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.