insulin resistance – Pål Jåbekk

The carnivore connection hypothesis

I just came across this article [1] and found that it’s really quite interesting. It’s about why we are insulin resistant. Even though the term «insulin resistance» is mostly used to describe a pathological condition, all tissues that can respond to insulin are, to some extent, insulin resistant and so we are all displaying various degrees of insulin resistance in various tissues all the time. Insulin resistance is simply when a tissue do not respond to insulin or responds poorly. So when muscles, for example, become insulin resistant, they do not take up as much glucose from the blood despite high blood insulin level. And they will keep burning a larger proportion of fat despite insulin trying to make them burn sugar.

«Certain metabolic adaptations were necessary to accommodate low carbohydrate intake because the brain and reproductive tissues had evolved a specific requirement for glucose as a source of fuel.»

«The amount of carbohydrate may have ranged from as little as 10 g up to 125 g a day, much lower than the typical 250 to 400 g per day consumed in modern diets.«

Brand-Miller, Griffin and Colagiuri looks at insulin resistance from an evolutionary perspective. The basis for the article is that the last 2 million years of human evolution was dominated by a low carbohydrate intake. This may have caused a selective pressure for insulin resistance. In addition, environmental pressures such as geographic isolation and/or starvation may have further increased the prevalence of insulin resistance genes in certain populations. The reason is that when carbohydrate intake is low it is important that the tissues that do not need to burn glucose and can burn fat become insulin resistant, thus freeing glucose for the tissues that need glucose and cannot burn fat.

«With the first severe Ice Age, global temperatures fell dramatically and resulted in moist African forest becoming dry, open woodland and savannah. Hominids that were unable to utilize grasslands became increasingly carnivorous.»

«In Africa and Eurasia, hunted animals displaced gathered plant foods as the principal source of food, leading to a diet low in carbohydrate and high in protein for most of the year. Increased meat intake from wild terrestrial and marine animals would have also provided greater amounts of omega-3 fatty acids such as docosahexaenoic acid essential for brain development, facilitating the larger brain size of H. sapien.»

The authors further hypothesize that the selective pressure for insulin resistance was relaxed with the advent of agriculture and the increasing amounts of carbohydrate in the human diet. Domestication of cereal grains first began in the Middle east, some 12 000 years ago, and spread across to Europe and East Asia. The logic thus goes that populations that only recently have adopted agriculture are more likely to become insulin resistant, overweight and at ill health than those populations longer exposed.

As examples of such cultures the authors mention the Pima Indians, Nauruans, and Australian Aboriginals. The Pima only adopted agriculture some 5000 years ago, about the same time as us Norwegians.

According to the authors the carnivore connection hypothesis hinges on five lines of evidence:

(1) During the last two million years of evolution, humans were increasingly carnivorous, that is, consumed a low-carbohydrate, high-protein diet.

(2) A low-carbohydrate, high-protein diet requires profound insulin resistance to maintain glucose homeostasis, particularly during reproduction.

(3) Genetic differences in insulin resistance and predisposition to type 2 diabetes can be explained by differences in exposure to carbohydrate during the past 12,000 years.

(4) Changes in the quality of carbohydrate can explain the higher prevalence of type 2 diabetes in susceptible populations.

(5) Habitual consumption of a high-glycemic-load diet worsens insulin resistance and contributes to the obesity and type 2 diabetes in all populations.

Food

As there are some tissues that are in great need of glucose, mostly those with few or no mitochondria, insulin resistance is a key mechanism by which these tissues are properly fed. But now a days insulin resistance occurs in combination with a high carbohydrate diet and is a sign of something being very wrong – the reason being that when carbohydrate intake is high, insulin sensitivity needs to be high in order to keep us from being sugar poisoned. Usually when we talk of insulin resistance we are referring to liver insulin resistance. Glucose is an important fuel for fetal growth and insulin resistance thus ensures enough glucose is directed at this process. Pregnant women naturally become more insulin resistant, but if you are already insulin resistant this may develop into gestational diabetes, a form of diabetes that normally improves after pregnancy. Women with polycystic ovarian syndrome are insulin resistant and PCOS can be seen as just another manifestation of the metabolic syndrome in women. Brand-Miller and coworkers believe that these women may represent a group that was highly fertile in a low carbohydrate environment. There is much indicating that insulin resistant mothers have insulin resistant babies and that each new generation is more metabolically challenged that the former. So in individuals well adapted to low carbohydrate living, increasing insulin resistance is caused by continuous high carbohydrate dieting.

«We propose that the selection pressure for insulin resistance was relaxed first in Europeans when dietary carbohydrate increased 12,000 years ago with the advent of agriculture. In accordance with this long-term exposure, Europeans have experienced a lower prevalence of diabetes, even when overweight and obese (see Section 6), compared to other population groups.»

One aspect of this article I particularly liked, was that they did not adhere to a common misconception of food availability. They mention Neel’s thrifty gene hypothesis which suggests that cycles of «feast and famine selected for a quick insulin trigger.» They also mention Gerald Raven’s similar hypothesis that suggests that «muscle insulin resistance was the key to survival during food scarcity because it conserved glucose by minimizing gluconeogenesis and preserving lean body mass.» Both of these hypotheses are based on an assumption that food must have been hard to come by during our recent evolution. To me this is a serious underestimation of humans and suggests that those doing the hypothesizing have themselves not spent much time outdoors. Luckily, Brand- Miller and coworkers are aware of the shortcomings of these hypotheses and write: «However, this is not supported by the scientific literature. While hunter gatherers would have been exposed to seasonal and geographical changes in food supply, severe food shortages or starvation were rare and more likely to occur after the transition to agriculture (preindustrialization).»

The authors also spend some time discussing types of carbohydrate and the transition from complex unrefined to refined easily digestible and the concomitant change in glycemic index. This might have further enhanced the insulin resistance promoting effects of our high carbohydrate diet.

Humans are well adapted low carbohydrate intakes, but it seems this ability might have come at a cost. Anyway, it seems many of us are fighting our genetic disposition by stuffing ourselves with carbohydrates. All in all a really interesting article and well worth a read.

1. Brand-Miller JC, Griffin HJ, Colagiuri S: The carnivore connection hypothesis: revisited. J Obes 2012, 2012: 258624.

Low fat – another nail in the coffin

So here’s an interesting study: «Effects of a lifestyle intervention in metabolically benign and malign obesity.«

From the intro:

“In the last few years it has been shown that metabolically healthy obese (MHO) individuals comprise roughly 30% of obese people and 10% of the adult general population [1– 5]. In addition to having insulin sensitivity that is similar to non-obese individuals, MHO individuals have lower liver fat content and lower intima media thickness (IMT) of the common carotid artery than obese insulin-resistant (OIR) individuals [6].”

A group of German researchers put 262 non-diabetic people on a 9 month lifestyle intervention. The intervention was of the traditional (insane) type:

“Counselling was aimed to reduce body weight by ≥5%, to reduce the intake of energy from fat to <30% and particularly the intake of saturated fat to ≤10% of energy consumed and to increase the intake of fibre to at least 15 g/4,184 kJ (1,000 kcal). Individuals were asked to perform at least 3 h of moderate sports per week. All participants completed a standardised self-administered and validated questionnaire to measure physical activity and a habitual physical activity score was calculated.”

262 participants entered the study. Of these, 43 were normal weight and 116 were overweight. The remaining 106 were obese.

The point of the study was to see how this lifestyle intervention affected people with different insulin sensitivity (IS). The obese individuals were (BMI≥30.0 kg/m2) were grouped, based on their IS and IS was estimated from an oral glucose tolerance test (OGTT). Those with the best insulin sensitivity were labeled metabolically healthy obese (MHO, n=26) while those with poor IS were labeled obese insulin-resistant (n=77, OIR).

Macronutrients and food reward

If you see one bright red swan, you are not likely to give up a theory that says that all swans are white; you will instead go looking for the person who painted it.

Imre Lakatos

Much is being said on this subject. Bet many are getting pretty fed up by now. But I still think this is an interesting discussion and so I will take this opportunity to add some thoughts. After all, the goal here is to find the truth; to find out how the world works. In that respect, I would also like to say that I do not agree with any one side in this discussion. Scientifically speaking, agreeing is not very scientific. That would mean confusing matters of opinion with matters of fact. Things are just what they are.

Chris Kresser is of course right in that there is no single cause of obesity. In animal studies obesity can be induced in a number of ways, just as in humans. The fat tissue is a large part of our body and it has a wide range of receptors and interesting signaling, so it should not come as a surprise that there are many ways to become fat.

If we are to look for a general cause, we could say that western, post agriculture lifestyle is to blame for obesity and our lifestyle diseases. But that does not mean you cannot get fat eating paleolithic foods, although if you did, you should blame your parents for the lousy chromosomes.

Neither carbohydrates nor food reward is able to explain all the observations. They both explain a part of the observations and so are both likely influential factors. Just how big a role each plays is an extremely difficult question to answer. Thus the current discussion.

The key question is: Why is not hunger down-regulated in humans becoming fat?

The Guru Walla
From what I can see, the Cameroonian Guru Walla is a bland food, overeating, fat gaining rite.

In the Guru Walla ritual, young Cameroonian men consume a diet made of red sorghum and cow milk (makes up over 95% of calories). The young men isolate themselves in different houses with a female attendant devoted exclusively to the preparation of Guru Walla meals. The diet and exclusion is supposed to lead to a certain level of purity. The men eat every 3 hour for 60 days, during which time body-weight can increase by an average of 17kg. Only 64-75% of the weight gain is fat [1].

Traditional food amongst these Cameroonians is about 75% CHO, 10% fat and 15% protein. During the Guru Walla it is 70% CHO, 15% fat and 15% protein.

The Guru Walla food is obviously fattening; at least if force fed and combined with minimal physical activity. The question we need to ask is: Would the Cameroonians be overweight if all they consumed was the Guru Walla diet?

It seems that the Cameroonians do not get fat because of the food itself. Rather they become fat because they force feed themselves. The newly gained weight is also lost after the ritual.

The reason I called the Guru Walla food bland, is that it most likely is very bland after the first few days. Try eating any one food exclusively for 2 months, and eat it even though you are not hungry (vomiting is also a part of the Guru Walla). The dopamine reward response should be minimal. Remember the Twinkie Professor who ate nothing but Twinkies, Oreos, donuts and similar crap but who lost 27 pounds in a 10 week experiment. He did consciously under eat, but my point is that we need to ask ourselves how lack of variation affects reward.

Food reward
While food reward might help explain why we overeat at a biochemical level, there is little evidence to indicate that a fat loss diet needs to be unrewarding, if by unrewarding we mean less palatable. We also need to know if it is possible to unconsciously overeat (become fat) on rewarding foods if we have a working metabolism and the rewarding foods do not mess with our metabolism. If not, whatever caused the metabolism to go out of whack is the real problem.

Stephan’s bland food through a straw experiment does not necessarily support a theory claiming that the study participants lost weight because of an inherently unrewarding quality of that particular diet. The finding could easily also support the theory that eating only one food, no matter how rewarding it may be when consumed intermittently, will make people lose weight because the rewarding quality of that food declines with increasing intake.

So we need to know if people could lose similar amounts of weight eating other foods exclusively.

Leptin
I am still having trouble seeing what’s the big fuzz about leptin. It is a signaling molecule. It signals energy surplus and the lack of leptin signals lack of energy. Leptin also increase fat oxidation. The leptin deficient animal models, that are obese, act and behave as they were starving and administering leptin normalize their behavior and induce weight loss. Either the body just needed to be told that it had stored energy to use, or we just needed to increase fat oxidation. If you increase fat oxidation by other means such as GH, ob/ob mice lose weight just as with leptin.

If for example high insulin levels cause leptin resistance, focusing on leptin does not add anything to obesity treatment. High insulin levels can also be caused (or at least be exacerbated) by factors other than carbohydrates. For example factors that messes with liver function.

“In particular, protein-rich foods such as beef can increase insulin secretion as much as certain starch foods such as pasta, or more.”

The quote takes the results from trials out of context. It is an unfair statement, just like “proteins are inherently satiating” statement. A few days of beef eating will likely lead to lower insulin than a few days of pasta. I’ve written some about satiating proteins here.

In overweight people, as in overweight animal models, the key issue seems to be a reduced fat oxidation. Reduced fat oxidation with a high energy intake cause fat deposition in most all tissues and also insulin resistance.

Anything that increase fat oxidation in overweight animal or humans, cause weight loss and reduced food intake.

Lessons from insulin resistance
Stephan claims that overweight people have high serum free fatty acids. This is not completely true, at least if we are to listen to Keith Frayn at [2]. The claim may be true in general, but there are lots of overweight people with normal FFA levels. This however does not change Stephan’s argument. Generally the fat tissues of the overweight give out more FFA indicating adipose tissue insulin resistance.

Here is how we imagine insulin resistance to occur (roughly):

The pancreas has a direct route to the liver. The reason for this direct route is that the liver controls blood sugar level through its production of glucose. When blood sugar rises, the pancreas notice and secretes insulin. When the liver receives this insulin, glucose production is reduced. As the cells in the body are utilizing glucose for fuel, blood glucose level drop.

Somehow the liver becomes insulin resistant and keeps sending out glucose despite the insulin being sent from the pancreas. The reason seems to be inflammation and/or buildup of fat (NAFL). In this insulin resistant state, the muscles also fill up with fat. Once glycogen stores are full they become insulin resistant to avoid sugar poisoning, but keep taking up fatty acids. Because of the high carb diet and/or lack of physical activity the muscles do not burn fat and so it builds up. Also, there is some loss of muscle and liver mitochondria function and probably fatty acid transport into mitochondria.

The fat tissue takes up both glucose and fatty acids and expands if it takes up more than it gives out. The expansion of fat tissue eventually cause fat cells to send out stress signals (probably caused by endoplasmatic reticulum stress) and macrophages invade the tissue, gathering around dying fat cells. In this state, the fat tissue secretes a lot of fatty acids that wreak havoc around the body. But if free fatty acids are not burned they need to be re-esterefied. A high FFA level does not mean that we are not gaining weight or that we are losing weight (that more fat is leaving than entering the fat tissue). FFA are measured fasting and although the level might be higher in overweight and insulin resistant in that fasted state, this does not mean that over time more fat is leaving the fat tissue than are entering.

Stephan Guyenet takes the high FFA-level often observed in the overweight to mean that the fat tissue is insulin resistant and that they could not be gaining weight. This might be a wrong assumption. They have definitely been gaining weight and most overweight people are either weight stable or gaining weight. Is it impossible to gain weight while still having high FFA level?

Lean people also get insulin resistant. As do animals and humans with lipodystrophies. Many massively overweight do not become insulin resistant, and it seems that what causes the overflow of free fatty acids from adipose tissue is that it reaches its limit – a limit of course determined by both genetics and lifestyle.

In the insulin resistant state (metabolic syndrome), free fatty acids are usually high and fat builds up everywhere. Anything that increases fat oxidation helps. Pharmacological inhibition of the oxidation of fatty acids in the liver stimulates food intake in both humans and rats and stimulation of hepatic fatty acid oxidation reduces food intake, weight gain and adiposity in rats with diet-induced obesity [3].

FFA’s come from food, the liver or fat tissue. Carbohydrates are largely responsible for the amount secreted by the liver. At a cellular level, insulin resistance/metabolic syndrome seem to come from a high total energy intake. There is a surplus of both glucose (glycogen) and fat and the body can’t handle it all. Reducing the dietary fat load helps (at least if hypocaloric), but reducing dietary carbohydrate is the most efficient treatment to date. The question, though, is still why these people overeat.

Insulin

“…for insulin to cause fat gain, it must either increase energy intake, decrease energy expenditure, or both.”

“If calories and protein are kept the same, high-carbohydrate meals cause equal or greater satiety than high-fat meals, and equal or less subsequent food intake, despite a much larger insulin response)”

Stephan Guyenet

Insulin will reduce hunger as long as there is energy coming from ingested food. Once that flow of energy stops or is reduced, a high insulin level cause hunger. In order for insulin to cause overweight, the level only needs to be high enough for allowing fat oxidation to be less than fat storage in that particular individual over time.

Injecting both glucose and insulin reduce hunger. Injecting insulin alone increase hunger. Long term satiety is better with low carbohydrate diets than high. We need to remember that we adapt to burning different fuels. If we normally eat high carb and suddenly eat high fat we are likely to be poor fat burners and thus more likely to get hungry. This might also explain higher leptin levels after high fat meals in acute feeding studies.

“If blood glucose decreases enough, it activates a system called the «counter-regulatory response», designed to maintain blood glucose at all costs to protect the brain from the effects of hypoglycemia. Part of this response is hunger and increased food intake. However, this system is not activated except in severe hypoglycemia, which is rare except in diabetics, thus it is not relevant to common obesity.”

This quote seriously needs references. It seems very unlikely.

These are just some thoughts. Nothing more.

References

1. Pasquet P, Brigant L, Froment A, Koppert GA, Bard D, de G, I, Apfelbaum M: Massive overfeeding and energy balance in men: the Guru Walla model. Am J Clin Nutr 1992, 56: 483-490.

2. Taubes G: Insulin resistance. Prosperity’s plague. Science 2009, 325: 256-260.

3. Ji H, Friedman MI: Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity. Metabolism 2007, 56: 1124-1130.

The causality of insulin resistance

There seem to be two large somewhat competing hypotheses trying to explain the causality of insulin resistance (as measured at a whole body level). The lipotoxicity hypothesis, explains to us how insulin sensitivity is reduced in tissues when too much fat builds up in the specific tissue cells; likely caused by high serum levels of free fatty acids and triacylglycerols. The other hypothesis is the inflammation hypothesis, which seeks to explain reductions in insulin sensitivity by high levels of inflammation, possibly caused by stress in general, endoplasmatic stress or dietary fatty acid composition and more.

Both inflammation and cellular lipid overload correlate with insulin resistance and the metabolic syndrome and looking at the literature it seems that both mechanisms have to be a part of a causal chain.

The big unanswered question here is the direction of causality. Overweight, atherogenic dyslipidemia, inflammation and other factors appear in concert with insulin resistance. But what comes first? Does obesity cause insulin resistance or is there some underlying factor causing both insulin resistance and obesity? And which tissues are the first to become insulin resistant?

Overweight

Clever scientists have succeeded in creating animal models that are extremely good at storing energy as fat. The funny thing is that this ability seems to protect against insulin resistance. The consequence of this research is the notion that if you are really good at getting fat, you are protected from insulin resistance. The existence of lean insulin resistant individuals would support this notion and would also cast doubt on overweight causing insulin resistance.

There is more to support the above mentioned. It has been proposed that insulin resistance develops because of an imbalance of fat distribution between the tissues. Consistent with this hypothesis is the observation that some obese individuals have few manifestations of the metabolic syndrome. Normoglycemic and normolipidemic obese individuals display improved postprandial fat storage compared with lean subjects. Presumably, the more efficient adipose tissue fat-storing capacity the better the protection against lipotoxicity in nonadipose tissues with reduced risk of insulin resistance.

The pool of FFAs in fat cells is released into the circulation in relation to its size and the greater total fat mass of adipose tissue in obese individuals result in elevated fatty acid flux to nonadipose tissues. Although this is commonly accepted at indisputable, it has proven difficult to find that overweight and obese individuals consistently have higher serum FFA levels. Insulin resistance is not likely caused by overweight in itself. We can conclude this way because there are lean insulin resistant people and as mentioned, many overweight people are also insulin sensitive. There must be some other cause.

Fructose

Non alcoholic fatty liver also correlates with insulin resistance. Fructose intake has been found to be associated with insulin resistance. Children with non-alcoholic fatty liver disease have been found to have diets high in fructose in addition to low activity patterns.

Fructose is indeed an interesting factor with respect to insulin resistance. It is also a likely candidate for a causal factor.

Gross et al examined nutrient consumption in the United States between 1909 and 1997, and found a significant correlation between the prevalence of diabetes and corn syrup. Both high fructose corn syrup and sucrose contribute to high intakes of fructose. The use of HFCS in the US has apparently increased by 1000% between 1970 and 1990.

Fructose is treated and metabolized differently from glucose in the liver. It is extremely lipogenic and makes the liver churn out large amounts of triacylglycerol leading to high levels of VLDL and small dense LDL. This fat producing ability is thought to contribute to cellular lipid overload and insulin resistance.

Chronic fructose consumption also reduces the adipocyte derived hormone, adiponectin, which also seem to contribute to insulin resistance. In addition, despite its low glycemic index chronic ingestion of fructose actually seem to stimulate hyperinsulinemia.

Dietary macronutrients

The metabolic syndrome consists of a cluster of risk factors for diabetes and cardiovascular disease. These are overweight (now commonly measured as waist circumference), hypertriacylglycerolemia, reduced HDL levels, increased blood pressure and increased fasting glucose. Insulin resistance is generally a common feature of the syndrome and a likely causative agent for several of these factors.

Volek and Feinman made a funny observation in 2005. They found that the factors that define the metabolic syndrome are the same factors that are greatly improved by carbohydrate restriction. They proposed that the metabolic syndrome may well be defined by the response to carbohydrate restriction.

Carbohydrate restriction is still not recommended as the standard treatment for the metabolic syndrome despite the fact that improvements in these factors don’t even require weight loss (as it does with low fat/calorie diets) on a low carbohydrate diet.

If carbohydrate intake can improve all the factors of metabolic syndrome and insulin resistance is an important part of this syndrome. And if we know how carbohydrates in general contribute to high levels of triacylglycerols and FFA, especially fructose, then dietary carbohydrate is indeed a very likely causative factor for insulin resistance.

Stress

There is a very strong relationship between “central” fat distribution and insulin resistance. Robert Eckel claims that the sum of the evidence indicate that the metabolic syndrome (read insulin resistance) begins with excess central adiposity. By this logic, whatever cause central obesity is then what we should focus on.

A side note to central adiposity is the interesting findings of the Womens Health Initiative. After 7 years of following a diet with more fruit, vegetables and grains and less fat the 19 541 person intervention group had increased their waist circumference. The depressing findings of what happens when women are advised to follow the national guidelines for dietary intake, lead the authors to the tragicomic conclusion:

“A low-fat eating pattern does not result in weight gain in postmenopausal women.”

Numerous clinical and experimental studies have linked stress to metabolic disorders. The obvious culprit is cortisol and subsequent hypercortisolemia. Cortisol has particularly strong effects on visceral fat. Giving corticosteroids in the drinking water of mice result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triacylglycerol levels, hyperphagia, and decreased locomotion.

As visceral fat storing is a trademark of the insulin resistance metabolic syndrome, and all the factors of the syndrome are greatly improved by dietary carbohydrate restriction it is also likely that the combination of stress and a high carbohydrate diet sets the stage for insulin resistance.

The causality

No matter the mechanisms, there are likely conclusions to be drawn. Although it seems that carbohydrate intake and composition, physical activity level and stress all contribute to insulin resistance in some manner, one factor seems to stand out. I would be quick to remove low physical activity level from my list, because I believe this is likely an effect of a fat tissue that is reluctant to release stored energy. Its reluctance is likely (for the most part) caused by high insulin levels caused by dietary carbohydrates. Exercising an overweight person on a high carbohydrate diet is like exercising an anorectic person. The energy is not there to be used. Carbohydrate intake must first be manipulated in order to increase fat release and oxidation.

If excessive carbohydrate consumption causes obesity, insulin resistance and metabolic syndrome (and it likely does), and all of these factors are improved or cured by removing dietary carbohydrates, then dietary carbohydrates are a strong, if not the strongest candidate for the causal role. This conclusion is reached by looking at the physiology only, and including evolutionary and epidemiological data, I believe would only serve to strengthen this hypothesis.

My proposed chain of causality is something like this:

Stress and high levels of FFA and triacylglycerol caused by high carbohydrate intake, stresses and pressures the fat tissue to grow. Inflammation occurs as a consequence, and the liver becomes insulin resistant because the inflammatory substances impair insulin signalling in the liver. The liver then does not decrease its glucose production in response to insulin. Increased glucose levels cause more inflammation by causing fat cells to grow even more. The cells grow due to hyperinsulinemia caused by high liver glucose output. The fat cells then become insulin resistant and do not reduce FFA production in response to insulin. This increases FFA levels which makes tissues fill up with fat (among them the pancreas, which results in abnormal insulin output) and become insulin resistant as well. All this is happening while the individual is getting more overweight and diabetic, and inflamed to the point of near combustion.

The trouble with insulin resistance, part III

I was in way over my head starting to ramble on about insulin resistance hoping I would identify a causal link. But I feel I should finish what I’ve started.

The trouble with insulin resistance is that it is so bloody hard to point to the exact cause at a cellular and molecular level. I’ve looked at how insulin resistance could in theory be caused by a lipid overload which through its effect on insulin signaling reduces the effect of insulin. In addition to lipid overload there is the inflammation hypothesis.

It is commonly accepted that chronic inflammation associated with obesity induces hepatic insulin resistance. Not long ago clever scientists discovered that the fat tissue was not simply a waste basket for surplus energy, but also an important endocrine organ. Many of the inflammatory substances thought to induce insulin resistance originate from the fat tissue.

Several inflammatory substances has been looked at with interest, among them are, CRP (C-reactive protein) TNF-α (tumor necrosis factor alfa), IL-1, IL-6 (interleukin 1 and 6) leptin and resistin. These are so called cytokines which are protein signalling molecules much like hormones. Other substances thought to play a part in an inflammatory led insulin resistance include; I-kappa-B-kinase beta (IKK-β), nuclear factor-κB (NF-κB), c-Jun N-terminal kinase (JNK), CC chemokine receptor 2 (CCR2) and macrophage migration inhibitory factor (MIF). And the list goes on. It is long and incomprehensible. But the big picture is clear. Obesity, insulin resistance and inflammation go hand in hand.

Some of the above substances are thought to inhibit insulin signalling in liver cells. This would then be classified as a hepatic insulin resistance. An insulin resistant liver in turn has an impaired suppression of glucose production by insulin. The result is hyperglycaemia.

Then why is the fat tissue so inflamed?

One theory claims that fat cells produce inflammatory cytokines because of endoplasmatic reticulum stress. Stress caused by the expanding of the fat cell as it fills up with excess energy thus promoting adipose tissue production of JNK, which inhibit insulin signalling. The stress also makes macrophages (white blood cells) travel into fat cells to a far larger degree than in lean people.

The source of many of the inflammatory signals originating from the adipose tissue is thought to be macrophages. Obesity-associated adipose tissue inflammation is characterized by an infiltration of macrophages into the adipose tissue. Macrophages also incorporate into artery walls and play an important part in atherosclerosis. According to Taubes quoting Anthony Ferrante, 5% of the adipose tissue in lean individuals is macrophages. In obese, the number comes close to 50%.

Ketogenic or carbohydrate restricted diets have been shown to decrease inflammation in both human and animal models. Although the mechanisms are still unclear the reduced inflammation is in thought to in part be because of reduced levels of reactive oxygen species (ROS). Hyperglycemia, as occurs in insulin resistance and type-2 diabetes, contributes to a breakdown in cellular function that leads to overproduction of reactive oxygen species. It is in fact a rather consistent feature common to all cell types that are damaged by hyperglycemia.

One way that carbohydrate restriction may decrease inflammation is through an altered fatty acid profile. Low-carbohydrate diets may result in profound alterations in PUFA (poly-unsaturated fatty acids), particularly affecting arachidonate, an omega 6 PUFA. When incorporated into membranes arachidonate is commonly assumed to have a deleterious effect on the overall inflammatory balance because of its conversion to proinflammatory eicosanoids (e.g., prostaglandin E2, thromboxane A2, leukotrienes B4).

In contrast, eicosanoids derived from long omega 3 PUFA have less inflammatory effects.

Less oxidative stress should result in better preservation of arachidonate since free radicals play a part in its metabolism. Inflammatory cytokines are known to increase production of free radicals which in turn initiate arachidonic acid release and breakdown.

Most evidence indicates that restricting dietary carbohydrate positively impacts inflammation.

Another part of the inflammation puzzle may lie in AGE (not age, but Advanced Glycation End products). These are proteins which have gotten attached to glucose probably because of hyperglycemia. These modified circulating proteins can then bind to AGE receptors and activate them, thereby causing the production of inflammatory cytokines.

Funny thing here is that mitochondria produce ROS. Researchers claim this is mostly because of an increased FFA flux with accompanying increased FFA oxidation by the mitochondria. The increased oxidation causes mitochondrial overproduction of ROS. Thus, it seems that too much fatty acids in the blood will both cause a lipid overload in tissues and cause a greater production of reactive oxygen species all of which will increase insulin resistance.

More trouble with insulin resistance

I’ll make an attempt to sum up some of my previous rambling.

When we talk about insulin resistance it is often important to include information on which tissues we are talking about. When insulin resistance is measured by clamp technique we are mostly measuring the hepatic insulin response.

The fact that insulin resistance is mostly measured at a whole body level, and that we thusly do not know how the resistance manifest itself in different tissues makes, finding a causal link difficult.

One of the main hypotheses proposed suggests that fat tissue become insulin resistant (poor response to insulin) and consequently sends out more fat than peripheral tissues can handle. The muscles for example, become resistant because they take up more fat without increasing fat oxidation and fill up with fatty byproducts like diacylglycerol and ceramides. Both muscle and liver insulin resistance and “fattening” have been blamed on increased FFA levels. Levels supposedly caused by the insulin resistant adipose tissue. Non alcoholic fatty liver diseases (often non-alcoholic steatohepatitis) seem to be getting more common by the day. A condition once found mostly in people with excessive alcohol consumption is now commonly found in association with lifestyle diseases.

I should mention though that serum FFA level does not only reflect adipose tissue lipolysis, but also intravascular lipolysis of triglyceride-rich lipoproteins (VLDL). These lipoproteins increase markedly on carbohydrate rich diets and decrease on low carbohydrate diets. The decrease in triglycerides is in fact one of the most notable changes observed when going from high carb to low carb.

We know that insulin resistant individuals very often have muscles that fill up with fat. But they don’t burn more fat and they become more insulin resistant. One of the big candidates for a causal factor for the skeletal muscle insulin resistance is this fat, more precisely diacylglycerol which impair insulin signaling.

Researchers also commonly propose mitochondrial dysfunction, as an underlying mechanism in the pathogenesis of insulin resistance. It is proposed as a cause of fat build up rather than as a consequence. This subject will definitely be discussed more in the years to come. Many will propose mitochondrial dysfunction as a cause of insulin resistance and will focus on finding very small molecules that can be blamed for all the metabolic havoc. Probably much will be written about transport molecules.

But there’s more trouble with insulin resistance. Endurance trained athletes also have large intramuscular fat stores, suggesting that fat in itself does not cause resistance. The athletes however, have a very high fat oxidation rate and highly insulin sensitive muscles, suggesting a causal role for whatever causes low fat oxidation. Athletes can increase the amount of IMTG in muscles by consuming a high fat diet, although in the more sedentary people, carbohydrates are the more likely cause of intramuscular fat build up.

The build-up of fat in muscles of the obese and overweight is coexisting with a low fat oxidation rate as measured by respiratory quotient. A low respiratory quotient (RQ) means you burn fat. A high RQ means you burn mostly carbohydrate. High RQ correlates with insulin resistance and it is therefore proposed as a causal factor. This is one proposed cause I don’t think we need to discuss for very long. Of course high RQ is common in the obese. That’s the whole problem. They burn glucose, because they eat high carbohydrate. If they were burning fat they wouldn’t be fat. If you take a muscle sample from an overweight person on a high carb diet you have a muscle sample with particularly ineffective fat oxidation skills. The muscles get good at what they do. Eat fat and burn fat and your muscles get good at burning fat. But to hypothesize that obesity may be caused by low fat oxidation is like saying obesity is caused by consuming more energy than you expend.

But just when it seemed that we had it all figured out and all the evidence were pointing at free fatty acids, along comes Taubes quoting Keith Frayn saying that FFA levels are not that different in the obese compared to the lean, which could then not explain their insulin resistance. Some studies have actually shown that the sensitivity or maximum insulin induced inhibition of adipose tissue lipolysis was greater in obese subjects than in normal weight controls. Some obese people display normal insulin sensitivity. One theory (supported by some animal models) says that these people have fat tissue with exceptionally large storage capacity which protect against lipotoxicity in nonadipose tissues. This suggest that enlargement of adipose tissue mass may protect against insulin resistance and diabetes.

The theory of free fatty acids causing insulin resistance is actually one of two major somewhat competing theories. The other being inflammation, which I will have to check out.

The trouble with insulin resistance

Been thinking a lot about insulin resistance lately. Most importantly how a resistance in different tissues might cause different pathologies. Gary Taubes must have been thinking a lot about insulin resistance as well. Way more than me anyway. The following is largely based on his article in Science Magazine July 2009.

It is better to be vaguely right than exactly wrong… I think…

There’s one factor that the major modern diseases have in common. Insulin resistance. Because obesity, cardiovascular disease and type 2 diabetes are so consistently co appearing they are commonly regarded as a single syndrome known as metabolic syndrome, previously known as insulin resistance syndrome. The syndrome is highly influenced by lifestyle factors and especially diet and exercise. In the middle of all this is the rather inconspicuous hormone, insulin. Its main function is to make sure our blood sugar doesn’t get to high and cause tissue damage.

So, how is insulin related to the tissues inability to respond to this very hormone? One explanation is that once tissues are insulin resistant the pancreas compensates by producing more insulin, the tissues answer by becoming even more resistant and a vicious cycle is at hand. But how did the tissues get insulin resistant to start with?

The trouble with finding the mechanisms causing insulin resistance is that insulin is not an idle molecule. Insulin is busy indeed. It is the main regulator of all tissues nutrition and metabolism. It stimulates fat and glycogen synthesis, the two major forms of energy storage. It inhibits the body’s own production of glucose (in type 2 diabetes, insulin peaks at too high levels because the liver keeps producing glucose even though blood glucose is already high). It makes fat cells store energy and it increases protein synthesis and make our muscles grow. The liver, which can be viewed as the main energy distributor of the body, is at the mercy of insulin. Too much insulin makes the liver fill up with fat causing what is commonly known as non alcoholic fatty liver disease. In addition insulin affects a large number of other metabolic pathways and growth factors.

Insulin makes tissues take up glucose to keep blood sugar at a decent level, but measurements of insulin-stimulated glucose uptake have shown that even in healthy individuals the glucose uptake varies greatly (by 600-800% according to Taubes 2009). Physical fitness can explain some of the variations in glucose uptake as muscles are one important site for glucose uptake, and exercised muscles are better at taking up glucose. The general rule is also that the more obese you are the more insulin resistant you are, and weight can also explain some of the variations. But, insulin sensitivity also varies in obese subjects and some even seem to have normal sensitivity. Unless we know in which tissue(s) insulin resistance first occurs and which exact tissues are being resistant we will not find the answer to this and other apparent paradoxes.

Insulin sensitivity is usually not measured at a cellular level, but at a whole body level. The most common test is the hyperinsulinemic euglycemic clamp technique. In this procedure, insulin is administered to raise the insulin concentration while glucose is infused to maintain glucose level (euglycemia). The glucose infusion rate needed to maintain euglycemia tells us how well insulin works. In addition an oral glucose tolerance test (OGTT) gives an insulin resistance related measure. But, not only do we not know which tissues are resistant, the resistance varies during the day and with different situations and lifestyle changes. If we do a fasting test for insulin sensitivity we mostly measure the liver response to insulin.

It was previously assumed that insulin resistance was directly related to the insulin receptors themselves. We now know that the primary defect is somewhere downstream in the insulin signaling pathway.

If fat cells become insulin resistant, we would expect an increased lipolysis and release of fatty acids into the bloodstream, as insulin makes fat cells store energy and the lack of insulin makes them release energy. Insulin resistance is in some studies correlated with an increased level of fatty acids (FFA) in the blood. Obese individuals may have double the level of FFA compared to lean. If your peripheral tissues aren’t in an acute need of energy and the fat cells keep releasing energy into the blood as free fatty acids, then other tissues need to take up this fat. Muscles do a large part of this work. Increased storage of fat in muscles cells are thought to contribute to muscle cell insulin resistance.

In the metabolic syndrome there is an excess storage of fat in muscles as intramuscular triacylglycerols (IMTG) or intramyocellular lipids (IMCL). It also seems that the excess fat storage is mainly in the slow twitch aerobic type I muscle fibers. In several different populations it holds true that the more fat inside the muscles the more insulin resistant they are. A funny side note to this is that in insulin resistance the muscles sometimes act as though they are starving, despite large intramuscular energy stores.

Our muscles utilize fat as fuel largely in proportion to the level of FFA in the blood. That is, the more energy your fat tissue provides the more fat do your muscles burn. This is some of the reason why high fat diets have frequently been tested as a means to increase endurance performance. But in obesity, where the level of FFA in the blood is high, the burning of fat in the muscles is not increased. And so the fat accumulates in the cells.

Obese individuals have reduced rates of fat oxidation compared to lean counterparts despite their apparent increased FFA levels. It also seems that this is related to the mitochondria; the site of fat oxidation.

Research has recently shown that the mitochondria of obese and type 2 diabetics can be 35% smaller than the muscle cell mitochondria of healthy lean individuals. In addition, the size of the mitochondria also correlates significantly with insulin action.

But as Berggren et al. 2008 reported, dramatic weight loss (~55 kg) using gastric bypass surgery significantly improved insulin sensitivity without changes in skeletal muscle fatty acid oxidation.

But none of the above can explain insulin resistance in lean individuals. And a correlation between body mass index and FFA level has actually proved hard to find, and increased FFA may not be as prevalent as previously thought. Increased levels of FFA do not seem to be a single causal factor for insulin resistance in muscles. Mitochondria might not work properly, but are they dysfunctional because of an excess lipid load or does lipids fill up because the mitochondria are dysfunctional? Does muscle cell insulin resistance mean that other tissues are resistant as well?

More trouble with insulin resistance to come…