abstract of the online preprint.

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.

A possible genetic component of Type 2 diabetes

Variance of the SGK1 Gene Is Associated with Insulin Secretion in Different European Populations: Results from the TUEF, EUGENE2, and METSIM Studies
Original source: PLoS ONE 3(11): e3506.
Authors: Björn Friedrich, Peter Weyrich, Alena Stančáková, Jianjung Wang, Johanna Kuusisto, Markku Laakso, Giorgio Sesti, Elena Succurro, Ulf Smith, Torben Hansen, Oluf Pedersen, Fausto Machicao, Silke Schäfer, Florian Lang, Teut Risler, Susanne Ullrich, Norbert Stefan, Andreas Fritsche (corresponding author), Hans-Ulrich Häring
Publication date: 5 November 2008
DOI (digital document ID): 10.1371/journal.pone.0003506
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors used a "classical candidate-gene approach" to examine genes that play a role in insulin secretion and their potential roles in the development of insulin-resistant diabetes. The gene they focused on is serum and glucocorticoid inducible kinase SGK1, which is encoded by the gene SGK on chromosome 6q23. The action of this gene is increased in the presence of corticoids and insulin, among other things, and seems to provide a molecular link between electrolyte activation and glucose stability. It also appears to play a role in both insulin signalling and insulin secretion and blood pressure.

The investigators looked at genetic variance in SGK, and potential associations with insulin secretory function, in two specific groups of people (the 725-person TUEF cohort and the 634-person EUGENE2 participants) whose diabetes risks had been examined for insulin secretion traits among those who were prediabetic. These were compared with the results of a study on an older, genetically-similar population (the 4457-person METSIM cohort) to determine whether their hypothesis was correct.

Insulin sensitivity and insulin production were measured using oral glucose tolerance tests (OGTT), measuring c-peptide levels or plasma insulin levels to determine insulin secretion, along with blood glucose levels to determine insulin sensitivity. BMI and waist-hip ratio were also measured in these populations. The patients were correlated to specific variations of one of four tagged alleles (rs9402571) of the SGK-1 gene.

There was no association of the specific tagged alleles with insulin sensitivity in either the TUEF screening population or in the EUGENE2 study, but the authors suggest that this expression of the gene's expression is based on BMI. They mention that the spot in which the SGK1 gene sits has been "associated with BMI progression in participants of the Framingham Heart Study."

On the other hand, the TUEF and EUGENE2 studies did report an increase in insulin secretion in lean patients with one specific variation of the rs9402571 allele. METSIM participants with this variation had a lower incidence of Type 2 diabetes. The authors suggest that this variation may protect against Type 2 diabetes, but that its effect may become blocked or blurred in overweight or obese individuals.

Their analysis suggests that the rs9402571 allele of the SGK1 gene is associated with altered insulin secretion and with Type 2 diabetes.


Reliability:
The authors are associated with accredited medical institutions and the results were published in a peer-reviewed journal. The subsets of the TUEF and EUGENE2 participants' data analyzed in the paper are relatively small. The correlation with an older population of similar genome poses a good initial check on the original hypothesis; the ongoing nature of the TUEF study (Tübingen Family Study) suggests that a more definitive correlation will be possible at some time in the future.

Practical Applications:
The developing discipline of genomics suggests that we might one day be able to base our healthcare on how our own particular genes work.

This synopsis was based on the entire article.

Diabetes and Risk of death from coronary events

Diabetes Mellitus and Mortality after Acute Coronary Syndrome as a First or Recurrent Cardiovascular Event
Original source: PLoS ONE Vol. 3, No. 10
Authors: Richard M. Cubbon, Afroze Abbas, Stephen B. Wheatcroft, Niamh Kilcullen, Raj Das, Christine Morrell, Julian H. Barth, Mark T. Kearney (corresponding author), Alistair S. Hall for the EMMACE-2 investigators
Publication date: 22 October 2008
DOI (digital document ID): 10.1371/journal.pone.0003483
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Diabetes has been associated with problems recovering from, and with higher risk of death from, acute coronary syndrome. The investigators were looking to find whether this increased risk was true for all persons with diabetes, or only for those persons with diabetes who already had cardiovascular disease, compared to people without diabetes (with, or without, diagnosed cardiovascular disease). The investigators wondered whether cardiovascular disease is diagnosed earlier in people with diabetes than in the general population, and if that early diagnosis, plus aggressive preventative treatment, reduced the risk of dying from acute coronary syndrome.

For the purposes of the study, "Acute Coronary Syndrome" covered unstable angina or myocardial infarction (heart attack). "Cardiovascular Disease" was devined as myocardial infarction, angina, stroke, peripheral vascular disease, or coronary revascularization (either the heart's circulatory system rerouting itself, or the need for stents, bypasses, or other surgical techniques to open or replace blocked blood vessels). Note that by these definitions, "acute coronary syndrome" is a subset of "cardiovascular disease".

The researchers looked at the data collected in the EMMACE-II observational study in 2003, which tracked just under 2500 patients. The investigators used the patients' previous medical records to split the patients into four groups: those without diabetes or previously-diagnosed cardiovascular disease; those without diabetes, but who had existing cardiovascular disease; those with diabetes but without a history of cardiovascular disease; and those with both diabetes and a history of cardiovascular disease. The data from these four groups were analyzed separately and compared.

The results showed that while patients with diabetes had an overall increased risk of death from acute coronary syndrome, the rates of death of patients with no history of cardiovascular disease were approximately the same, regardless of whether or not they had diabetes.

After adjusting for age and gender, there was still an increased risk of death for patients with diabetes and a history of cardiovascular disease over patients from the other three groups; however, when the results were adjusted for levels of Troponin I -- which was used to indicate how much of the heart muscle had died due to cardiovascular disease, the correlation between mortality and diabetes disappeared. This lack of correlation remained even when the investigators broadened or narrowed the definition of cardiovascular disease used in their analysis.

These findings suggest that the risk of dying from acute coronary syndrome may be related to the degree to which the heart's blood vessels have been blocked, and that the reduced degree of blockage in patients with diabetes, but no history of cardiovascular disease, may be related to aggressive preventative treatment that is not routinely offered to people without diabetes.

Reliability:
The authors are from accredited medical institutions and the research is published in a peer-reviewed journal. The size of the study is large enough to show potential trends and suggest directions for further research. The authors note limitations of the study include the absence of several key risk indicators (such as albuminuria -- protein in the urine -- and obesity) and details of any preventative therapy the patients may have received. They also note that patients with a history of previous cardiovascular disease are less likely to receive prescriptions for preventative drugs (such as statins and ACE inhibitors) than patients being discharged after their first acute coronary event, and because this is counterintuitive to standard practice, understanding the reasons for this difference would also help to quantify the differences in risk.

Practical Applications:
Understanding the true origins of the risks of death from acute coronary syndrome can help our doctors better treat us and help us reduce those risks to the greatest degree possible.

For further reading:
The British Cardiac Society Working Group definition of myocardial infarction: implications for practice -- abstract describing the EMMACE-II study.

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.

Can metformin help Type 1 diabetics?

Effect of Adjunct Metformin Treatment in Patients with Type-1 Diabetes and Persistent Inadequate Glycaemic Control. A Randomized Study
Original source: PLoS ONE 3(10): e3363
Authors: Søren Søgaard Lund (corresponding author), Lise Tarnow, Anne Sofie Astrup, Peter Hovind, Peter Karl Jacobsen, Amra Ciric Alibegovic, Ida Parving, Lotte Pietraszek, Merete Frandsen, Peter Rossing, Hans-Henrik Parving, Allan Arthur Vaag
Publication date: October 9, 2008
DOI (digital document ID): 10.1371/journal.pone.0003363
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Despite intensive insulin use, many people who have had Type 1 (autoimmune) diabetes for a long period of time have trouble maintaining adequate glucose control and achieving an HbA1c of under 7%, which is considered a threshold beneath which the risk of developing complications of diabetes is reduced. There are a number of reasons -- physiological (medical), environmental, and psychological -- for poor control. One of the physiological reasons may be the development of insulin resistance over time. This study looks at the potential for adding the use of metformin -- an initial drug of choice in treating Type 2 (metabolic) diabetes (which often includes insulin resistance) -- to the use of insulin to improve blood glucose control in Type 1 diabetes.

The study included 100 Type 1 diabetes patients with poorly-controlled blood glucose levels (defined as HbA1c over 8%). A one-month period in which all of them received identical placebo pills was followed by a three-week period in which the pills of half of the patients was gradually changed to include 1000 mg metformin, twice daily. The other patients continued to receive placebo pills. The patients were followed at one- to three-month intervals, for a period of a year after maximum/target dose was achieved.

The study was conducted as a double-blind study, which means that neither the investigators nor the patients knew who was taking metformin and who was not.

At each clinic visit before and during the study, patients were tested for HbA1c, c-peptide levels (a protein used as an indicator of remaining beta-cell function), and blood glucose level. Their body mass index (BMI -- a comparison of weight to height) was also measured. They were asked to estimate the average of the blood glucose measurements they took themselves at home. They were also requested to report serious adverse effects (including life-threatening events requiring hospitalization, or which resulted in persistent or significant loss of physical abilities, or which caused an adverse reaction due to a birth defect, and hypoglycemic events which resulted in unconsciousness or which required the intervention of a third party) and minor adverse effects (including hypoglycemia mild enough for the patient to be able to treat himself). They were also asked to report any changes to their insulin prescriptions and treatments (change of type of insulin, number of injections per day, sites used, and dosage).

In addition to analyzing the HbA1c measurements of the entire groups (metformin and placebo), researchers counter-checked changes in HbA1c with changes in patient weight and insulin dosage. They also analyzed the measurements from overweight and obese patients separately from those of normal weight, and the results from those taking higher amounts of insulin daily from those taking smaller amounts, since insulin resistance is often treated with higher doses of insulin; it is also associated with overweight and obesity.

The results of the analysis showed no significant changes in HbA1c level for either group. However, the metformin users lost, on average, a little more than a kilogram of body weight and were able to reduce their daily insulin usage by, on average, 0.03 units per kilogram of body weight. By comparison, those patients on placebo did not lose weight and, on average, needed to increase their insulin usage by 0.03 units per kilogram of body weight. (This corresponds to average total daily insulin use of 3 units less per day for the metformin group, and about 2.5 units more per day for the placebo group.)

The results of this study were compared to the results of previous studies, and the strengths and limitations of both this study and those were examined.

Reliability:
The authors are professionals in the fields of endocrinology and diabetes care, associated with accredited institutions. The results were published in a peer-reviewed journal.

The study size was small, so there is some potential for skew.

The use of double-blinding and placebos removed the variables of being able to attribute all good effects to the use of the drug, as well as that of all positive effects being due to the suggestion of the pills being effective.

The duration of the study was long enough to determine whether metformin would have any effect on HbA1c; however, the reduction in insulin use among the metformin patients may have counteracted the drug's effects on lowering HbA1c. The authors note that had they specified that the patients not drop their insulin dosages, there may have been a greater risk of serious hypoglycemic events.

Practical Applications:
The authors suggest that the mild weight reduction and apparent improved insulin sensitivity among the patients treated with metformin may lower these patients' diabetes-related cardiovascular risks; however, metformin does not appear to be a useful tool for improving glycemic control in patients with long-duration Type 1 diabetes.


This synopsis was based on the entire article.

Are moderate-protein diets better than low-protein diets for people with metabolic syndrome?

Moderate carbohydrate, moderate protein weight loss diet reduces cardiovascular disease risk compared to high carbohydrate, low protein diet in obese adults: A randomized clinical trial

Original source: Nutrition & Metabolism 2008, 5:30
Authors: Denise A Walker Lasker (corresponding author), Ellen M Evans, and Donald K Layman
Publication date: 7 November 2008
DOI (digital document ID): 10.1186/1743-7075-5-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
This study compares the effectiveness of the standard USDA Food Pyramid diet with a higher-protein, lower-carbohydrate diet for weight loss in general, for fat loss in particular, and for lowering the blood-based indicators of cardiovascular risk and insulin resistance. A total of 50 people completed the testing, split between the two dietary approaches.

Both diets under test had the same amount of calories, with about 30% of total calories coming from fats. Carbohydrates supplied about 55% of the Food Pyramid diet group's caloric intake, and protein, the remaining 15%. The people assigned to this group were instructed to eat whole grains for their bread products. About 30% of the high-protein group's calories came from protein, with the remaining 40% coming from carbohydrates. (This is the same protein-carbohydrate-fat distribution advocated by the Zone Diet.) This group was instructed to eat primarily "high quality protein", including lean meats, dairy, and eggs. Both groups had similar amounts of fruits and vegetables in their daily diets. All subjects were instructed on portion sizes, dietary substitutions, how to weigh foods, and how to keep a food diary. There was no difference in exercise between the two groups.

Baseline measurements (weight, body fat percentage, cholesterol, and postprandial insulin) were taken at the start of the experiment. The subjects followed their assigned diet plans for four months, at which time the same measurements were repeated.

• The moderate-protein group lost about 5 pounds more per person than the USDA group, and more of their weight loss was from fatty tissues.
• Fasting glucose levels were unchanged, but fasting insulin levels decreased in the moderate protein group, while it increased in the USDA group. In addition, postprandial insulin levels dropped 85% for the protein group, but only 50% for the Food Pyramid group. (High plasma insulin levels are indicative of insulin resistance, which is often a predecessor to Type 2 diabetes.)
  
• There was a greater drop in total cholesterol in the USDA group than in the protein group. LDL ("bad") cholesterol dropped in the USDA group but rose in the protein group; on the other hand, HDL ("good") cholesterol dropped in the USDA group but rose in the protein group. The protein group also showed greater improvement in triglyceride levels than the USDA group. (High triglyceride levels are associated with increased risk of heart attack.)
  

Reliability:
The study was small scale, with only 50 people completing the four-month study. While the two groups of subjects were selected to be closely-matched, there is still opportunity for the results to be skewed. An initial run-in period put all subjects on as close to an even footing as possible before the trial started.
The authors are associated with an accredited university; the paper was published in a peer-reviewed journal.
Longer-term studies of larger groups may be needed to determine the long-term safety and effectiveness of high-protein diets.

The principal investigator (Denise A Walker Lasker) received funding from the National Cattleman’s Beef Association, The Beef Board and Kraft Foods. Both Beef associations have a vested interest in increasing protein consumption (in the form of beef).
The investigators have made no comparison between a higher-fat restricted-carbohydrate diet and a higher-protein restricted-carbohydrate diet.

Practical Applications:
The 30/40/30 protein/carb/fat (PCF) ratio is the basis of the Zone Diet. While this diet is higher in protein than traditionally advised for people with diabetes, recent publications suggest that this is not as high a risk as formerly perceived.

For further reading:
WebMD evaluates the Zone Diet
Wikipedia entry on the Zone Diet

This synopsis was based on the entire article.

Could antioxidants fight diabetes?

The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile
Original source: Nutrition Journal 2008, 7:29
Authors: Daria Brambilla, Cesare Mancuso, Mariagrazia Rita Scuderi, Paolo Bosco, Giuseppina Cantarella, Laurence Lempereur, Giulia Di Benedetto, Salvatore Pezzino, and Renato Bernardini (corresponding author)
Publication date: 30 September 2008
DOI (digital document ID): 10.1186/1475-2891-7-29
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors discuss the use of antioxidant foods and supplements in the treatment of chronic disease. They are particularly interested in the effect of dietary antioxidants on the management of cancer and neurological and immune disorders. They are particularly interested in antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which may be directly affected by the presence of antioxidants in the diet. They believe these enzyme systems may efficiently reduce oxidative damage and minimize the progression of disease-related oxidative stress. The clinical effects of dietary antioxidants is still under debate. Along the same lines, the excess consumption or bioavailability of fat-soluble vitamins has been associated with increased incidence of cancer.

The concepts of "free radicals" and "oxidative stress" are defined, and are said to damage the body's proteins, DNA, and lipids (fats). The authors mention some of the pathways in which oxidative stress occurs and can be measured, how oxidation can affect the digestive and immune systems, and how micronutrient deficiencies can cause the immune system to be depressed. This includes the discussion of methods for determining how the human body uses vitamins, minerals, and antioxidants, how chronic and autoimmune diseases may be affected by oxidative stress, and how antioxidants -- both alone and along with other chemicals -- may affect the disease process.The authors caution that the potential benefit of using antioxidants to reduce this damage must be weighed against the possible damage they might cause if overused, and that a thorough understanding of how these nutrients act chemically, in the cellular environment, and on a person as a whole.

Reliability:
The authors are associated with the pharmacology departments of their universities. The issues discussed are related to the pharmacological properties of nutrients and nutrient supplements (nutriceuticals). This is a general article; while specific diseases, oxidants, and disease pathways are mentioned, no quantitative analysis is given. The authors are optimistic about the use of antioxidants in the management of chronic illnesses, but are concerned about people blindly adding antioxidant supplements before their effects are thoroughly tested.

Practical Applications:
While neurological disorders are given particular emphasis, that the authors touch on "chronic diseases" and "autoimmune disorders" suggests that their findings may be useful in the use of dietary supplements for both Type 1 and Type 2 diabetes. Better understanding of how oxidative stress affects diabetes, and controlled experiments using particular antioxidants, are both needed both to verify whether or not this will work for most people, and to determine what specific antioxidants and combinations should be taken.

For further reading:
Check the authors' bibliography for studies relating to specific diseases.

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.

Where do beta cells come from? A new method of studying human islet cell development

Beta Cells within Single Human Islets Originate from Multiple Progenitors
Original source: PLoS ONE 3(10): e3559
Authors: Raphaël Scharfmann, Xiangwei Xiao, Harry Heimberg, Jacques Mallet, Philippe Ravassard (corresponding author)
Publication date: October 29, 2008
DOI (digital document ID): 10.1371/journal.pone.0003559
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Beta cells are the insulin-producing cells within the Islets of Langerhans, located in the pancreas. Most of our understanding of how beta cells develop is based on studies of mice and rats. The authors' goal was to develop a model to transfer genes into developing human pancreas cells and to see if the gene transfer worked by looking at how the cells multiplied and specialized.

Pancreas cells were removed from human fetuses and tagged with a specific virus tag, called a replication-defective lentivirus, and islet-cell specific DNA from human pancreas tissue. These tissues were were grafted onto mice whose were treated to not reject the transplant. This technique had previously been tested to make sure it would be able to grow new human cells from the grafted cell, and that the tags would only show up on new cells grown from the grafted tissue. The tagged cells were allowed to grow and differentiate, to create new islet bodies. The new human islets contained both tagged and untagged cells, suggesting that islet cell growth is more than a simple matter of cell multiplication.

Reliability:
The authors are professionals in the fields of medicine, medical research, and diabetes research, and associated with accredited institutions. The research was published in a peer-reviewed journal. The article explained the technical details of tissue preparation and growth. The research was funded, but not directed, by grants from a combination of diabetes-research foundations.

Practical Applications:
This investigation falls under the heading of primary research -- how islet cells form and develop -- which is considered one of the key issues involved in understanding and curing diabetes.

Ethics note:
Studies using human cells -- such as the fetus cells and human pancreas cells used in this experiment -- must meet certain ethical standards. In this case, the fetuses came from pregnancies the parents chose to abort between the 9th and 11th weeks of pregnancy, and the cells were taken with the informed consent of the mothers. The human pancreas cells were taken from a pancreas that had been lawfully donated for transplantation and research.

This synopsis was based on the entire article.

Adapting "quality of life" measures to a local audience

Evaluating the reliability, validity and minimally important difference of the Taiwanese version of the diabetes quality of life (DQOL) measurement
Original source: Health and Quality of Life Outcomes 2008, 6:87
Authors: I-Chan Huang (corresponding author), Jung-Hua Liu, Albert W Wu, Ming-Yen Wu, Walter Leite, Chyng-Chuang Hwang
Publication date: 28 October 2008
DOI (digital document ID): 10.1186/1477-7525-6-87
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors' goal was to develop ways to measure Health-Related Quality of Life (HRQoL) in the Chinese language, primarily for use in Taiwan. They translated a standard survey (called DQOL) to measure diabetes-related HRQoL, put it to a test, and tried to find out where it worked and where it needed tweaking.

There are a number of standards for measuring HRQoL in general, and diabetes-related quality-of-life in particular. One issue is that even among the diabetes-specific surveys, there are differences: some look at quality of life based on energy, mobility, ability to function, and social aspects along with the issues of testing and maintaining control; others look at the effect of medical treatment and satisfaction with that treatment, as well as concern about eventual development of complications. In order to be meaningful, the surveys have to pose questions that have meaning within the culture in which they are presented, and which put the patient at enough ease to answer truthfully. (For example, questions about sexual activity will not be answered in a society where that discussion is taboo.) One aspect of this is rewriting the survey in the local dialect.

A major issue with health-related quality of life surveys is determining what the patient means, and way he perceives the care he is receiving, and what changes to his responses mean over the course of time. There are several methods of statistically analyzing these responses and comparing them to an "impartial" standard -- physical measurements of the patient's health.

The clinical measurements used to validate the survey included HbA1c (a measurement of average long-term blood glucose levels), blood glucose levels two hours after meals ("two-hour postprandial"), fasting blood glucose levels, and the presence of some of the most common complications of diabetes (neuropathy - loss of sensation; foot ulcers, infections, and amputations; cardiovascular issues such as heart disease; and cerebrovascular (brain circulation) issues such as stroke).

In addition, two other diabetes-related quality of life surveys were translated and made more appropriate to Taiwanese culture, and used to verify the results of the Taiwan-adapted DQOL and to make those results meaningful to researchers and public health professionals.

The authors discuss their methods of translating and localizing the DQOL, their analysis of the data, and the limitations of their research.

Reliability:
The authors are all professionals in either public health or medicine, and interested in how patients perceive their quality of life.
The sample used was relatively small, but of a reasonable size to test the effectiveness of the surveys being developed; however, all of the respondents were from the same health center in Taiwan, and only four had Type 1 diabetes. The authors also noted that this analysis was done over a cross-section of patients at one time, and one of the real strengths of measuring quality of life is how it is perceived to change over time.

Practical Applications:
This is a first step in being able to understand, from the Taiwanese patient's viewpoint, the effects of diabetes on his quality of life. Applying this information to medical practice will help improve the level of care, and the effect of care, provided to these patients.

This synopsis was based on the entire article.

Effects of adding a second drug to Metformin

Outcomes of adding second hypoglycemic drug after metformin monotherapy failure among type 2 diabetes in Hungary
Original source: Health and Quality of Life Outcomes 2008, 6:88
Authors: Gyorgy Jermendy, Diana Erdesz, Laszlo Nagy, Don Yin, Hemant Phatak, Sudeep Karve, Samuel Engel and Rajesh Balkrishnan (corresponding author)
Publication date: 31 October 2008
DOI (digital document ID): 10.1186/1477-7525-6-88
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors' goal is to determine how well patients' blood glucose levels are controlled, and how the patients felt about their quality of life with diabetes, when metformin was not sufficient to control their diabetes and a second drug was added. The medical records of patients who had been on two oral diabetes drugs for at least a year were followed back for at least one year when they were on the two drugs, and going back as far as six months before the second drug was added. Other medical conditions that might affect the choice of medications, or that might need different medications, were tagged.

The goal of diabetes care was to achieve an HbA1c of under 6.5%. HbA1c is a long-term measure of average blood glucose levels; it is believed that sustained high blood glucose levels are the cause of many of the complications of diabetes. One issue that complicates this goal is that the HbA1c level includes the effects of unusually or dangerously low blood glucose -- hypoglycemia.

414 patients, average age 60 years, participated in this survey, in which they were asked about hypoglycemic incidents, satisfaction with their treatment, and overall health-related quality of life (HRQoL).

Hypoglycemic episodes were ranked as mild (little disruption to activities), moderate (requiring the to interruption of normal activities), or severe (requiring immediate medical assistance). The patients were also asked to report any swelling, weight gain, and digestive discomfort that might have occurred since starting the second drug. They were also given a standardized questionnaire to determine whether or not they took one, or both, drugs as prescribed.

27 percent reported hypoglycemic incidents, one third of that group reporting at least one moderate or severe hypoglycemic incident. Three-quarters of the patients did not meet their HbA1c goal after a year of therapy; many blamed their weight for this, though the surveys suggest it is more likely that this failure was because they were not taking their medications correctly. Reasons for not taking medications included side effects and the belief that the medications would cause them to gain weight. Patients who did not get their HbA1c below 6.5% were as a whole heavier than those who reached the goal, and they were less likely to be satisfied with the change in treatment. The participants felt that hypoglycemic incidents reduced their health-related quality of life; also, the longer they had diabetes, the lower their self-reported HRQoL.

Reliability:
The group of patients examined was relatively small, and because the individuals reported their issues themselves, it is possible that some did not admit to not using their drugs correctly, or to other issues that might affect the results of their care.

The results were published in a peer-reviewed journal, and the effectiveness of oral diabetes drugs is a hot issue. This study shows some possible reasons for why dual-drug therapy is not always successful.

It is important to note that all but one of the authors works for Merck, either as a direct employee or a paid consultant. Merck is the manufacturer of sitagliptin (Januvia), which is in a different class of oral diabetes drug from those used in the study (DP-4 inhibitors). The failure rates of both sulfonylurea and thiazolidinedione drugs used in the study could be used to build a case for the preferential use of Merck drugs Januvia and Janumet (Januvia plus Metformin) for diabetes management, which would be very profitable for Merck. Merck paid for the study.

Practical Applications:
The care protocols recently issued by both the American Diabetes Association and the European Association for the Study of Diabetes suggest either adding a sulfonylurea (a class of drug which helps the pancreas make more insulin) or moving directly to insulin injections if metformin by itself does not provide effective results. While some second-tier drugs such as Actos and Byetta were mentioned, the use of these and other classes of oral diabetes drugs (including DP-4 inhibitors such as Januvia) were considered more expensive and not as well-tested.

Another issue to consider is that the time-frames for changing ineffective therapy are much shorter in the current recommendations than those followed by the doctors in this study. Since diabetes is a progressive disease, it is possible that by the time the second medication was added, the disease had progressed too far for that medication to be effective.

For further reading:
New Major Changes in Recommendations for the Treatment of Type 2 Diabetes by ADA and EASD -- a synopsis of the new treatment recommendations from Diabetes In Control
Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy -- the abstract of the new treatment protocols, as published in Diabetologia

This synopsis was based on the entire article.

Primary Care Physicians as point-of-care for Type 2 diabetes

Family physician and endocrinologist coordination as the basis for diabetes care in clinical practice
Original source: BMC Endocrine Disorders 2008, 8:9
Authors: Alejandra Duran, Isabelle Runkle, Pilar Matía, Maria P de Miguel, Sofia Garrido, Emilio Cervera, Maria D Fernandez, Pilar Torres, Tomas Lillo, Patricia Martin, Lucio Cabrerizo, Nuria Garcia de la Torre, Jose R Calle, Jose Ibarra, Aniceto L Charro, and Alfonso L Calle-Pascual (corresponding author)
Publication date: 31 July 2008
DOI (digital document ID): 10.1186/1472-6823-8-9
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The investigators looked at diabetes patients with peripheral circulation and capillary circulation issues and sought to find out whether there was any measurable difference in the results whether the patient was treated by a primary care physician (PCP) or an endocrinologist.

One of the issues surrounding diabetes care in Spain is that primary care physicians (PCPs) may not be as aggressive in treating multiple risk factors and signs of complications of diabetes as a hospital-based endocrinology team. A program in which PCPs are trained to address all these factors and to consult with the hospital-based team was instituted. This study attempts to evaluate the effectiveness of this program.

In the "Area 7" section of Madrid, Spain, 126 patients with Type 2 diabetes and peripheral circulation issues were studied over a 30-month period. After an initial three-month period of treatment by the Diabetes team at St Carlos Hospital, the patients were broken up into two groups: one to continue care at St Carlos, the other to return to their program PCPs for diabetes care. Nine patients moved out of district over the period of the study, leaving 117 patients from which to evaluate this program.

The investigators looked at the folloiwng markers as indicators of care effectiveness: HbA1c (%); Total Cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides; blood pressure; albumine-to-creatinine excretion ratio (ACR); body mass index (BMI) and waist circumference (WC); anti-aggregation treatment; and smoking status.

At the end of the follow up, no differences were found between the groups for the following counters:

• more than 37% of diabetic patients achieved a HbA1c <>
• more than 50% a ACR <>
• more than 80% reached low risk values for cholesterol, LDL cholesterol, triglycerides, and diastolic blood pressure
• more than 80% were on aspirin therapy against platelet aggregation
• 12% remained smokers.

On the other hand,

• less than 45% achieved a systolic blood pressure <>
• only 49% of the men and 30% of the women had a waist circumference of low risk.

The largest difference between the groups is that while 23% of the patients cared for by the diabetes care team achieved a BMI less than 25, less than 12% of the patients cared for by family physicians achieved this level. Neither of these results was considered satisfactory and were attributed to focus on risk factors other than overweight.

The investigators concluded that good metabolic control can be achieved at the primary care level, if the PCP coordinates patient care with the endocrinologist. This will result in better results than being treated by an untrained primary care physician without endocrinological support.

Reliability:
The study was small enough that it could be a pilot project -- evaluation of a small-scale implementation before bringing this program to all of Madrid, or to all of Spain. The follow-up time was 2.5 years, which is an intermediate timeframe. Two of the authors work at the St Carlos hospital and clinic; the third is associated with the evaluation of primary care in the "Area 7" section of Madrid. The research was published in a peer-reviewed journal, which suggests a level of reliability to the results.

Practical Applications:
Moving Type 2 diabetes follow-on care out to the primary care practitioner can simplify care delivery from the patient's point of view. It also allows the PCP to do a better job of treating the entire patient, rather than a single aspect of that patient's care. In addition, teaching PCPs more about diabetes, and giving them consultation access to endocrinologists, can improve both initial diagnosis and ongoing diabetes care.


This synopsis was based on the entire article.

How "Bedside Manner" affects Self Care in Type 2 diabetes

The emotional context of self-management in chronic illness - A qualitative study of the role of health professional support in the self-management of type 2 diabetes
Original source: BMC Health Services Research 2008, 8:214
Authors: John Furler (corresponding author), Christine Walker, Irene Blackberry, Trisha Dunning, Nabil Sulaiman, James Dunbar, James Best, Doris Young
Publication date: 17 October 2008
DOI (digital document ID): 10.1186/1472-6963-8-214
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
One role of health-care professionals is to support patients with regard to both the clinical and emotional aspects of living with diabetes. The authors of this study tried to find approaches to make these professionals more effective at this task. They asked patients with Type 2 diabetes how they took care of their diabetes and how their relationships with their support teams affected this. They looked at groups who had been telephoned by nurses in the patients' general practitioners' offices to "coach" them about their diabetes and encourage them to become more actively-engaged their own health care and in their relationship with their family doctors. Their goal is to make these nurses more effective in this mission.

A total of 52 patients, ranging in age from 50-80, were split into four focus groups. Most of the participants were either unemployed or retired, and had had at least one visit with a diabetes educator. There were two English-language focus groups, plus one in Arabic and one in Turkish -- the two main languages of lower-income immigrants in the Melbourne, Australia urban area.

The groups focused on the role of personal control of diabetes and how one's relationships with one's healthcare team influenced this.

The investigators found that overall, the English speakers tended to see diabetes as life-limiting, almost punitive, and requiring self discipline. Dietary changes were viewed in terms of sacrifice -- for example, "having to give up" one's favorite foods. They looked at their entire care team as separate but equally important entities. They were more likely to "shop around" to find professionals who would give them "the right answers"; they needed information to be able to exert control their conditions.

Arabic and Turkish speakers saw diabetes as an integrated part of life, possibly indicative of stress. They saw self-management techniques as part of an integrated effort to restore personal calm. Dietary changes were put in a positive light -- using higher-quality foods rather than lesser quality ones, for example. They also relied primarily on their relationship with their General Practitioner, expecting him to provide them with all the information necessary to care for themselves. When they attended education sessions, or saw specialists, it was only upon the strong recommendation of their primary care physicians.

The investigators saw in the English-speakers the emerging concept of "patienthood", and doctor-patient relationships evolving to the ideal of the actively-engaged patient. (This is the model that is fostered by medical professional societies and by health insurers.) In contrast, they felt there was a potential danger in being completely uncritical of one's primary care physician, with the potential for insufficiently aggressive care and poorer long-term outcomes. The authors believe their findings suggest that a patient will see better results if his or her health-care professionals take the time to understand their patients' social, cultural, and emotional contexts and work from there to help them develop an effective approach to self care.

Reliability:
The study size was very small. The authors note that several aspects of its design could have skewed the results, and their specific results are not applicable outside of the particular community studied. The authors are a multidisciplinary group of professionals in medical practice, medical education, public health, and patient advocacy. The research was published in a peer-reviewed journal. The information should be considered more as a start-off point for your own relationships with your health-care team -- or if you are a practitioner, your patients.

Practical Applications:
There are many reasons that one's social and cultural background can either help or hinder self-care. I've often stated -- and even blogged -- that being willing to learn about the beliefs and cultural contexts of others, and by using those contexts as a starting point, the information or discussion you provide will be more easily understood, more appropriate to that other person, and where health information is concerned, more likely to get a positive response. I am encouraged to see this approach, and hope that it will improve diabetes care not just in Melbourne, but throughout the world.

This synopsis was based on the entire article.