I ran into a couple of interesting references to bears, diabetes, and hibernation. This got me (and others) wondering about the connection. While most of the folks speculated that bear metabolism might give clues to “curing” our “disease” of diabetes, I instead wondered if this might just be a pointer to very unused metabolic pathways in humans and a kind of “hibernation lite”.
Humans are Euarchontoglires, some members of which hibernate.
Euarchontoglires (synonymous with Supraprimates) is a clade and a superorder of mammals, the living members of which belong to one of the five following groups: rodents, lagomorphs, treeshrews, colugos and primates.
There’s a reason bunnies and lab rats are useful for medical testing, they are our distant cousins. Squirrels are in there too along with beavers in the rodent group. Many of these animals have facultative hibernation or winter torpor states.
Now evolution tends to be a a pack-rat for metabolism. It doesn’t just toss out a system wholesale because it isn’t needed at the moment. Usually it finds a way to just adjust the trigger mechanism to shut it off. For this reason, you can do interesting things with various animals. The most extreme one I read about decades ago (so no references that I know of now) has to do with “chicken teeth”. Some enterprising biologist took a sample of chicken gum tissue and transplanted it “somewhere else” on their body. There, removed from the local hormones of the mouth and jaw, it formed teeth. Yes, chicken teeth. See, when they evolved from dinosaurs and developed the beak, they didn’t just drop all tooth genes; only shut off the actual formation of teeth step in the location of the mouth.
Now this raises an interesting question: Did all those Euarchontoglires which have some sort of hibernation evolve it separately, or was it an inherited primitive that some of us have turned off? We don’t know, but we DO know that if you inject the hibernation trigger molecule into lab rats they go into hibernation, so at least some of the Euarchontoglires ‘had it and lost it’; and that argues for a more wide spread set of genes for it.
But that’s all off in the Rodents & related lines, not Primates. do ANY Primates hibernate? If so, that would argue the original ‘metabolic skill’ ought to be widely shared in the whole group, not just a rodent thing.
First discovery of a hibernating primate outside Madagascar
December 3, 2015
University of Veterinary Medicine — Vienna
Up to now, three species of lemurs on Madagascar were the only primates known to hibernate. Researchers at Vetmeduni Vienna in Austria, now show for the first time that another primate species that lives in Vietnam, Cambodia, Laos and China, the pygmy slow loris, also uses hibernation to save energy. The results were published in Scientific Reports this week.
So Lemurs and Loris both hibernate. Not exactly chimps and baboons, but spread from Madagascar to Asia…
While not proof, it does argue for a common metabolic system throughout the lot of us. Some biochem examination (and / or genetic examination of the system) ought to show degree of common source vs independent evolution.
Presuming it’s more likely a bit of common source… (and having some vague memory of someone inducing a hibernation like state in several animals and maybe even people with a sulphur gas /compound some years back causing a ‘stir’ about us being able to hibernate too, or some such) The most likely conclusion is that we either have the full blown metabolic paths in us, or somewhat disused and perhaps slightly broken by uncorrected mutations set of such metabolic paths (and states).
The Paper Chase
So OK, up front, the “paper” that caused the rush of folks after bear hibernation as diabetes state was withdrawn. The reason was ONE of several researches had fudged some data that showed up in 2 graphs. The sponsors and the other authors are re-doing the paper without him and stand by the conclusions. Time, one hopes, will sort it out. In the mean time I’m presuming that there is some “there there” on the basic biochem of finding diabetic markers in hibernating bears.
Retraction of grizzly bear-diabetes study follows departure of Amgen scientist for data manipulation
The retracted paper made the cover of the August 2014 issue of the journal. (Cell -EMSmith)
A study that looked to hibernating bears to understand the mechanisms behind diabetes has been retracted because an author based at the biotech company Amgen “manipulated specific experimental data” in two figures.
Gee, “manipulated specific experimental data” is called “adjustment & correction” in “Climate Science”, maybe he needs to start studying bears as climate proxies ;-)
LOTS of links in this quote in the original…
According to the The Wall Street Journal, Amgen discovered the manipulation while reviewing the data following publication of the paper,”Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.” Published in Cell Metabolism last year, the paper has been cited 8 times, according to Thomson Scientific’s Web of Knowledge.
A press release from the journal last year — coverage in Science and Nature followed — explained the purpose of the study:
While diabetes rates are on the rise and are having serious effects on millions of people’s health, researchers studying grizzly bears have now discovered a natural state of diabetes that serves a real biological purpose and is also reversible. Investigators reporting in the August 5 issue of the Cell Press journal Cell Metabolism note that grizzly bears are obese but not diabetic in the fall, become diabetic only weeks later in hibernation, and then somehow become “cured” of diabetes when they wake up in the spring. The research reveals how natural biology, through evolutionary experimentation, can teach us new things about how animals naturally cope with conditions that would cause disease in humans.
And here’s the retraction note, which details the study’s problems:
This article has been retracted at the request of the authors.
Amgen requested the retraction as an outcome of an internal review where it was determined that one of the Amgen authors had manipulated specific experimental data presented in Figures 1 and 3. Because of data manipulation, this author is no longer employed by Amgen. The authors at Washington State University and University of Idaho are confident that the physiological data generated for this manuscript are accurate and representative of the true metabolic responses of these grizzly bears and are currently repeating the mechanistic portions of the study. Amgen deeply regrets this circumstance and extends their sincere apologies to the scientific community.
OK, I’m willing to stick with the physiological parts.
The original article:
Cell Metab. 2014 Aug 5;20(2):376-82. doi: 10.1016/j.cmet.2014.07.008.
Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.
Nelson OL1, Jansen HT2, Galbreath E3, Morgenstern K4, Gehring JL5, Rigano KS5, Lee J6, Gong J6, Shaywitz AJ7, Vella CA8, Robbins CT5, Corbit KC9.
The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of “healthy” obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition.
So ponder for just a moment. What triggers bears to gorge for hibernation? Less sunlight? Less activity? Perhaps a surge of fructose as fruit all ripens in fall? Just getting really fat enough? What has modern life brought to humans? Less sunlight. Less activity. A gigantic surge of fructose in whole swaths of “modern foods”. Getting rather fat enough… and then some.
So as we sit around in our “people caves”, not getting sunshine or activity, stuffed with fructose and gross calories, we get fat. This starts a fatter, lazier, less active cycle. Oddly, it tends NOT to start an ‘eat less’ cycle… just like the bears… Eventually it DOES seem to depress mental activity too. We eventually become more listless and “just want a nap on the couch”. (I can support this by pointing out I just woke up from my unexpected nap after a few blueberry muffins for lunch…)
Just how is this really any different from the bear cave or the squirrel curled up in a tree hole or underground? Stuffed, lethargic, in the dark.
Now when actively hibernating, the metabolism shifts. Metabolism of blood sugar is suppressed via insulin resistance and metabolism of fats is encouraged. In humans, we become “insulin resistant”, but instead of a ‘long long nap’ working off the fat stores, we keep shoving in the carbs… which have to go somewhere.
For some folks, that’s obesity. Sometimes lots of it, without an insulin issue. Still in the Fall mode, as it were. For other folks, they seem to shift to the winter mode of low metabolic rate and not forming fat. The blood sugar rises and we end up in a diabetic end of things as sugar gets, literally, pissed away. Still lethargic and still munching. Almost like we’re stuck 1/2 way into hibernation, but not getting the whole way.
This would be in agreement with the observational evidence for exercise and fasting as helpful in treating, or even ‘cures’ for T2 Diabetes. We are, essentially, putting ourselves into an artificial Spring and breaking the hibernation state.
Perhaps even the color and length of lighting matters to the trigger. This could vary by person, depending on how much of the primordial hibernation process and trigger systems existed in them.
Sabretoothed has a set of links on human light sensitivity starting about here (H/T Sabretoothed):
Earlier I’d noted the link between too much blue (too late at night) and insomnia from LED bulbs:
So who knows, perhaps running some cheap LEDs early in the morning to get jump started, running on the treadmill (real or metaphorical), then cooling down with 2700 K incandescents at night over a dinner of meat & leaves (Spring time fare) could shift a person back to a more Spring / Summer and less Fall / Winter mode…
Having put on a few pounds since functionally retiring last year, and “suddenly” having my first ever blood sugar not perfectly normal experience, I’m giving it a try. While I’m in the “normal” range, I’ve already shown I can drive it to “pre-diabetic” with a bout of lethargy and starches, yet get out of it with “meat & leaves” meals and dancercize to the TV.
So, in keeping with my “It’s my body and I’ll experiment If I want to!” theme; I’ve put two of the Dreaded Insomnia LED bulbs in my office space. I’ll be using them in the mornings especially on days I’m not outside. Shifting to the 2700 K (CFL / IC) mix in the evenings.
I’m also moving to add a lot more leaves to the diet, and have already dropped most all sugar (other than what the spouse bakes into things, like those muffins ;-)
So salads, sauerkraut, Brussels sprouts, choy, cabbages & such much more; noodles and potatoes and sugary cereals not so much. Coffee and tea black. Sugary drinks not at all. It’s springtime, after all… Think sauerkraut & wieners, not fruit tart and mashed potatoes.
We’ll see what happens. I’m not an ideal test subject, since my “after a dinner of potatoes and limas lots of starch” sugar was only 165. High, but only by about 20 points from any “while digesting starches” reading normal. Full diabetics could be hitting a few hundred by then. Still, IF I start plating 90s after dinner, we’ll know something happened ;-)
Clearly I need to add some exercise to the pattern too. Sleepy bears lay in caves all winter. Spring Bears are out running around. Had not planned a garden this summer (the space is a mess after 2 years of neglect), but I think that “yard time” is not optional. So I need to schedule in some shovel time, it seems. Need to go rooting around for those leaves and berries, after all ;-)
Odds & Ends & Links
Some Misc. bits are collected here, including links to some other stories based on this same source paper.
How hibernating animals are helping doctors treat diabetes and Alzheimer’s
Unlocking the secrets of hibernation could help doctors solve some of medicine’s most pressing problems
One such brain pathway helps to activate hibernation in ground squirrels when a chemical called 6N-cyclohexyladenosine (CHA) attaches to a cell surface protein called the A1 adenosine receptor (A1AR). When the action of CHA on these receptors is blocked in the squirrels, Drew’s team in Fairbanks has shown that hibernation is prevented. They also have shown that giving CHA to non-hibernators, such as rats, makes them appear to hibernate too, provided they are put in a cold environment.
“This tells us that CHA might have a potential role in therapeutic hypothermia,” suggests Drew, but there’s also another factor. Natural hibernators ‘get sick’ as they enter hibernation, and then ‘cure’ themselves when they awaken. This could have profound implications for how we assess illness and the types of treatments mounted against it.
Consider the respiratory system, for instance. In the midst of an asthma attack, and in patients with chronic obstructive pulmonary disease (COPD), airways constrict, causing the lungs to over-inflate similar to an expanding balloon. Research on Syrian hamsters shows that their lungs over-inflate to prevent lung collapse as the breathing rate decreases down to two to three breaths per minute. This happens as the animal’s core body temperature drops during the onset of torpor, a kind of short-duration hibernation. Along with overinflation, a plethora of different proteins appear on the surfaces of lung cells in human COPD and asthma. This is called molecular remodelling and it happens not just in lung disease but also in hamsters entering torpor.
As the hamsters come out of torpor, the pulmonary changes reverse, as do changes occurring in other organ systems. Decreasing body temperature in hibernation is associated with a drop in heart rate. Physiologically, the change looks like what physicians call second-degree heart block. As the animal heats up, the heart rate returns to normal. By studying the mechanisms underlying the reversals in hibernators, scientists may uncover new treatment strategies for pulmonary and cardiac disease in humans.
Elsewhere, with type 2 diabetes, patients produce the hormone insulin but the insulin is not effective because sensitivity of cells to insulin is abnormally low. Because of the reduced insulin sensitivity, cells do not absorb sugar from the blood. Scientists at the University of Tennessee have shown that essentially the same thing happens in black bears as they enter hibernation; they become insulin resistant. This keeps their cells from absorbing blood sugar (glucose), which enables them to draw energy from fats that have built up in the weeks prior to hibernation. In terms of blood chemistry, hibernating bears look like diabetic humans, but on revival from hibernation the chemistry returns to normal. This suggests there must be a chemical pathway underlying insulin sensitivity that can be adjusted. If scientists can get a hold on such a pathway, they might be able reverse the same effect in diabetic people.
But perhaps, the greatest beneficiaries of hibernation research will be those suffering from degenerative conditions in the brain. Synapses are connections between nerve cells, akin to the electronic connections in a computer. Learning and creation of memory are associated with formation of new synapses in the brain. In dementia, especially in people with Alzheimer’s disease, recent memories deteriorate along with the ability to form new ones. This happens as synapses disappear. During hibernation, connections between neurons in the brain deteriorate, just as they do in Alzheimer’s, but what happens as the animals start waking up? You guessed it; synapses are restored. In fact, on revival, hibernators go through a so-called hypersynaptic state, characterised by an overabundance of connections. Subsequently, the brain settles down to its pre-hibernation connections.
Note that it also references Alzheimer’s that is looking like Type 3 Diabetes:
So what if these are less diseases and more operating machinery out of specifications?
(Has an ad-blocker nag, so I’ve copied more freely to save you the grief)
August 5 2014
An ability of grizzly bears to cope with obesity and diabetes during hibernation could provide lessons for the care of humans, say researchers.
Every autumn, the bears prepare for winter by stuffing themselves with food and becoming obese.
Weeks later during hibernation they enter a state similar to type 2 diabetes, only to “cure” themselves when they wake up in the spring.
US scientists studying the bears made the surprising discovery that when grizzlies are at their fattest they are also most sensitive to the blood sugar regulating hormone insulin.
This was achieved by shutting down the activity of a protein called PTEN in fat cells.
Also, in contrast to humans, blood insulin levels in diabetic grizzlies did not change. Instead, cells that the hormone communicates with turned their response off and back on again when it was time to stop hibernating.
Lead scientist Dr Kevin Corbit, from the US biotech company Amgen Inc, said: “Our results clearly and convincingly add to an emerging paradigm where diabetes and obesity – in contrast to the prevailing notion that the two always go hand-in-hand – may exist naturally on opposite ends of the metabolic spectrum.
“While care must be taken in extrapolating preclinical findings to the care of particular patients, we believe that these and other data do support a more comprehensive and perhaps holistic approach to caring for patients with diabetes and/or obesity.”
Cellular mechanisms leading to obesity may in fact protect certain patients from diabetes, said Dr Corbit.
In other patients, mechanisms leading to diabetes may protect against obesity.
Humans with low levels of PTEN were likely to possess the bear-like quality of remaining highly insulin-sensitive even if obese.
“Moving forward, this more sophisticated understanding of the relationship between diabetes and obesity should enable researchers not only to develop therapies targeting these mechanisms, but also to identify the appropriate patients to whom these therapies should be targeted,” Dr Corbit added.
“Develop therapies”? Might we not just realize we’ve got the same or very similar metabolic pathways and apply the expected natural processes and triggers to “make it Spring again” for our bodies?
6 August 2014
Grizzly bears become ‘diabetic’ when they hibernate
By Philippa Skett
Some bears can have their cake and eat it too. Grizzly bears become “diabetic” during hibernation, and then recover when they awake.
Lynne Nelson at Washington State University in Pullman and her colleagues investigated insulin activity in tissue samples taken from six captive grizzly bears over the course of a year.
As the bears put on weight in preparation for the winter, they responded normally to insulin – which prevents the breakdown of fatty tissue. But during hibernation, insulin effectively stopped working. That is a symptom in people with type 2 diabetes, in which high fat levels in the blood induce insulin resistance.
OK, so get those blood fat levels down. Exercise a lot more, eat a lot less… Avoid sugars (and starches) so your metabolism must shift to fat burning.
“Diabetes and obesity may exist naturally on opposite ends of the metabolic spectrum,” says co-author Kevin Corbit of biotechnology firm Amgen in Thousand Oaks, California. “The cellular mechanisms that could be protecting people from diabetes, and the mechanisms leading to diabetes in other patients, may also be what protects them from becoming obese.”
The results suggest there is a chemical pathway involved in altering sensitivity to insulin. This pathway could hold the key for developing treatments for type 2 diabetes.
Or maybe, just maybe, they are two ends of a metabolic oscillator designed to keep us in pace with the seasonal shift of food availability. Putting on the pounds when summer and fall arrive with lots of fruits, starches and all; but burning them up during a long winter fast and the occasional critter on the BBQ.
To the extent that is true, just getting in sync with seasonal food availability and types ought to help.
Maybe it just confuses the food storage / burning switch to be stuffing ourselves to the gills year round and never being hungry chasing dinner. Perpetual Fall Feasting might just be a Very Bad Idea.
There seems to be lots of anecdotal evidence for a fasting “cure” for T2 Diabetes:
Which would be in keeping with the idea of diabetes as Hibernation Lite. So after the Fall Feasting, you need a (maybe very short) Winter Fast, and they you are again ready for the Spring “meat & leaves” while you wait for those Fall pies, roots, and fruits again…