Prenatal diet may affect insulin resistance for multiple generations

Insulin sensitivity is normalized in the third generation (F3) offspring of developmentally programmed insulin resistant
(F2) rats fed an energy-restricted diet
Original source: Nutrition and Metabolism 2008, 5:26
Authors: Daniel C Benyshek (corresponding author), Carol S Johnston, John F Martin and William D Ross
Publication date: 17 October 2008
DOI (digital document ID): 10.1186/1743-7075-5-26
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
A number of studies have shown that the way animals develop before birth can affect the birth weights, blood pressure, and glucose metabolisms of their children, grandchildren, and so on. Most research to date has only gone two generations beyond the original parents. This study takes observation to the third generation (great-grandchildren) and focuses on impairments to the animals' glucose metabolisms. A parent generation of female rats were fed protein-deficient diets while pregnant and nursing, and both they and three generations of their offspring were fed low-calorie diets, to see how this affected the insulin sensitivity of multiple generations of their offspring. A group of control rats was fed normal-calorie diets over the same number of generations.

The first generation of offspring (children) tended to be of low birth weight, while the second and third generations (grandchildren and great-grandchildren) were of normal birth weight. All generations were of lower than normal weight as adults, due to the caloric restriction. The first=generation offspring had normal insulin metabolism, While the second generation, as adults, had reduced insulin sensitivity and reduced insulin production -- a set of symptoms consistent with impaired glucose tolerance. The third generation did not show insulin resistance -- indeed, the males were even more insulin-sensitive than the control animals, whether they were fed calorie-restricted diets or allowed to eat at will.

Previous studies of this type showed insulin resistance in the first-generation offspring, which was not found in this particular study; however, the second-generation female offspring in this study were insulin-resistant.

The investigators are unsure why the third-generation offspring did not show impaired glucose tolerance or insulin resistance, even though both of those traits are considered to be adaptive traits that show up in "nutrient poor environments" (reduced protein, reduced calories). They suggest that one reason for this may be that the second-generation mother's insulin resistance left more energy in the bloodstream to be used by the fetus. On the other hand, the relative insulin sensitivity of previous-generation mothers (who had not been fed sufficient calories after weaning) made fewer nutrients available for the developing fetus, resulting in insulin resistance in the offspring.

The investigators suggest that more research is required to determine how pregnancy and nursing diets, and maternal insulin sensitivity, affects the insulin sensitivity of her offspring.

Reliability:
The authors are from accredited institutions, across a number of medical and social disciplines. The research was published in a peer-reviewed online journal. References are all from peer-reviewed journals. Therefore the experiment design is reliable. Since only four female rats from each child generation were bred, the study was small in size and therefore subject to skew. The authors did note that further research was warranted to find out why they got the results they did.

Practical Applications:
The normal birth weight and increased insulin sensitivity of child generations born to insulin-resistant mothers suggests a parallel mechanism for the large baby size common for human mothers with diabetes. While this study was conducted on rats, the rats are intended to be a shorter-lived and expendable model for human childbirth and development. A closer understanding of which maternal nutrients affect insulin resistance may lead to improved recommendations for pregnancy and nursing diets and supplements, and will ideally prevent insulin resistance in future generations of human adults.

This synopsis was based on the entire article.

Discovering and Preventing Type 2 Diabetes in New Mothers

Gestational diabetes mellitus: postpartum opportunities for the diagnosis and prevention of type 2 diabetes mellitus

Original source: Nature Clinical Practice Endocrinology & Metabolism (2008) 4, 552-558
Authors: Rhonda Bentley-Lewis (corresponding author), Sue Levkoff, Alison Stuebe and Ellen W Seely
Publication date: 9 September 2008
DOI (digital document ID): 10.1038/ncpendmet0965
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
This Continuing Medical Education (CME) course is aimed at obstetrician/gynecologists and primary care physicians, who take care of women before, during, and after childbirth. A woman who has had gestational (pregnancy) diabetes is at increased risk of developing Type 2 diabetes. The aim of this course is to look at the need to monitor these women in order to prevent, or to quickly diagnose, Type 2 diabetes following childbirth. This requires screening for diabetes at one or more points after delivery.

In current medical practice, there are a number of conflicting guidelines for diabetes screening after delivery: while the American Diabetes Association (ADA) suggests either fasting blood glucose measurement or an Oral Glucose Tolerance Test at 6-12 weeks after delivery, with follow-ups every three years if the tests are normal, or every year if the test indicates impaired glucose tolerance. The World Health Organization (WHO) suggests a single follow-up six weeks or longer after delivery. The American College of Obstetricians and Gynecologists has no specific recommendation for diabetes screening after delivery. As a result, many women who have had gestational diabetes do not get follow-up screening.

Beyond the differing guidelines, the authors suggest several reasons that women may not be receiving appropriate postpartum diabetes screening. These include confusion as to whether this should be done by the obstetrician or the woman's primary care physician, whether or not she had a postpartum visit with the obstetrician, and whether or not she was instructed to get this screening.

The authors suggest several known methods for minimizing the risk of developing Type 2 diabetes after childbirth, including diet and exercise, weight loss, breastfeeding, and the preventative use of oral antidiabetes medications.

The authors suggest both monitoring new mothers who have had GDM 6-12 weeks after birth, and continuing to monitor them regularly thereafter.

Reliability: The authors are medical doctors with additional qualifications in public health, women's health, and psychiatry, and are associated with top-name institutions. The course is presented in conjunction with a peer-reviewed publication; the information is well-documented and the source publications are also peer-reviewed.

Practical Applications: The goal of CME courses is for doctors to keep up with current research and medical practice, with the end result of improving their ability to keep their patients healthy. Vigilant screening and attention to other diabetes risk factors will keep these mothers healthier for longer periods of time, lessen their risk of complications of diabetes, and potentially provide healthier role models for their children.

For further reading: The article's bibliography section has a number of online sources for follow-on reading.

This synopsis was based on the CME version of the complete article.

Does "dashboard dining" make you fat?

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

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

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

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

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

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

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


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

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

This synopsis was based on the entire article.

Is Uric Acid level a risk indicator?

Uric Acid and Cardiovascular Risk
Original source: New England Journal of Medicine Volume 359 — October 23, 2008 — Number 17
Authors: Feig (corresponding author), D. I., Kang, D.-H., Johnson, R. J.
Publication date: October 23, 2008
DOI (digital document ID): (not available)
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The original publication is a review article: it summarizes a number of previous publications concerning uric acid (a waste product that our blood carries to our kidneys for excretion) and possible links to high blood pressure (hypertension), diabetes, metabolic syndrome, kidney disease, and cardiovascular disease.

The authors note that the average levels of uric acid in the blood have been rising, along with our risks of these diseases. This does not necessarily mean that one or more of these diseases cause uric acid levels to rise, or that high uric acid levels raise the risk of developing cardiovascular disease, kidney disease, diabetes, metabolic syndrome, etc.

The authors examine research in which uric acid levels are examined in the cases of people and test animals with kidney disease, hypertension, metabolic syndrome, and kidney disease. Some observations include the possibility that high consumption of fructose is a factor in increased uric acid levels, and that increased uric acid levels may be partly responsible for the development of hypertension, insulin resistance, and weight gain. High uric acid levels may also be a factor in, or a result of, impaired kidney function.

In all of these cases, lowering uric acid levels -- particularly with the drug allopurinol -- seems to alleviate the symptoms of the other conditions. However, these studies were conducted in small, specific groups of people and animals. The researchers are not sure that this is necessarily from lowering uric acid levels rather than specifically from the use of allopurinol (other drugs to lower uric acid levels did not provide as dramatic results). They note that allergy or sensitivity to allopurinol can be fatal, so it's not necessarily a drug of choice. They state that more research needs to be conducted -- both on the whole-body effects of uric acid levels and of possible alternatives to allopurinol.

Reliability:
Review articles are based on taking previously-published research and examining it in a new light. Sometimes this means taking small studies from a lot of different groups and compiling or comparing them; sometimes it means creating a general overview of a topic. In this case, the authors reference a number of publications (follow the links in the "References" list) and their conclusions, come up with a theory (that high blood levels of uric acid may be the cause of other metabolic diseases), and point this out as something that needs further testing to prove whether this is true, or just coincidence.

Practical Applications:
Uric acid is one of the items measured in a standard "metabolic panel" blood test -- the blood test most of us get every time go to the doctor for a check-up. It is one of the waste products that is processed by our kidneys into urine. High uric acid levels have been associated with gout, which -- like metabolic syndrome -- is one of many conditions that are associated with obesity. If researchers can prove a definite cause-and-effect relationship between high uric acid levels and other metabolic conditions, it may give doctors another set of tools to improve the health of some people with cardiovascular disease, diabetes, and/or metabolic syndrome.

This synopsis was based on the CME version of the complete article.

Association = Coincidence

One phrase that often pops up in medical research is the phrase, "is associated with". Eating quickly is associated with obesity, diabetes is associated with increased risk of heart attack, high triglyceride levels are associated with high consumption of dietary fructose, etc.

Taken at face value, association means... nothing. Only that the two items are often seen at the same time. It could be coincidence, such as two students in the same grade getting out of school at the same time. The two students might be friends, enemies, frenemies... or completely unaware of each other. Just as someone would need to look further to find out whether the students were friends, researchers need to look further to see whether eating quickly causes obesity, or why people with diabetes may be more likely to get heart attacks. What an "association" article does is point out that we often see these two medical issues in the same person, at the same time -- and in doing so, points out a direction for further research. Eventually, researchers may find a relationship between the two conditions (for example, one causes the other -- or both are caused by a third condition). Or they may find out that the two conditions are completely unrelated.

The article simply asks the question in a logical manner.

Metabolic syndrome increases risk of heart attack and stroke

Effect of metabolic syndrome or type II diabetes mellitus on the occurrence of recurrent vascular events in hypertensive patients
Original source: Journal of Human Hypertension (2008) 22, 358–365
Authors: A L M Vlek, Y van der Graaf, W Spiering, F L J Visseren (corresponding author), SMART study group
Publication date: published online 14 February 2008
DOI (digital document ID): doi:10.1038/jhh.2008.5
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
People with high blood pressure and vascular disease (diseases of the blood vessels) are at increased risk for recurrences of vascular disease, and for developing additional cardiovascular diseases such as heart disease, stroke, peripheral artery disease, and aneurysms. This study aims to find out whether having metabolic syndrome, and/or Type 2 diabetes, increases those risks even further.

Over 2000 people who were part of the Second Manifestations of Arterial Disease study (SMART) were followed for up to 10 years afterward for death, strokes, and heart attacks. These were used to calculate the risks of cardiovascular disease for people with high blood pressure only, for high blood pressure and metabolic syndrome, and for people with high blood pressure and diabetes.

Of this group, patients with metabolic syndrome (but without diabetes) had higher rates of stroke, heart attack, and sudden deaths related to cardiovascular issues. Patients with Type 2 diabetes had even higher risks than those with metabolic syndrome (but without diabetes). The increased risk of people with metabolic syndrome was not explainable by diabetes.

Further lowering of blood pressure did not seem to reduce the increased risk of heart attack and stroke in patients with metabolic syndrome.

Because people with metabolic syndrome have been shown to have higher risk of cardiovascular disease, investigators suggest more attention should be paid to diagnosing metabolic syndrome and treating it aggressively.

Reliability:
A large number of people were observed over a relatively long period of time. The authors work in a university medical center. The research was published in a peer-reviewed journal. The results should be relatively reliable.

Practical Applications:
Patients and healthcare providers should pay more attention to identifying the signs of metabolic syndrome and treating it with diet, exercise, and drugs (where appropriate).

Health insurance and life insurance actuaries will want to account for this relationship in their risk tables when determining coverage and premiums.

This synopsis was based on the entire article.

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

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

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

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

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

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

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

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


This synopsis was based on the entire article.

Investigating Insulin Resistance in the Liver

Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance
Authors: Markus Hafner, Anton Schmitz, Imke Grüne, Seergazhi G. Srivatsan, Bianca Paul, Waldemar Kolanus, Thomas Quast, Elisabeth Kremmer, Inga Bauer and Michael Famulok
Original source: Nature Volume 444, pp. 941-944
Publication date: 14 December 2006
DOI (digital document ID): doi:10.1038/nature05415
Requires subscription? For complete article
Publicly-available abstract: Yes

Synopsis:
G proteins regulate biochemical "switches" in all living systems. They are switched on and off by chemicals called "guanine nucleotide exchange factors" or GEFs. Finding chemicals which increase or inhibit GEFs may be useful both to find out how GEFs work and to treat diseases in which the G proteins are affected.

A specific class of GEFs called "cytohesins" includes some GEFs that are associated with insulin production and signalling. The investigators found that in humans, a chemical called "SecinH3" might inhibit the cytohesins associated with insulin signalling. To test this theory, mice were treated with SecinH3 and observed to determine whether or not they showed increased signs of insulin resistance.

The mice exhibited increased glucose production, reduced glycogen storage and glycogen-to-glucose conversion, a reduced ability to metabolize fatty acids and ketones, and increased plasma insulin. These are all symptoms of insulin resistance, suggesting that increased levels of SecinH3, and/or decreased activity of cytohesins, may be responsible for insulin resistance.

The importance of this finding is that insulin resistance is one of the first signs of Type 2 diabetes.

Reliability:
The initial hypothesis was based on the isolation of SecinH3 and its effects in isolated human liver tissue, so even though this experiment took place in mice, it has a good probability of being directly transferrable to people. The article was published in a peer-reviewed journal, and the authors are professional researchers in biochemistry and immunology.
This leads to high confidence in the results.

Practical applications:
This research is still very early on in the process of developing new treatments for insulin resistance and Type 2 Diabetes.

This synopsis was based on the abstract only.

Metabolic syndrome increases risk of heart disease and diabetes

Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study
Authors: C M Ballantyne (correpsonding author), R C Hoogeveen, A M McNeill, G Heiss, M I Schmidt, B B Duncan and J S Pankow
Original source: International Journal of Obesity Volume 32, Supplement 2, pp. S21-S24
Publication date: May, 2008
DOI (digital document ID): doi:10.1038/ijo.2008.31
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
The investigators studied over 15,000 middle-aged Americans in four communities for a period of approximately ten years to try to determine the role of metabolic syndrome in the development of cardiovascular (heart and artery) disease and diabetes. The particular study is called Atherosclerosis Risk in Communities (ARIC).

Metabolic syndrome is diagnosed by the presence of three or more of the following characteristics: waist circumference greater than 40" in men or 35" in women; high triglycerides (over 150 mg/dl); low HDL or "good cholesterol" (less than 40 mg/dl in men or 50 mg/dl in women); high blood pressure (over 130/85 mm Hg); and high fasting glucose levels.

The investigators studied the numbers of those with and without metabolic syndrome to determine how much greater a risk someone with metabolic syndrome has of developing atherosclerosis, heart disease, stroke, or diabetes.

• ARIC participants who had metabolic syndrome were two to three times more likely to have coronary heart disease than those without, with the highest additional risk in black men and white women.
• The walls of the carotid arteries of persons with metabolic syndrome were about 5% thicker than those without.
• The increased risk of stroke for those with metabolic syndrome was an additional 35-40 cases per 10,000 person years.
• Of those participants with three or more indicators of metabolic syndrome, who did not have diabetes, those with obesity and/or elevated fasting glucose levels had significantly increased risk of developing diabetes.

Reliability:
This is a large study, conducted over a long period of time, and the article was published in a peer-reviewed journal. Both this, and the academic credentials of the authors, result in high levels of confidence in the results.

Further reading:
More information on the design of the ARIC study and publications based on information collected during the study can be found at the ARIC home page.

This synopsis was based on the entire article.

Why Detechnified?

One of the mixed advantages of spending over a decade working on an abstracts journal of interest to the National Aeronautics and Space Administration (NASA) and its counterparts (such as the European Space Agency) is exposure to highly technical information across a wide range of disciplines -- ranging from aircraft and spacecraft design to the health of the pilots and astronauts who fly them -- and the ability to compress the information down to a one-paragraph abstract and six key phrases by which that paragraph could be recalled. Another is the ability to search for almost anything, and come up with an answer... somewhere.

When I was diagnosed with diabetes, high blood pressure, and high cholesterol in 2002, I found myself in the information drought that too often accompanies these diagnoses: a handful of prescriptions, a couple of self-contradictory diet sheets, and "have a nice life". I had to apply the skills I learned on the job to find out how best deal with the medical hand I'd been dealt. I learned of something called "Syndrome X", or "Metabolic Syndrome" -- a new diagnostic label which was unknown to my medical team. I learned a lot more about diabetes, hypertension, and high cholesterol, and the methods of treating them. I would (and still do) routinely hand my doctor printouts of the research I've been reading, and if they apply to my own conditions, we'll discuss them.

Today, there are a number of online communities to support people with diabetes; I'm a member of several of them. Many have places to post information about new advances in medical research. If I post the title and link to an original article published at Nature, The Lancet, the New England Journal of Medicine or BioMed Central, I meet with the equivalent of blank stares: most of us, no matter how interested we are in the medical issues and treatments for diabetes, can't easily understand writing that is aimed at doctors, and at other medical researchers.

There are also a number of health-oriented newswires which publish press releases and synopses of current research. What seems to be missing are an evaluation of both the immediate and long-term importance of the research, and a quick way to tie the synopsis to the original publication so an interested reader can pursue the issue further.

This is what I hope to address -- to make the technical understandable, to put it into context, and to leave a clear path for someone to research further -- to not have to take my understanding at face value. I hope this will help bring greater understanding to people with diabetes, and open up the dialog between us and our medical care teams.