Category Archives: Fat and Oil

New Study: How High-Fat Diet Promotes Insulin Resistance

FatHypoxiaInsulinResistance

Diagram from the study showing: A high-fat diet leads to low oxygen in the fat cell, initiating an inflammatory response, resulting in insulin resistance and increased glucose output from the liver.

Since I was just talking about this (Mechanism By Which Dietary Fat Can Raise Blood Glucose And Insulin) I thought I’d post this study that appeared in my inbox this morning:

Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation And Insulin Resistance In Obesity, Cell, 5 June 2014

Here’s the press release:
The Connection Between Oxygen and Diabetes, A Lack Of O2 In Fat Cells Triggers Inflammation And Insulin Resistance In Obesity, University of California, San Diego School of Medicine, 5 June 2014

It’s known that dietary fat, both the quantity and the degree of saturation, promotes an inflammatory response. That inflammation promotes insulin resistance. These researchers say that fat-induced inflammation may be caused by increased oxygen consumption in mitochondria.

Researchers at the University of California, San Diego School of Medicine have, for the first time, described the sequence of early cellular responses to a high-fat diet, one that can result in obesity-induced insulin resistance and diabetes.

In today’s Cell paper, the scientists describe the earliest stages of [the development of systemic insulin resistance and diabetes], which begins even before obesity becomes manifest.

They observed that the abundant saturated fatty acids in the diet activated adenine nucleotide translocase 2 (ANT2) … [which] caused increased oxygen consumption, which meant less was available for the rest of the cell. The result was a relative state of hypoxia or inadequate oxygen supply, one that subsequently induced production of a protective transcription factor in fat cells called HIF-1alpha. In turn, HIF-1alpha triggered release of chemokines, proteins that signal cellular distress, launching the immune system’s inflammatory response. A sustained high-fat diet ensured that the process continued unabated, leading to obesity, chronic low-grade tissue inflammation and eventually, insulin resistance in the mice.

Mechanism By Which Dietary Fat Can Raise Blood Glucose And Insulin

Back in 2008, I began writing about the effect of dietary fat on insulin sensitivity, and blood levels of glucose and insulin. Here’s one of the studies:

Effects Of Isoenergetic High-Carbohydrate Compared With High-Fat Diets On Human Cholesterol Synthesis And Expression Of Key Regulatory Genes Of Cholesterol Metabolism, American Journal of Clinical Nutrition, 2001

It was a small randomized crossover study on healthy subjects that compared:

  • High-fat diet (40% carbohydrate, 45% fat)
  • High-carb diet (55% carbohydrate, 30% fat)

During the oral-glucose-tolerance test, both glucose and insulin rose to higher concentrations after the high-fat diet than after the high-carb diet, showing lower glucose tolerance and insulin sensitivity with the high-fat diet.”

Over the years I learned that saturated fat decreased insulin sensitivity more than other fats, e.g. the KANWU Study.

One mechanism by which dietary fat decreases insulin sensitivity, raising blood glucose and insulin levels is through reduced action of the glucose transporter GLUT4. There seems to be both a reduced expression of the GLUT4 gene, and a reduced translocation or movement of GLUT4 to the cell membrane in the presence of a high-fat, especially high-saturated fat diet.  (GLUT4 is one of the glucose transport proteins that move glucose from the bloodstream into muscle and fat cells. Its insertion into the membrane is controlled by insulin. See diagram.)

When glucose cannot enter cells, blood glucose levels rise. When normal amounts of insulin fail to clear blood of glucose, the pancreas responds by releasing more. The result is impaired glucose tolerance, hyperinsulinemia, and eventual development of type 2 diabetes. Over time, compensatory insulin output from beta cells in the pancreas diminishes and a person with type 2 diabetes may find themselves injecting insulin instead of just taking oral meds.

Glut4

Here are some studies and reviews that address this:

1. A High Fat Diet Impairs Stimulation of Glucose Transport in Muscle, The Journal of Biological Chemistry, October 1998

Rats fed a high (50% of calories) fat diet for 8 weeks showed 50% decreases in insulin-stimulated glucose transport.

“Our findings provide evidence that … impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.”

2. Insulin Resistance in Morbid Obesity: Reversal With Intramyocellular Fat Depletion, Diabetes, January 2002

Subjects were deprived of dietary fat (via gastric surgery that decreases predominantly fat absorption). After 6 months “insulin resistance was fully reversed and GLUT4 expression was restored.”

“We conclude that lipid deprivation selectively depletes intramyocellular lipid stores and induces a normal metabolic state (in terms of insulin-mediated whole-body glucose disposal, intracellular insulin signaling, and circulating leptin levels) despite a persistent excess of total body fat mass.”

3. Transcriptional Regulation Of The Insulin-Responsive Glucose Transporter GLUT4 Gene: From Physiology To Pathology, American Journal of Physiology, Endocrinology and Metabolism, July 2008

Regulation of gene expression by dietary fats has a significant impact on the development of insulin resistance and its related pathophysiologies. … FFAs also attenuate insulin signaling and GLUT4 translocation through activation of the IκB kinase (IKK) pathway. … Low-fat diet improves glycemic control.” (He cited Barnard’s study.)

4. Dietary Fat Differentially Modulate The mRNA Expression Levels Of Oxidative Mitochondrial Genes In Skeletal Muscle Of Healthy Subjects, Nutrition, Metabolism, and Cardiovascular Diseases, December 2013

“[A meal high in saturated fat] was associated with a marked reduction in the expression of GLUT4 genes.”

5. Moderate GLUT4 Overexpression Improves Insulin Sensitivity And Fasting Triglyceridemia In High-Fat Diet–Fed Transgenic Mice, Diabetes, July 2013

Mice that were fed a high-fat diet and that became obese were protected against insulin resistance and the high glucose and insulin levels of their counterparts when they were bred to have more GLUT4.

6. A Comprehensive Review On Metabolic Syndrome, Cardiology Research and Practice, March 2014

A good description of the pathogenesis of insulin resistance. It adds to what I said above with discussion of intracellular response to insulin binding:

“Binding of insulin results in a tyrosine phosphorylation of downstream substrates and activation of two parallel pathways: the phosphoinositide 3-kinase (PI3K) pathway and the mitogen activated protein (MAP) kinase pathway. The PI3K-Akt pathway is affected, while, the MAP kinase pathway functions normally in insulin resistance. This leads to a change in the balance between these two parallel pathways. Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial NO production, resulting in an endothelial dysfunction, and a reduction in GLUT4 translocation, leading to a decreased skeletal muscle and fat glucose uptake.”

That reduction in endothelial NO (NO is nitric oxide) production contributes to high blood pressure.

There are multiple mechanisms by which a diet high in fat can lead to insulin resistance.  (See also: Fatty acid-induced NLRP3-PYCARD inflammasome activation interferes with insulin signaling, Nature Immunology, May 2011.)   There is an acute effect of fat in a meal which is distinct from and may be additive to the effect of diets that are chronically high in fat (details of each are still being sussed). Also, the fat we eat can change the composition of lipid in cell membranes.  A diet high in saturated fat has been shown to make membranes less fluid and may impair GLUT4 insertion.

These are just a few I have time to post about. There really is abundant research on the role of dietary fat in the development of insulin resistance, a condition which manifests as elevated glucose, elevated insulin, and the development of type 2 diabetes.

“Fat Affects Your Blood Sugars”

I was reading a post, “Gary Taubes and the Cause of Obesity” on a site called ScienceBasedMedicine. The author, Harriet Hall, said:

“… serum insulin levels are driven by the carbohydrate content of the diet.”

Many people think this. As you know, it is inaccurate. Dietary carbohydrate is not the sole driver of serum insulin. But it persists in people’s minds. It is the reason people go on low-carb diets … thinking they can reduce their blood glucose and insulin by eating fewer carbs. Unfortunately, that means eating more fat and…

High-fat diets have been shown to increase insulin levels, because fat (especially saturated fat) can decrease insulin sensitivity. When cells become resistant to insulin, the pancreas produces more insulin to compensate, resulting in high serum insulin levels or hyperinsulinemia.

Also, when cells becomes resistant to insulin, glucose in the blood can’t enter cells so blood glucose levels rise.

Here’s an unfortunate result … high insulin levels can feed insulin resistance, which can feed high insulin, which can feed insulin resistance … in a self-propagating manner:

Insulin Resistance and Hyperinsulinemia, Is hyperinsulinemia the cart or the horse? Diabetes Care, 2008

That quote in my title, “Fat Affects Your Blood Sugars” came from this video out of the Joslin Diabetes Center. People think it’s just the carbs that affect blood sugar; it’s the fat too:

Animal Fat Is A Natural Reservoir For Environmental Pollutants

BaconFat3With all the debate about weather fat in the diet is good or bad, one morsel getting lost in the discussion is that animal fat is a natural reservoir for environmental pollutants. Persistent Organic Pollutants (POPs) are largely hydrophobic, meaning they don’t dissolve well in water but they dissolve easily in fat. They also bioaccumulate, meaning they are found in higher, more concentrated amounts in animals higher in the food chain (such as tuna, salmon, fish-eating fowl, and farmed animals fed fish meal and other animal products), and, of course, ourselves:

“POPs are lipophilic chemicals that can pass through biological phospholipid membranes and bio-accumulate in fatty rich tissues of humans.”

Consumption of fat and cholesterol has been repeatedly linked to weight gain, arterial plaque buildup, blood glucose abnormalities, even cancer progression. Could it be the chemicals dissolved in that animal fat that are contributing to these ailments? Yes, says researcher Jerome Ruzzin from the University of Bergen in Norway:

Public Health Concern Behind The Exposure To Persistent Organic Pollutants And The Risk Of Metabolic Diseases, BMC Public Health, April 2012

There is now solid evidence demonstrating the contribution of POPs, at environmental levels, to metabolic disorders. Thus, human exposure to POPs might have, for decades, been sufficient and enough to participate to the epidemics of obesity and type 2 diabetes.”

“The general population is exposed to sufficient POPs, both in term of concentration and diversity, to induce metabolic disorders. This situation should attract the greatest attention from the public health and governmental authorities.”

No mincing of words there!

What are POPs?

“Persistent organic pollutants (POPs), including dioxins, furans, polychlorinated biphenyls (PCBs), and organochlorine pesticides, are chemicals mainly created by industrial activities, either intentionally or as by-products [13]. Because of their ability to resist environmental degradation, these substances are omnipresent in food products, and found all around the world, even in areas where they have never been used like Antarctica [14]. Thus, virtually all humans are daily exposed to POPs.”

What foods contain the most POPs?

“In the general population, exposure to POPs comes primarily from the consumption of animal fat like fatty fish, meat and milk products; the highest POP concentrations being commonly found in fatty fish [15–26].”

Some diseases linked to POPs (from a variety of studies: humans, animals, cell models):

Bio-accumulation of PCBs has been linked to non-alcoholic fatty liver disease (NAFLD) and elevated blood pressure.

Animals exposed to environmental levels of POP mixtures through the intake of non-decontaminated fish oil (obtained from farmed Atlantic salmon) exhibited insulin resistance, glucose intolerance, abdominal obesity and NAFLD [44]. In rats fed decontaminated crude salmon oil, which contained very low levels of POPs, these metabolic disturbances were almost absent.

The presence of POPs in farmed Atlantic salmon fillet was found to accelerate the development of visceral obesity and insulin resistance in mice.

Another important issue is the regulation of organochlorine pesticides, which are chemicals strongly linked to type 2 diabetes [29, 32, 33, 37, 44, 45] as well as breast and prostate cancer [94] and Parkinson disease [95]

It looks like we can’t get away from DDT, even though it was banned here in 1972:

“Not surprisingly, a recent US monitoring study revealed that DDT and its metabolites as well as endosulfan and aldrin, are still largely present in food, and daily consumed by humans.”

Children are at greater risk of exposure:

“Because of their high food intake per kilogram body weight required to maintain whole-body homeostasis and growth, children are likely to be at higher risk for environmental pollutant exposure. Not surprisingly, many scientific studies have highlighted that children are over-exposed to dioxins and dl-PCBs, and exceed the TDI of 2 pg/kg body weight.”

SalmonFillet3Finally, here’s a list of limits set by the European Union:

  • Ruminants: 4.5 pg/g fat
  • Poultry and farmed game: 4.0 pg/g fat
  • Pigs: 1.5 pg/g fat
  • Marine oils: 10 pg/g fat

You can see that the limit for marine oils is double that for fat from land animals. Why? They need to get together on this and create standards that apply across the board, and are based on public health, not commerce. Speaking of salmon, he says that “eating 1 g of fat from a fatty fish fillet could induce an exposure to 70 pg.”

What are Paleos eating? I mean, you can’t be Paleo and vegan at the same time. How do you avoid all these dissolved POPs?

Regulating vehicle emissions, pesticides, and industrial wastes is at odds with economic growth. Which is why I think pollution and its attendant chronic disease load is here to stay.

Eggs, Dietary Cholesterol, And Heart Disease

Dr. Greger is taking on eggs today (again):

So, do eggs and other sources of dietary cholesterol raise the risk for heart disease? Dr. Greger argues they do.

EggsScrambled2As I’ve come to understand, you have to look at the whole diet. For instance, for a given amount of saturated fat eaten, a given amount of dietary cholesterol (eggs) eaten at the same time will raise serum LDL cholesterol higher than if that dietary cholesterol was paired with a polyunsaturated fat, such as corn oil.1

Also, is any of that dietary cholesterol oxidized? Because if it is (and unless you eat it raw and very close in time to the demise of its source, some of it will be) it will contribute to the development of atherosclerosis and heart disease (and to the growth of cancer, as I just wrote). So says Fred Kummerow, a 98-year-old emeritus professor of comparative biosciences at the University of Illinois:

“Oxidized lipids contribute to heart disease both by increasing deposition of calcium on the arterial wall, a major hallmark of atherosclerosis, and by interrupting blood flow, a major contributor to heart attack and sudden death.”

And Professor Kummerow is of a mind that cholesterol is actually good for your heart! (Fortunately, our bodies manufacture all we need.)

Also, fruits and vegetables contain compounds that act as anti-oxidants, slowing further oxidation of consumed fats. You have to look at the whole diet.

You can’t judge well the effect of a single nutrient outside the context of the whole diet. It’s also risky to generalize the effects you may see of a nutrient in a small and perhaps homogeneous group. Nutrients, like dietary cholesterol, act differently in men vs. women, in old vs, young, in healthy vs. diseased (e.g. diabetes).

What is helpful, in my opinion, is to reflect upon the body of evidence. In this case, it looks like their exists a credible body of evidence to support limiting egg (and other dietary cholesterol) consumption.

1 Hypercholesterolemic Effect Of Dietary Cholesterol In Diets Enriched In Polyunsaturated And Saturated Fat, Atherosclerosis, Thrombosis, and Vascular Biology, 1994

Eskimos’ Fat-Rich Diet Turns Out To Be Really Unhealthy

EskimoDiet2This new review that analyzed the diets and health of Eskimos and Inuits found that all their oily fish, far from being “heart-healthy” was, to use the lead author’s word, “dangerous”:

“Fishing” For The Origins Of The “Eskimos And Heart Disease” Story. Facts Or Wishful Thinking?, Canadian Journal of Cardiology, 14 April 2014

“During the 1970s, two Danish investigators, Bang and Dyerberg, upon being informed that the Greenland Eskimos had a low prevalence of coronary artery disease (CAD) set out to study the diet of this population. Bang and Dyerberg described the “Eskimo diet” as consisting of large amounts of seal and whale blubber (i.e. fats of animal origin) and suggested that this diet was a key factor in the alleged low incidence of CAD. This was the beginning of a proliferation of studies that focused on the cardioprotective effects of the “Eskimo diet”.

In view of data, which accumulated on this topic during the past 40 years, we conducted a review of published literature to examine whether mortality and morbidity due to CAD are indeed lower in Eskimo/Inuit populations compared to their Caucasian counterparts. Most studies found that the Greenland Eskimos as well as the Canadian and Alaskan Inuit have CAD as often as the non-Eskimo populations. Notably, Bang and Dyerberg’s studies from the 1970s did not investigate the prevalence of CAD in this population; however, their reports are still routinely cited as evidence for the cardioprotective effect of the “Eskimo diet”. We discuss the possible motives leading to the misinterpretation of these seminal studies.”

One thing you can say for sure … their diet is not protecting them from heart disease.

The press release:
Investigators Find Something Fishy With Classical Evidence For Dietary Fish Recommendation

Lead investigator George Fodor said:

“Bang and Dyerberg’s seminal studies from the 1970s are routinely invoked as ‘proof’ of low prevalence of CAD in Greenland Eskimos ignoring the fact that these two Danish investigators did not study the prevalence of CAD. Instead, their research focused on the dietary habits of Eskimos and offered only speculation that the high intake of marine fats exerted a protective effect on coronary arteries.”

Not only do Eskimos develop CAD at the same rate as non-Eskimos, but

“[Eskimos] have very high rates of mortality due to cerebrovascular events (strokes). Overall, their life expectancy is approximately 10 years less than the typical Danish population and their overall mortality is twice as high as that of non-Eskimo populations.”

Fodor et al. said the reason CAD prevalence was thought to be less 40 years ago was because Eskimos’ rural lifestyle and inaccessible geography prevented access to medical care which led to inaccurate and incomplete death records.

Dr. Fodor:

“Considering the dismal health status of Eskimos, it is remarkable that instead of labeling their diet as dangerous to health, a hypothesis has been construed that dietary intake of marine fats prevents CAD and reduces atherosclerotic burden.”

Salmon is not a health food.

Ancient Elite Egyptians Ate A Lot Of Animal Food, Developed Arterial Plaque

MummiesAtherosclerosis3I mentioned in a comment that I had read about atherosclerosis in Egyptian mummies. Here’s one citation:

Atherosclerosis and diet in ancient Egypt, Lancet, February 2010

“Atherosclerosis and vascular calcification are usually regarded as circulatory phenotypes associated with advanced modern lifestyles. However, although rare, such conditions have been identified in human remains from some early societies. Examples occur in an elite Chinese burial (c. 700 BCE), and among Canadian Eskimos (c. 400 CE to c. 1520 CE) whose diet was almost entirely meat. They have also been reported since the early 20th century in the mummified remains of the rulers and elite of ancient Egypt.

Interpretation of the hieroglyphs indicates that the diet consisted mainly of beef, wildfowl, bread, fruit, vegetables, cake, wine, and beer. Many of these food items would obviously have contributed to an intake of saturated fat, and our analyses of the individual meat and wildfowl they consumed would demonstrate that all provided greater than 35% of energy from fat. Goose, which was commonly consumed, contains around 63% energy from fat with 20% being saturated, while the bread that was eaten differed from that consumed today, often being enriched with fat, milk, and eggs. The cakes were typically made with animal fat or oil. Although it is difficult to calculate exactly how much was consumed in terms of portion size, variance in food storage, preparation, and cooking methods, it is still evident from a conservative estimate that the dietary energy was more than 50% from fat with a significant portion of this coming from saturated fat.

It is important to point out that there was a marked difference between the mainly vegetarian diet most Egyptians ate and that of royalty and priests and their family members whose daily intake would have included these high levels of saturated fat. Mummification was practised by the elite groups in society, ensuring that their remains have survived to provide clear indications of atherosclerosis; by contrast, there is a lack of evidence that the condition existed among the less well-preserved remains of the lower classes.

The explanation for these frequent pathological findings almost certainly resides in a diet rich in saturated fat that was confined to the elite, while most of the population remained vegetarian. In consequence, there is unequivocal evidence to show that atherosclerosis is a disease of ancient times, induced by diet, and that the epidemic of atherosclerosis which began in the 20th century is nothing more than history revisiting us.”

It is credible to me that a mummy earned the right to be embalmed because of his or her status in the community. And that status may have afforded the person access to foods that weren’t available to the masses.

So, atherosclerosis, or as my mother called it, hardening of the arteries, isn’t new. It’s likely a result of lifestyle, specifically a diet high in animal foods.

The Link Between Dietary Fat And Diabetes

FatsVisibleInvisible2I often read in comments elsewhere that people don’t understand how the fat we eat affects blood glucose levels. Here’s a recent one I saw:

“I still can’t figure out HOW meat and fat are supposed to cause diabetes when it has a practically zero effect on your blood sugar.”

They talk about carbohydrates, but fat and protein, they say, have no effect … that you can eat as much fat, as much saturated fat, as you want and it won’t affect glucose levels or glucose uptake.

Truth be told, everything we eat affects glucose clearing in one way or another. The macronutrients … carbohydrates, fat, and protein … all contribute to glucose clearing in unique ways.

Regarding dietary fat, Ricardi et al., in their review…

Dietary Fat, Insulin Sensitivity And The Metabolic Syndrome, Clinical Nutrition, 2010

… Describe several mechanisms for how dietary fat impacts glucose uptake. I’ll highlight two of them.

1. “Consumption of energy-dense/high fat diets is strongly and positively associated with overweight that, in turn, deteriorates insulin sensitivity, particularly when the excess of body fat is located in abdominal region.”

That’s an indirect method. The middleman there is overweight.  But what if you delete the middleman? What if you eat a high-fat, particularly high-saturated-fat diet but keep your weight within a healthful range? Can it still lead to insulin resistance? Yes. Studies have shown it can.

The composition of our cell membranes is determined, in part, by the amount and type of fat we eat. Saturated fat is less flexible than unsaturated fat, and will contribute to less flexible, or less ‘fluid’ cell membranes. (e.g. less saturated vegetable oils are more fluid at room temperature than more saturated butter and lard.), and:

2. “Given that insulin signaling and recruitment of GLUT4 to the cell membrane in skeletal muscle are largely membrane-associated events, a more fluid membrane might be expected to be associated with improved insulin sensitivity.”

Indeed, Ricardi cites studies, including intervention studies, that bear this out … the more saturated fat in the cell membrane (and the more saturated fat we eat), the more insulin resistant the cell. (GLUT4 is a glucose transporter or “door” for glucose to enter the cell.)

I’ll add a third mechanism that they don’t address but I’ve read about (e.g. Polyunsaturated Fatty Acids: From Diet To Binding To PPARs And Other Nuclear Receptors, Genes and Nutrition, 2006).

3. Fatty acids (FAs) themselves can affect the expression of genes. For example, FAs can bind to proteins in the nuclear membrane, acting as transcription factors. (A group of these transnuclear proteins are known as PPARs. Some of the best known PPAR ligands are the thiazolidiediones … a class into which the diabetes drugs Avandia and Actos fall.) By controlling gene expression, FAs can and do control many processes, from lipid storage (lipid synthesis) to lipid oxidation (lipid breakdown), which, taken together, affect insulin sensitivity.

In sum:
1. Fat can affect body weight and body composition, which can affect insulin sensitivity.
2. Fat can make cell membranes more or less fluid, affecting insulin sensitivity.
3. Fatty acids can control how genes get expressed, affecting insulin sensitivity.

There must be something else working too, something more immediate, because when you give people with type 1 diabetes a high-fat meal and a low-fat meal, they need more insulin to cover the high-fat meal, even though both meals contain the same amount of carbohydrate and protein.

From:
Dietary Fat Acutely Increases Glucose Concentrations and Insulin Requirements in Patients With Type 1 Diabetes, Diabetes Care, April 2013

I thought this was interesting, from Ricardi, about omega-3 (n-3):

“The n-3 very-long-chain polyunsaturated fatty acids characteristic of fish intake were weakly negatively associated with insulin sensitivity. This tends to confirm earlier findings that n-3 polyunsaturated fatty acid intake can impair insulin sensitivity.”

So, fish oil may contribute to insulin resistance as well. It’s already been shown to increase LDL cholesterol.1

There has been a lot of study in the area of diet and insulin resistance.  That’s why comments like the one at the top of this post surprise me. There remain questions, but the body of evidence so far points to the notion that high-fat, especially high-saturated-fat diets increase insulin resistance, affect blood glucose levels, and contribute to the development of type 2 diabetes.

* “Insulin sensitivity” refers to how sensitive cells are to insulin, and how well cells take up glucose. If cells are insulin sensitive, that’s good. If cells are “insulin resistant”, that’s not good. It means cells are resistant to taking up glucose from the bloodstream, which can lead to high blood glucose and over time diabetes.

1 Effects Of Dietary Saturated, Monounsaturated And N-3 Fatty Acids On Fasting Lipoproteins, Ldl Size And Post-prandial Lipid Metabolism In Healthy Subjects, Atherosclerosis, 2003.