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.
    Advertisements




    Sugar-Sweetened Beverages, Diet Coke & Health. Part I.

    14 03 2010

    At Medical and Technology of Joseph Kim, the upcoming Grand Rounds host, I saw the blog post “Need your help on Facebook to get Diet Coke to Donate $50,000 to the Foundation for NIH”.

    National Heart Lung and Blood Institute has started a national campaign in the US, The Heart Truth®. They issued a challenge in support of heart health, raising awareness on the fact that  heart disease is the #1 killer of women, to identify risk factors and take action to lower them. Diet Coke is one of their corporate-partners, helping to spread the word through visibility on 6.7 billion packages of Diet Coke featuring The Heart Truth and Red Dress symbol. It has also started a Facebook cause: Diet Coke will donate $0.50 for every person that joins the cause and $1.00 for every person that donates $1, for a total donation of up to $50,000!

    O.k. Donation Fine, NIH fine, but Coca Cola as a main sponsor to raise awareness against heart disease?? Its almost feels like a tobacco company raising awareness against lung cancer. It is as odd as McDonalds, Lego & Mars preaching online advertising awareness to kids...

    You could object that any money to raise awareness is  a welcome bonus and that diet coke, unlike normal coke, doesn’t contain any calories. But then you could ask whether diet coke is really healthy… Plus Coca Cola does sell a lot of beverages with loads of sugar, with a possible adverse effect on health, including cardiovascular disease (see below). It looks a lot like hypocrisy to me, meant only to improve the BRAND.

    Well, I was to write about sweetened beverages anyway, since I came across several interesting news items the last weeks.

    Sugar-Sweetened Beverages Have Major Effects on Diabetes and Cardiovascular Health

    During the joint EPI/NPAM Conference (Cardiovascular Disease Epidemiology and Prevention &- Nutrition, Physical Activity and Metabolism), Mar 2-5, 2010 (link), Litsa Lambrakos presented a posterSugar-Sweetened Beverage Consumption and the Attributable Burden to Diabetes and Coronary Heart Disease” that was covered in a press release and in the media (Elsevier Global Medical News; All Headline News)

    Based on data from several large observational studies demonstrating a link between higher rates of sugar-sweetened beverages (SSB) consumption and subsequent risk of incident diabetes, Lambrakos and colleagues assumed that daily consumption of SSBs is associated with an increased risk of incident diabetes (RR 1.32 for those with daily consumption compared with adults consuming less than one sugar-sweetened beverage per month).  Next they estimated that the increased consumption of sugar-sweetened beverages (including sugar-sweetened soda, sport and fruit drinks) between 1990 and 2000 contributed to 130,000 new cases of diabetes, 14,000 new cases of coronary heart disease (CHD), and 50,000 additional life-years burdened by coronary heart disease over the past decade. They derived these data from the 1990-2000 National Health and Nutrition Examination Survey (NHANES) on consumption of sugar-sweetened beverages, combined  with the CHD Policy Model, a computer simulation of heart disease in U. S. adults aged 35-84 years.

    Through the model, the researchers also estimated that the additional disease caused by the drinks has increased coronary heart disease healthcare costs by 300-550 million U.S. dollars between 2000-2010. This is probably an underestimation, because it does not account for the increased costs associated with the treatment and care of patients with diabetes alone.

    How does this ($300.000.000-$550.000.000) compare to the $50,000 (max) that Coca Cola is willing to contribute to The Heart Truth?

    Admitted, the comparison is not entirely fair. There are far more soft drinks than the sodas from Coca Cola. More importantly, the reliability of the  figures is highly dependent on the accuracy of the assumptions. Furthermore it is hard to review a study that is not yet published.

    Other studies on possible harm of SSB consumption. 1. Effects on BMI, overweight & obesity.

    To get an idea about the evidence on the ‘harm’ of SSB I did a quick search in PubMed (see PubMed tips).

    First I searched for secondary (aggregated) sources.

    ((Dietary Sucrose AND beverages) OR soft drink* OR sugar-sweetened beverag* OR soda*[tiab]) AND “systematic”[Filter]

    This yielded 27 hits.

    Five Publications centered on the effect of beverages on weight, obesity or BMI.

    The effect on overweight seems the most obvious side-effect of SSB’s. First the increase in obesity over time has been paralleled by an increase in soft drink consumption. Second the daily sweetener consumption in the United States increased by 83 kcal per person, of which 54 kcal/d  from soda. If these calories are added to the normal diet without reducing intake from other sources, 1 soda/d could lead to a weight gain of 6.75 kg in 1 year. [refs in 2]

    Still the evidence is not that clear.

    Malik [2], and an almost overlapping systematic review [3] conclude that large cross-sectional studies, well-powered prospective cohort studies with long follow-up, and short-term experimental studies (including 2 RCT’s), show a positive association between greater intakes of SSBs and weight gain and obesity in both children and adults and yield sufficient evidence for public health strategies to discourage consumption of sugary drinks as part of a healthy lifestyle.

    Two later reviews [4,5] point out that Malik et al. had erroneously concluded that the evidence was ‘strong’, because “several studies were reported as positive when only a selected sub-group had a positive result, or classified as ‘positive non-significant’ where coefficients are near zero and P values in excess of 0·2. Furthermore, the results of two studies were confounded by the inclusion of diet soft drinks.”[4]

    On the contrary, Forshee et al [4] conclude that the  association between SSB consumption and BMI was near zero. Interestingly, the funnel plot analysis was consistent with publication bias against studies that do not report statistically significant findings!

    Gibson [5] concludes that that the effect of SSB on body weight is small except in susceptible individuals or at high levels of intake. She also points out that the totality of evidence is dominated by American studies (including the positive NHANES study), “that may be less applicable to the European context where consumption is substantially lower and composition or formulation may differ (high-fructose corn syrup v. sucrose, proportion of diet v. non-diet, etc).”
    Indeed in a systematic review primarily including European studies [6], overweight was not associated with the intake of soft drinks, but with lower physical activity and more tv watching time.

    Thus the effect of SSB (alone) on BMI and overweight is inconclusive, based on the current body of evidence.

    It is not excluded though that high intake of SSB alone or regular consumption of SSB in combination with other unhealthy lifestyle factors (unsaturated fat, lower physical activity) do contribute to obesity.

    Since lack of sleep is also unhealthy (and possibly obesogen), I will leave it here.

    Next time I will discuss any cardiovascular or other harmful effects of sugar sweetened beverages ànd diet sodas.

    Meanwhile enjoy the sugar and coca cola video below.

    Whatever the evidence, daily consumption of SSB, with many calories and no nutritional value, doesn’t seem overtly healthy to me. I won’t allow my kids to drink soda as a habit.

    ResearchBlogging.org

    References

    1. Litsa K Lambrakos, Pamela Coxson, Lee Goldman, Kirsten Bibbins-Domingo (2010). Sugar-Sweetened Beverage Consumption and the Attributable Burden to Diabetes and Coronary Heart Disease, poster  365, Joint Cardiovascular Disease Epidemiology and Prevention &- Nutrition, Physical Activity and Metabolism – Conference Mar 2-5, 2010.
    2. Malik VS, Schulze MB, & Hu FB (2006). Intake of sugar-sweetened beverages and weight gain: a systematic review. The American journal of clinical nutrition, 84 (2), 274-88 PMID: 16895873
    3. Wolff E, & Dansinger ML (2008). Soft drinks and weight gain: how strong is the link? Medscape journal of medicine, 10 (8) PMID: 18924641
    4. Forshee RA, Anderson PA, & Storey ML (2008). Sugar-sweetened beverages and body mass index in children and adolescents: a meta-analysis. The American journal of clinical nutrition, 87 (6), 1662-71 PMID: 18541554
    5. Gibson S (2008). Sugar-sweetened soft drinks and obesity: a systematic review of the evidence from observational studies and interventions. Nutrition research reviews, 21 (2), 134-47 PMID: 19087367
    6. Janssen I, Katzmarzyk PT, Boyce WF, Vereecken C, Mulvihill C, Roberts C, Currie C, Pickett W, & Health Behaviour in School-Aged Children Obesity Working Group (2005). Comparison of overweight and obesity prevalence in school-aged youth from 34 countries and their relationships with physical activity and dietary patterns. Obesity reviews : an official journal of the International Association for the Study of Obesity, 6 (2), 123-32 PMID: 15836463

    Photo Credits

    1. Diet Coke: http://en.wikipedia.org/wiki/File:Diet_Coke_can_US_1982.jpg
    2. Sugar in Coca Cola: http://www.sugarstacks.com/
    They used data from the 1990-2000 National Health and Nutrition Examination Survey (NHANES) on consumption of sugar-sweetened beverages. She combined that with the Coronary Heart Disease Policy Model, a computer simulation of heart disease in U. S. adults aged 35-84 years.




    Does the insulin Lantus (glargine) cause cancer?

    7 07 2009

    Last week my eyes were caught by a post of Kevin MD at his blog entitled

    Does insulin cause cancer, and should you stop taking Lantus?”.

    Kevin linked to the blog of Dr. Mintz, a board-certified internist, who had a strong opinion on this. Dr. Mintz  posted 3 blog articles on the matter, entitled: A new problem with insulin: cancer (June 29), Lantus causes cancer! Why doesn’t anyone seem to care? (July 1) and Lantus and cancer – A closer look is not reassuring (July 2). Dr. Mintz’s conclusion was based on 4 recent publications in diabetologica (1-4)6-7-2009 10-14-07 dr Mintz + foto

    Alarming. Especially since Dr. Mintz is an expert, often prescribing insulins. Also, I’m suspicious  about any substance with an IGF (insulin growh factor)-like action, because I know from previous work in the lab that some tumor cells (i.e. prostate and breast cancer) thrive on IGF. On the other hand there have been several examples in the past, where retrospective studies initially “showed” drugs to cause cancer, which have later been invalidated by more thorough studies (i.e. statins).

    “Lantus causing cancer” is a serious allegation, that might cause panic in those many diabetic patients using Lantus. Are fears justified and should Lantus be “banned”?

    After reading the publications (1-5), news articles and some blogposts (i.e. a balanced blogpost at Diabetesmine, a blog of a patient) and a very thorough blogpost in Dutch), I rather conclude that the recent publications in Diabetologica, dr Mintz* refers to, do not support a causal role for Lantus in cancer. However, they still give reason for some serious concern in a subset of patients (explained below).

    Now what is Lantus and what have preclinical and clinical trials revealed?

    Insulin glargine (Lantus) is the first of the long-acting insulin analogues, introduced in 2001. This analogue is a so called designer molecule made by the recombinant DNA technique. It has three amino-acid substitutions, that cause a lower solubility of the insulin molecule  at the injection site, forming a depot from which insulin is slowly released (9, 10).  The advantage is that stable 24hr blood glucose concentrations are reached by a once daily subcutaneous injection without a blood glucose peak upon injection as seen with the short acting insulins. However, insulin replacement remains far from ‘natural’, “the insulin is injected in the wrong site (subcutaneously instead of intraportally), in shots (instead of a continuous low secretion associated with a prompt release in response to a meal, with a total lack of the physiological pulsatile secretion”).lantus pen + kineticsInsulins not only bind to the insulin receptor, leading to the intended glucose lowering, but also to the insulin growth factor receptor (IGF-R), which mainly induces cell proliferation. Importantly, glargine has a much higher affinity for both receptors than insulin. This can lead to a sustained activation of the IGF-receptor, resulting in enhanced cell growth.

    Indeed, Preclinical Research has shown that only glargine showed a significantly higher proliferative effect on breast cancer cells compared to regular insulin among a panel of short- or long-acting insulin analogues (6) . Futhermore,  insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells (thus they stimulate cell division and prevent programmed cell death of cancer cells (8).

    Experimental animal studies haven’t shown a tumorigenic or teratogenic potential of glargine, except for histiocytomas in male rat (Product information Lantus). Such studies don not examine tumor promoting properties (see below)

    Clinical Studies (published in Diabetologica 2009)

    Based on the insulin analogue characteristics and the in vitro results there was already concern about possible increased cancer risk of glargine. But the concern was boosted by a prominent diabetes researcher forecasting an “earthquake” event compromising the safety profile of Lantus,  and the subsequent publication of five studies in  the European journal Diabetologia, the Journal of the EASD (European Association for the of Study of Diabetes).

    Except for one small study, which was a post-hoc analysis of a randomized study by Sanofi-Aventis itself [5], all other studies were retrospective. The Sanofi study didn’t find an increase in cancer, but given its small size (1000 patients), it is not  convincing enough to exclude a higher risk of cancer.

    The first, German, study [1] was submitted a year ago, but because of the uncertainties and the expected high impact, researchers from other European countries were asked to replicate the findings before announcing them formally. Studies were carried out using databases from Sweden, Scotland, and the UK.

    The German study (n= 127,031 patients, exclusively on human insulin or on one type of insulin analogues (lispro, aspart or glargine; glargine: n=23,855 ; mean follow-up time 1.63 years) found an overall increase in cancers, independent of the insulin used. After statistical modeling, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p<0.0001): with an adjusted HR of 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU, meaning that out of every 100 people who used Lantus insulin one additional person was diagnosed with cancer over the study period. The baseline characteristics were different between the groups. It was not possible to break the analysis down to type of cancer.

    The Swedish and Scottish studies [2-3], both based on matching of national databases for cancer and diabetes, showed no overall increase in cancer, but an increased incidence rate of breast cancer in women using insulin glargine monotherapy (no other types of insulin or combination) as compared with women using types of insulin other than insulin glargine. Although this can be caused by chance, it is striking that both studies had a similar outcome. The enhanced risk was abolished in patients using glargine together with other insulins. These were mostly younger patients with diabetes type 1.

    The fourth smaller study [4] found that patients on insulin were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. No harmful effect on cancer development, including breast cancer were observed: there was only a higher risk versus metformin, which has known anti-cancer properties.

    In Conclusion:

    • Diabetes patients using insulin should never stop using insulin, as this is very dangerous.
    • Long term studies have shown ‘natural’ insulins to be effective and safe.
    • The reported studies do NOT show that Lantus can CAUSE cancer. Moreover, the time span (less than two years) is too short for any drug to cause cancer.
    • The enhanced risk was only observed for breast cancer (2-3) and/or if Lantus was used on its own, thus not with other insulins (1-3) or metformin (4). The association was clearest in type 2 diabetes patients. It is not clear whether the association reflects the effects of Lantus or the inherent differences between for instance diabetes I/younger  and diabetes II/older patients (also because the latter often use Lantus alone ). In addition, it should be noticed that diabetes patients already have a higher cancer risk (possibly related to overweight, often seen in type 2 diabetes)
    • At the most Lantus might promote existing cancer to grow and divide. Lantus might for instance provide a survival advantage of percancerous or cancerous cells. This would be consistent with its in vitro mitogenic effect on breast cancer cells.
    • On the basis of the current evidence there is no need to switch to other treatments when a long acting insulin is necessary to keep blood glucose under control. However, Lantus treatment could be reconsidered in diabetes II patients, with good control of blood glucose, for whom a clear benefit of Lantus has not been shown or  in patients with a higher cancer risk.
    • Levamir is considered as a good alternative by some, because this long acting insulin analogue lacks the greater affinity for IGF-R. However, absence of proof is no proof of absence: Levamir has only recently been introduced, it has not been included in these studies and clinical experience is limited.
    • More conclusive evidence is to be expected from analysis of the large combined analysis of the databases available worldwide, by EASD and sanofi-aventis. Results are expected within a few months.

    Video-editorials featuring Prof. Ulf Smith, Director EASD, and Prof Edwin Gale, editor-in-chief Diabetologica (part 1 and 2)

    *dr Mintz reformulated this in his last post, where he stated that “it is unlikely that Lantus actually causes cancer alone, because it takes years to develop most cancers. However, it is more likely that Lantus causes existing cells to grow and divide more rapidly.

    Journal ArticlesResearchBlogging.org

    1. Hemkens, L., Grouven, U., Bender, R., Günster, C., Gutschmidt, S., Selke, G., & Sawicki, P. (2009). Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study Diabetologia DOI: 10.1007/s00125-009-1418-4 (Free full text)
    2. Jonasson, J.M., Ljung, R, Talbäck, M, Haglund, B, Gudbjörnsdòttir, S, & Steineck, G (2009). Insulin glargine use and short-term incidence of malignancies—a population-based follow-up study in Sweden Diabetologia (Free full text)
    3. SDRN Epidemiology Group (2009). Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group Diabetologia (Free full text)
    4. Currie, C., Poole, C., & Gale, E. (2009). The influence of glucose-lowering therapies on cancer risk in type 2 diabetes Diabetologia DOI: 10.1007/s00125-009-1440-6 (Free full text)
    5. Smith, U., & Gale, E. A. M. (2009). Does diabetes therapy influence the risk of cancer? Diabetologia (Free full text)
    6. Mayer D, Shukla A, Enzmann H (2008) Proliferative effects of insulin analogues on mammary epithelial cells. Arch Physiol Biochem 114: 38-44
    7. Arch Physion Biochem (2008), vol 1141 (1) is entirely dedicated to “Insulin and Cancer”, i.e. see editorial of P. Lefèbvre: Insulin and cancer: Should one worry?” p. 1-2
    8. Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H (2009) Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 25: 41-49 (PubMed record)

    Information about Lantus

    9.  http://content.nejm.org/cgi/content/extract/352/2/174

    10. http://products.sanofi-aventis.us/lantus/lantus.html

    11. http://www.informapharmascience.com/doi/abs/10.1517/14656566.2.11.1891?journalCode=eop





    Grand Rounds 5.35 at Healthcare Technology News

    19 05 2009

    healthcare technology News GRAND ROUND may 19Grand Rounds is up at Healthcare Technology News. This edition of Grand Rounds, the Best of the Medical Blogosphere, focuses on Health Care Reform.

    The Grand Round begins with a stunning quote of type 1 diabetic blogger Kerri Sparling that really hits the mark with her post at Six Until Me:

    “Why, Insurance Company, are you so against proactive care? Why do I need to pay more for a brace or a shot or an extra visit when you’re more content paying for a several thousand dollar surgery instead? Not enough bang for your buck? Why do you fight me tooth and nail against coverage for a continuous glucose monitoring device?* Is my life not worth the investment to keep my legs on instead of paying 100% to amputate them in a few decades? I know I’m expensive as a chronic disease patient, but I’m healthier than 85% of the people I know. I eat well, I exercise regularly, and I am on top of my disease. Yet you deny me life insurance, you won’t let me purchase a private health insurance policy, and you would rather see me on an operating table than taking up a doctor’s time in an office visit. (And it’s not like I’m taking up more than 5 – 7 minutes of a doctor’s time, because that’s about all we get, on average. Pathetic.)”

    After a few more examples of the Patient and Consumer Perspective on why we do need reform, this edition continues with:

    • Providers, Prevention and Self-Management
    • Meaningful Use and Enabling Technology
    • Dollars and Sense
    • What’s Working Elsewhere?

    Please read the whole edition here

    Next Grand Round will be hosted by See First, Insights into the uncertain world of Healthcare.

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    * I saw the same problem mentioned on a Dutch Blog “Diabetesblog“, where the story was told of a patient who has hypo-unawareness: she can’t feel when her blood glucose is low. Therefore she suffers many complications of diabetes, i.e she has poor sight and has recently fainted in front of the children. The only thing which she feels would work is the (FDA approved) continuous glucose monitoring device (CGMS). The problem is that the her insurer won’t cover CGMS, as it’s efficacy has yet to be proved.

    Coincidentally I’m gathering the evidence on “the effectiveness of the CGMS in the management of type I diabetes” for a Cochrane Protocol (not approved yet). However, it will take some time for the authors to finish the review after the protocol has been approved.

    See the full Story on Diabetesblog (in Dutch) here

    Some excerpts:

    Sinds een jaar of vijf draagt ze daarom een insulinepomp die continue een klein beetje insuline afgeeft. ‘Maar dat zegt natuurlijk niks over mijn bloedsuikergehalte op dat moment’, zegt Judith. Meer baat zou de Losserse volgens haar internist hebben bij een continue glucosemeter met implanteerbare sensor, een apparaat dat is overgewaaid uit de Verenigde Staten. De sensor meet 24 uur per dag de bloedsuikerspiegel en geeft een waarschuwingssignaal als de waarde te laag dreigt te worden.

    Het probleem is echter dat de zorgverzekeraar van Judith, Menzis, het apparaat – kosten: 40 à 50 euro per stuk; één exemplaar gaat maximaal drie dagen mee – niet wil vergoeden, ook niet nadat de internist van Judith daarop heeft aangedrongen. Te duur, oordeelt Menzis. En bovendien, zo motiveert een woordvoerder het standpunt van de zorgverzekeraar, ‘heeft het College voor zorgverzekeringen (CVZ) onlangs besloten de sensor niet te vergoeden’.

    Ook een tweede verzoek dat de arts onlangs indiende heeft niets opgeleverd. Volgens de woordvoerder van Menzis is de zorgverzekeraar zelfs strafbaar als het apparaatje vergoed zou worden, omdat het onvoldoende getest zou zijn. Onzin, zegt Getkate. ‘Niet voor niets heeft de Diabetesvereniging Nederland een positief advies gegeven. Er zijn bovendien andere zorgverzekeraars die het al wèl vergoeden.’

    En dus ligt de Losserse in de clinch met haar zorgverzekeraar. Wat haar nog het meeste steekt is ‘dat Menzis eigenlijk op de stoel van de arts gaat zitten’…..