If you are taking Avandia or Actos and you have been reading about heart disease you may be concerned and you should be. As a class, these drugs increase your risk of heart disease and recent studies are confirming what we already suspected: Avandia is a bit worse on the heart than Actos.

However, there is something you can do to protect yourself. It seems that exercise does a very good job of reversing the problems caused by Avandia. I came across this clinical study last week and I wanted to share it with you.

The 1 year study was performed by a team of Greek doctors headed by Dr. Nikolaos Kadoglou and was published in the journal: Metabolism in November 2009. They chose 100 people in their late 50s or early 60s with type 2 diabetes who had not achieved good glycemic control with the combination of gliclazide (a sulfonylurea drug) and metformin. They were all overweight but were not taking any lipid lowering drugs and did not have any vascular complications. These patients were divided into 4 groups. The control group (we’ll call them the CO group) kept on as before. The next group received rosiglitazone (Avandia) in addition to their current therapy (let’s call them the RSG group). Group 3 exercised in addition to keeping up their original therapy (the EX group). Finally, the last group added both Avandia and exercise to their original therapy (the RSG+EX group). All patients were carefully examined before the start of the study to establish their fitness level as well as their lipid profiles, glycemic index, level of insulin resistance, and many other parameters. They were measured again after 1 year to provide the results of the study.

The exercise regimen started with a standard 45 min to 1 hour aerobic fitness class run at a local fitness center. The intensity of the exercise was tailored for each patient so that they were not in danger of hurting themselves or being asked to perform at an impossible level. Indeed the authors made the point that the exercise level began quite low and only slowly increased until individuals could achieve a reasonable level of effort (officially, 50% of V_O2 peak). After the first month the exercise was further tailored to the individual with some running and some walking or using an exercise bicycle. After 8 months, the patients were on their own with individual exercise programs and simply checked in periodically so that the researchers could see how they were doing. Out of the 100 patients, 11 dropped out of the study for a variety of reasons, none of which involved dislike of the exercise.

The results were quite impressive. Nobody lost weight but then we already know that weight loss cannot be achieved by exercise alone unless we are talking enormous amounts such as a multiday mountaineering expedition – not exactly the sort of thing you plan on doing any time soon. Glycemic control, as measured by the amount of glycosylated hemoglobin, was about 0.5% higher in the CO group. In the EX group it dropped 0.3%. In the RSG group it dropped 0.8% and in the RSG+EX group it dropped 1.4%.

Lipid profiles also responded favorably with exercise. As seen in other studies Avandia treatment (the RSG group) resulted in an increase in total and LDL cholesterol. For the groups that exercised, however, HDL levels (the good lipids) increased while LDL levels and cholesterol (the bad lipids) decreased. Also, various other measures of lipids that are somewhat more specialized such as ApoA and ApoB1 showed improvement but only in the groups that exercised. Measures of inflammation (inflammation increases insulin resistance) also showed marked improvements both with exercise and with Avandia. The combination of Avandia plus exercise markedly improved this parameter.

Another issue that increases the risk of a cardiac event is fluid retention. Increased fluid causes an increased workload for the heart and Avandia has effects on the kidney that increases fluid retention. This was seen in the current study. The CO group showed no significant change in body water content while the RSG group experienced a significant change of 2.4% (+/- 1.4%). When Avandia was combined with exercise (the RSG+EX group) the number dropped to 1.6% (+/- 1.2%) and was no longer statistically significant.

Blood pressure, another measure that is associated with increased cardiac risk, was increased in the CO group and decreased in the EX, RSG, and RSG+EX groups.

Perhaps the most interesting and surprising result from the study was that Avandia alone improved V_O2 max. This is a measure of aerobic capacity. Improving V_O2 max is the Holy Grail for anyone who is involved in a sport that involves lots of movement. Fly fishing probably doesn’t get easier but tennis or basketball or soccer certainly does. The RSG+EX group saw a synergistic improvement in V_O2 max which was much greater than the EX group.

So to sum up, the exercise groups performed about 2.5 to 3 hours of exercise a week for a year. They experienced marked improvements in insulin resistance, fasting glucose levels, lipid profiles and blood pressure. Avandia provided the expected improvements in glycemic control with the equally expected increases in fluid retention and cholesterol associated with increased cardiac risk. Exercise markedly reduced these cardiac risk factors while synergizing with exercise to improve glycemic control. Remarkably, Avandia actually improved the capacity of the study group making them more fit and capable of greater improvements in fitness.

Here are some questions. How much exercise do you need to do to achieve these benefits? Does Actos have the same properties or is this unique to Avandia? As usual, we end with the researchers’ mantra – “more work is necessary to unravel these important issues”. In the meantime, it wouldn’t hurt to go take a walk today.

The storm continues to rage. Congress has issued an angry report on Avandia in which neither GlaxoSmithKline nor the FDA was spared. The results of these clinical trials were not surprising. Numerous clinicians have been discussing cardiac events for all of the thiazolidinediones (TZD) as a drug class for at least a decade. Rosiglitizone (Avandia) was issued a black-box warning in 2007 about the possibility of cardiac events although it included a statement that these data were still inconclusive. As far as I can tell there seems to be two camps. On one side are the clinicians who are focused on the data which show that rosiglitazone causes more heart failure events than other blood glucose lowering therapies and on the other side are the clinicians who are focused on the similarity in numbers of deaths and of hospitalizations among the groups.

Having looked at the data myself I firmly believe that indeed rosiglitazone does have a greater cardiac risk. However, I have also been struck by the numbers for more general measures of hospitalizations and deaths. Here is my reasoning as to why this is of interest. All drugs have risks and benefits which may not be readily apparent. The only way we can assess these unknown risks and benefits is to look at a generalized measure such as death or hospitalization by any cause and to carefully stratify the patient population so as not to be comparing apples and oranges.

Dr Juurlink and colleagues, in the Canadian retrospective study I discussed in the last post, looked at exactly this sort of measure. Just to remind you, Dr. Juurlink and colleagues looked at several thousand people of age 66 or older who had been prescribed either Actos (pioglitazone) or Avandia (rosiglitazone) and followed their medical records for a number of years. The graph of the data maps the proportion of the Actos treated population that had died over 3 years from the start of Actos treatment and compares this to the proportion of the Avandia treated population that had died over the 3 years since the start of that treatment. The two lines do diverge and it does look like the Avandia group had more deaths. Here are the numbers that I gleaned from making measurements from the graph provided (figure 4 from the report). The Actos treated group showed a consistent almost linear increase in the number of deaths from day 1 to year 3 with a total of about 7.2% of the group dying from any cause. The Avandia group, after about 6 months, began to show some increased deaths and this increase bounced around somewhat. In other words, the line was more “squiggly”. At its greatest separation from the Actos group there were about 0.9% greater number of deaths. This happened just before year 2 and again around year 3. At its closest approach the two populations showed a difference in deaths of around 0.15% of the population. To my eye, the two lines were not diverging but seemed to be tracking each other in a roughly parallel fashion. I say this because the distance between the two lines was about the same just before year 2 and again at year 3. The authors have reported “One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone.” This would continue to be true if the lines do not dip again and the two populations retain that 0.9% difference. If the distance between the two lines dips to 0.15% again we would be looking at one additional composite outcome (death) for every 1500 patients. In my read of the data, this is the range of the risk between Actos and Avandia: 1 in 93 or 1 in around 1500.

In the RECORD trial (I’m looking at the data published in the Lancet now) the graph from all cause death is virtually the opposite of that seen in the Canadian retrospective trial. Now keep in mind that this was a different trial. It compared 3 groups: rosiglitazone plus a sulfonylurea, rosiglitazone plus metformin, or the combination of a sulfonylurea plus metformin. The two rosiglitazone groups were combined. Also the patients were younger. At any rate the all cause death graph looked at 6 years of data. By year 6 about 7% of the sulfonylurea/metformin group had died while the combined rosiglitazone groups had a death rate of about 6%. Again, the 2 lines were not diverging so much as rising together – sometimes getting closer together and sometimes getting farther apart.

How should we interpret these numbers? We know that heart disease is one of the major causes of death today. One would think that if a medication doubled the rate of cardiac events we should see a rather large difference in the all deaths measurement. We do not. This may be due to the complexities of life and death drowning out the specific numbers of cardiac deaths in a sea of other events. Alternatively, if we have faith in the power of our statistical analysis, perhaps these numbers are saying something else about rosiglitazone.

Just to play devil’s advocate here, what if rosiglitazone provided some additional protection to patients in addition to its role in dropping blood sugar levels? The truth of the matter is that we already are aware of at least one additional function for this class of drugs. They provide a strong protection from lung cancer.

The data for lung cancer protection consists of both analyses of human clinical trials as well as animal models. For example, a study headed by Dr. Rangaswamy Govindarajan retrospectively examined the records of US veterans with diabetes from 1997 to 2003, amounting to 87,687 individuals. The results were published in the Journal of Clinical Oncology in 2007. They found that use of either of the current TZD drugs on the market; Actos or Avandia, resulted in a 33% drop in lung cancer rates. They also looked at colorectal and prostate cancer rates and found them to be only slightly changed and this was below the level of statistical significance. When race was considered, African American males did especially well. As stated in the study, “After adjustment for age, BMI, HgbA₁C, insulin use, and the use of other oral antidiabetics, the TZD-associated risk reduction for lung cancers was 26% among white and 62% among African American patients.”

We do not yet understand exactly how TZD drugs protect us from lung cancer. Indeed that is the point. There is still a lot about the TDZ drugs that we do not understand. Thus there is ample room for the possibility of additional protective functions for these drugs and we do not yet know whether Actos or Avandia will be better at those protective functions.

Perhaps the best way to end this particular discussion is to invoke the concept of balance. Therapeutics of all sorts cause changes in our physiology which acts in both beneficial ways and in ways that increase our risk. We can mitigate some of that risk through changes in behavior. In the case of the TZD drugs, for example, mild exercise has been shown to be efficacious in reducing cardiac risk. We can even extend this balancing act to include societal issues. If a doctor knew that their patient well enough to know that they exercised regularly, then a TZD prescription would be less of a concern. Ultimately, personalized medicine will help us to tailor therapies to minimize risk. When we understand that complex dance between nature and nurture that creates that which we are, we will know who is at greater risk of heart attack and who is at greater risk for cancer. Until that time we can only place our bets and take our chances.

In the previous post we looked at some possible mechanisms which could contribute to Avandia’s issues with cardiac events. Here I would like to look more closely at the actual data so that we can come to our own conclusions about Avandia.

The most recent is the re-analysis of the results of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes) trial which is available in pre-print form online through the European heart Journal. Rosiglitazone is the pharmacological (scientific) name for Avandia. Because the studies often use the pharmacological name for this drug and I will be quoting from them, I will also use rosiglitazone and Avandia interchangeably. The original RECORD trial was published as an interim analysis in 2007 in the New England Journal of Medicine and in final form in the Lancet in 2009. This study looked at 4458 people with type 2 diabetes in which glucose levels were not sufficiently controlled with either metformin or one of the sulfonylurea drugs. The metformin treated patients were then divided into half which got the addition of a sulfonylurea and half which got rosiglitazone (Avandia). Similarly the sulfonylurea group received either metformin or rosiglitazone. So we now have 3 groups: rosiglitazone plus a sulfonylurea, rosiglitazone plus metformin, and the sulfonylurea drug plus metformin. (There are a host of sulfonylurea drugs on the market and since they are pretty similar we are just going to refer to them by their pharmacological name). In both reports (2007 and 2009), the authors claimed no additional deaths were observed in the rosiglitazone (Avandia) groups as compared to the metformin/sulfonylurea group. In the abstract the final sentence stated “…rosaglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs.”

The trial was criticized on several levels in an editorial by Drs. Bruce Psaty and Curt Furberg, published in the New England Journal of Medicine in July, 2007. They felt that the definition of the primary outcome (all hospitalizations and deaths from cardiac causes) was too weak and promoted the likelihood of a null outcome. In other words, because life is complicated, there would probably be many reasons other than rosiglitazone that might bring the patient to the hospital and so we would lose the specific effect of rosiglitazone in the larger ebb and flow of events. Primary outcomes in clinical trials, also called endpoints, are the actual things that are measured and compared statistically between the various treatment groups. A trial may have multiple parameters which are measured but usually there is just one primary endpoint to establish if the trial is a “success” or a “failure”. Furthermore, continued Psaty and Furberg, the number of actual cardiac events seemed far too low for such an at risk population, suggesting problems with hospital reporting. As this was a multi-country study this was a valid concern.

This third analysis of the RECORD data, now in preprint form, addresses the criticisms of Psaty and Furberg and tells a different story. Rather than use all hospitalizations and deaths from cardiac causes as the endpoint, they established a Clinical Endpoint Committee which independently decided upon the appropriate parameters that should be measured. For example, they looked at time to first heart failure (HF) event and found that by this measure the rosiglitazone groups appeared to be double that of the metformin/sulfonylurea group. Similarly, fatal HF events were higher in the rosiglitazone group. From these and other measures the authors now conclude “These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that agent should not continue to be used in people developing symptomatic HF while using the medication.”

Another recent study was performed in Canada by a group headed by Dr. David Juurlink and published in the British Medical Journal in 2009. They did something called a “population based retrospective cohort study”. Since medical records in Canada are quite searchable, this group made use of the many thousands of people within their population who had been treated over the years. The fact that the patients had already been treated and the outcomes recorded is the retrospective part. The patients included in the study were the people who happened to live in Ontario, were 66 years or older, and were treated between the dates of April 1, 2002 and March 31, 2008. This is the population cohort part of the study. They examined 16,951 people who had been prescribed Actos and 22,785 people who had been prescribed Avandia. They then looked at death rates from any cause. After accounting for the variables within the population they found that indeed more Avandia patients had died than Actos patients. Their assessment was 1 extra death for every 93 patients. Interestingly, while cardiac deaths were increased, there was no difference in the rate of heart attack (myocardial infarction).

The Canadian study was preceded by a host of earlier studies. These were aggregated in something called a “meta-analysis” in which, through careful statistics, the results of many trials are compared. This is a tricky business in that each trial involves different investigative groups and designs. In some ways, it is an attempt to compare apples and oranges. The statisticians must come up with reasonable conversions to allow different populations and trial end points to be compared. One meta-analysis, published by Drs Nissen and Wolski in the New England Journal of Medicine looked at 42 separate clinical trials for a total of 12,282 patients. In some of these trials the rosiglitazone group had a few more cardiac events while in other trials the control group had a few more cardiac events. When everything was tallied up here is what they found: within the rosiglitazone groups from all of the trials considered, 86 patients had myocardial infarctions and 39 patients suffered death from cardiac causes. In the control groups from all of the trials considered, 72 patients had myocardial infarctions and 22 patients suffered death from cardiac causes. These and other measures do pretty much show that rosiglitazone does cause more cardiac events than other glucose lowering strategies.

Whether or not you choose to switch from Avandia to some other glucose lowering therapy is a decision you and your doctor should discuss. I do not necessarily think that Avandia should simply be abandoned. I keep thinking about this one measure that keeps cropping up in these studies: the all deaths or all hospitalizations measures. Given that heart disease is a major cause of death, why would the all deaths measure be so similar among the various groups in all of these clinical trials. Ruminations on this topic will be the subject of the next post.

The New York Times (NYT) has just reported that the popular diabetes drug, Avandia, causes heart attacks. The information came from an internal FDA study in which the fate of Avandia has been argued for months. Is this a media scare or is this real?

First of all, one of the major complications of diabetes is heart disease. The tissues that make up the heart must expand and contract thousands of times a day to pump blood and anything that alters tissue flexibility will result in an increased work load for the heart and ultimately heart disease. Elevated blood glucose does this which is why diabetic patients who do not control their blood glucose are at great risk of heart complications. (To read more about why glucose does this click here).  Avandia, like all of the thiazolidinedione drugs, works by promoting the expression of glucose transporters on the surface of cells. When glucose levels in the blood rise, the glucose molecules find their way into these glucose shaped holes in the cell membrane and so bring blood glucose levels down again. The specific gene that is affected is called GLUT4. Normally insulin is responsible for generating the signal for increased GLUT4 expression. Thiazolidinedione drugs target the gene which produces GLUT4 in a manner that is independent from insulin. Thus when you take Avandia, irrespective of your level of insulin resistance, you increase your ability to transport glucose out of the blood and greatly reduce the damage to the heart caused by glucose. In comparison with doing nothing, then, Avandia actually protects the type 2 diabetic person’s heart. So, if you have type 2 diabetes and are taking Avandia and then subsequently suffer a heart attack, was it because of the diabetes, the Avandia, or from some other reason? Perhaps you can now understand how difficult it has been to tease apart the variables and get to the heart (sic) of the matter.

There exist other thiazolidinedione drugs, however, and so one can compare the fate of patients on Avandia as compared to Actos for example. Additionally, one can compare thiazolidinedione treatment to other glucose lowering therapies like metfomin or the host of sulfonylurea drugs currently on the market. Apparently, patients taking Avandia were found to have more heart attacks. According to the NYT, the FDA report predicted that if every type 2 patient was switched from Avandia to Actos, 500 heart attacks and 300 heart failure events could be prevented per month. That is a strong statement. Let’s assume for the moment that it is true (we will look closely at the evidence in the next post). Why might this be so?

One reason we might have a problem here is that thiazolidinedione drugs do not target the GLUT4 gene directly. Instead, they bind to a protein called a transcription factor. This particular transcription factor has the name PPAR gamma (PPARg). Transcription factors are proteins that bind to DNA just next to the gene and nucleate the building of a large transcription machine that will copy the gene into messenger RNA and ultimately into protein. The power of this system is that transcription factors do not just bind to one gene. They bind to many genes and serve to orchestrate the expression of complex sets of genes to take care of our needs. PPARg does not just bind to the GLUT4 gene so when you take Avandia you elicit lots of changes in gene expression. Could one of these other changes explain the heart complications at issue here? Both Avandia and Actos bind to PPARg. The two drugs are different molecules, however, with subtly different shapes. When either binds to PPARg it will change the shape of PPARg such that it can now bind to DNA. One possibility is that the shape assumed by the PPARg-Actos complex is slightly different from the PPARg-Avandia complex and this will result in changes in gene expression. As it happens, when Avandia binds to PPARg it creates a complex that activates gene expression more strongly than does Actos. PPARg responsive genes in the kidney include a sodium channel that promotes sodium retention. The connection between salt and heart disease is pretty certain by now so this makes some sense. Also, the lipid profile seen with Actos treatment is superior to that seen with Avandia treatment and this also would likely contribute to the risk of cardiac events.

Another possibility to consider is that drugs are seldom absolutely specific. By this I mean that we may design a small compound to bind to a target protein; for example, PPARg. How do we know that it does not bind to other proteins? Up to a point we can do various sorts of experiments to look for this but we can never say for sure that one small molecule only binds to some other molecule or protein and never ever to anything else. Hence another reason for the cardiac effects of Avandia might be that this molecule (and not Actos) binds to something else that is involved in heart function. We would call this an off-target effect.

At present we do not have enough information to distinguish between these two possibilities. Both PPARg dependent and independent mechanisms have been implicated. Clinical trials are still coming out looking at comparisons between different thiazolidinediones as well as comparisons between thiazolidinediones and other diabetes therapies. In the next post we will look at some of them in detail.

Kelly Mager used to run a haut café in Victoria but she realized that she disliked the city life and the clientele that went with it.

“the soup would have been nicer if it was served in a red bowl” complained one of her customers.

When she met Marco Delesalle she knew that her new path was into the mountains. I had eaten Kelly’s cooking at Fairy Meadows so I knew that it would be a challenge to keep from over eating this trip.

Kelly, the chef of the Abbey

Never served us a meal that was shabby

Until Marco, her beau

Said, “chef honey? No!”

But he learned: never make your mate crabby!

Marco was commenting on the fact that Kelly was not a graduate of a culinary institute – as if we cared! Working with a bare bones kitchen she served up such delicacies for breakfast as fresh croissants and scones, eggs Benedict, and the most delicious pancakes I have had in a while (served, of course, with real maple syrup).

For several lunches (which we packed before going out) she had this wonderful round bread that we would break into pieces and cut to make sandwiches. When we got back she had appetizers such as soups, baba ganoush, and little baked things that were far too tasty (that alone probably added a pound to my body weight). For my friend, Peter, the soups were his downfall. I remember one afternoon he consumed 5 bowls and still had room for dinner. Granted, we had climbed around 4,000 feet that day and skied the equivalent on some challenging terrain but 5 bowls?? That is one of the great things about a mountaineering vacation; you cannot over eat. I should add that the soups were really wonderful. My wife, Stephanie, also fell under their spell but she managed to limit herself to just a couple of bowls. My home assignment is to try to approximate them.

There was once a skier named Max

Who was inordinately fond of his snacks

Despite all that he climbed

His friends loudly opined

That soon he would not fit his slacks

Max’ friend, Rich; one of the Colorado boys, came up with that one. Dinners were quite the affair. We sat crowded into a long table with mountains of wonderful food. This was not the time for a delicate 3 dimensional tower of some small tasty bits. The meals were both hearty and subtle. We could afford calorie rich meals since we were working so hard each day. Probably we could have done with one or two less bottles of wine but it was vacation after all. One of the most outstanding meals I remember was a pork stew. I cannot describe it adequately. Its presentation was simple but its flavor was complex. This is, at least on these sorts of trips, the hall mark of Kelly’s cooking: complex flavor in a simple presentation.

A few bottles of wine into dinner and the poetry would start. Robeson, our host was a master of the ballad and recounted several over the week. We began to try our best to imitate using the events and stories that surrounded us.

Robeson that man debonair

Was ski cutting a slope without care

‘till a slide caught him silly

And endangered his Willie

He almost soiled his guide underwear

As you can see we have a long way to go.

Perhaps the most amazing thing about all of this was that Kelly did all of her morning work, cleaned everything up, and then caught up with us around lunchtime. She easily out skied us (I think she would give Lindsey Vonn a run for her money). Then, back at the hut, she would start whipping out these delectable appetizers and dinners while we just sat around …whipped.

Kelly graciously offered her pancake recipe which I reproduce here:

Glorious Breakfast Oatcakes

2 cups Rolled Oats

2 cups Buttermilk

3 Eggs-beaten

2 Tbs Sugar

4 Tbs Veg oil

½ cup Flour(May use whole Wheat or any other flour)

1 tsp Baking Powder

1 tsp Baking Soda

1 tsp Salt

Soak Oats in Buttermilk overnight or at least ½ hour.

Add rest of ingredients and mix. Fry on a non-stick griddle if possible.

**May add bananas or blueberries

Serve with CANADIAN Maple Syrup!

Kelly calls her operation the Backcountry Bistro. To see her web site click below:

http://greatdividemountaineering.com/bistro.htm

Jan 10:

It is snowing now. When I look out the window, all I can see are the flakes falling on the nearby trees and formations of cracked granite. Robeson is working on the electrical system in the kitchen and all I hear from that corner of the hut is laughter. Robeson Gmoser is the son of the famous Hans Gmoser who, along with the equally famous Bill Putnam, built the Battle Abbey hut in the 1970s. He has been running the Abbey for about 5 years now that Hans has retired. Apparently Bill had done the wiring given its randomness.

The radio blares and we hear Marco’s voice calling in. He has taken the boys out to Schooner pass to find some good lines.  An early snow left a layer of instability, keeping us off of the summits this trip. The boys are a group of forty somethings from Colorado and California who have abandoned their wives and children to have a week of reunion and bonding. They are a boisterous friendly bunch who are quick to share their stories and their drink. Usually, we are all out climbing but today several of us have rediscovered the joys of sloth and are kicking back in the hut.

Kelly made some amazing soup for lunch (she used to run a haut bistro in Victoria) and we looked at old photos of Bill Putnam, Hans, and other members of the climbing community. Here one feels less like a guest and more like a distant relation welcomed back into a branch of the family that was hidden until now.

Bill Putnam is quite the character. He made his name in broadcasting, wrote a number of books, and built several huts in the mountains of Canada. The Battle Abby hut (where we are comfortably ensconced) was built due to an argument. Bill had built the Fairy Meadows hut in collaboration with the Alpine Club of Canada. I’ve been there and it is a solid but simple affair. Apparently, Bill had a falling out with the club and proceeded to take everything that was his (whether nailed down or not!) to this nearby location in the Battle Range and with the help of Hans Gmoser and many friends, built what is now this much larger and very comfortable hut. He wanted to bring his mistress, Kitty to the hut but she refused unless flush toilets were installed. Thank you Kitty!! Being able to pee comfortably at night on a mountaineering trip is insane luxury and we love it.

To enjoy mountaineering, one must enjoy climbing. I don’t necessarily mean the vertical sort with ropes (class 5) but rather just the act of going higher. For me there is a sort of excitement that builds as I ascend from forest to those sparse islands of tiny knurled alpine evergreens called krumholtz and on to the carpet of micro vegetation known as alpine tundra. It is difficult to enjoy this sort of thing unless you are in shape so it definitely helps to visit the gym regularly. Several of the boys packed a respectable belly and yet all kept up a ferocious pace of climbing and skiing. I would bet if we measured their insulin sensitivity we would find it to be quite good. This brings up the important point that as far as type 2 diabetes goes, activity is key. My guess is that diabetes is not in their future and that this is solely because of their choice to live an active lifestyle (heart disease is another matter however…). Interestingly, over drinks one evening it became clear that several of the group were brought into this active lifestyle by virtue of their friendship. I’ve heard this story over and over again and it is still music to my ears. Whether we are talking biking or tennis or ice climbing, socializing around a sport is a fantastic way to keep motivated and keep moving.

Skis open up the terrain to winter ascent. The carpet of vegetation is covered with deep snow and skis afford a way to stay on top of it. Often the wind scours the snow above tree line leaving it with a tough crust covering the soft fluffy stuff below. Skiing it is tricky as you don’t want to break through the wind crust but you need to cut into it to carve your turn. Once back in the trees, one plays the slalom game trying not to wind up topsy turvy in a tree well. Many times though the snow fall exceeds the wind and we get to ski powder above tree line.

Descending on skis in any condition is a treat. As any hiker can tell you, the decent is hard on the knees and feet and it seems to go on forever. Even for someone as unskilled as me, skis transformed the descent. The ability to substitute several thousand steps with several dozen face plants is definitely worth it. I can still remember one camping trip where I kept trying to turn while my heavy pack which, slave to Newton’s laws, kept on its inexorable straight line and the results were predictable. (Ski mountaineering requires a certain degree of humor.) It took some time to become proficient (years) but now the down hill path is sheer joy. It is a very different experience from the developed ski hill. First of all, there is only you and your friends. The balance between solitude and camaraderie is delicate but somehow it is maintained in the backcountry setting while lift skiing on the weekend sometimes feels like commuting in heavy traffic. Second, the ski hill runs are usually groomed while the backcountry snow is extraordinarily varied. No two days in the backcountry are alike. Third, the backcountry holds many dangers both obvious and hidden and one must be fully present in the moment. Decisions as to route and timing can have serious consequences. We turn back quite often if the conditions are sketchy. The mountains will still be there tomorrow. Knowing that you and your friends made the right decision brings you closer together than any day on the ski hill.

One way to get around at least some of the dangers of making a bad decision while mountaineering is to go with a guide. We don’t bother with this on our own turf but up here in the big mountains of Canada it makes good sense. The guides of Canada are world class and I routinely trust them with my life. Marco Delesalle, our current guide, trained for almost a decade before becoming fully certified in all aspects of mountaineering.

(Jan 9: Marco led a group over to ski “The Waterfall” on the way down to Butters Creek about 1500 feet below the Abbey. We were hoping to summit Little Ahab that day and the creek descent was necessary to get to the base of our objective. “I don’t recommend my line,” he shouted up. “and your line doesn’t look so good either!” I was soooo glad I went with Robeson’s group where all we had to contend with was mystery moguls with unknown surprises below each one. Once again our snow pit on the summit approach warned us away but the ski descent was fantastic and the dinner table was again wild with traded stories.

Robeson is done with the wiring and Jeff has finished chopping wood. Kelly suggests a run up to the pass and a hair raising decent down the only moderately rocky “Kitchen Envy”. A warm cup of tea or a hair raising run? Ahhh……vacation!

If you are interested in trips run by Marco Delesalle click here.

Robeson Gmoser also runs trips (often with Marco – his boyhood friend) and can be reached by clicking here.

To see pictures of Battle Abby click here.

February 6:

Even biologists have to take a break sometime. My wife and I do not do warm vacations…we gravitate to the snow. Furthermore, if sharp metal objects, remote locations, and verticality are involved; so much the better. This is how I found myself stepping into a Bell 212 helicopter along with 7 other people, many pairs of skis, climbing gear, FAR too much alcohol and food, and arguably one of the most experienced pilots to be found in the Canadian mountains.

One does not actually step into a helicopter. Rather, one runs – bent as low as possible so as not to loose one’s hat to the rotor wash; grabs at anything available and scrambles into a seat. The sound is deafening and ear protection is rather useful. They used to have headsets that were patched into the pilot’s communication channel but in the past passengers would forget that they were wearing them and exit with the headset still on their heads. This tended to break the fragile cable and so now you must bring your own.

The rotor is surprisingly fragile. Something as small as a ball cap, should it get caught up in the rotor, could create thousands of dollars of damage. Needless to say we listened closely to the safety instructions and did exactly what we were told.

The helicopter flew out of Golden, British Columbia which is along highway 1, the big trans-Canadian highway that goes through Banff and Lake Louise. Golden is just west of Yoho National park and the drive there is extraordinarily beautiful. The company that supplies the helicopter and pilot is called Alpine Helicopters. Our pilot was Don McTighe who has been flying various routes in the surrounding mountains for almost 30 years. Don knows all the guides and has worked closely with them getting clients such as ourselves into and out of remote spots in almost any kind of weather.

Our destination was a hut called Battle Abby. The flight, all 15 min of it was quite exciting. With the rotors slowly rotating, various people scurried around the helicopter loading supplies in the tail compartment and the side baskets. Then as they moved away, the sound of the rotor got louder and a fine vibration traveled through the compartment. Our helicopter, as it rose, tilted to begin its trajectory away from Golden. It is that tilt that tells me the adventure has really begun. We are flying and it feels really fast.

The mountains surround Golden. To the east are the Canadian Rockies and to the West is the Purcell range. Just after the Purcell range comes the Selkirk range and this is our destination. The mountains rise quite sharply but we don’t really bother to gain altitude until we are fairly close. Then, in breathtaking fashion we rise up, following a gully and pop over a pass. The snow is only feet below us. As we level off, we see the trees drop downward to a valley perhaps 1000 feet below us and then just as quickly rise up as we approach the next mountain pass. We are not really above the mountains at all. They rise on either side. We are flying among them – between them – almost within them. The Purcell range is fairly tame. We cross the great valley that separates the Purcell Mountains from the Selkirk range and the peaks get really sharp. We see hanging glaciers above us. I fell like I could reach out the window (was it open) and touch the sharp rock face as we fly by. The peaks are several hundred feet higher. We are that close.

We don’t approach the hut from above. We approach from below. The slope is very close now and we seem to be brushing the tree tops as we rise upward. Then suddenly, we come about and there is the bright green roof of the hut just below us. We come down oh so gently and I thank the mountain gods that we did not have to fly in fog or a storm. If the weather is too bad the pilots do not fly and we made sure to give ourselves an extra day before catching our flight back to the US just in case. The definition of “too bad” however is not up to me and I gather that Don can get us into places in all kinds of weather. Basically if he can see anything and the winds are short of gale force, he can get us there. Luckily it was a beautiful day and we got to see everything.

The rotors did not stop. We got out of the helicopter like soldiers in the battle field, running to our safety zone. I saw several bodies prone over piles of gear and from past trips recognized that they were protecting the gear from being blown by the rotor wash as well as protecting the fragile helicopter rotor. This was the outgoing group. From our safety zone by the door of the hut we watched as our gear was expertly piled once the rotors had slowed somewhat. The out going group ran one by one to the helicopter, heads down and torsos bent forward, scrambling as we had done. The rotors kicked up the snow and, as if in a blizzard, we had to turn our heads to keep from being blasted.

We watched as the helicopter first rose, then circled just above the hut, and then soared down the hill – its roar fading. We looked at the glistening peaks around us. Ours now. A smiling face beaconed us and we turned from those white flanks and walked down the snow steps into the welcoming glow of Battle Abby.

(I’ve attached a short video of our take off from the hut after our trip was concluded. Simply click on the link below. You can see a fellow sprawled over the gear of the incoming group and the snow blowing everywhere.  As we come around, you can get a good view of Battle Abby perched upon the side of the mountain.)

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To cure type 1 diabetes we need to do 2 things. Firstly, since the patient has no more pancreatic beta cells to produce insulin we need to make new beta cells. This is what we are going to discuss here. Additionally, we will need to somehow get the immune system to stop attacking beta cells but this is a topic for another article.

How do we make pancreatic beta cells? The principle involves transcription factors and their regulation of the genes that make a beta cell a beta cell. Remember that genes encode proteins and the genetic code is transcribed into RNA which is then translated into protein. Proteins are the infrastructure of the cell. They are the machines that build things through directed chemical reactions (enzymes). They are the components of the vast information network that detects transfers, integrates, and ultimately acts on environmental information (receptors and signal transduction proteins). They give the cell its shape (cytoskeletal proteins), handle its waste (transporters), and do at least 100 other things.

Think about all the different cells in your body. Kidney cells are different from brain cells, which, in turn, are different from pancreatic beta cells etc. Now, all of these cells have exactly the same DNA. Keep in mind that the DNA encodes your genes and your genes are the blueprints for all of the proteins that are going to get made. Your pancreatic cells do pancreatic type stuff because of the proteins present in those cells. This means that the pancreatic beta cell somehow knows which blueprints to read (i.e. which genes to transcribe).

Genes, being long stretches of DNA, have parts that code for protein and other parts that serve to regulate when the gene will be transcribed. We call these regulatory parts of a gene the “promoter”. Ultimately, an enzyme called RNA polymerase has to physically sit down at the right spot on the DNA and start copying the DNA sequence into RNA. Before that can happen, a special landing pad needs to be constructed to guide the polymerase to the right spot. This is accomplished by a special class of proteins that have the ability to recognize and bind to a specific sequence of DNA in the promoter. These proteins are called transcription factors.

Going back to the pancreatic beta cell, all of the blueprints for making and operating a beta cell have promoter sequences that beta cell transcription factors will bind to, thus activating those genes. As you might imagine, some genes are needed in all cells and these will have somewhat more general promoters while other genes may be needed in some combination of specific tissues (say in the brain and in the pancreas) and these will have appropriate promoter sequences to make this happen.

Pancreatic beta cells are beta cells cells, in part, because of the collection of transcription factors found there. Think about what is unique about a beta cell. It makes and secretes insulin for one thing. This means it needs all of the genes turned on (including the insulin gene) to make insulin, package it into secretory vesicles, and construct docking sites on the cell membrane so that those vesicles can fuse and release their contents. In addition, it needs to somehow detect the need for insulin and respond with an appropriate amount of vesicular fusions. The things that it will need to detect are surprisingly many; including glucose levels as well as a variety of hormones that are secreted by the gut and by the nervous system. These hormones are secreted in anticipation of a need for changing the status quo. For example, you decide to eat lunch. Even before the food hits your stomach, the beta cells know due to hormone secretions and are busily preparing. So, all of these capabilities require a complement of genes. What would make a lot of sense is for many of these genes to have similar promoters such that they are transcribed as functional groups. Satisfyingly, this is the case. Promoter sequences allow genes to be organized into overlapping groups based on function. Indeed many proteins fit together to make larger machines (like the transcription complex) so it makes quite a bit of sense to have them transcribed together.

And yet…… this seems unsatisfying in a way because we have simply pushed back the big question one level. Where did those transcription factors come from? Of course, since they are proteins, they came from genes which encoded those proteins and, in turn, there must have been other transcription factors which activated the genes for those beta cell specific transcription factors to be made in some sort of proto-beta cell during development. How circular. It is beginning to smack of the chicken and egg problem. Now we have a special name for these sorts of transcription factors. We think of them as master regulatory switches. As we move backwards through development we move through a lineage of different transcription factor genes, each of which, turns on different groups of genes to build the embryo.

There is one final concept needed to complete the picture. The egg and many of the subsequent cells of the early embryo physically store RNA encoding transcription factors in different parts of the cell. When that cell divides, the two daughter cells will have different transcription factor RNAs and thus will each go in a separate developmental direction as those RNAs are translated into proteins and those different transcription factor proteins will promote the transcription of different genes. Thus do we get different tissues.

Now enters that contentious cell – the human embryonic stem cell. If we know what master switches to activate, we can guide the stem cell to become a pancreas. If the stem cell comes from your body, then the pancreas will be identical to your tissues and this will decrease the likelihood of immune attack. This is the fundamental concept. Introduce the right transcription factors and voila…a pancreas is made!

I am off climbing some mountain or other in a remote part of Canada and will return Feb 14 (weather permitting). This article was originally published on my Examiner.com page and I have republished it here for your reading pleasure.

Nicholas Freudenberg reviewed two books on obesity in the Lancet this week: “The End of Overeating: Taking Control of the Insatiable Appetite” by David Kessler and “The Evolution of Obesity” by Michael Power and Jay Schulkin. From his description they look like they are worth reading. He then went on to discuss how the global food industry contributes to obesity. It is certainly true that the goal of the food industry is to sell us products. What is interesting here is the question of motivation and of responsibility. As a free people do we not have a responsibility to understand how our behavior affects us? Do not corporations have a responsibility to avoid selling us dangerous products? The motivation of the food industry is simple: profit. Our motivations are quite a bit more complex. We eat for fuel but also for comfort. No one should deny the emotional power of the brownie; the consolation of mac and cheese.

The downfall of big tobacco was not just that some people who smoked got lung cancer or chronic obstructive pulmonary disease but that the companies deliberately formulated their product to maximize addiction. Can the same be said for the food industry? Indeed at a recent convention of the Confectioners Association and Chocolate Manufacturers Association, Susan Smith, an official of the Association stated that “They are looking at the tobacco model, turning their sights on sugar the same way they did on tobacco”. If we can become addicted to sugar it would have far reaching consequences. Think about dieting. When the cocaine addict goes off the drug, he or she undergoes intense withdrawal symptoms that are not just psychological but physical. Does a dieter go through milder but ultimately similar physiological changes? It would certainly explain why dieting is so hard and why so many fail at the attempt. The legal system is salivating over the possibilities (another addiction problem I suspect).

A search for the terms “addiction” and “sugar” in the National Library of Medicine pulled up 451 peer-reviewed papers as of this writing. Clearly there exist a number of researchers who think the two terms should be linked. But, addiction is a loaded term. Researchers use the word in very specific ways which may or may not correlate with what we think of as a lay public. When we use the cocaine or heroin model as an example of addiction we are considering a state of physical dependence. In turn, psychiatrists consider addiction as a state of compulsion where the patient pursues a behavior no matter how detrimental it is to the rest of his or her life. While these two states overlap they are not synonymous.

Addiction circuitry associated with dependency has been mapped and central to this circuitry is the nucleus accumbens. A nerve tract called the median forebrain bundle synapses within the nucleus accumbens and releases dopamine as well as endogenous opiates. We can give a rat heroin or cocaine and observe exactly the same changes in behavior and in physiology as we see in people. Turning to sugar, numerous laboratories have given rats the choice of a sugary food versus a non-sugary food and (no surprise) they chose the sugar. In other experiments where fat was substituted, again the rats chose the fat. Is this addiction? Perhaps. In the case of sugar, withdrawal was observed in the rats upon removal of the sugar but withdrawal was not observed with other carbohydrates or with fat. Then a group performed a clever twist on this experiment. They asked whether it was the sugar itself that caused the addictive properties or if it was the taste of the sugar. These are two very different things. Keep in mind, heroin addicts do not make heroin soufflés; they inject the stuff. When sugar was injected, the neurobiological changes that had been observed all went away. The rats were not addicted to the sugar per se. They were addicted to the sensation of eating sugar. Another issue is the timing of the sugar. When the rats were exposed to sugar intermittently and allowed to gorge, they developed the best examples of withdrawal. Constant access was not as successful at producing an addiction phenotype.

While addiction has been associated with the release of dopamine and opiate neurotransmitters within the nucleus accumbens we cannot simply associate the presence of these neurotransmitters with addiction. This is because many simply pleasurable activities also activate these circuits. This could involve winning a contest or simply looking at someone you love. However, we can distinguish between the firing of neurons associated with addiction (for example cocaine addiction) from the firing of neurons associated with a merely pleasurable experience if we use the right tools. In both rats and monkeys researchers, using electrophysiological techniques, were able to distinguish a pattern of neuronal firing that was different when the addicted animal was given a cocaine reward versus a food reward. The pattern seen with food rewards was the same for addicted and non-addicted animals. When constant exposure to sucrose was examined it elicited a pattern of neuronal activity that was far more similar to a pleasurable experience than addiction.

While the eating of sugar may simply be a pleasurable experience there is ample evidence that intermittent reinforcement is a very powerful modulator of behavior. Consider gambling casinos. Millions of dollars have been spent determining exactly the right rate of pay-out on slot machines to motive continued playing behaviors. Dog trainers know very well that by only giving a treat some of the time, their canine students perform far better than if they receive a treat each time they act appropriately upon their cue.

Putting this all together, it seems that there is a component of addiction but it is not the sugar or fatty food. Addiction may come instead through the way we eat the food. Ask yourself; have you ever binged on something for comfort after a really bad day? When food is cheap and ample and comforting, it is extraordinarily easy to travel down this dangerous road.

Returning our gaze to the food industry, are they then blameless? Freudenberg uncovers the smoking gun and it is portion size. Apparently, the size of prepared food portions has been growing steadily bigger over time. This makes little sense from the commercial point of view except that it caters to and encourages our need to binge. A friend of mine who recently became a diabetes educator told me that the biggest hurdle to overcome is the clean your plate mentality. When you have a pile of food on your plate, there is a strong sense that if you do not eat it all, you are wasting resources.

Dr. Freudenberg has presented a reasonable case for some degree of regulation. It will only help us if we help ourselves.

“Most startup companies fail. This is not due to a mistake in the valuation of the founding concept or due to the competency of the workers hired to turn that concept into reality. Rather it is due to a failure in management.” So said the founder of a start up company to my wife who worked there for a time. When the venture capital people put in bad management, he left as did my wife eventually.

If we think of ourselves as start up companies where our components (our workers) are the genes with which we are born, the numbers are vastly different but the forces at play are the same. By and large, most of us are successful. We live long lives as compared to our ancestors. We get more than enough to eat, we pass on our genes for better or for worse, and we get to play far more than was ever possible. When we fail, it is sometimes due to a failure of a component part (think cystic fibrosis for example) but far more often it is a failure of management.

Now I bet you are thinking I am about to go on a rant about lifestyle. I could, I suppose, but actually the motivation for today’s post is a recent paper in the Proceedings of the National Academy of Sciences (PNAS) about genome wide association studies looking for sequences associated with type 2 diabetes. Notice I didn’t use the word “gene” in the last sentence. This was deliberate. In actuality, this research examined sequences that were intragenic. They exist in that mysterious 99% of our genome that does not code for genes. Does it have a function and if so what? We believe that much of it does have a function and that function is, in a word, management.

The research I am about to describe involved a genomic entity called a SNP and this needs some explanation. SNP stands for single nucleotide polymorphism and essentially it is a 1 base pair change in the sequence of DNA. Another more common word for this is mutation. From the early 1900s onward, biomedical researchers have been convinced that genetics would be the key to unraveling human disease. Indeed the success of genetics has been astounding. Initial work involved things that segregated with a simple Mendelian pattern (i.e. traits that involved a single gene). Diseases like cystic fibrosis and others were mapped and the dysfunctional genes discovered in this fashion. However, many diseases (such as type 1 and type 2 diabetes) were not so easy to analyze.

Let’s go over some nomenclature so as not to get confused. For all chromosomes except the X and Y chromosomes there are 2 copies in all normal people. These chromosomes (very long DNA molecules) encode around 20,000 genes; blueprints for proteins. Each gene can have many variants. These arose by mutation and account for the vast differences in a biological population. We call each of these variants an allele. So, each of us can have up to 2 alleles and occasionally we might have 2 copies of the same allele for some gene or other. We refer to a location on the genome as a locus and say that a person is heterozygous at such and such locus; meaning that they have 2 different alleles. Conversely, if they have 2 copies of the same allele we would say that they are homozygous at that locus. Since families obviously share a smaller pool of genes than the species as a whole, we might find it useful to examine the alleles in a family that is prone to some disease in order to better understand how that disease may be affected by those genes. As I mentioned above, many human diseases appear to involve more than one gene. We can begin to get a handle on this by analyzing how often two alleles of separate genes might be found together in an individual that has the disease being studied. If we find that the 2 alleles are found together far more often that would be the case due to random chance we say that the 2 alleles are in linkage disequilibrium. In other words, when these 2 particular genes get together (sort of like two otherwise good teenagers) bad things tend to happen. Geneticists nowadays, take blood samples from a family and then analyze the genome of each family member for markers that span the genome. These markers tell the researcher what alleles are present. It took thousands of years of work (spread out over hundreds of genetics labs) to establish markers that are useful for this enterprise.

As scientists began to analyze the genome at the sequence level (this was long before we had the entire genome sequenced) it was noticed that there were regions that had lots of repetitive sequence. The repetitive sequence is usually from 2 – 6 base pairs in length. It can be repeated tens and sometimes hundreds of times. Interestingly, the number of repeats can vary from person to person. We call these repeats microsatellite markers or sometimes simple sequence repeats (SSRs). We have no idea as to their function. When children were examined, it was found that one could identify the regions of DNA that were inherited from the mother and the father based on the microsatellite lengths found. These were used extensively but they had a problem: they were spaced too far apart. The minimum distance between 2 of these markers was a million base pairs. Several genes could be present within the space between 2 of these marks so the resolution of inheritance, using this technique was rather low. By the late twentieth century, a new kind of mark had become predominant; the SNP. SNPs are found on the order of 1 every 100 – 300 base pairs. Thus each gene contains numerous SNPs. I just did a search of the National Center for Biotechnology Information (NCBI) SNP database and found over 13 million entries within the human genome. More are being submitted each day. That is a LOT of data to crunch. With the rise in the use of computers to store and analyze huge amounts of data we can now begin to look for patterns in SNPs among populations who are suffering from a particular disease: such as type 2 diabetes. Furthermore, several companies have developed technologies to allow the simultaneous measure of thousands of SNPs at once.

This brings us back to our featured article. The authors begin by noting a number of seminal studies that identified 3 groups of SNPs that segregated in type 2 diabetic as well as obese populations done around 2007. One fascinating observation that came out of these reports was that almost all of these SNPs were found in non-coding regions of the genome. In other words, they did not have anything to do with some sort of poorly functioning gene. Now this group has been working on an idea – namely that there exist mysterious regions of the genome that somehow control large regions consisting of many genes. They have referred to these regions as genomic regulatory blocks (GRBs). They have hypothesized that these regions play a role in determining the timing and strength of expression of genes that control development. These genes would be transcription factors (of which I have written before) that sit on the regulatory sequence of genes and nucleate the formation of (or inhibit the formation of) the transcription complex thus determining which genes get made and when they get made. How these GRBs might do this is unknown. In this paper they extended their hypothesis to consider the possibility that many of the risk factors that have been identified for complex human diseases (such as type 2 diabetes) do not actually involve the nearest gene but instead involve some subtle (and as yet unidentified) change in how the GRB functions – which would mean that they worked through transcription factors within each of the GRB locus positions. In turn these transcription factors would affect many downstream genes to ultimately set things up for increased disease risk. In effect, disease is caused by a failure of management.

So, their goal was to see if they could indentify GRBs for each of the 3 groups of SNPs, identified in the 2007 studies that were in linkage disequilibrium and then find transcription factors that would play some global role suitable for altering the risk for type 2 diabetes. Indeed they did find that in each case the SNPs fell within or partially within a different GRB region. This was done by computer (bioinformatics analysis). One block of SNPs fell within a region than contained 3 genes: HHEX, KIF1, and IDE. Using their concept of GRB regulation they looked at the genomes of lots of different species and concluded that only HHEX, a transcription factor that is involved in the development of the pancreas, was part of this linkage disequilibrium when considered in this new way. The fact that it regulated pancreatic development (the source of insulin) made it an attractive candidate gene for type 2 diabetes risk. So far so good. A second block of SNPs was located in the CDKAL1 locus. Unfortunately, unlike HHEX, CDKAL1 was not a transcription factor and had nothing to do with anything that seemed to relate to diabetes. However, again by using their GRB concept they were able to link CDKAL1 to another gene: the transcription factor SOX4. Now SOX4 has been associated with both pancreatic development and with insulin secretion so again they found a good candidate gene. The third group of SNPs that was in linkage disequilibrium with type 2 diabetes was within the FTO locus. Unfortunately the transcription factor associated with this locus, IRX3 had no literature that associated it with pancreatic development or any other aspect of type 2 diabetes.

Undaunted, the researchers went to the bench and started doing experiments. Their favorite model organism is the zebra fish. There are a variety of technical reasons why zebra fish are really good genetic model organisms and perhaps some other time I’ll talk about it. Using some fancy molecular biology they actually uncovered a relationship between IRX3 and another transcription factor known to affect pancreatic development:Nkx2.2. It turned out that IRX3 was needed for full Nkx2.2 function. So…3 groups of SNPs associated with type 2 diabetes were associated with 3 transcription factors that played a role in pancreatic development. The important point here is that none of these genes was damaged or mutated in any way. The mutations were in regions that we assume somehow physically manage the timing and intensity of expression of these critical developmental regulators. How these regions work is anyone’s guess.

The authors state up front that they have not proved anything. Rather, they have presented an intriguing new relationship between genetic markers for disease and what these markers are marking. Numerous experiments need to be done manipulating these regions by directed mutagenesis (probably in mice) and examining the effects on pancreatic development, metabolism (especially insulin release), and diabetes susceptibility.

By this point (and congratulations for making it this far) you are probably wondering what good this is going to do for anyone. The answer is personal medicine. We are not simply our genes. It is absolutely clear to us now that all sorts of environmental factors play subtle roles in the shaping of our development. We are just beginning to get a glimmer of the majestic dance that is played between nature and nurture. If we can understand it, perhaps we can guide it. For example, if we know that certain SNP combinations create an increased risk of obesity, perhaps we might find some new diet or therapy administered at some critical juncture that guides the patient safely past that decision point. Of course this is the medicine of the future. It will be important to avoid the sort of “Brave New World” envisioned by Aldus Huxley but I have hope that we can use this sort of power for empowerment and not for enslavement. For the present, my consciousness has enough problems making decent decisions. I just hope my genome can fend for itself.