FREE FATTY ACIDS (FFA), A LINK BETWEEN OBESITY AND INSULIN RESISTANCE

Guenther Boden, M.D.

Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, PA

Received 1/21/98 Accepted 1/31/98

5. FFA AND HEPATIC INSULIN RESISTANCE

The issue of whether FFA inhibit insulin suppression of hepatic glucose production (HGP), i.e., causes hepatic insulin resistance remains somewhat controversial. We and others have reported that acute elevation of plasma FFA increased HGP in patients with Type II diabetes and in non-diabetic controls during hyperinsulinemic clamping (14, 38-41) "figure 7". On the other hand, lowering of plasma FFA with nicotinic acid or acipimox, a nicotinic acid analog, has been reported to increase (40) to decrease (42-44) or not to change HGP (45). There are probably two main reasons for these discrepant results. One, while there is good in vitro and animal evidence that FFA promote gluconeogenesis (46-50), there is also evidence to suggest that increased gluconeogenesis does not necessarily increase HGP. There appears to be an intrahepatic mechanism which regulates HGP by decreasing glycogenolysis when gluconeogenesis is elevated and vice versa (45,51). Two, FFA are insulin secretagogues. Therefore, elevated plasma FFA levels may increase HGP by stimulating gluconeogenesis, on one hand, but on the other hand, they may raise insulin secretion which will then inhibit HGP. Evidence in favor of a stimulatory effect of FFA on HGP was obtained in overnight fasted normal volunteers in whom plasma FFA were raised acutely by infusing lipid/heparin while insulin was clamped at basal concentrations (by infusing somatostatin and basal insulin replacement) (12). Under these conditions, HGP and plasma glucose levels rose dramatically "figure 8". Therefore, the available human data suggest that FFA can increase HGP but that the extent of the increase is controlled to some extent by the FFA mediated stimulation of insulin secretion.

Figure 7. Plasma glucagon and hepatic glucose output (HGO) in healthy men. Effect of euglycemic-hyperinsulinemic clamping at high (open triangles, n =4), medium (open circles, n = 4) and low FFA concentrations (filled circles, n = 6) on plasma glucagon concentration and on rates of HGO. * p < 0.05 comparing high or medium with low FFA concentrations. Adapted from Boden et al. (14*).

Figure 8. Effect of FFA on plasma glucose and hepatic glucose production (HGP). Triglyceride (Liposyn II, 0.5 and 1.5 ml/min or 2.15 and 4.3 mmol/min) plus heparin (0.4 U/min) were infused in 6 healthy volunteers during pancreatic clamping (somatostatin, 305 nmol/h; insulin, 0.33 pmol/kg min; glucagon, 0.25 ng/ kg min). FFA produced marked increases in HGP and plasma glucose concentrations. * p < 0.05; ** p < 0.01 vs. Saline controls. A , lipid; D , saline. Adapated from Boden and Jadali (13).

in maternal fat deposition during the early part of pregnancy and as result of increased plasma levels of lipolytic gestational hormones (for instance, human placental lactogen and human chorion gonadotropin) (53). The resulting insulin resistance preserves carbohydrate for the growing fetus. In obesity, however, the FFA induced insulin resistance becomes counterproductive since there is no need to spare glucose. The insulin resistance in obesity is associated with several cardiovascular risk factors including hypertension, dyslipidemia, hyperuricemia and abnormal fibrinolysis (54). Whether or not any these are cause and effect relationships is presently not clear. Moreover, whether or not the FFA mediated insulin resistance will result in deterioration of glucose tolerance depends largely on the ability of the FFA to stimulate insulin secretion. Appropriate insulin secretory responses would largely avoid the need to compensate for the FFA induced insulin resistance with additional, hyperglycemia stimulated insulin secretion. Defective insulin responses, on the other hand, would worsen hyperglycemia.