Role of elevated plasma free fatty acid in type 2 diabetes

Tale of type 2 diabetes and FFA

The number of people affected with type 2 diabetes has reached epidemic proportions worldwide. It is estimated that by the year 2020 there will be approximately 250 million people affected worldwide. Although the primary factors causing this disease are unknown, it is clear that insulin resistance plays a major role in its development. Insulin resistance is a common pathological state in which target tissues fail to respond properly to normal levels of circulating insulin. Over 80% of people with type 2 diabetes are obese and virtually all are insulin resistant. It has been found that high concentration of plasma free fatty acid (FFA) is one of the factors that contribute to the underlying pathophysiology including development of insulin resistance in periphery and liver.

Free fatty acid (FFA) – understanding their role

Elevated plasma FFA plays an important role in the establishment of insulin resistance in muscle. Chronic elevation in plasma FFA levels is commonly associated with impaired insulin-mediated glucose uptake in skeletal muscles and often coexists with obesity and type 2 diabetes. In 1963, Randle and his co-workers proposed a mechanism for fat-induced insulin resistance, which implicated fatty acid oxidation as the cause of this defect. They demonstrated that FFA effectively compete with glucose for substrate oxidation in isolated rat heart muscle and therefore speculated that increased fat oxidation might cause the insulin resistance associated with diabetes and obesity. The postulated mechanism has been that increased free fatty acid oxidation ultimately led to increase of glucose 6 phosphate concentration. About 30 years later, Shulman and his co-workers challenged the conventional Randle hypothesis with an elegant series of studies. The use of novel technology such as NMR spectroscopy allowed a more direct study of glucose metabolism in vivo, and led them to propose that glucose transport itself as being responsible for the observed defects. Shulman and co-workers demonstrated that an elevation of the plasma fatty acid concentrations results in a decrease in the concentration of glucose 6-phosphate rather than increase, in muscle. The initial defect appeared to be an alteration in glucose transport in response to insulin.

Revisiting Randle’s hypothesis – on muscle insulin resistance
How is FFA involved in the development of muscle insulin resistance? Several modifications were made since Randle’s hypothesis. Boden and co-workers investigated the possible mechanisms. They reported that a high plasma FFA lowered insulin stimulated glucose uptake in the type 2 diabetes patients. Insulin-stimulated rates of muscle glycogenesis and whole body glucose oxidation were altered very rapidly compared with controls. The observed fall in intramuscular concentration of Glucose-6- phosphate reflected an inhibition of glucose Figure 2 Inhibitory effects of FFAs on glucose uptake transport and/or phosphorylation. It was proposed that the earliest effect of high plasma FFA level was (1) inhibition of carbohydrate oxidation followed by (2) inhibition of glucose transport/phosphorylation and then (3) inhibition of glycogen synthesis (Figure 2). These studies supports the hypothesis that elevated FFA induce insulin resistance principally at the level of glucose transport.

Targeting free fatty acid – a new approach to type 2 diabetes management

Although several factors are proposed to link obesity and insulin resistance in type 2 diabetes patients, promising candidates include elevated plasma level of free fatty acids amongst others. Pharmacological agents that effectively lower FFA are likely to have significant effect in reducing fasting plasma glucose. Therefore it is logical that FFA can be a potential target in obesity and type 2 diabetes. What is required is a definitive change in lifestyle and exercise therapy that would reduce weight. This would decrease circulating FFA and insulin sensitivity of type 2 diabetes individuals will improve. Controlling FFA levels in plasma would benefit patients with type 2 diabetes and obesity. This approach of therapy has potential to control the growing epidemic.