Excessive fat oxidation (β-oxidation) drives diabetes

An association between intracellular fat accumulation and insulin resistance has been found. But an association is not a cause…

The hypothesis was that β-oxidation is too slow and as a result, fats start to accumulate in the cells and this causes insulin resistance, thus the inability to transport glucose into the cell and reduce glucose oxidation.

However a recent study found that excessive β-oxidation, instead of insufficient β-oxidation, was the cause of intracellular fat accumulation and insulin resistance.

The finding came from this study right here:

Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance

But how is this possible?

Timothy Koves and his team found that:

“lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial b-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1”

Fats are removed from their carrier protein in the blood (which is very low density lipoprotein (VLDL), low density lipoprotein (LDL), albumin and chylomicrons, via the enzyme lipoprotein lipase (LPL)), and are then transported into the cell via transporters namely, fatty acid binding proteins (FABP), fatty acid translocase (FAT), which is also known as cluster differentiation 36 (CD36) and fatty acid transport proteins (FATP).

Once in the cytoplasm, fats need to be transported by the enzyme carnitine palmitoyltransferase 1 & 2 (CPT-1 & 2) across the mitochondrial outer and inner membrane respectively. Inside the mitochondria the fat is broken down by beta-oxidation to acetyl-CoA, where it can be used in the Kreb cycle.

Glucose is transported into the cell through the transporter GLUT4, which is controlled by insulin. When insulin is high, GLUT4 takes up glucose into the cells, and the fat transporters are inhibited, thus inhibiting fat uptake into the cell. But when the cells are insulin resistant, the fat transporters stay open, thus allowing fats and small amounts of glucose to enter the cell (depending on the level of insulin resistance).

So CPT is the rate limited step for fat transport into the mitochondria.

CPT is reduced by malonyl-CoA. Malonyl-CoA is produced via de novo lipogenesis. When lots of reactive oxygen species (ROS) are created through the electron transport chain, it inhibits the enzyme aconitase.

The more aconitase is inhibited, the more DNL will be active and will thus create more malonyl-CoA.


So as you can see from the picture above, saturated fatty acids (SFA) creates more reactive oxygen species (ROS) than polyunsaturated fatty acids (PUFA). The ROS from SFA inhibit the aconitase enzyme to a greater degree than PUFAs, thus creating more malonyl-CoA.

Malonyl-CoA in turn inhibits CPT and allows less fat to enter the mitochondria. SFAs inhibit CPT to a greater degree than PUFAs. The enzyme malonyl-CoA decarboxylase (MCD), which breaks down malonyl-CoA, will prevent malonyl-CoA from inhibiting CPT due to less available malonyl-CoA.

Mcd knockout mice (mice without the mcd enzyme), had “a marked preference for glucose utilization” and “Muscle lactate levels were lower and pyruvate content trended higher”. This directly indicates that fat oxidation inhibits glucose oxidation and converts the glucose to lactate, instead of to CO2.

PUFAs inhibit CPT to a lower degree than SFAs and allow for excessive beta-oxidation to occur leading to diabetes…

However, it’s not only because of excess β-oxidation, but also because of incomplete oxidation.

“The high rates of fatty acid catabolism in insulin-resistant muscles were attributed principally to ‘‘incomplete’’ fat oxidation, in which a large proportion of fatty acids entering the mitochondria are only partially degraded”


“high rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates” (1)

These partially oxidized lipids that are floating around the mitochondria are then prone to oxidation by ROS, and create even more toxic byproducts such as 4-hydroxynonenal (4HNE). Only PUFAs can be oxidized by ROS, which is called lipid peroxidation. In this study (2), researchers blocked CPT-1, and as a result lipid peroxides and oxidative stress reduced significantly.

As to the hypothesis in the beginning, intracellular fat isn’t the culprit for insulin resistance, because muscles from exercise-trained subjects are highly insulin sensitive, despite having intramyocellular fat levels that are similar or even higher than those found in obese and diabetic individuals.

Goodpaster et al. were the first to report an increase in intramyocellular lipid in endurance athletes without consequent impaired glycemic control, which they termed “Athlete’s Paradox”. (3)

Another study done by the same researcher in 2005 found that (emphasis mine):

“a 2-week exercise intervention in mice fed a chronic HF (high fat) diet lowered muscle acylcarnitine levels in association with increased TCA cycle activity and complete reversal of glucose intolerance”

The popular supplement carnitine, which is touted to enhance exercise performance by increasing fatty acids oxidation, also contributes to insulin resistance and glucose intolerance. As it is stated in the study:

“Conversely, resistance to insulin became progressively more severe when fatty acid treatment was combined with increasing doses of carnitine.”

It’s clear to me that PUFAs directly contribute to mitochondria dysfunction, excessive β-oxidation and diabetes.

In order to lower circulating free fatty acids (and thus the availability of fats to the cells), use anti-lipolitic substances such as niacinamide, aspirin and/or vitamin E.

The drug Acipimox is a niacin derivative and is used to improve glucose tolerance and insulin sensitivity by lowering free fatty acids.


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