FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis.
Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with (2)H(2)O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (~450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 micromol/l (P < 0.001), EGP from 15.7 to 2.0 micromol x kg(-1) x min(-1) (P < 0.01), GNG from 8.2 to 3.7 micromol x kg(-1). min(-1) (P < 0.05), and GL from 7.4 to -1.7 micromol x kg(-1). min(-1) (P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 micromol/l (P < 0.001). EGP decreased 64% less than during insulin alone (-5.1 +/- 0.7 vs. -13.7 +/- 3.4 micromol x kg(-1). min(-1)). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (-2.6 vs. -4.5 micromol x kg(-1). min(-1), not significant). In contrast, GL decreased 66% less than during insulin alone (-3.1 vs. -9.2 micromol x kg(-1). min(-1), P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.
Boden
Guenther
G
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University Health Sciences Center, Philadelphia, Pennsylvania 19140, USA. bodengh@temple.edu
Cheung
Peter
P
Stein
T Peter
TP
Kresge
Karen
K
Mozzoli
Maria
M
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D012016:Reference Values; D013004:Somatostatin / Q000008:administration & dosage
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D013004:Somatostatin; D006003:Glycogen; D005934:Glucagon; D005947:Glucose; D006854:Hydrocortisone