Diabetes Type 2 (T2D), Metformin and The Microbiome

Microbiome analysis is coming soon to a doctor near you. Microgenomics is going to be part of nearly everyone’s future. This week Nature magazine published an article which indicates that at least part of the action of the anti-diabetic medication Metformin may be occurring via the microbiome. At the leastMicrobiome Metformin there is a dramatic difference between the gut microbiota between those with type 2 diabetes (T2D) treated with Metformin (T2D-Metformin+)and those not treated  (T2D-Metformin-).

The article has an excellent discussion both of the direct effects of Metformin and the indirect effects and potential interactions of various gut bacteria

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Reference:

Forslund, K., et al. (2015). “Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.” Nature advance online publication. Accessed Dec. 2, 2015

Dementia and Alzheimer’s Disease: Exercise is Good – Studies, Not Always

There is significant evidence that exercise is helpful in lowering one’s risk of dementia by regular moderate to vigorous exercise. And every month a plethora of articles appears reporting on positive impact or no impact at all on a variety of factors from diet and supplements to exercise.

A number of studies have indicated that starting and maintaining an exercise program has been helpful. But, we also need to define what may not be helpful. Exercise below a certain aerobic level, may just not count as preventative exercise for dementia and cognitive decline.

And I realize my bias in favor of exercise, so I must admit that some reviews have found the evidence is weak that exercise is helpful in avoiding cognitive decline.

Reported studies need to be subject to evaluation. One can not blindly accept the authors’ interpretation of the results. The results and protocol need to be rationally evaluated in an absence of hype.

I’m not sure that a recent study by Sink et. al. which did not find a positive correlation between activity and cognition was scrutinized thoroughly in the media. Looking closely at this study we find that they used a good number of patients and controls. But we see that the inclusion criteria of being able to cover 400 meters in 15 minutes is not what many would consider to be an aerobic exercise activity. The study was restricted to those over 70. And the data was not gathered using a Fitbit, Pedometer, GPS motion detector or observation. The data was self-reported.

So what do we know as a result of this study:

  • Being able to move at a speed of 1 mile/hour for 30 minutes  (400 meters in 15 minutes) several times a week is not enough exercise to measurably diminish cognitive decline (it may have other benefits though).
  • Data acquisition by self-reporting may not be optimal. An objective measurement should be used in conjunction with a device to do and record these measurements.
  • The life style changes here may have been too little and too late to have an impact.
  • Commencing exercise prior to age 70 may be better than beginning later. If beginning later, results may only be seen if the individual is capable of exercising a moderate level.
  • Media coverage is often limited in interpretation and assessment of the meaning  of a study’s results.

In a predefined subgroup of those aged 80 and over and with worse starting fitness they did find an improvement in “executive function”.

“Despite the lack of overall benefit, our prespecified subgroup analyses of participants aged 80 years or older and those with lower baseline physical performance demonstrated that the physical activity group had better performance on executive function tasks than those in the health education group at 24 months. This finding is important because executive function is the most sensitive cognitive domain to exercise interventions,40 and preserving it is required for independence in instrumental activities of daily living. Future physical activity interventions, particularly in vulnerable older adult groups (eg, ≥80 years of age and those with especially diminished physical functioning levels), may be warranted.”

The authors did consider as the first possible explanation that the exercise level was insufficient to produce changes in the cognitive measures, but this escaped the media blitz. In reading the article, conclusions and discussion, the study was well designed, properly randomized and controlled, used an adequate sample size. The possibilities leading to the observed results were thoroughly discussed. But again, the subtleties were not discussed in the media and the headlines you saw were that exercise was not useful in preventing cognitive decline. As with most studies the media would lead you to believe that the current study overturns all previous thinking and is the only thing to follow.

Bayesian reasoning allows for new information to be added into the mix of the prior thought and research on any topic. That should be done and the meaning of that should be clear to anyone writing about science literature. One study doesn’t usually replace all thinking, it is added to it in that successive approximation of the truth that we reach for through science.

So the same recommendation to exercise, in my mind, holds. It still has the most evidence pointing in its favor. And for those older individuals who are not able to exercise as vigorously, exercise is still likely to have positive impact on mood and other neurological and physical functions not measured in this study.And I’d suggest more education on EBM and study evaluation for those charged with distributing results of medical studies. And please read the study.

References:

Effect of a 24-Month Physical Activity Intervention vs Health Education on Cognitive Outcomes in Sedentary Older Adults Sink, KM et. al. JAMA. 2015;314(8):781-790. doi:10.1001/jama.2015.9617.

Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Intlekofer, K, Cotman, C.  NEUROBIOLOGY OF DISEASE · JUNE 2012

Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin Interv Aging. 2014 Apr 12;9:661-82. doi: 10.2147/CIA.S55520. eCollection 2014.  Carvalho ARea IMParimon TCusack BJ

Erickson, KI, Barr, LL, Weinstein, AM, Banducci, SE, Akl, SL, Santo, NM, Leckie, RL, Oakley, M, Saxton, J, Aizenstein, HJ, Becker, JT, Lopez, OL. (in press). Measuring physical activity with accelerometry in a community sample with dementia. Journal of the American Geriatic Society.

Weinstein, AM, Voss, MW, Prakash, RS, Chaddock L, Szabo, A, White, SM, Wojcicki, TR, Mailey, E, McAuley, E, Kramer, AF, Erickson, KI. (2012). The association between aerobic fitness and executive function is mediated by prefrontal cortex volume. Brain, Behavior, and Immunity, 26:811-9.

 

Erickson KI, Miller DL, Roecklein KA. (2012). The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist, 18: 82-97.

Okonkwo, O, Schultz,S et. al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology November 4, 2014 vol. 83 no. 19 1753-1760

 Brown, B, Bourgeat, P et. al. Influence of BDNF Val66Met on the relationship between physical activity and brain volumeNeurology. October 7, 2014 vol. 83 no. 15 1345-1352

Addendum:

Abstract of a British J of Sports Medicine editorial (Exercise is medicine, for the body and the brain, 2014):

“Cognitive decline is one of the most pressing healthcare issues of the 21st century. Worldwide, one new case of major cognitive decline (ie, dementia) is detected every 4 s. Given that no effective pharmacological treatment to alter the progress of cognitive decline exists, there is much interest in lifestyle approaches for preventing or treating dementia. Ideally, such strategies should be cost-efficient and widely accessible at a societal level to have the largest benefit for older adults with varying income and functional status levels.

One attractive solution that aligns with the above criteria is exercise. However, despite a large and consistent pool of evidence generated over the past five decades linking exercise to improved cognitive functions in older adults,2 there is a reluctance among academics, healthcare practitioners and the public alike to embrace exercise as a prevention and treatment strategy for cognitive decline. For example, the National Institutes of Health (NIH) consensus statement from 20103 concedes that there appears to be preliminary data to support the efficacy of exercise in improving cognitive function. However, they caution that there is currently no strong evidence to suggest that modifiable lifestyle factors can alter the trajectory of cognitive decline. Adding fuel to the fire are publications such as a 2013 systematic review of randomised controlled trials (RCTs) (prior to 31 October 2011) reporting ‘weak’ evidence for the effects of exercise on cognition.4 We must highlight that the search strategy used in that systematic review failed to capture many pertinent papers providing evidence from RCTs that exercise promotes cognitive and brain plasticity not only in healthy older adults but also in those with cognitive impairment. Furthermore, there are a number of animal studies that provide insight into the molecular and cellular mechanisms by which exercise promotes neuroplasticity.”

Let’s Get Physical – Olivia Newton John

Exercise is good for the mind and the soul

Another study has demonstrated that those who exercise regularly have a decreased incidence of depression.

The new study titled “Depressive Symptoms and Physical Activity During 3 Decades in Adult Life” appeared in JAMA Psychiatry in the issue published Oct 15, 2014.

At each age group, those who exercised had a lower incidence of depression than those who did not. Those who took up exercise were doing better 5 years later than those who continued to not exercise.

This is one more reason to exercise regularly. Exercise is good for ails you or for what might ail you in a few years!

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Moving is Exercise (Competing Tunes below)

Summer Running Tips

It’s that time again. Hot and sticky. Take a quick look at some summertime do’s and don’ts.

1. Wear socks made of synthetic fibers that wick moisture away from your skin to help prevent blisters and athlete’s foot. For long distance running and long duration exercise, cotton is rotten.

2. Fit your running shoes or other sports shoes with the type of sock you intend to wear them with. Get fit each time you buy new shoes.

3. Don’t wear sandals when playing sports! Shoes (or barefoot where appropriate and safe) is a better bet. Barefoot beach volleyball, beach or groomed, safe, outdoor surface Frisbee, and running is just fine for many people. In general though, be careful when running or walking barefoot outside. Cuts and bee stings are not fun for your feet.

4. Build up to your longer distance training slowly. Consider running your long distance runs earlier than usual to avoid midday heat and pollution.

6. Break in new sport shoes before racing or using them for a long run or workout.

7. Use sunscreen to prevent solar injury to your skin. UVA and UVB protection are important. Don’t forget your feet at the beach. Try to avoid mid-day exposure between the hours of 10am-2pm. Protect your eyes with UV safe glasses.

8. Don’t forget to replace your fluids on long runs, but avoid overhydration on events over 4 hours.

9. Do wear sport specific running shoes. Running shoes do not have the lateral support needed for tennis. Help yourself avoid ankle sprains and other injuries and do fit your running shoes or other sports shoes with the type of sock you intend to wear them with. Do replace your running shoes often. Replace them at least every 350 – 450 miles run.

10. Be careful running in low light conditions both because of road traffic, uneven pavement and also be aware of increased balance problems.

See Dr. Pribut On Running in The Heat for more information.

Resveratrol: 700 Bottles of Wine On The Wall

Red wine has long been hailed as good for your health. Years ago it was found to contain resveratrol, adding to the good reputation of red wine. Nearly 10 years ago resveratrol was first believed to have beneficial actions by virtue of its activating sirtuin 1 (SIRT1) which

Resveratrol (image courtesy Wikipedia)

is an NAD+ dependent deacetylase thought to protect against several metabolic disorders including  type 2 diabetes, Alzheimer’s disease, hearing loss (actually SIRT3), and cardiovascular disease. The actions of sirloins are believed to mimic the effect of caloric restriction on lifespan and disease in mammals. The actual caloric restriction needed to have beneficial effects though is too great for humans to attempt although gluttony is clearly both the opposite and detrimental to good health.

Recent research shows that things are more complicated than that, as research seems to do in many fields. Apparently it there is an intermediary reaction in which phospodiesterases which hydrolyze cAMP are inhibited. Skeletal muscle and white fat tissue responds to resveratrol by increasing the levels of cAMP. We need more research before we are able to use resveratrol as medicine.

Nature Reviews Molecular Cell Biology (Feb 29, 2012) quotes Andrew Murray, interviewed by the Telegraph of Cambridge University, UK about how much red wine it would take to ingest enough resveratrol to have physiological action. He is quoted as saying “you would need to drink about 700 bottles [of red wine] to get a meaningful dose.”

In short, it may be that researchers who like red wine, hail the miracles of red wine, those who like coffee, hail coffee. And the same may go for chocolate. Perhaps the effects of each augment the other which would be better than canceling each other out.

 

Is Exercise Bad For You? Shocking News Reports!

Some say a meta-analysis is like a large pile of small, weak, and insignificant studies lumped together into one ugly mess. Sort of like a stew made up of left-overs that might be getting a bit moldy. Others say that by aggregating studies which alone would be too small to amount to anything of significance, the data can gain significance by having a larger number of subjects from different studies put together to be counted.

Couch Potato
Couch Potato

Study Title: Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?

Study Citation: Bouchard, C, Blair, S et. al. (2012) Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?

Study Premise: There is a variability in peoples response to exercise. Some may experience adverse response to exercise. The authors state no study has addressed adverse changes in cardiovascular and diabetes risk factors can occur. The risk factors chosen to be studied include: “Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified.”

Study Conclusion & Media Announcements: Adverse response to exercise may occur. Some individuals do not respons positively in the measured according to the authors this analysis of 6 previous studies (a meta-analysis) revealed the shocking truth that some overweight people did not have a positive response to exercise and the variables mentioned above worsened. 7% had two variables worsen over the course of an exercise program.

Analysis: Why should one expect 100% positive response to any intervention? The fact that 90% had a positive or non-adverse impact on risk factors is an overwhelming number of individuals for whom exercise is likely quite good. Emphasizing the negative in which case “the minority is the new majority” seems to be the in thing to do in current culture and society. In everything from politics to social policy a majority may be declared at 40% (the U.S. Senate) or at 12-17% as was seen in misused statistics during health care reform debates. The fact that 8% to 12% is neither a majority, nor a vast number, and the “adverse events” were not death, disease or morbidity and mortality should alert those reading this article and the large headlines in the paper that hyperbole is at play.

There is an overwhelming amount of information that says exercise is good for you in many, many ways. In many cases exercise is the missing link to the best health you can have. Exercise is something that almost everyone should be undertaking (to avoid the undertaker). In fact a famous saying goes “where there is no exercise, the people perish”. Well, maybe it was “where there is no vision the people perish”.The reality is that where there is no exercise the people develop sarcopenia (muscle wasting), osteoporosis, obesity, depression, diabetes, high blood pressure, and dementia. So whether or not your high blood pressure goes down and your HDL-C goes up, there are many positive benefits to be achieved by exercising regularly.

Exercise and diet are both vital to overall health. All of the individuals in the studies this meta-analysis selected to include were overweight. Improper diet plays a large role in being overweight or obese.

Successful implementation of a healthy life plan should actually include more than a mere exercise program. It needs life habit modifications that would include good sleep habits, healthy diet, and avoiding the excessive consumption of things that are bad for you (too much alcohol, drugs, etc.). But exercise may be the largest change that is easy to make. Diet is also critical and often needs a tune up. Let’s sum this up in one sentence!

You can exercise and have a great shot at doing as well as you can or you can sit on a couch and take your chances!

Notes:

  • The study group only included overweight people with a BMI from 25-30
  • Normal variablility in tests – is greater than zero

References:

Bouchard, C, Blair, S et. al. (2012) Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?

Bouchard C, Rankinen T (2001) Individual differences in response to regular physical activity. Med Sci Sports Exerc 33: S446–S451

deMello, V et. al. Insulin Secretion and Its Determinants in the Progression of Impaired Glucose Tolerance to Type 2 Diabetes in Impaired Glucose-Tolerant Individuals
The Finnish Diabetes Prevention Study.
Diabetes Care February 2012 vol. 35 no. 2 211-217. Published online before print December 30, 2011, doi: 10.2337/dc11-1272

Study Notes

an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors.

Parenthetically Speaking: Colons, Math and the New York Times (repost 2008)

Science, Numbers, Journalism and Critical Thinking

I believe it was on a Merlin Mann podcast, where someone jokingly mentioned the concept of an iColon website which in typical Web 2.0 fashion people could share the images and films of their colonoscopy procedures. This week the New York Times managed to demonstrate where their heads were at regarding simple mathematics and statistics. An article by one of their most popular reporters reviewed a new study that showed that colonoscopies were not all they were cracked up to be as far as picking up colon cancer and in their ability to prevent future cancers from developing from detection and removal of polyps.

The American Cancer Society still strongly recommends the colonoscopy as a useful  screening procedure. and the physicians I know who both perform this procedure and recommend it all strongly feel that it is one procedure that can actually save lives. We will however take a quick and simple look at the use of math and see a lack of simple math skills and the failure of editorial checking at the New York Times.

The NY Times reported on a study that demonstrated that colonoscopy missed virtually all polyps on the right side of the colon. The  article stated that 40% of all cancers and polyps originated on this side. Of those on the left side of the colon up to 30% of those were missed. The article then went on to quote and conclude that rather than preventing up to 90% of colon cancer from devleloping it might only be useful in preventing 60% to 70%. Now, this seems to be a fairly simple math problem. And a quick glance by anyone even one with only minimal math skills just looks and sounds wrong on the surface of it all.

If 40% of the lesions occur on the left side but are undetectable, than you have remaining 60% of the lesions to deal with that you can find. If 1/3 of these ones are not found, by splitting them into 3 equal parts of 20% 20% and 20%, and you remove 1/3 you are then left with 40% of the lesions that you would be able to find.
Hence, it is clear that it is not 60%-70% number of lesions that you’ll expect to find, but a number significantly less than 50% and which clearly looks to be 40%. The physician interviewed in the New York Times encourages people to have the colonoscopy as a screening procedure, but to not necessarily expect to be safe for the next 10 years. It is strongly recommnended that you follow the colon cleaning procedures prescribed prior to undergoing the procedure.

There will be more studies in the future and likely ones that will be quite positive on colonoscopy. Techniques will likely be modified that also result in improved detection of right sided lesions. Until then, we now and always will need clear heads to do the math and keep evidence based medicine, based on evidence and not on an easily obtained quote.

Up soon we may dissect an article published within the last few months that looked at the longevity of runners and non-runners. If you know the study, here’s a hint: check out the disparate population groups studied and see if it looked like a well designed and controlled study.

New Math From the New York Times:

“In the new study, the test missed just about every cancer in the right side of the colon, where cancers are harder to detect but about 40 percent arise. And it also missed roughly a third of cancers in the left side of the colon.

Instead of preventing 90 percent of cancers, as some doctors have told patients, colonoscopies might actually prevent more like 60 percent to 70 percent.”