Category Archives: Insulin Resistance

High-Fat, High-Fructose Combination Worse Than High-Fat Or Low-Fat Alone

I’ve been saying this for years1,2 … a diet that is both high in fat and high in refined carbohydrates is worse (that is, leads to more metabolic disorders such as weight gain, diabetes, fatty liver, cancer) than a diet high in one or the other. The combination is particularly deleterious. (Although diets high in fat alone come with their own risks related to their higher levels of fat-soluble environmental toxins, increased systemic inflammation, and, as this study found, promotion of insulin resistance and fatty liver.)

This new study found that:

Fructose Supplementation Worsens The Deleterious Effects Of Short Term High Fat Feeding On Hepatic Steatosis And Lipid Metabolism In Adult Rats, Experimental Physiology, 27 June 2014

RatsHighFat2014Adult male rats were fed either a low-fat, high-fat, or high-fat/high fructose diet for 2 weeks. The high-fat/high-fructose diet was worse than the high-fat diet, which was worse than the low-fat diet. Another way of saying that … the low-fat diet was the healthiest.

Some significant bits:

“From our results, it appears that hepatic mitochondrial impairment is an early event induced by increased lipid content of the diet, since it is already evident after 2 weeks of dietary treatment, and that the presence of fructose does not have a further impact on mitochondrial function.

Significantly lower mitochondrial oxidative capacity but significantly higher oxidative stress was found in rats fed high fat and high fat-high fructose diet compared to rats fed low fat diet.”

During high fat feeding an increased lipid supply to peripheral organs, and particularly to the liver, arises mainly from dietary lipids.”

They say that mitochondrial impairment is linked to insulin resistance, and that it is dietary fat which initiates insulin resistance. It occurs because there is a reduced capacity by mitochondria to deal with the increased lipid supply. The extraneous fat is deposited ectopically or outside of the cell, leading to a fatty liver, which exacerbates insulin resistance. Adding fructose to this impaired state compounds the problem.

This is exactly what Dr. McDougall says happens. (Insulin Resistance Is A Normal Adaptation To A Rich Diet)

By the way, the rats fed a low-fat, high-carbohydrate diet (from cornstarch) by the end of the study weighed less, had less body fat, less liver fat, fewer plasma free fatty acids, and lower plasma cholesterol than the rats fed a high-fat diet, even though they ate the same amount of food (in calories) as the high-fat rats.

1 High-Fat High-Sugar Dietary Pattern (“Meat & Potatoes”) Linked To Colon Cancer, Diabetes, Fanatic Cook, July 2010
2 “Meat And Potatoes” Dietary Pattern And Risk For Colon Cancer, Fanatic Cook, May 2010

Insulin Resistance Is A Normal Adaptation To A Rich Diet

Dr. McDougall on how insulin resistance and type 2 diabetes develop:

“It’s a normal adjustment of the body, when we eat all this rich food, to become diabetic.

The body says, “Hey! That’s enough! You’ve put on 30 or 40 pounds, I need to stop gaining weight.” And so what happens is a normal adaptation, and that is, the body becomes insulin resistant. It resists the effects of the hormone insulin.

Insulin is a powerful hormone that drives sugar into your normal cells and drives fat into your fat cells. Well, the body says, “Hey, you’ve driven enough fat into the fat cells, we got to stop doing this. You’re going to become 50, 100, 200, 500 pounds overweight, and we can’t allow that, that’s a survival issue. You won’t be able to get through the door, or climb up the tree to get away from the tiger.”

So the body becomes insulin resistant. And as a result, the fat doesn’t go into the fat cells as easily, and, as a result, the sugar doesn’t go into the regular cells, and, as a result, the blood sugar goes up, and then you’re told you’re a type 2 diabetic.

You’re still making lots of insulin, often you’re making twice as much insulin as somebody without diabetes. It’s just you now have insulin resistance, which is appropriate. Your body is trying to make adjustments for all those extra calories, all that extra fat, all that extra sugar. You can fix this really easily. You just stop that kind of eating, all that rich food.”

Dr. McDougall supports consumption of a low-fat, whole food, plant-based diet – one based on starches such as potatoes, rice, and corn, and which excludes animal foods and added oils.

Proposed Warning Label For Meat: “Eating Meat Contributes To Insulin Resistance And Diabetes”

SodaWarningLabelThe California Senate just passed a bill requiring warning labels on sugar-sweetened beverages:

“Drinking beverages with added sugar(s) contributes to obesity, diabetes, and tooth decay.”

It’s a shame that sweetened beverages are being singled out. I would like to see a similar label on meat:

“Eating meat contributes to insulin resistance and diabetes.”

Why? Because meat-eating is a risk factor for developing diabetes:
Meat Consumption As A Risk Factor For Type 2 Diabetes, Nutrients, February 2014

Researchers evaluated studies that examined different amounts and types of meat consumption and the risk for developing diabetes. They found that meat-eaters had a significantly higher risk of developing diabetes compared with non-meat-eaters. Here’s a chart summarizing the results of one of the included studies, Type of Vegetarian Diet, Body Weight, and Prevalence of Type 2 Diabetes, Diabetes Care, 2009:


Mechanisms for meat’s effect on diabetes risk:

  • Effect on body weight – “Nearly all observational studies comparing meat-eaters with those who avoid meat show higher body weights among the former group, a finding mirrored in the results of intervention studies using meatless diets.”
  • Effect on visceral fat (fat around organs in abdominal area) – “Visceral adipose tissue is associated with insulin resistance as a result of increased proinflamatory cytokines.”
  • Effect on intracellular lipid (fat inside cells) – Impairs insulin action. This would involve, in part, the glucose transporter (GLUT4), which I discussed here.
  • Effect on iron balance – “Meat provides a substantial quantity of heme iron … a prooxidant that encourages the production of reactive oxygen species, which may damage body tissues, including insulin-producing pancreatic cells.” Even moderately elevated iron stores are associated with insulin resistance and type 2 diabetes.
  • Nitrates in processed meats – Nitrites and sodium are both linked to elevated diabetes risk.
  • Systemic inflammation – “A 2014 Harvard study reported that as total red meat consumption increased, so did biomarkers of inflammation.”
  • One they didn’t mention was presence of persistent organic pollutants (POPs): Animal Fat Is A Natural Reservoir For Environmental Pollutants. “There is now solid evidence demonstrating the contribution of POPs at environmental levels, to metabolic disorders … such as obesity and type 2 diabetes.”

Do you think a meat label could come to pass? There certainly is enough justification for it.

New Study: How High-Fat Diet Promotes Insulin Resistance


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.


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:

Dietary Fat Raises Blood Glucose

Here you are. Dietary fat raises blood sugar:

Here’s the study it was based on:

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

Each person had a chance to eat the high-fat meal and the low-fat meal. When they ate the high-fat meal they needed more insulin to cover the same amount of carbohydrate. The meals had identical carbohydrate and protein, but different fat content (60 grams vs. 10 grams).