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

nature15766-f2

 

 

 

 

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

Examine Your Models and Theories Often

I’ve been spending far too much time doing 140 character mini blogs or actually enjoying MOOCs (massive open online courses). My favorite MOOCS may be found at EdX.org and Coursera.org. If you are not currently involved in a formal course of study, there probably is no better way to spend time learning than these. But it is time for at least a short blog.

So, off we go to theory. We see many theories proposed and many adopted with little study. We may see a study of 13 people or 20 people that some purport to change all thinking on a long standing medical problem. This is not the proper way to approach a poorly designed and implemented study or even a well designed but entirely all to preliminary study.

We would not change the treatment of heart disease, any type of cancer, or try to prevent Alzheimer’s disease on evidence as weak as this, but somehow it is deemed worthy of a sea change for running injuries. A shower and a change into clean clothes is likely a better use of your time.

But allowing models and theories to last for far too long can be an equally troubling problem. But this is why models and theories must be thoroughly examined. There is no need to adopt an untested theory. And there is no value in making a theory about how to treat a clinical entity and proposing that is how all such entities should be treated without testing clinical results.

Now on to yesterday, in the hope of having a better tomorrow, today!

 

Quinta_Essentia_(Thurneisse)_illustration_Alchemic_approach_to_four_humors_in_relation_to_the_four_elements_and_zodiacal_signs-small

 

Examine your theories and models often.

The model of “humors” as the cause of diseases persisted for over 2,000 years. The Greeks refined this concept in about 400 BC and it persisted for far too long.

Aristotle’s scientific publications also lasted for far too long as unquestioned dogma. And there is even recent praise in both film and print for the wonders of his study of biology. While Aristotle may have been the first to take a systematic approach to science, it is even more important to know your failings and where your knowledge is lacking. A recent book and a documentary by evolutionary biologist Armand Leroi called “Aristotle’s Lagoon” have interesting points to bring forward about Aristotle and his study of Biology. But I’m in the camp of believing that he may have done more harm than good by not successfully encouraging others to better study and verify or disprove his theories. He certainly was a busy thinking man for his time. But unexamined, he dominated western thinking for far too long.

Old knowledge isn’t necessarily knowledge at all. It is more likely a historical artifact or relic. Most medical studies from 100 years ago would not past muster today. So using them to justify someone’s completely unscientific theories is absurd. And I, like many, will even have questions about studies performed last week.

And below we have David Attenborough describing (via Louis Armstrong’s words) what a wonderful world is and Otis Redding performing Sam Cook’s song of that name. (And via the wonders of Youtube you can also find Sam Cook, Dr. John, and even Joey Ramone doing one or the other of these songs.)

 

 

 

 

 

Epidemic of Thin Hypothyroid People?

Professional runners are lean, but not usually mean. And while they may overtrain, which has a host of manifestations, they aren’t usually found to have overt hypothyroidism.

One endocrinologist in particular has apparently been diagnosing and treating many thin, lean, athletes with “subclinical hypothyroidism.” That is a real diagnosis, in which the TSH values are below what is generally considered abnormal. The estimates of the incidence of this condition range from 5%-10%.thyroid

So many things are altered by overtraining and by having a negative caloric balance in the case of withholding calories that one wonders if it is wise to give athletes synthetic thyroid hormane when they have a normal, but borderline TSH level. Could giving thyroxine lead to heart arrhythmia or decrease heat tolerance? Could it enhance performance although it isn’t on any prohibited list? The answers regarding performance enhancement seem to be both no and yes from the same sources. How common are TSH levels in the range of 2-5 mU/Liter among high level and hard training athletes? Does rest or an improved diet have an impact on these levels? All worthwhile questions which are not entirely answered.

The Wall Street Journal presents the side of the doctor who has diagnosed about 17% of the “Nike” athletes training with Salazar as having this condition. Carl Lewis was diagnosed with it before attempting to qualify for his fourth Olympics. The doc compares himself to “House” of TV fame as a mystery solver. I always considered House a sad story. He was addicted to Vicodan and usually needed at least five to seven attempts before he’d come up with the right diagnosis.

Flo Track presented a mature discussion on the topic with Lauren Fleshman saying that if only one doctor in the country was giving athletes the answer they wanted to hear, something just might be wrong with the picture.

I believe subclinical hypothyroidism exists. And I believe over training exists even more often. I’d recommend any athlete considering treating hypothyroidism while having a body fat of less than 12% should research the topic thoroughly and hope to soon find better statistics on training and endocrine hormone levels.

For all of us non-elite, non-professional athletes – make sure you pay attention to your body. Take the breaks you need, rest well, and eat well. And always avoid too much, too soon, too fast, too often, with too little rest. If you have signs of hypothyroidism, be sure to see your doctor.

References:

The treatment of Subclinical Hypothyroidism Is Seldom Necessary. Chu, J and Crapo, L. Journal of Clinical Endocrinology & Metabolism. JCEM. October 2001,

Flo Track discussion on WSJ article and Subclinical Hypothyroidism

U.S. Track’s Unconventional Physician in Wall Street Journal

Subclinical Hypothyroidism: An Update for Primary Care Physicians Vahab Fatourechi, MD Mayo Clin Proc >v.84(1); Jan 2009 >PMC2664572

 

The Beatles “I’m Down” (Cause my thyroxine is low & my TSH is high?)

 

The Science of Bone and Tendon Injuries (slideshare)

Perhaps one day I’ll break this up into 5 slideshares and 5 articles. But for now, here are the slides from a lecture presented at the Sports Medicine Section of the  American Podiatric Medical Associations Annual Scientific Conference.

I believe that basic science and research is an important component for advances clinical medicine. This lecture highlights some of that research from barebones systems biology to mechanotransduction. Cell mechanics, structure and biology are where the action is.

 

Slideshare: Overuse bone and tendon injuries – science and theories of tomorrow

Achilles Tendon Stretches: Do’s and Don’ts (repost)

Achilles tendinitis prevention and recovery are issues faced by many runners. As anyone knows who has spent time on my web site, I am not a fan of excessive stretching for this problem. In individuals who are experiencing pain, I advise against the stair stretch, particularly if you’ve been trying it already for 6 weeks or more and found only more pain, and no improvement. In early cases of pain, I like to restrict stretching, than  graduate to the wall stretch, and then the wall stretch with a bent knee.

Roxanne Darling of Beachwalks with Rox does an excellent job of demonstrating a variety of stretches from the hard to the easy. For those without pain, you may carefully follow Rox’s example of the stair stretch if you’d like. If you have pain, skip that one for now and start with the straight leg, wall stretch and about 3 weeks – 4 weeks later add the bent knee portion. Read the article on Achilles Tendonitis (and Achilles Tendinopathy). A small portion of that article is summarized below. In the meantime, if you need a little downtime and some chilling, visit Beachwalks With Rox for words of wisdom, thought and relaxation.

Stretching With Rox

Achilles Tendonitis / Achilles Tendinopathy Brief Summary of Treatment

Full Text (Achilles Tendonitis)

Exercises to Avoid
Excessive stretching is not good for your Achilles tendon. The stretch that I most often recommend is the “wall stretch”. I do not recommend the “stair stretch”, the “incline stretch”, or the “put a towel around your feet and pull up until it hurts stretch”. If any of these are working for you, that’s great, you don’t need any advice. In most cases, for the patients I see, these stretches put too much tension on the already tender achilles tendon. Contracting the muscle when it is in a stretched position, as initial therapy of an injured achilles tendon is not a good thing. However, as seen in Rox’s video, she demonstrates some super stretches, and if you are not in acutely painful phase, you may cautiously give them a go. But, if you have found the stair stretches to be painful and counter productive, skip them, and look at the others.

Treatment Outline:

Relative rest
Cut back mileage
Lower intensity
Avoid hills, speedwork, plyometrics

Avoid over-stretching
Gentle stretch after warm-up
Start with Straight leg calf stretch, build up much later to bent leg, consider eccentric stretch later.
Ice Massage 10 to 20 minutes after exercise

NSAIDs (note: some recommend avoiding NSAIDS)
– Aleve, Motrin, Ibuprofen, etc. 10 – 14 days.

Check Running Shoes
– Replace if heel is worn
-Replace if excessive heel shock absorption (soft air sole cushion, excessive gel shock absorption)
Replace if shoe is excessively stiff at the “break point” (ball of foot).
Consider using a “heel lift”

Physical Therapy Modalities
HVGS (electrical stimulation)
Ultrasound
Exercise instruction: Strength and flexibility

Current Concepts of Achilles Tendonitis and Achilles Tendinopathy

While Achilles tendon problems are widespread, the terminology used to describe them is often inaccurate and is undergoing a significant transition. First to be precise we must consider where along the course of the tendon does the problem exist. This may be in one of three main areas:

1. Insertion
2. Musculo-tendinous Juncture
3. Non-insertional (main body of tendon)

While the term that most people use and that most individuals will search for on the web is “tendonitis”, most Achilles tendon problems could better be called a tendinopathy and more specifically a tendinosis and are a non-inflammatory problem of the tendon. Inflammatory cells are not found on microscopic examination.

Clinically there may be two differing entities in acute achilles tendinopathy:

Peritendonitis

o Inflammation in the tissue surrounding the tendon
o Often 2 – 6 cm above insertion

o Possible crepitus with long standing injury (paratenon with fibrin exudate)
o In chronic tendinopathy approximately 20% of the injured peritendinous area are scar forming myofibroblast cells.

Tendinosis
o Impairment of circulation with resulting damage to tendon structure
o Focal areas of tendon degeneration

Much future research and better understanding of these injuries is needed. In spite of the vagaries of scientific understanding of these entities a successful approach using training modification, stretching, strengthening and appropriate return to exercise may be undertaken. At this time there are few significant clinical studies with valid results for treatment. There is often disagreement on approach and much is likely to be changed in the future. At this point treatment and treatment recommendations for this problem remain an art practiced with varying degrees of success. When evaluating new research, it is hard to recommend major paradigm changes in thought and recommendations based on studies of fewer then 20 cases or even 50 cases.

Travelling, Running, and Starving – A New Approach To Your Circadian Rhythms (repost 2008)

For many people, long trips disturb the natural rhythms so much that normal functioning on both the physical and intellectual planes is impaired. Clearly, there is a need for some method to improve the travel experience and the race results for those on a tight schedule. First class? Sounds great, but isn’t practical and probably won’t get the job done.

Circadian rhythms may affect racing performance. Most world records have been set in the afternoon or evening rather than in the morning. It may be a matter of when the races are run, but it also may follow along with optimal body rhythms. Workouts seem easier in the afternoon, joints are stiffer in the morning, and some old lecture notes I have indicate that muscles are weakest at 8 AM & 8 PM and strongest at 5 PM. Body temperature reaches a peak around 5PM. (Spiking fevers when you are ill, do not spike in the morning, but late afternoon or evening.) Measured VO2 MAX is greater in the afternoon.

Adapting:

Suggestions

  • Start sleeping on the schedule of where you will be racing (or working).
  • If you can, train on the schedule of where you will be headed.
  • Get there early if you can, for optimal performance one day for every hour time difference. Otherwise follow all the other suggestions.
  • Melatonin
  • Bright lights for wake up time on new schedule and wake up also.
  • Eat lightly 2 days before travel, then start eating on the arrival schedule

The suggested eating change, of eating on the new arrival schedule comes as a result of a new study on circadian rhythms published in this weeks Science Magazine. The article notes that when food is readily available, circadian rhythms are greatly impacted by the light-dark cycle. If food is only available at night, the animal will shift its circadian rhythms to match the time when food is available. This led to studies of the gene clock Bmal1 and found that the dorsomedial hypothalamic nucleus seemed to impact the role of food and feeding on the circadian timing system (CTS). Light has previously been found to play a role via retinal ganglion cells containing melanopsin which generates signals to the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN then effects a tuning of the circadian rhythms via synaptic and humoral mechanisms. The studies described here were done on mice.

The authors conclusions were:

Our data indicate that there is an inducible clock in the DMH that can override the SCN and drive circadian rhythms when the animal is faced with limited food availability. Thus, under restricted feeding conditions, the DMH clock can assume an executive role in the temporal regulation of behavioral state. For a small mammal, finding food on a daily basis is a critical mission. Even a few days of starvation, a common threat in natural environments, may result in death. Hence, it is adaptive for animals to have a secondary “master clock” that can allow the animal to switch its behavioral patterns rapidly after a period of starvation to maximize the opportunity of finding food sources at the same time on following days.

The biological clock for mammals, clearly resides in the hypothalamus. In some insects and snails, the clocks seem to be located in the retina. In birds, the pineal gland has been thought to come into play, along with the hypothalamus. Photoreceptors are usually linked into the timing system, to synchronize the clock with the 24 hour day. Old studies showed light to be able to assist in resetting the clock by impacting genes, sleep patterns, alertness, and body temperature.

As we noted above, exercising on the new schedule, can also help. Recent research agrees with this as per the study “Scheduled exposures to a novel environment with a running-wheel differentially accelerate re-entrainment of mice peripheral clocks to new light–dark cycles (Yujiro Yamanaka, Sato Honma and Ken-ichi Honma Genes to Cells (2008) 13, 497-507)

A study from 2001 demonstrated the liver enzyme production could be shifted 10 hours within 2 days by altering feeding. (Science 19 January 2001: Vol. 291. no. 5503, pp. 490 – 493 Entrainment of the Circadian Clock in the Liver by Feeding. Karl-Arne Stokkan, Shin Yamazaki, Hajime Tei, Yoshiyuki Sakaki, Michael Menaker)

Larks and Owls
While we don’t have studies to cite here, others have noted that some people are better at staying up late than others, while others are happy to wake up at 5 or 6am, but can’t stay up to party, play MMORPGs, or text their buddies in the middle of the night.

Some feel that it is easier for Larks to travel west to east and for owls to travel from east to west. The larks have little trouble staying up late, and have probably already shifted in part to the western time zone.

Viva La Différence: Exercising Sitting Down vs. Standing Up (repost 2007)

The New York Times had an article today which discusses how bicyclists come in all shapes and sizes. Gina Kolata mentions that that many cyclists did not meet her conception of what an in shape cyclist would look like. The reality is that runners come in all shapes, sizes and ages also and this can be seen at many marathon events. The other part of the reality is that elites among both runners and cyclists have different morphological characteristics including a lower body fat content, higher MVO2 and various other items.

But, there is hope for all of us. George Sheehan once said “We are all athletes, some of us are in training and some are not.”

“When I first got into cycling, I would see cyclists and say, ‘O.K., that’s not what I perceive a cyclist to be,’ ” said Michael Berry, an exercise physiologist at Wake Forest University. Dr. Berry had been a competitive runner, and he thought good cyclists would look like good runners — rail-thin and young.

But, Dr. Berry added, “I quickly learned that when I was riding with someone with a 36-inch waist, I could be looking at the back of their waist when they rode away from me.”

He came to realize, he said, that cycling is a lot more forgiving of body type and age than running. The best cyclists going up hills are those with the best weight-to-strength ratio, which generally means being thin and strong. But heavier cyclists go faster downhill. And being light does not help much on flat roads.

But on the other hand, there are differences that make cycling a bit more forgiving:

“In running, when you see someone who is obviously overweight, they will be in trouble,” Dr. Hagberg said. “The more you weigh, the more the center of gravity moves and the more energy it costs. But in cycling, there are different aerodynamics — your center of gravity is not moving up and down.”

The difference between cycling and running is like the difference between moving forward on a pogo stick and rolling along on wheels. And that is why Robert Fitts, an exercise physiologist at Marquette University who was a competitive runner, once said good runners run so smoothly they can almost balance an apple on their heads.

Sunscreens: Hype and Reality (repost 2007)

Sunscreens are helpful in reducing exposure to the harmful effects of UVA and UVB. These types of solar radiation contribute to the development of premature skin aging, wrinkling and both malignant and non-malignant skin cancer. Basal Cell Cancer and Melanoma, among other types of skin cancer has an increased incidence in sun exposed individuals. Some have estimated that only about 20% of melanomas are related to skin cancer. Other disfiguring cancers, including basal cell though seem to have a very high correlation with sun exposure.

Melanoma has multiple risk factors which include fair complexion, blonde or red hair color, blue, blue/green eye color (skin phototypes I/II), total sun exposure and a history of blistering sun burns. Genetics, or inherited risks may include genetically linked disorders such as the dysplastic nevus syndrome. The overall risk has increased dramatically over the last 50 years or so. In 1935 the lifetime risk for developing melanoma was 1:1500 in 1935 and grew to 1:74 in 2000. It is estimated that it will grow to 1:50 in 2010. It is estimated that over 53,000 new cases of melanoma are diagnosed now each year. A good number of these are diagnosed at an early stage.

Today’s New York Times implicitly criticizes Neutrogenia for a campaign in which they imply that not using sunscreen and their products is akin to suicide. It includes a clip in which a woman holds up a photo and says “My sister killed herself. She died of skin cancer.” Since melanoma can occur in people with little sun exposure and the majority of it may, this is in bad taste. There isn’t even a campaign that strong for lung cancer sponsored by Nicorette. Continue reading Sunscreens: Hype and Reality (repost 2007)

Testosterone: Epitestosterone Ratio: Cheating or Genes?

(repost from 01/2011)

The Case Against Lance Armstrong” is the title of an article in the January 24, 2011 issue of Sports Illustrated. The case that is made within this article is based on in large part on what a few people with gripes against Lance have said. The other “hard” evidence is based on several tests detailing a very high Testosterone:Epitestosterone ratio. Before 2005 the tests normal was considered up to 6:1 and was then lowered to 4:1. Several tests over the years, which may have been Lance’s were considerably higher than this.

According to SI “Three results stand out: a 9.0-to-1 ratio from a sample collected on June 23, 1993; a 7.6-to-1 from July 7, 1994; and a 6.5-to-1 from June 4, 1996.”

Each time the ratio was found to be high, the “B” Sample was tested and found to not confirm the preliminary test. The second test is usually a carbon isotope test that is more specific to studying the makeup of the individual’s testosterone.

While the article goes on to say that one high number (of the T:E ratio) should be a once in a blue moon occurrence, there are significant genetic factors that can come into play.  A 2008 article published in The Journal of Clinical Endocrinology & Metabolism titled “Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme for Testosterone Glucuronidationshowed that if an individual had two alleles for the UGT2B17 gene, there was a large chance that they would not test positive for cheating even after having taken a large dose of synthetic testosterone. The estimates were that 40% of individuals could pass the ratio examination just by virtue of having two copies of this gene. On the other hand with mixed alleles (ins/del) or in the absence of  this allele there was a fair chance that the ratio would always be abnormal. Estimates were that in a normal population, up to 9-14% of people would have a false positive result and fail the test.

It seems that if you have the del/del or ins/del variations of alleles, you are going to pretty consistently fail the test. The authors suggest that this gene should be tested and the results modified based upon the genotype of the individual.

Understanding the purpose of the Testosterone:Epitestosterone ratio testing and doing at least a brief look at  factors that might affect this test, not just once but repeatedly are important when an article such as the SI one is written. This specific gene and its implication on testing is widely known and has been covered in a variety of journal articles. The Canadian Medical Journal detailed, in an editorial titled “Doping, Sport, and the Community“, the difficulties in testing for Growth Hormone abuse and Testosterone. The editorial also mentioned research I came across elsewhere which indicated that many Asians (up to 40%) had the version of this gene that would give a false negative.

So, let’s get all the evidence out. And let’s make sure the public sees all the scientific information on the validity and the problems that exist with this particular test. For another perspective on heroes in American culture, you can seek out one of George Carlin’s last specials in which he expresses his opinion on hero worship and in particular on Lance Armstrong, Tiger Woods, and Dr. Phil.

The next test is to determine if the song “Bike” by Pink Floyd was written in a drug free state. In case you can’t make them out the lyrics begin:

I’ve got a bike
You can ride it if you like
It’s got a basket
A bell that rings
And things to make it look good
I’d give it to you if I could
But I borrowed it

Available video of Pink Floyd’s Bike (blocked currently at Youtube)

and if Pink Floyd is just not your cup of tea. Here is Queen performing their song “Bicycle Race”

Overuse Injuries: All The Small Things (repost 10/2010)

Podiatry Management (October, 2010) has just published an article I’ve written titled  Overuse Injuries: All The Small Things . You are just another click away from the PDF version. This is a challenging article. It introduces mechanotransduction, a theory of cellular and tissue function, which is little known in the sports medicine community. The article touches lightly on this topic and then reviews the latest literature and theory on overuse injuries to bone and tendon.

The Needle - Kenneth Snelson
The Needle - Kenneth Snelson

The cellular level is where things start and where we will find many answers. I expect to add more details on the web site on mechanotransduction and mechanobiology for those with hardcore, deep science interest. The article is limited in size, but was longer than many published in PM Magazine. But, I didn’t even touch on the theory canalicular flow and osteocyte induction or mechanotransduction and control of stem cell development by matrix stiffness. Research in the field of mechanobiology is growing daily and the outlook is great that it will be fruitful.