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.

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.

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.

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

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

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

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

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

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

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

This synopsis was based on the entire article.

Adapting "quality of life" measures to a local audience

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

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

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

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

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

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

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

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

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

This synopsis was based on the entire article.

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

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

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

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

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

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

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

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

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

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

This synopsis was based on the entire article.

Merck analyzes Januvia safety studies

Safety and tolerability of sitagliptin
Original source: BMC Endocrine Disorders 2008, 8:14
Authors: Debora Williams-Herman, Elizabeth Round, Arlene S. Swern, Bret Musser, Michael J. Davies, Peter P. Stein, Keith D. Kaufman and John M. Amatruda
Publication date: 27 October 2008
DOI (digital document ID): 10.1186/1472-6823-8-14
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors are trying to assess the safety and of sitagliptin (Januvia) by combining the results of 12 separate double-blind human trials of up to 2 years in duration. (Double-blind trials are ones in which neither the investigators nor the patients know who is getting the drug under test and who is getting an alternate therapy or no drug therapy. This helps keep the results unbiased.)

A total of 6139 patients were involved in the studies; 3415 were either given 100 mg Januvia per day or the equivalent dose of another oral anti-diabetic pill; 2724 were given a placebo (a pill that has no drug action to it). The shortest study ran 18 weeks (about 4 months) and the longest ran 2 years. The patients were either given sitagliptin (Januvia) alone, or with metformin (similar to Janumet), or as addition to other antidiabetic drugs such as metformin (Glucophage), sulfonylurea, pioglitazone (Actos), and/or rosiglitazone (Avandia). The patients not getting the Januvia were getting either a placebo or one or more of the above antidiabetic drugs.

A number of known adverse reactions and side effects were examined in both the sitagliptin groups and the various control groups. According to the abstract, the only significant side effect was an increase in patient-reported hypoglycemic events among those patients who were also taking sulfonylurea drugs. The definition of "hypoglycemia" was somewhat loose, not requiring the patient to test his blood glucose and add it to the report. The authors do examine the frequency of reports of nausea and stomach pain, pancreatitis, immune system suppression, nose and throat discomfort, skin reactions (hives, discoloration, redness, etc.), and swelling in the heart and chest. These adverse reactions were considered to be similar in frequency between those taking Januvia and those who were not. The reasons for other studies reporting different results were discussed and discounted. (In at least one case, it was one of the longer-term studies that was looking specifically for adverse effects.)

The authors conclude that Under most circumstances, sitagliptin is safe and effective compared to other oral antidiabetic medications.

Reliability: The research was published in a peer-reviewed journal. One of the authors is a medical doctor.

All of the authors work for Merck, or worked for Merck during the period the research was being done. Merck manufactures Januvia, so the authors have a bias towards proving this medication safe and effective.

While a large number of patient experiences were collated into this analysis, most of the component studies were very small in scale.

Since most of the studies aggregated in this analysis only went on for four to six months, it is easy to misinterpret the data as indicating the drug is as safe over two years as it is over four months. People taking drugs to manage Type 2 diabetes are likely to stay on the same drug for much longer than the two-year longest studies examined -- so there is a possibility that there will be side effects from long-term use that have not yet shown up in laboratory and clinical studies.


Practical Applications:
Based on the authors' analysis, Januvia -- for the short-term and intermediate term -- is as safe as other drugs used to manage Type 2 diabetes.

However, because the severe reactions and deaths that have been tied to other new drugs* didn't start showing up in the media until the drugs were out in the marketplace for more than five years, and being taken by tens of thousands of patients, it is probably premature to say that Januvia is safe to be taken by the everyone covered by the prescribing instructions for the entire length of time one might expect it to be used. As with any medication, discuss the pros and cons with your doctor, as well as any additional concerns and risk factors you might have. Untreated Type 2 diabetes can cause serious complications up to and including death.

*Avandia (rosiglitazone), made by Glaxo Smith Kline, is the most recent drug with this sort of safety issue.

For further reading:
Januvia prescription information for doctors: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf
Januvia site for consumers: http://www.januvia.com/sitagliptin/januvia/consumer/index.jsp
Merck website: http://www.merck.com/
Drugs.com consumer information for Januvia: http://www.drugs.com/cdi/januvia.html
Drugs.com professional information for Januvia: http://www.drugs.com/pro/januvia.html

This synopsis was based on the provisional (online preprint) 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.

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.