In the last article on diabesity and metabolic syndrome, we discussed the complex relationship between body weight and type 2 diabetes (T2DM). We learned that although obesity is strongly associated with T2DM, a subset of “metabolically healthy obese” (MHO) people have normal blood sugar and insulin sensitivity and don’t ever develop diabetes.
In this article we’re going to talk about the mirror reflection of the MHO: the “metabolically unhealthy nonobese” (MUN). These are lean people with either full-fledged type 2 diabetes or some metabolic dysfunction, such as insulin resistance.
Perhaps these folks have been overlooked because type 2 diabetes has been historically viewed as a disease of gluttony and sloth, a self-inflicted outcome of eating too much and not exercising enough. But the very existence of the MUN phenotype proves that there’s more to T2DM than overeating and a sedentary lifestyle.
Remember that one in three type 2 diabetics are undiagnosed. It’s possible that a significant number of these people that are lean. They don’t suspect they might have T2DM because they’re under the impression that it’s not a condition that affects thin people. This is one of the biggest dangers of the myth that “only fat people get diabetes”.
It’s well-known that high blood sugar can precede the development of T2DM for as long as ten years. It is during this time that many of the complications associated with diabetes – nerve damage, retinal changes, and early signs of kidney deterioration – begin to develop. This is why it’s just as important for lean people to maintain healthy blood sugar as it is for the overweight and obese.
What Causes High Blood Sugar and T2DM in Lean People?
Not surprisingly, the causes of T2DM in lean people are similar to the causes of T2DM in the obese. They can be loosely grouped into the following categories:
- Genetics
- Fatty liver
- Inflammation
- Autoimmunity
- Stress
Let’s discuss each of them in turn.
Genetics
Studies of the lean, otherwise healthy offspring of type 2 diabetics has revealed that they are much more likely to be insulin resistant than the lean offspring of non-diabetics. One explanation for this is an inherited defect that causes mitochondrial dysfunction. People with this defect are not able to burn glucose or fatty acids efficiently, which causes lipotoxicity and an accumulation of fat inside of muscle cells.
I will discuss the contribution of genetics in more detail in the next article. What I want you to understand here is that the genetic mechanisms I described above are capable of causing insulin resistance and high blood sugar independently of overweight or obesity.
Fatty Liver
Studies of lean, Asian Indian men have found that they have a 3- to 4-fold higher incidence of insulin resistance than their caucasian counterparts. They also have a much higher prevalence of non-alcoholic fatty liver disease (NAFLD) and hepatic (liver) insulin resistance.
NAFLD is an independent predictor of type 2 diabetes. Cross-sectional studies have shown that fatty liver and metabolic abnormalities occur together. It has also been proposed that fatty liver is not just a result, but also a cause of insulin resistance and type 2 diabetes.
Now, keep in mind that these Asian Indian men with NAFLD were not overweight. They were lean, and in some cases, even underweight. This proves that NAFLD occurs in lean people, and together with the evidence above, suggests that NAFLD may be a primary cause of insulin resistance and T2DM in lean people.
If you’re thinking NAFLD might be a rare problem confined to Asian Indian men, you should know that up to 30% (almost 1 in 3) of people in industrialized nations suffer from it. This is a disturbingly high prevalence of a condition that is known to progress to severe liver inflammation and cancer in a small percentage of people – in addition to contributing to T2DM and metabolic syndrome.
While there may be a genetic component that predisposes people to developing NAFLD, we also know that dietary factors play a significant role. Rodent studies have shown that feeding large amounts of sugar and industrial seed oils (like corn, safflower, sunflower, etc.) promote NAFLD, whereas saturated fats such as butter and coconut oil do not. And in human infants, tube-feeding with industrial seed oils causes severe liver damage, whereas the same amount of fat from fish oil does not.
Fructose, especially the high-fructose corn syrup (HFCS) found in sodas, candy and several packaged and refined foods, is perhaps the most significant dietary cause of NAFLD. The liver processes fructose by converting it to fat. The more fructose consumed, the more fatty the liver becomes. Feeding rodents high amounts of fructose promotes NAFLD, and the consumption of soft drinks (by humans) can increase the prevalence of NAFLD independently of metabolic syndrome.
Let me say that again: high fructose intake can cause fatty liver disease independently of overweight, obesity or type 2 diabetes. Do you think that might be a problem in a country where soft drinks account for nearly 10% of total caloric intake?
Since fructose is handled by the liver in the same way the liver handles alcohol, excess fructose produces a similar range of problems as alcohol abuse: hypertension, high triglycerides and low HDL, obesity, cirrhosis and insulin resistance.
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Inflammation
In the study of lean Asian Indian men above with T2DM, it was found that they had a 2-fold increase in plasma levels of the inflammatory protein IL-6 when compared to lean subjects without T2DM. In a previous article I showed that chronic, low-grade inflammation associated is an important mechanism in decreasing insulin signaling and causing insulin resistance in muscle, liver and fat cells.
Also, inflammation has been shown to precede the development of diabetes. Infusion of inflammatory cytokines into healthy, normal weight mice causes insulin resistance, and people with other chronic inflammatory conditions are at higher risk of developing T2DM. For example, about one-third of chronic Hepatitis C patients develop T2DM, and those with rheumatoid arthritis are also at higher risk.
Autoimmunity
However, recent research has demonstrated that the line separating these two conditions may be much blurrier than previously thought. It is now known that type 1 diabetes, which normally begins in childhood, may slowly develop later in life. This form is referred to as latent autoimmune diabetes (LADA) or more informally as type 1.5 diabetes.
Studies suggest that type 1 diabetes in adults is frequently misdiagnosed as T2DM, and up to 10% of adults with T2DM may actually have the autoimmune form.
Even more relevant to this article is the finding that fully 1 in 4 lean people with T2DM produce antibodies to GAD, the same enzyme in the pancreas that is attacked in type 1 autoimmune diabetes.
These findings suggest that a significant number of lean people with T2DM may be suffering from autoimmune diabetes. This will obviously require a different treatment strategy than those who have the non-autoimmune form. (The way to find out whether you’re in this group is to have your GAD antibodies tested. It’s a fairly standard blood test and is available through Labcorp and Quest.)
(Interestingly enough, approximately 5% of patients with autoimmune thyroid conditions also produce antibodies to GAD. So if you have Hashimoto’s or Graves’ disease along with blood sugar symptoms that don’t respond to dietary changes, you should have your GAD antibodies checked.)
Stress
Under conditions of stress, the body produces higher levels of the hormone cortisol. Cortisol plays a number of important roles, but one of it’s primary functions is to raise blood sugar. This is an incredibly helpful evolutionary mechanism that is part of the “fight or flight” response that prepares us to deal with a challenge or threat.
However, that mechanism was only designed for short bursts of stress.
Why? Because cortisol is capable of raising blood sugar to unhealthy levels even when a person is fasting. What that also means is that you can be lean, eat a perfect diet, and still have high blood sugar (and thus T2DM) if you suffer from chronic stress. I’ll be writing more about the connection between stress and diabetes in a future article.
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Michael,
Thanks for your comment. I couldn’t agree more about measuring post-meal blood sugars. I’ll be writing an article about that in this series. It’s a fantastic, affordable and highly effective way to measure carbohydrate tolerance.
I am a thin type 2 diabetic. I am what is called a Ketosis Prone Type 2 diabetic. I don’t particularly disagree with what you are saying. It is more a point of emphasis. KPD’s can be a mix of BMI’s so weight isn’t that grand of an issue. In fact, heavier KPD’s tend to have lower A1c’s then thin ones. KPD’s also tend to be people of color. This is largely due to the fact that darker skinned people tend to live where Malaria is endemic. What we seem to have is a genetic adaptation that gives us some resistance to malaria. Think about it, this adaptation has been around for thousands of years but our susceptibility of going DKA really only becomes an issue in the last fifty.
As I see it, this is an issue purely of diet. What we are eating is at some level poisonous. What those things are, it seems to me are myriad. Rather than pass out more advice on diet, I have rather opted to suggest to people that the one thing they can do is test their blood sugars and see how they are effected by what they eat. This simple bit of advice would have saved me and a lot of KPD’s much suffering.
TimL:
It’s not just refined vs. non-refined, because we have to consider the impact of toxins present in whole grains. That’s why even whole wheat bread and other whole grain products are problematic.
I think a LC diet is useful for weight loss (for most people), and I recommend it and use it with my patients. But I don’t believe it’s necessary for the general population.
There’s no single cause of diabetes & MetS. As I explained in my most recent article, several factors (genetics, toxic load and gut permeability – among others) contribute and are interrelated. For one person, eating bread may not be a huge problem. For another, it might be a life-threatening problem (i.e. someone with celiac). Also, there’s some evidence that the gluten in Europe even today is much less toxic than the gluten in the U.S. grain products.
Could you explain more what that means (gluten toxicity in Europe vs US) or suggest a reference? Thanks.
Chris and Russ,
Thanks so much for addressing these questions, I learn almost as much from these comments as I do from the posts.
So one question I have is this — you say that the difference is between refined vs. not refined, but wouldn’t that mean that “whole grains” are a-ok then? I obviously ask that because I’ve read here and elsewhere to the contrary — that all wheat/grains, regardless of refining, are bad.
And besides the diabetes issue, what about general weight/obesity? Management of diet based on GI/GL/Carbs has been a hugely successful strategy for people to lose weight. How does that stack up with your position? Are you recommending that people stop modifying their diets this way, even though it’s been very successful for so many?
Finally, a burning question I’ve had regarding advice against grains/wheat/refined flour:
Cultures throughout the world, especially Europe, have been eating these things for centuries (bread, pasta, etc.). Diabetes/metabolic syndrome/cardiovascular disease are largely modern, 20th century diseases (certainly in terms of prevalence). Why didn’t these problems develop much earlier? Why didn’t we see these rates of disease before now?
I should have been more clear about the weight I lost as well. Because of my background – I wasn’t ‘obese’ to begin with, even though I did lose 30 pounds. I went from a bodyweight of 235 @ 16-17% bodyfat (still in the healthy range), to a weight of 205 pounds and bodyfat percentage of 11-12%. So while losing 30 pounds sounds wonderful, it should also be noted almost half of that was LEAN tissue.
My eating habits were not the best – but they were essentially masked by my training. Leaving me to wonder how much local enivromental factors and/or various protein supplements played a role in developing Type I at my age. One silver lining being my wallet is a lot fatter now having realized that all the protein supplements and what not are largely un-necessary; if not completely un-necessary for the majority.
No worries Chris, I am in agreement with you. The ROOT is imflammation – I am simply making a non-exhaustive list of the most likely suspects inducing the imflammation.
..which as Chris alluded to all induce imflammation – something at that root of just about everything that may ail the human body.
These are just my perspectives as a fitness professional/former competitive athlete diagnosed with diabetes around age 30 – though not type II – who once went through the low-carb honeymoon dropping 30 pounds and 5-6% bodyfat until my health starting turning for the worse – who now enjoys 3-5 pounds of potatoes, rice and other evil foods on a weekly basis and now has much better blood sugar control, mood, and a return of my strength.
Russ: I was speaking only in the context of carbs and certain dietary factors. As you’ll see as I continue this series, I agree with you that the overall picture involves several other factors – some in our control, and some not.
Still, I maintain that many of the other factors like pollutants and toxins that contribute to diabetes do so via inflammation and oxidative damage.
…I would say it would be more accurate to say diabetes and metabolic syndrome are more likely caused by a storm of factors that include:
– overconsumption of calories in general combined with lack of movement (note this doesn’t mean exercise or working out; there is a difference between sitting in front of a TV/computer/desk for 10-12 hours/day and simply getting off your butt and MOVING every now and then)
– consumption of processed and franken-foods
– omega 3/6 imbalance
– insulin resistance resulting from an ever disappearing full nights sleep that gets shorter and shorter each decade. It only takes one night of insufficient sleep to induce a 25% increase in insulin resistance. Multiply that effect on a daily basis for an entire career.
– known/unknown enviromental factors – this week a national study was released that linked air pollution and diabetes. I live in Pittsburgh, and the southwest area of PA has a disproportionately large population of folks with diabetes/diabetes complications/metabolic syndrome. We also were the world’s largest steel producer for decades – the smoke stacks are still visible. One wonders how much that has detrimentally effected the local population’s health over the past century – as from talking to friends we also have higher rates of Down’s.
(1) Down syndrome is caused by chromosomal non-disjunction, (2) lack of sleep does not cause a 25% increase in insulin resistance (and you can’t even describe insulin resistance in that way – you can decrease insulin sensitivity but not increase insulin resistance), (3) “franken foods” as you call them do not cause diabetes, you clearly don’t understand genetics or transgenics at all, and (4) your area probably has a high rate of diabetes and obesity due to poor diet and lack of exercise, not the random assortment of fake facts you listed.
The idea that diabetes/metabolic syndrome is caused by carbohydrate intake and high GI foods is a gross oversimplification- especially when one does not take into account whether whatever carbohydrate is ingested in processed/refined or not.
Couldn’t have said it better myself, Russ. The idea that high carbohydrate intake alone causes diabetes is false. Otherwise, the Kitavans and traditional Asian cultures that eat a lot of white rice would have high rates of T2DM – which they don’t.
The key question regarding carbohydrates is whether they’re refined or not. And the reason that probably makes such a difference is that refined carbs are pro-inflammatory, whereas natural carbs are not.
The idea that even natural carbs in excess cause diabetes is based on the “tired pancreas” theory (i.e. repeated intake of high carb meals causes excess insulin secretion, which exhausts the beta cells and causes insulin resistance). Turns out that theory doesn’t hold water, with the Kitvans and Asian cultures being a case in point.
Instead, my argument is that inflammation is the primary mechanism driving diabetes. That means that anything in the diet that causes inflammation (food toxins like refined flour, seed oils and liquid fructose in particular) will contribute to diabetes, but natural carbs alone do not.
TimL,
I am sure Chris will chime in when he gets time but…
Why or how is it pretty much fact?
The idea that diabetes/metabolic syndrome is caused by carbohydrate intake and high GI foods is a gross oversimplification- especially when one does not take into account whether whatever carbohydrate is ingested in processed/refined or not.
Foods are also generally not even in a vacuum like they were for the GI testing – by adding fats and proteins to your meals like you normally would – you get an ENTIRELY different GI response as compared to the GI itself.
Chris,
Thoroughly enjoying this series, as well as the rest of your blog.
One question I have regarding this series and your writing in general is that dietary carbohydrate intake and glycemic index/load hardly figure in at all. My understanding for a while has been that diabetes and metabolic syndrome in general are at least partially caused by overconsumption of carbohydrates and high GI foods. At the very least, they trigger your body to put on fat, which generally isn’t healthy.
But lately I’ve been reading writing from you and others (like Stephan Guyenet) that high GI carb consumption isn’t really a problem. How can that be? Isn’t it pretty much fact that those things make many people fat, and that many people have lost weight as a result of going on low-carb diets? What am I missing?
Thanks so much for all the work you do, please keep it up.
Just wanted to say thanks for writing an article that actually mentions us who develop Type 1 as adults – even while lean – it seems we don’t exist in the medical world! I should have the GAD’s tested to confirm – but only needing about 6 units of insulin a day seems to indicate I don’t have much of an insulin sensitivity issue. I also fare much better on a more moderate carb intake than a VLC intake.
Great article, Chris, thanks.
Stress is really a huge factor today. Nothing in balance, everything in chaos. That´s for sure not healthy. As others before mentioned I also ate tons of fat+protein on keto/VLC and gained sometimes weight, had elevated cortisol levels and low fT3. Now I slowly reintroduced some carbs, first carrots than potatoes. I estimated to regain some weight but it´s still stable. BG is fine with 90 after eating a huge meal of carbs (+fat). Finding is, it´s important to take some things easy. Long ago fat was my biggest enemy now I make peace again with carbs. Everything´s in balance. It´s just food.
When I strarted my scientific journey with T2DM more than four years ago I had one idea where I started: “hepatic insulin resistance is a cause for type 2 diabetes.” Fat content of the liver goes hand in hand with the severity of the disease so fat in the liver is related to the problems.
When I looked what causes BG to rise in T2DM I found out that adipose tissue derived lactate might explain atleast part of that. Increased lactate from AT was a result metabolic malfunction of the adipocytes (low mitochondrial oxidation & increased flux of glucose to lactate) which is related to activation of the Randle cycle. Randle cycle activation is caused by increased lipolysis from triglyserides. Then we come back to the question how is lipolysis regulated?
Some studies says that inflammation in the AT will lead to the decreased adipogenesis and perhaps increased FFA avaibility in the visceral deposit:
http://www.ncbi.nlm.nih.gov/pubmed/20018865
High sucrose diet or ethanol use will lead to the development fatty liver and T2DM but I’m not sure that it is in causal relation to increased de novo lipogenesis in the liver by fructose or ethanol because happenings in the AT has such a big effect on the liver metabolism. Importance of this is seen studies with PPARg agonists which reverse metabolic dysfunction.
Wow, that explains my skinny grandma who lost her eyesight and legs to T2DM. Thanks Chris!
I figured out last winter that I’m something of a cortisol junkie and will invent stress where little or none exists, just to feel “normal”. Your post above about cortisol and blood sugar made my relationship to food make a lot more sense. I’m looking forward to hearing more on the subject.
I don’t check my blood sugar (so far), but I have noticed that like Lynn, I do better on a moderate carb diet compared to a VLC. And for me, the best news about that is that I managed to just accept it as being the best fit for my body (n=1), and not stress over “failing” at VLC. For a cortisol junkie, that’s progress!
Thanks so much for your very helpful posts.
My blood sugars are MUCH better since switching from a VLC to a moderate carb diet. Now, I did start natural thyroid around about the same time, so maybe that is a confounding variable. However, I always felt hungry and craving on VLC no matter how much meat I ate. So, I am thinking that in certain people, ketosis does not reduce appetite (I found it did the opposite for me) and hence the person eats way too much protein and blood sugar rises. Not good.
My current diet of meat, vegetables, fruit, gluten free bread, potatoes and dark chocolate keeps me satiated and my blood sugar is normally in the 95-105 range two hours after eating. I want to get it even lower and your website (along with optimising my potassium levels) is helping me with that. I do feel inflammation is a huge factor for me, so I eagerly await your posts on HOW to reduce inflammation, since I already have the common bases of a gluten free diet and careful carb intake covered.
Finally, can you tell me why my post meal sugars have really improved, but my fasting blood sugar is still in the 90’s? Is the fasting figure the last to improve?
To reduce inflammation, try shifting to a low-fat, minimally-processed plant-based diet (see Dr Esselstyn, Ornish, McDougall, Barnard). Most breads, even gluten-free, are not healthful. Excess animal products, especially animal fats are inflammatory. Fats carry the bacterial products (ie LPS, cell wall remnants) which trigger inflammation. Because most animals are raised in crowded/stressful/unsanitary conditions, fed a diet to maximize growth and body fat, they are typically prone to infections. A large portion of all antibiotics goes to keeping such animals alive. Unfortunately rampant antibiotic use promotes antibiotic-resistant strains which can occasionally mutate to infect humans.
Um NOT! Completely wrong on every point.
In your view, can eating a low-carb diet result in a level of blood sugar that would spur the secretion of cortisol, thus leading not only to an increased blood glucose level but also a higher-than-usual heart rate and hypertension?
This would only be likely on an extremely low-carb (i.e. ketogenic) diet that is also low in protein. With 200 calories of glucose and 400 calories of protein (which most low-carb dieters easily get), the body’s glucose needs will be met. However, the maintenance of stable blood sugar throughout the day (in addition to fasting glucose and A1c) is crucial, and any significant fluctuations can provoke cortisol release (and epinephrine/adrenaline if cortisol is low). Repeated adrenaline stimulation could certainly cause CVD and hypertension.
This may seem like a silly question, but what exactly is generalised inflammation? I know inflammation is associated with conditions such as arthritis and such, but what exactly do you mean by inflammation in regards to diabetes? Could you write or have you written an intro on the specific phenomenon of inflammation?
Wikipedia is often a good source for this type of general information. Check out their entry on inflammation. It’s our body’s way of handling harmful stimuli, so it’s a natural response to acute injury or illness. The problem is when inflammation becomes chronic, due to continued activation of the immune system by dietary toxins, pathogens, stress, altered gut flora or autoimmunity.