The Relationship of Fasting Free Fatty Acids, Adipose Tissue, Insulin Resistance, and Fasting Glucose Concentrations with Subsequent ß-Cell Function in Nondiabetic Subjects

Abstract

Elevations in both plasma free fatty acids (FFA) and glucose concentrations during fasting are associated with impaired β-cell function and predict progression from prediabetes to diabetes. Their interaction and subsequent effect on β-cell function as quantified by Disposition Index (DI) is unknown. We therefore measured total, saturated, mono-unsaturated and poly-unsaturated FFA concentrations using LC/MS in 120 nondiabetic subjects (across a range of fasting glucose < 6.9 mmol/l) who underwent a 2 hour oral glucose tolerance test (OGTT). Insulin secretion and action were quantified using the oral minimal model. The adipose tissue insulin resistance index (Adipo-IR) was calculated for each subject. Subjects were categorized by normal (NFG) or impaired (IFG) fasting glucose and by 2-hour glucose into normal (NGT) or impaired (IGT) glucose tolerance. Fasting total FFA were increased (p < 0.01) in IFG/IGT (835 ± 47 μmol/L) and in NFG/IGT (835 ± 30 μmol/L) but, intriguingly, not in IFG/NGT (593 ± 26 μmol/L) when compared to NFG/NGT (652 ± 29 μmol/L). These differences were no longer apparent within 60 minutes of OGTT and all groups suppressed FFA to the same nadir (166 ± 12 vs. 191 ± 18 vs. 184 ± 12 vs. 174 ± 17μmol/L, p = 0.59). On the other hand, an inverse relationship (p < 0.01) of fasting FFA (r = -0.33) and of Adipo-IR (r = -0.28) was observed with insulin action (Si). Fasting FFA did not correlate with β-cell responsivity (ϕ, r = 0.04). However, higher Adipo-IR was associated with higher values of ϕ (r = 0.36, p < 0.01). Fasting glucose concentrations did not alter these relationships; specifically no interaction of glucose with FFA during the fasting state to influence DI was evident. It remains to be ascertained whether the elevation in FFA reflects defects in production or in uptake, and whether the effect of changes in fasting glucose concentrations on DI is modulated by fasting FFA concentrations. Disclosure M.D. Hurtado: None. J. Adams: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Dalla Man: None. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. R.A. Rizza: None. M.D. Jensen: Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG.