Fatty acid composition and EGP

Original article:
The role of plasma fatty acid composition in endog-enous glucose production in patients with type 2 diabetes mellitus. Clore JN, Allred J, White D, Li J,
Stillman J. Metabolism 2002; 51(11): 1471–7.

Summary
Hepatic insulin resistance and increased endogenous glucose production (EGP) are associated with increased circulating plasma free fatty acids (FFA). However, the contribution of FFA composition to the regulation of EGP is unknown. In this study, six obese type 2 diabetic subjects and six age-, gender- and BMI-matched obese non-diabetic subjects were studied for EGP after an overnight fast and 3-day prolonged fasting.
No differences were observed in plasma poly-unsaturated fatty acid (PUFA) concentrations between the diabetic and non-diabetic subjects. Nor was there any relationship between EGP and either total FFA or fatty acid composition after the 3-day fast. However, the authors found that increased rates of EGP and gluconeogenesis in type 2 diabetic subjects, measured using the oral heavy water method, after overnight fasting were associated with total saturated fatty acid (SFA) concentrations despite identical fasting plasma insulin levels in both groups (Fig. 1).


Fig. 1: Relationship between rates of endogenous glucose production (Ra) and (A) total plasma FFA and (B) SFA in obese diabetic and non-diabetic subjects.

Comment
The effect of increased FFA with intravenous infusion of lipid emulsion has been shown to impair insulin-mediated suppression of EGP in some, but not all, diabetic subjects. Because intravenous SFA is not available, the emulsion is made up entirely of PUFA. The reason why SFA concentrations are increased in type 2 diabetes is unclear, because the estimated rate of elongation, desaturation of FFA and dietary intake with de novo lipogenesis seems to be identical to that in non-diabetics. A possible explanation for the increased SFA may be that it is caused by decreased oxidation. Recent studies have suggested that SFA impairs insulin action through inhibition of protein kinase B/AKT by ceramides [1]. Another possible explanation for impaired regulation of EGP is through glucose-6-phosphatase activity, which is related to FFA concentration and inversely correlated to fatty acid chain length and degree of unsaturation [2]. Although aberrant plasma SFA accumulation is unlikely to account entirely for the diverse array of defects found in hepatic glucose handling, the findings presented in this article implicate SFA as a potentially important mediator of the deleterious effects of increased EGP in type 2 diabetes.

References
1. Chavez JA, Knotts TA, Wang L et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 2003; 278: 10297–303.
2. Fulceri R, Gamberucci A, Scott HM et al. Fatty acyl-CoA esters inhibit glucose-6-phosphatase in rat liver microsomes. Biochem J 1995; 307 (part 2): 391–7.