and this is a summary of some of the points which came up in the comments (there is a lot of information and links from the comments about possible causes and management for those interested) added to the figure:
While I was raiding this paper I thought I would also put up Table 1, the characteristics of the control and diabetic offspring groups:
Now you have to be very, very careful with these groups. They have been exceedingly carefully preselected. Fortunately the pre selection process is laid out in some detail in a previous paper from 2004:
"All subjects were recruited by means of local advertising over a two-year period (2001 to 2003) and were prescreened to confirm that they were in excellent health, lean, nonsmoking, and taking no medications. A birth weight above 2.3 kg (5 lb) and a sedentary lifestyle, as defined by an activity index questionnaire,(21) were also required. Qualifying subjects (more than 150 persons) underwent a three-hour oral glucose-tolerance test (with a 75-g oral glucose load), after which two subgroups of subjects were consecutively selected to identify extreme phenotypes for insulin resistance and increased insulin sensitivity.
Insulin-resistant subjects (3 men and 11 women) were defined as having an insulin sensitivity index (22) of less than 4.0 (indicating insulin resistance; lower values indicate greater insulin resistance), at least one parent or grandparent with type 2 diabetes, and at least one other family member with type 2 diabetes. Insulin-sensitive control subjects (five men and seven women) were defined by an insulin sensitivity index of greater than 6.3 (with or without a family history of type 2 diabetes)."
As I read this it looks like over 150 people were screened for insulin resistance. Of those 150 those with the best and worst insulin sensitivity were selected as controls or subjects respectively. BUT you were only allowed in to the insulin resistant group if you did have a relative with T2DM. We get no idea of how many people had awful ISI and no diabetic relatives, ie if there were any index cases who might represent the red scrible on the second picture. Maybe there were loads, maybe not. I can't find that information in the paper. So we have to be very careful, the T2DM-relatives aspects MIGHT be a complete red herring. The insulin resistance is not.
Soooooo, with that caveat in place, we can see that (completely observationally) the insulin resistant group had, by definition, elevated insulin (and poor ISI) and the control group didn't. The control group weighed 61kg, the insulin resistant group weighed 66kg. Hmmmm. Observational, cross sectional. Fascinating.
You could simply say that the insulin resistant group were only hyperisulinaemic BECAUSE they were 10% porkier than the svelt control group. Indeed, if you consider porkiness to be a result of simple overconsumption of calories, for whatever reason, this would have to be an effect, not a cause.
Shulman's group extend the concept of mitochondrial failure in muscles to a potentially related mitochondrial failure in beta cells during the discussion. That's an interesting idea. Let's go one further and think about mitochondrial failure in adipocytes... I know it's odd to think that adipocytes (or indeed their mitochondria) might have anything to do with obesity, but stranger ideas have been floated.
Peter
BTW they also mentioned genes which control mitochondrial biogenesis:
"In this regard it is of interest that a common Gly482Ser polymorphism of the peroxisome proliferator–activated receptor γ coactivator 1, a transcriptional regulator of genes responsible for mitochondrial biogenesis and fat oxidation, has been linked to an increased relative risk of type 2 diabetes in Danish populations as well as to altered lipid oxidation and insulin secretion in Pima Indians."
I just noticed that the alpha form of peroxisome proliferator–activated receptor γ coactivator 1 got an honourable mention back in one of the Fiaf posts on the control of host metabolism by the gut mircobiota...
15 comments:
Perhaps we should think of a human as a colony of cells rather than a single organism. This creates a scenario of individual cells competing for resources. In the case of adipocytes the resources are carbohydrates. This then creates a powerful positive feedback loop where increasing numbers of adipocytes demand more carbohydrate to reproduce themselves.
The family history of Type 2 is required because most people who are insulin resistant never become diabetic. The number of people with diabetes in the overall population stays fairly close to 9% but the number of obese and insulin resistant people keeps growing to where it is somewhere between 1/2 and 2/3rds of all older adults.
This is only one of several studies that finds high IR in the lean relatives of people with Type 2.
Many obese people with IR have the ability to grow new beta cells to keep up with the demand for insulin. People with diabetes don't.
Jenny:
Thanks for the important distinction (beta cell functioning) between T2 diabetics and insulin resistant individuals that don't develop diabetes. Your blog is so informative.
Very interesting post from a physiological perspective. However,
I would not want to know the status of my mitochondria and would not be willing to test. I would rather hold on to the illusion of functioning mitos as I am very energetic and physical. The more tests, the more disease labels, the more one can feel defective and unwell. There is a strong psychological component to wellness. It is enough for me to know my father is type 2 and that I am glucose intolerant. Solution at least for now: LOW CARB.
That's interesting. Peroxisome proliferator-activated receptor gamma coactivators alpha and ss are important regulators of mitochondria thermogenesis.
I agree with Jenny in this sense;
The literature tends to equate IR with diabetes, as if diabetes is the eventual outcome of IR, when in reality diabetes is a very specific manifestation of glucose intolerance and not everyone has the genetics (or environmental damage) to develop it. This is much in the way that severe obesity is also a very specific manifestation of glucose intolernace, and not all glucose intolerant people will gain much if any weight - it requires a certain set of traits in place (rapid insulin processing in adipocytes + relative insulin sensitivity of adipocytes as compared to other tissues + strong genetic potential for adipocytes to respond to insulin with hyperplasia).
If trying to predict DM2, it is a good idea to preselect people with DM2 relatives.
@ Jenny
Another reason the obese can avoid diabetes is that people prone to type 2 diabetes literally make a lot more blood sugar in the liver than non-type 2 diabetics. I don't mean mere hepatic insulin resistance, an absense of insulin signaling to suppress gluconeogenesis... I mean that their liver , all the time, is making like three times the amount of sugar as a non type 2 diabetic. This is why type 1 ketoacidosis can occur at sugar levels of 400 or 500, and this is the full extent of a type 1 making blood sugar full on... but a type 2 diabetic can have his or her sugar go into the THOUSANDS, and still not ever enter ketoacidosis or ketosis for that matter, because he still has the insulin required to suppress lipolysis/ketoacidosis. Yet, clearly, his liver is spewing horrific amounts of sugar, far higher than a "normal" liver with no insulin signaling (as typified of a metabolically normal untreated type 1 who peaks at about 500 before they die).
This is a major genetic trait that greatly predisposes to the development of diabetes. If you have a liver which just makes a TON of sugar all the time you can easily develop hyperglycemia under trivial insulin resistance of liver.
The obese also avoid diabetes because in a lot of ways having the genes for white fat cell hyperplasia under duress of abnormally high insulin is a free pass to get out of dialysis/amputation/heart attacks. The more you can grow new white fat cells under stimulation of insulin, the more easily you can keep your sugar under control as those new fat cells are very insulin sensitive depots for fat and sugar. YOu will remain "metabolically healthy" and will avoid that horrible inflammatory visceral fat as long as your arms and legs are expanding to the size of small children due to tumor like replication of the fat cells under your skin on limbs.
Side note, this is also why many females are "metabolically healthy" relative to males, all that estrogen and progesterone allows for insulin (in response to glucose intolerance) to cause new fat cell growth - in absence of estrogen/progesterone (male endocrine system), the insulin does not cause this new fat cell growth and so boom, fatty liver and triglycerides of 1000 and toes are lost and off to dialysis for you.
The type 2 diabetic is often given drugs which mimic obesity genes: many diabetic drugs work for no other reason than they make the body grow new fat cells.
"YOu will remain "metabolically healthy" and will avoid that horrible inflammatory visceral fat as long as your arms and legs are expanding to the size of small children due to tumor like replication of the fat cells under your skin on limbs"
jeez, it's hard to clean between the keys after you've spit your egg salad all over them.
Woo, why the heck don't you have a blog?
Shel
I second that woo. Always enjoy your comments.
blogblog, I think the brain likes to get its oar in everywhere and does control as much as it can as well as it can. But there are limits with broken tools...
Jenny, yes. It's the pancreas of steel which avoids diabetes for longest but you do need functional adipocytes too. Lots of trade offs. Even I have to accept some genetic input. Those poor old Pima were pretty porky and diabetic in pre crap-in-a-bag days. Might be interesting to put up the paper to that effect which came up in comments recently.
Peter
@Peter,
I agree the brain does it's best. However we make it very hard for this poor organ to do it's job properly.
Since now you are fascinated by this line of research, you will probably enjoy this.
http://cardiovascres.oxfordjournals.org/content/early/2011/09/29/cvr.cvr258.short?rss=1
Hi Bolalbi,
There are some interesting ideas in that abstarct. I think we will come back to Ca2+ signalling and mitochondrial swelling when we finally get to look at the brain, amongst other places...
Peter
As someone intimately familiar with Shulman's work I would appreciate if you would refrain from editing published figures to include silly speculations.
There is a wealth of literature on aging, environmental toxicology, and maternal transmission of metabolic traits (through mtDNA mutations, mitochondrial function is irrelevant) which is backed by actual experimental data. A good rule of thumb is: if message board speculators can come up with a hypothesis that sounds reasonable, a graduate student already tested it in 1972. Noteworthy results would be appreciated by now.
"Many obese people with IR have the ability to grow new beta cells to keep up with the demand for insulin. People with diabetes don't. "
What about us half-and-halfs?
One side of my family has IR in non-overweight folks, but only males go on to develop diabetes. I'm right on the cusp - well my Phase 1 insulin is pretty non-existent but my Phase 2 still works pretty well, if I overcarb I can generate Reactive Hypoglycemia.
This recent TV programme
http://www.bbc.co.uk/programmes/b013ywz4#synopsis
looked at IR in the south Asian population, starting in children, and again leading to diabetes but not necessarily obesity.
They blamed epigenetics, which may be one of many factors. Sadly I doubt a low carb diet would be affordable (and of course they don't eat beef).
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