Elevated Nonesterified Fatty Acids (NEFA) Are Associated with Blunted Hyperglycemia-Induced Increments in Brain Glucose Levels

Abstract

Recently, we have demonstrated that obesity and T2DM are associated with blunted brain glucose transport capacity during acute hyperglycemia in humans, which was also associated with higher total NEFA levels. Palmitic acid has been shown in vitro to suppress brain glucose uptake by downregulating GLUT1 expression in brain endothelial cells. Thus, this current study was undertaken to determine whether specific NEFA composition is associated with blunted human brain glucose transport capacity. Plasma NEFA composition was assessed using Gas-Chromatography Mass-Spectroscopy in 8 healthy lean (HC) (4F/4M, age 33±11 years, BMI 23±2 kg/m2, HbA1C 5.0±0.2), 10 obese (OB) (6F/4M, age 34±11 years, BMI 39±6 kg/m2, HbA1C 5.3±0.3), and 6 T2DM individuals (5F/1M, age 52±5 years, BMI 33±2 kg/m2, HbA1C 9.5±1.3) at the end of a 2-hour hyperglycemic clamp (220mg/dl) and correlated with previously measured changes in intracerebral glucose levels. Blunted rise in brain glucose levels was observed in OB and T2DM vs. HC individuals (p<0.05). Plasma long-chain non-esterified fatty acids (LCFA) including saturated (myristic acid, palmitic acid, stearic acid), monounsaturated (palmitoleic acid, oleic acid) and polyunsaturated (linoleic acid, an essential fatty acid) were different across all 3 groups (p<0.05). Moreover, these LCFAs negatively correlated with hyperglycemia-induced change in brain glucose levels (myristic r=-0.45; p=0.03, palmitic: r=-0.49, p=0.02; stearic r=-0.44, p=0.04; palmitoleic r=-0.49, p=0.02; oleic r=-0.49, p=0.02; linoleic r=-0.41, p=0.05). Our results demonstrate an inverse relationship between elevated LCFA levels and blunted brain glucose uptake in humans, which appears to be non-specific for NEFA composition. As the ability to transport glucose into the brain is crucial for energy homeostasis, these findings highlight a potential role for NEFAs to modulate brain glucose transport and metabolism and in turn cognitive function. Disclosure W. Lam: None. L. Jiang: None. G. Butrico: None. G. Cline: None. E. Sanchez Rangel: None. M. Hamza: None. L. Parikh: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. D.L. Rothman: None. G.F. Mason: Consultant; Self; UCB, Inc., Sumitomo Dainippon Pharma Co., Ltd. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc.. J. Hwang: None.