Free Fatty Acids and Insulin Resistance during Pregnancy1

Abstract

The purpose of this study was to determine whether elevation of plasma free fatty acids (FFA) in early pregnancy would cause alterations in insulin-stimulated glucose disposal similar to those occurring in late gestation. Seven glucose-tolerant women underwent 4-h euglycemic hyperinsulinemic (1 mU/kg.min) clamping during the early second trimester of pregnancy (14-17 weeks) on 2 consecutive days, receiving either lipid (Liposyn II; 1.5 mL/min) and heparin (0.4 U/kg.min; L/H) or saline/glycerol (2.25 g/h; S/G) infusions. Rates of total body glucose disposal (6,6-2H2 glucose) and of carbohydrate and fat oxidation (indirect calorimetry) were determined at hourly intervals. Blood glucose was clamped at about 85 mg/dL. Plasma FFA increased from 290 +/- 50 to 1000 +/- 139 mumol/L during L/H infusion and decreased from 351 +/- 60 to 35 +/- 11 mumol/L during S/G infusion. L/H infusion inhibited insulin stimulation of total body glucose disposal by 28% compared with S/G infusion (from 6.7 +/- 0.7 to 4.9 +/- 0.6 mg/kg.min; P < 0.01). L/H infusion increased fat oxidation from 0.73 +/- 0.04 to 1.26 +/- 0.2 mg/kg.min (P < 0.05) and decreased carbohydrate oxidation from 2.0 +/- 0.2 to 1.6 +/- 0.2 mg/kg.min (P < 0.05). Endogenous glucose production decreased equally by approximately 70% during L/H and S/G infusions. These data showed that elevating plasma FFA levels during early pregnancy inhibits total body glucose uptake and oxidation. We conclude that elevation of plasma FFA can contribute to the peripheral insulin resistance commonly observed during late pregnancy.

Plasma Levels of Free Fatty Acids in Women with Gestational Diabetes and Its Intrinsic and Extrinsic Determinants: Systematic Review and Meta-Analysis

“…Another hypothesis could be that healthy pregnant women at 14-17 weeks of gestation, show an acute elevation of free fatty acids due to insulin resistance and a decrease in glucose oxidation in a dose-dependent manner [42]. Though we cannot know whether first trimester elevation of free fatty acids that contribute to the development of gestational diabetes or the production of hyperglycemic placental molecules such as tumor necrosis factor- α (TNF- α ), resistin, and leptin induces an increase on free fatty acids [43], animal studies have shown that the intentional addition of free fatty acids in pregnant rabbits induce insulin resistance, while their reduction has the contrary effect [44, 45].…”

Insulin resistance and cardiovascular disease

“… 44 The contribution of elevated FFA plasma levels to IR is also clearly demonstrated in late-term pregnant women, who commonly develop IR in the presence of increased FFA levels. 46 Clearly, IR and lipotoxicity create a vicious cycle and a proatherogenic profile. 20 , 47 , 48 Mitochondrial dysfunction in obese WAT is also producing lipid metabolites, ultimately contributing to IR.…”

Fuel Metabolism During Pregnancy

“…27 Therefore, we have investigated whether elevations of plasma FFAs in early gestation (when insulin sensitivity is normal) would produce deterioration of insulin sensitivity comparable to that commonly seen in late gestation. 28 Seven healthy pregnant women were studied. Three of the women were lean (body mass index BMI < 27.3) and four were overweight (BMI > 27.3).…”