Hyperlipidaemia and insulin resistance

ABSTRACT

There is reason to believe that increased plasma fatty acid (FFA) levels may be a cause for the strong association between fat ingestion and obesity. It has been recently shown in offspring of parents with non-insulin dependent diabetes mellitus (NIDDM), known to be at high risk to develop the disease, that elevated FFA levels were associated with insulin resistance. Moreover, 80-85 percent of patients with NIDDM are obese, are insulin-resistant, and many have elevated FFA levels which correlate with glucose tolerance. In support of the notion that plasma FFA are responsible for the insulin resistance observed in obesity, it was demonstrated more than 30 years ago that increased availability of FFA decreased CHO oxidation and glucose uptake in perfused rat heart and to a lesser extent in rat diaphragm. Based on these findings, the researchers proposeda glucose-fatty acid cycle presumed to be of fundamental importance for the control of blood glucose and insulin sensitivity both in normal and in diabetic subjects. This intriguing concept has remained controversial mainly because many investigators were unable to reproduce the fatty acid-mediated inhibition of glucose uptake in striated muscle that had been observed in perfused rat hearts. We have recently reinvestigated that onset and duration of the inhibitory effect of intravascular lipolysis, produced by intravenous infusion of triglycerides and heparin, on total body CHO oxidation and glucose disappearance in normal men during euglycaemic-hyperinsulinaemia. These studies demonstrated that the fatty acid-mediated inhibition of insulin-stimulated CHO oxidation occurred early, i.e., within the first 20 minutes while the inhibition of glucose uptake developed after only 3-4 hours of fat infusion. Thus, insufficient time of fat infusion (2 hours in most studies) was the most likely reason why the inhibitory effect of FFA on glucose uptake was not found in many studies. In subsequent studies, we have examined the dose dependency of the fatty acid effect on insulin-stimulated glucose uptake. The results showed that FFA inhibited glucose uptake in a dose-dependent fashion throughout the physiological range of plasma FFA concentration (AU)