Kaleidoscope #3: 2011 Wk 12

23 03 2011

It has been long since I have posted a Kaleidoscope post with a “kaleidoscope” of facts, findings, views and news gathered over the last 1-2 weeks. There have been only 2 editions: Kaleidoscope 1 (2009 wk 47) and 2 (2010 wk 31).

Here is some recommended reading from the previous two weeks. Benlysta (belimumab) approved by FDA for treatment of lupus.

Belimumab is the first new lupus drug approved in 56 years! Thus, potentially good news for patients suffering from the serious auto-immunity disease SLE (systemic lupus erythematosus).  Belimumab needs to be administered once monthly via the intravenous route. It is a fully human monoclonal antibody specifically designed to inhibit B-lymphocyte stimulator (BLyS™), thereby reducing the number of circulating B cells, and the produced ds-DNA antibodies (which are characteristic for lupus).
Two clinical trials showed that more patients experienced less disease activity when treated with belimumab compared to placebo. Data suggested that some patients had less severe flares, and some reduced their steroid doses (not an impressive difference using “eyeballing”). Patients were selected with signs of B-cell hyperactivity and with fairly stable, but active disease. Belimumab was ineffective in Blacks, which are hit hardest by the disease. The most serious side effect were infections: 3 deaths in the belimumab groups were due to infections.
Thus, overall the efficacy seems limited. Belimumab only benefits 35% of the patients with not the worst form of the disease. But for these patients it is a step forward.

  1. Press Announcement (fda.gov).
  2. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK,Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Feb 26;377(9767):721-31. Epub 2011 Feb 4. PubMed PMID: 21296403.
  3. Belimumab: Anti-BLyS Monoclonal Antibody; Benlysta(TM); BmAb; LymphoStat-B. Drugs in R & D (Open Access): 28 May 2010 – Volume 10 – Issue 1 – pp 55-65 doi: 10.2165/11538300-000000000-00000 Adis R&D Profiles (adisonline.com)

Sleep-deprived subjects make risky gambling decisions.

Recent research has shown, that a single night of sleep deprivation alters decision making independent from a shift in attention: most volunteers moved from seeking to minimize the effect of the worst loss to seeking increased reward. This change towards risky decision making was correlated with an increased brain activity in brain regions that assess positive outcomes (ventromedial prefrontal activation) and a simultaneous decreased activation in the brain areas that process negative outcomes (anterior insula). This was assessed by functional MRI.

One co-author (Chee) noted that “casinos often take steps to encourage risk-seeking behavior — providing free alcohol, flashy lights and sounds, and converting money into abstractions like chips or electronic credits”

Interestingly, Chee also linked their findings to empirical evidence that long work hours for medical residents increased the number of accidents. Is a similar mechanism involved?

  1. Venkatraman V, Huettel SA, Chuah LY, Payne JW, Chee MW. Sleep deprivation biases the neural mechanisms underlying economic preferences.  J Neurosci. 2011 Mar 9;31(10):3712-8 (free full text)
  2. Sleep deprived people make risky decisions based on too much optimism (Duke Healthpress release)

Grand Rounds

Grand Rounds is up at Better Health. Volume 7, Number 26 is an “Emotional Edition” where posts are organized into emotion categories. My post about the hysteria and misinformation surrounding the recent Japanese earthquake is placed under Outrage.

There are many terrific posts included. A few posts I want to mention shortly.

First a post by a woman who diagnosed hers and her sons’ disease after numerous tests. Her sons’ pediatrician only tried to reassure, so it seems. (“don’t worry…”).

I was also moved by the South African surgeon, Bongi, who tells the tragic story of a missed diagnosis that still haunts him. “For every surgeon has a graveyard hidden away somewhere in the dark recesses of his mind…”

Bongi’s blog Other Things Amanzi is one of my favorites. Another blog that has become one of my favs is 33 Charts by Dr. Bryan Vartabedian. Included in this Grand Round is “And a child will lead them“. It is a beautiful post about the loss of a young patient:

….”And facing Cooper’s parents for the first time after his passing was strangely difficult for me.  When he was alive I always had a plan.  Every sign, symptom, and problem had a systematic approach.  But when faced with the most inconceivable process, I found myself awkwardly at odds with how to handle the dialog”….

Other Medical Blogs

Another of my recent fav blogs is the blog of cardiologist, dr. Wes. Two recent posts I would especially like to recommend.

The first asks a seemingly simple question: “So which set of guidelines should doctors use?” The answer, however,  may surprise you.

In another post dr Wes describes the retraction of an online-before-print case report entitled “Spontaneous explosion of implantable cardioverter-defibrillator” with dramatic pictures of an “exploded ICD” .(here is the PDF of the cache). This retraction took place after dr. Wes reported the case at his blog. Strange enough the article was republished this February, with another title, “Case report of out-of-hospital heat dissipation of an implantable cardioverter-defibrillator.” (no explosion anymore) and no shocking photos. Food for thought….  The main conclusion of dr Wes? Independent scientific peer-reviewed journals might not be so independent after all. Library matter

Sorry, but I had to laugh about David Rothman’s Common Sense Librarianship: An Ordered List Manifesto. As put it so well by Kathryn Greenhill at her blog Librarians Matter: “It is a hot knife of reason through the butterpat of weighty bullshit that often presses down as soon as we open our mouths to talk about our profession.”

Oh, and a big congrats to Aaron Tay for his  Library Journal moversShakers award. Please read why he deserves this award. What impresses me the most is the way he involves users and converts unhappy users “into strong supporters of the library”. I would recommend all librarians to follow him on Twitter (@aarontay) and to regularly read his blog Musings about Librarianship. Web 2.0

The iPad 2 is here. A very positive review can be found at Techcrunch. The iPad 2 has a camera, is thinner, lighter, and has a much more powerful dual-core chip. Still many people on Twitter complain about the reflective screen. Furthermore the cover is stylish but  not very protective as this blogger noticed 2 days after purchase.
Want to read further: You might like “iPad 2: Thoughts from a first time tablet use” (via @drVes)

It has been five years since Twitter was launched when one of its founders, Jack Dorsey, tweeted “just setting up my twttr’. Now Twitter nearly has 200 million users who now post more than a billion tweets every week. (see Twitter Blog)

Just the other week  Twitter has told developers to stop building apps. It is not exactly clear what this will mean. According to The Next Web it is to prevent confusion of consumers third-party Twitter clients and because of privacy issues. According to i-programmer the decision is mainly driven by the desire of Twitter to be in control of its API and the data that its users create (as to maximize its -future- revenue). I hope it won’t affect Twitter-clients like Tweetdeck and Seesmic, which perform much better (in my view) than Twitter.com.

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What One Short Night’s Sleep does to your Glucose Metabolism

11 05 2010

ResearchBlogging.orgAs a blogger I regularly sleep 3-5 hours just to finish a post. I know that this has its effects on how I feel the next day. I also know short nights don’t promote my clear-headedness and I also recognize short-term effects on  memory, cognitive functions, reaction time and mood (irritability), as depicted in the picture below. But I had no idea of any effect on heart disease, obesity and risk of diabetes type 2.

Indeed, short sleep duration is consistently associated with the development of obesity and diabetes in observational studies (see several recent systematic reviews, 3-5). However, as explained before, an observational design cannot establish causality. For instance, diabetes type 2 may be the consequence of other lifestyle aspects of people who spend little time sleeping, or sleep problems might be a consequence rather than a cause of diabetogenic changes.

Diabetes is basically a condition characterized by difficulties processing carbohydrates (sugars, glucose). Type 2 diabetes has a slow onset. First there is a gradual defect in the body’s ability to use insulin. This is called insulin resistance. Insulin is a pancreatic hormone that increases glucose utilization in skeletal muscle and fat tissue and suppresses glucose production by the liver, thereby lowering blood glucose levels.  Over time, damage may occur to the insulin-producing cells in the pancreas (type 2 diabetes),  which may ultimately progress to the point where the pancreas doesn’t make enough insulin and injections are needed. (source: about.com).

Since it is such a slow process one would not expect insulin resistance to change overnight. And certainly not by just partial sleep deprivation of 4-5 hrs of sleep.

Still, this is the outcome of a study, performed by the PhD student Esther Donga. Esther belongs to the study group of Romijn who also studied the previously summarized effects of previous cortisol excess on cognitive functions in Cushing’s disease .

Donga et al. have studied the effects of one night of sleep restriction on insulin sensitivity in 9 healthy lean individuals [1] and in 7 patients with type 1 diabetes [2]. The outcomes were practically the same, but since the results in healthy individuals (having no problems with glucose metabolism, weight or sleep) are most remarkable, I will confine myself to the study in healthy people.

The study design is relatively simple. Five men and four healthy women (mean age 45 years) with a lean body weight and normal  sleep pattern participated in the study. They were not using medication affecting sleep or glucose metabolism and were asked to adhere to their normal lifestyle pattern during the study.

There were 3 study days, separated by intervals of at least 3 weeks. The volunteers were admitted to the clinical research center the night before each study day to become accustomed to sleeping there. They fasted throughout these nights and spent 8.5 h in bed.  The subjects were randomly assigned to sleep deprivation on either the second or third occasion. Then they were only allowed to sleep from 1 am to 4 am to secure equal compression of both non-REM and REM sleep stages.

(skip blue paragraphs if you are not interested in the details)

Effects on insulin sensitivity were determined on the day after the second and third night (one normal and one short night sleep) by the gold standard for quantifying insulin resistance: the hyperinsulinemic euglycemic clamp method. This method uses catheters to infuse insulin and glucose into the bloodstream. Insulin is infused to get a steady state of insulin in the blood and the insulin sensitivity is determined by measuring the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia (low blood sugar). (see Figure below, and a more elaborate description at Diabetesmanager (pbworks).

Prior to beginning the hyperinsulinemic period, basal blood samples were taken and labeled [6,6-2H2]glucose was infused  for assessment of glucose kinetics in the basal state. At different time-points concentrations of glucose, insulin, and plasma nonesterified fatty acids (NEFA) were measured.

The sleep stages were differently affected  by the curtailed sleep duration: the proportion of the stage III and stage II sleep were greater (P < 0.007), respectively smaller (P < 0.006) in the sleep deprived night.

Partial sleep deprivation did not alter basal levels of glucose, nonesterified fatty acids (NEFA), insulin, glucagon, or cortisol measured the following morning, nor did it affect basal endogenous glucose production.

However, during the CLAMP-procedure there were significant alterations on the following parameters:

  • Endogenous glucose production – increase of approximately 22% (p< 0.017), indicating hepatic insulin resistance.
  • Rate of Glucose Disposal – decrease by approximately 20% (p< 0.009), indicating decreased peripheral insulin sensitivity.
  • Glucose infusion rate – approximately 25% lower after the night of reduced sleep duration (p< 0.001). This is in agreement with the above findings: less extra glucose needed to maintain plasma glucose levels.
  • NEFA – increased by 19% (p< 0.005), indicating decreased insulin sensitivity of lipolysis (breakdown of triglyceride lipids– into free fatty acids).

The main novelty of the present study is the finding that one single night of shortened sleep is sufficient to reduce insulin sensitivity (of different metabolic pathways) in healthy men and women.

This is in agreement with the evidence of observational studies showing an association between sleep deprivation and obesity/insulin resistance/diabetes (3-5). It also extends results from previous experimental studies (summarized in the paper), that document the effects on glucose-resistance after multiple nights of sleep reduction (of 4h) or total sleep deprivation.

The authors speculate that the negative effects of multiple nights of partial sleep restriction on glucose tolerance can be reproduced, at least in part, by only a single night of sleep deprivation.

And the media conclude:

  • just one night of short sleep duration can induce insulin resistance, a component of type 2 diabetes (Science Daily)
  • healthy people who had just one night of short sleep can show signs of insulin resistance, a condition that often precedes Type 2 diabetes. (Medical News Today)
  • even a single of night of sleep deprivation can cause the body to show signs of insulin resistance, a warning sign of diabetes (CBS-news)
  • And this was of course the message that catched my eye in the first place: “Gee, one night of bad sleep, can already disturb your glucose metabolism in such a way that you arrive at the first stage of diabetes: insulin resistance!…Help!”

    First “insulin resistance” calls up another association than “partial insulin resistance” or a “somewhat lower insulin sensitivity” (as demonstrated in this study).  We interpret insulin resistance as a disorder that will eventually lead to diabetes, but perhaps adaptations in insulin sensitivity are just a normal phenomenon, a way to cope with normal fluctuations in exercise, diet and sleep. Or a consequence of other adaptive processes, like changes  in the activity of the autonomous nervous system in response to a short sleep duration.

    Just as blood lipids will be high after a lavish dinner, or even after a piece of chocolate. And just as blood-cortisol will raise in case of exercise, inflammation or stress. That is normal homeostasis. In this way the body adapts to changing conditions.

    Similarly -and it is a mere coincidence that I saw the post of Neuroskeptic about this study today- an increase of blood cortisol levels in children when ‘dropped’ at daycare, doesn’t mean that this small increase in cortisol is bad for them. And it certainly doesn’t mean that you should avoid putting toddlers in daycare as Oliver James concludes, because “high cortisol has been shown many times to be a correlate of all manner of problems”. As neuroskeptic explains:

    Our bodies release cortisol to mobilize us for pretty much any kind of action. Physical exercise, which of course is good for you in pretty much every possible way, cause cortisol release. This is why cortisol spikes every day when you wake up: it helps give you the energy to get out of bed and brush your teeth. Maybe the kids in daycare were just more likely to be doing stuff than before they enrolled.

    Extremely high levels of cortisol over a long period certainly do cause plenty of symptoms including memory and mood problems, probably linked to changes in the hippocampus. And moderately elevated levels are correlated with depression etc, although it’s not clear that they cause it. But a rise from 0.3 to 0.4 is much lower than the kind of values we’re talking about there.

    So the same may be true for a small temporary decrease in glucose sensitivity. Of course insulin resistance can be a bad thing, if blood sugars stay elevated. And it is conceivable that bad sleep habits contribute to this (certainly when combined with the use of much alcohol and eating junk food).

    What is remarkable (and not discussed by the authors) is that the changes in sensitivity were only “obvious” (by eyeballing) in 3-4 volunteers in all 4 tests. Was the insulin resistance unaffected in the same persons in all 4 tests or was the variation just randomly distributed? This could mean that not all persons are equally sensitive.

    It should be noted that the authors themselves remain rather reserved about the consequences of their findings for normal individuals. They conclude “This physiological observation may be of relevance for variations in glucoregulation in patients with type 1 and type 2 diabetes” and suggest that  “interventions aimed at optimization of sleep duration may be beneficial in stabilizing glucose levels in patients with diabetes.”
    Of course, their second article in diabetic persons[2], rather warrants this conclusion. Their specific advise is not directly relevant to healthy individuals.

    Credits

    References

    1. Donga E, van Dijk M, van Dijk JG, Biermasz NR, Lammers GJ, van Kralingen KW, Corssmit EP, & Romijn JA (2010). A Single Night of Partial Sleep Deprivation Induces Insulin Resistance in Multiple Metabolic Pathways in Healthy Subjects. The Journal of clinical endocrinology and metabolism PMID: 20371664
    2. Donga E, van Dijk M, van Dijk JG, Biermasz NR, Lammers GJ, van Kralingen K, Hoogma RP, Corssmit EP, & Romijn JA (2010). Partial sleep restriction decreases insulin sensitivity in type 1 diabetes. Diabetes care PMID: 2035738
    3. Nielsen LS, Danielsen KV, & Sørensen TI (2010). Short sleep duration as a possible cause of obesity: critical analysis of the epidemiological evidence. Obesity reviews : an official journal of the International Association for the Study of Obesity PMID: 20345429
    4. Monasta L, Batty GD, Cattaneo A, Lutje V, Ronfani L, van Lenthe FJ, & Brug J (2010). Early-life determinants of overweight and obesity: a review of systematic reviews. Obesity reviews : an official journal of the International Association for the Study of Obesity PMID: 20331509
    5. Cappuccio FP, D’Elia L, Strazzullo P, & Miller MA (2010). Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes care, 33 (2), 414-20 PMID: 19910503
    The subjects were studied on 3 d, separated by intervals of at
    least 3 wk. Subjects kept a detailed diary of their diet and physical
    activity for 3 d before each study day and were asked to maintain
    a standardized schedule of bedtimes and mealtimes in accordance
    with their usual habits. They were admitted to our clinical
    research center the night before each study day, and spent 8.5 h
    in bed from 2300 to 0730 h on all three occasions. Subjects fasted
    throughout these nights from 2200 h. The first study day was
    included to let the subjects become accustomed to sleeping in our
    clinical research center. Subjects were randomly assigned to sleep
    deprivation on either the second (n4) or third (n5) occasion.
    During the night of sleep restriction, subjects spent 8.5 h in
    bed but were only allowed to sleep from 0100 to 0500 h. They
    were allowed to read or watch movies in an upward position
    during the awake hours, and their wakefulness was monitored
    and assured if necessary.
    The rationale for essentially broken sleep deprivation from
    2300 to 0100 h and from 0500 to 0730 h, as opposed to sleep
    deprivation from 2300 to 0300 h or from 0300 to 0730 h, was
    that in both conditions, the time in bed was centered at the same
    time, i.e. approximately 0300 h. Slow-wave sleep (i.e. stage III of
    non-REM sleep) is thought to play the most important role in
    metabolic, hormonal, and neurophysiological changes during
    sleep. Slow-wave sleep mainly occurs during the first part of the
    night, whereas REM sleep predominantly occurs during the latter
    part of the night (12). We used broken sleep deprivation to
    achieve a more equal compression of both non-REM and REM
    sleep stages. Moreover, we used the same experimental conditions
    for partial sleep deprivation as previously used in other
    studies (7, 13) to enable comparison of the results.