Type 2 Diabetes Classification - A Straw Man Scale for Progression

Many people in the diabetes online community (DOC) are concerned about the label "prediabetes", its predecessor term "borderline diabetes", and its colloquial counterparts (e.g., "a touch of the sugar"). The prevailing attitude is that one either has diabetes, or one does not. This may seem counterintuitive to the general understanding that a woman who was diagnosed with gestational diabetes (GD), but whose postpartum glucose metabolism has returned to reference normal (RN), does not have Type 2 diabetes mellitus (T2DM), but is at increased risk for developing T2DM later in life. It also contrasts with the popular belief -- even espoused by some in the mainstream medical community -- that if a person diagnosed with T2DM can bring his glucose metabolism back to RN by changes to his diet and exercise regimen (D&E) without the use of antidiabetic medications, then he no longer has diabetes.

Two biases of significant note: (1) current medical understanding is that at the point of T2DM diagnosis, a person has lost 50% of beta cell function (AACE, p. 16), and (2) the diabetes online community is primarily informed by persons with Type 1 diabetes mellitus (T1DM), an autoimmune disorder for which there is currently no cure.

Based on the above attitudes and biases, the belief would be that the new mother, having been diagnosed with GD during pregnancy, would be considered to have T2DM, even if it can be mediated without frank lifestyle adjustments. Similarly, the person who was diagnosed with T2DM is considered to still have T2DM, even if it is mediated completely by D&E.

Unlike most presentations of T1DM, T2DM is currently understood to be a progressive condition. Our understanding of its progression in a given individual is informed by both quantitative and qualitative benchmarks. The most common quantitative benchmarks are the individual's fasting blood glucose level, serum fructosamine level, and amount of glycosylated hemoglobin. Other quantitative benchmarks -- such as c-peptide level -- may be useful in determining both insulin resistance and degree of remaining beta cell function. Qualitative benchmarks include signs and symptoms of known complications of diabetes at all levels of their development.

One analogy for cataloguing the degree of progression of T2DM is that used for cataloguing hypertension or cancer: a stage chart. In Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), hypertension is categorized from consistently slightly-elevated blood pressure ("prehypertension") through progressively elevated levels, and the response of those levels to pharmacotherapy.

An initial straw man chart can be derived from the American Association of Clinical Endrocrinologists' Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus (2007) examples for initial pharmacotherapy of T2DM:

Classification of Type 2 Diabetes Mellitus (based on initial therapy algorithms)

Progression Level	HbA1c (untreated)
Stage 1 (Prediabetes)	5.7 - 6.4
Stage 2	6.5 - 7.0
Stage 3	7.0 - 8.0
Stage 4	8.0 - 10.0
Stage 5	> 10.0

Other issues that play into determining the progression of T2DM include the deterioration of endogenous insulin production, the development of complications of diabetes, and the degree to which a person's blood glucose levels and HbA1c are responsive to pharmacotherapy. A more complex table of progression might include these in a manner such as this:

Classifications of Type 2 Diabetes Mellitus (proposed)

Level	HbA1c (Goal)1	Effective Therapy	Evidence of Complications	c-peptide (relative)
Stage 1 (Pre-Diabetes)2	< 6.03	ILM. Oral medication optional for aggressive treatment.	none	high
Stage 2	< 6.5	Oral medication and/or insulin sensitizer required	none	high
Stage 3	< 7.0	Combination therapy and/or insulin required	possible; possible comorbid conditions	varies
Stage 4	< 7.0	Insulin therapy required, with or without oral medications and/or pramlintide (Symlin)	probable; possible comorbid conditions	low
Stage 5	< 8.0	Intensive insulin therapy required, possibly in conjunction with insulin sensitizers	obvious; one or more comorbid conditions	low

1 While the HbA1c goals at the more advanced levels of diabetes progression are high enough that complications are likely to develop or intensify, those goals may not be realistically achievable with current medical and pharmaceutical technology.
2 Includes all previous diagnoses of gestational diabetes or Type 2 diabetes in which pharmacotherapy is not currently indicated
3 More aggressive practitioners may argue for an HbA1c goal of under 5.5 for Stage 1, under 6.0 for Stage 2, and under 6.5 for later stages of T2DM. The less-aggressive goals are informed in part by the (ACCORD) study, in which the tested combination therapy suggested a higher mortality risk for intensive control.

A classification scheme of this sort may remove the ambiguity of a diagnosis of "prediabetes" and its associated laissez-faire ("It's not diabetes") attitude, as well as the popular belief that once diagnosed, one can become "undiagnosed" (or perhaps "de-diagnosed"). It can also alert a medical practitioner to the need for ongoing monitoring and assessment of a person's glucose metabolism. On the other hand, classification will add to the pool of people indicated to have diabetes those who do not consider themselves to be currently affected by diabetes -- and in an environment where a positive diagnosis can mean the denial of employment, medical insurance, or healthcare, this can have worse repercussions than living with undiagnosed or untreated Stage 1 (or even Stage 2) T2DM.

Making it Easier for Patients to Help Themselves

Text messages could hasten tuberculosis drug compliance
Original source: The Lancet Volume 373, Issue 9657
Authors: Eliza Barclay
Publication date: 3 January 2009
DOI (digital document ID): 10.1016/S0140-6736(08)61938-8
Requires subscription? No
Publicly-available abstract: No

Synopsis:
The use of SMS (Short Message System) technology is examined as an option for improving patient compliance in terms of taking pills for the treatment of tuberculosis. Techniques examined include text messages to cellphones with follow-ups if the patients do not respond to the messages, pill bottles with SIM cards that alert a central server when the bottle has been opened (ostensibly for the patient to take the medication), asking patients to speed-dial a special cellphone number after taking their medication, or asking patients to text back a code from a post-medication urine test. The use of financial and other incentives to follow the regimen is also discussed.

Reliability:
The compliance techniques are currently being investigated. The letter does not address the possibility of false compliance (response to the message without taking the medication; opening the pill bottle without removing a pill; speed-dialing the appropriate phone number without taking the medication).

Practical Applications:
While these techniques are being investigated for the management of tuberculosis patients in Africa, there are many people in industrialized nations who don't take their medications because they forget, or because they have not correctly processed a change in their medication regimens, or because they have so many medications that it is difficult to keep track of which one to take when. This is particularly, but not exclusively, true of elderly patients. There are also patients who don't correctly take their medications for economic reasons.

People with Type 2 diabetes, who are often on several medications in addition to those for glycemic control, fall into this category. In addition, many of us don't test as often as we should, or log our blood glucose readings reliably.

Some insurance companies and hospitals offer a reminder service where they phone these groups of patients to remind them to take their medications. The SMS techniques discussed in this letter may be useful either as adjuncts to the phone-reminder services, or as a new service where none currently exists.

This synopsis was based on the complete article.

Can combined oral therapy improve muscular fitness?

Combined thiazolidinedione–metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle
Original source: Diabetologia Volume 52, Number 1
Authors: N. Temofonte, M. P. Sajan, S. Nimal, T. Pastoor, C. Fumero, L. Casaubon, J. L. Powe, M. L. Standaert1, and R. V. Farese (corresponding author)
Publication date: January, 2009
DOI (digital document ID): DOI: 10.1007/s00125-008-1180-z
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
Impaired insulin responses in Type 2 diabetes can make it difficult for glucose to get to muscles, where they are needed. It is believed that this is because certain insulin-activated protein enzymes (atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt)) are not as thoroughly activated as they should be. Both metformin and thiazolidinediones (a class of oral diabetes-management drugs that includes rosiglitazone (Avandia) and pioglitazone (Actos)) improve this deficiency. The investigators wanted to know if adding both drugs together would create an even greater improvement.

Combined metformin-thiazolidinedione therapy was administered to Type 2 test ubjects for 5-6 weeks and the results measured. The investigators observed improved glucose movement and improved insulin-induced activity of four muscle signalling factors (insulin receptors plus two protein kinases). Despite this improved activity, the levels of aPKC in muscle tissues were not improved.

Because of the improvement in the four signalling factors, the investigators consider this test successful.

Reliability:
The number of patients tested was not available in the abstract, nor was any CONSORT statement, so it's difficult to tell whether the sample size was large enough to counteract small-sample skew. Several of the investigators are associated with a Veteran's Administration (VA) center. VA patients often get the worst possible levels of care, so it is hard to tell how far along the subjects' T2 had progressed, or how well it had been treated before the test. That we are looking at combined therapy and it is being called "therapeutically useful" even though depressed muscular aPKC levels were not affected by the treatment suggests that this is the sort of experiment that would be funded by a drug manufacturer, with an eye towards pushing more expensive drugs (such as Avandamet, a combination of Avandia and metformin) on the T2 public.

Practical Applications:
Improved muscular uptake of glucose could improve physical performance, and with it, positive incentives toward exercise. This could result in T2 patients being more interested in exercising, and thereby, improving both physical fitness and insulin sensitivity.

This synopsis was based on the abstract only.

Tesofensine - initial trials of a potential weight-loss drug

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

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

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

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

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

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

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

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


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

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

This synopsis was based on the abstract only.

On the Low Birth Weight Risk for Insulin Resistance

Altered PI3-Kinase/Akt Signalling in Skeletal Muscle of Young Men with Low Birth Weight
Original source: PLoS ONE 3(11): e3738
Authors: Christine B. Jensen, Malgorzata S. Martin-Gronert, Heidi Storgaard, Sten Madsbad, Allan Vaag, Susan E. Ozanne (corresponding author)
Publication date: November 17, 2008
DOI (digital document ID): 10.1371/journal.pone.0003738
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Low birth weight (LBW), an indicator of stress or an adverse fetal environment, is associated with increased future risk of insulin resistance and type 2 diabetes. The investigators are reporting continuing research on a specific insulin signaling pathway may be altered in skeletal muscle of young adult men with LBW. This would help increase our understanding of the mechanisms of insulin resistance in this particular population.

Muscle biopsies were obtained from 20 healthy 19-yr old men who had been in the lowest 10% birth weight for full-term babies and compared them to 20 physically similar men of normal birth weight. The samples were checked for fasting blood glucose and insulin levels, and after four hours in which insulin-production was medically stimulated.

The researchers looked at several previously-unstudied proteins and pathways related to muscular function and muscular glucose metabolism to see if there was any difference between the two groups of men. They found significant differences in the levels of several proteins after insulin stimulation. Some of these differences seen in the LBW group are similar to those seen in patients with insulin-resistant Type 2 diabetes.

The authors conclude that these differences in skeletal-muscle response to insulin precede, and may contribute to, the development of whole-body insulin resistance and type 2 diabetes in men with LBW.


Reliability:
The tests were done on a small number of subjects and a small number of controls. The small sample could skew the results obtained. Also, these were spot observations. Longitudinal observation of these subjects (over a period of time) might give the researchers better information about whether or not insulin resistance progresses in this manner in these subjects.

Practical Applications:
This is one of a series in basic research of how diabetes may develop in specific populations.

In many areas, low birth weight is associated with maternal malnutrition and/or poor prenatal care -- which are further associated with low-income communities and minority communities. Type 2 diabetes is more common in these groups than in the general population. Proving a definite link and path may bring more interest in providing education, and medical and dietary services, to this high-risk group.

Ethics note:
Written informed consent was provided from all participants and approval was obtained from the regional ethics committee.

This synopsis was based on the entire article.

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.