Free fatty acid theory of insulin resistance

The free fatty acid theory of insulin resistance, also known as the Randle cycle, proposes that elevated levels of free fatty acids (FFAs) in the blood inhibit the oxidation of glucose, leading to insulin resistance. This theory was first proposed by Randle and colleagues in the 1960s 1.

According to this theory, when the body is deprived of glucose, FFAs are released from tissues and their oxidation blocks the oxidation of glucose, even when glucose becomes available from the breakdown of protein caused by cortisol 5. This leads to a decrease in insulin sensitivity and an increase in insulin levels, which in turn promotes the storage of fat.

Research has shown that excess fat, particularly polyunsaturated fatty acids (PUFAs), can elevate FFA levels and contribute to insulin resistance 6. Additionally, studies have found that limiting carbohydrate intake, particularly sugar, does not necessarily improve insulin sensitivity, but rather that reducing fat intake and inhibiting the excessive liberation of FFAs can improve insulin sensitivity and lower insulin levels 2.

It is worth noting that some researchers have suggested that impaired mitochondrial ATP production, possibly due to excess unsaturated fats, low thyroid, low magnesium, or low copper, may also contribute to insulin resistance 2. However, the underlying pathomechanism of insulin resistance is still not fully understood, and further research is needed to clarify the relationship between FFAs, insulin resistance, and other factors.

The Randle cycle has been observed in various studies, including those involving non-insulin-dependent diabetes, where impaired glucose-induced insulin secretion was related to chronic exposure of pancreatic beta-cells to FFAs 3. Similarly, research has shown that essential fatty acid deficiency can prevent autoimmune diabetes in nonobese diabetic mice through a positive impact on antigen-presenting cells and Th2 lymphocytes 4.