Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver
Tóm tắt
We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects. Studies were performed using positron emission tomography (PET) and [18F]-2-fluoro-2-deoxyglucose ([18F]FDG) during euglycaemic hyperinsulinaemia (0–120 min) and an Intralipid/heparin infusion (IL/Hep; −90–120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data. Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81±7% in the SAL study (p≤0.01). Both M (−28±7%) and HGU (−25±9%) were significantly lowered by NEFA elevation (p=0.004 and p=0.035 respectively). In the whole data set, the decreases in M and HGU were positively correlated (r=0.78, p=0.038). No evidence of [18F]FDG outflow was detected during the scanning time. HGU was correlated with the phosphorylation rate parameter (r=0.71, p=0.003) as derived by compartmental modelling. In healthy men, NEFA impair insulin-mediated HGU and whole-body glucose uptake to a similar extent. Our data suggest that multiple intracellular NEFA targets may concur to down-regulate glucose uptake by the liver.
Tài liệu tham khảo
Cherrington AD (1999) Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes 48:1198–1214
Radziuk J, Pye S (2001) Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis. Diabetes Metab Res Rev 17:250–272
Barzilai N, Rossetti L (1993) Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem 268:25019–25025
Iynedjian P, Jotterand D, Nouspikel T, Asfari M, Pilot P (1989) Transcriptional induction of glucokinase gene by insulin in cultured liver cells and its repression by the glucagons-cAMP system. J Biol Chem 264:21824–21829
Edgerton DS, Cardin S, Emshwiller M et al. (2001) Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism. Diabetes 50:1872–1882
Iozzo P, Geisler F, Oikonen V et al. (2003) Insulin stimulates liver glucose uptake in humans: an 18F-FDG PET Study. J Nucl Med 44:682–689
Basu R, Basu A, Johnson C, Schwenk W, Rizza R (2003) Type 2 diabetes alters the insulin dose response curves for both stimulation of splanchnic glucose uptake (SGU) and suppression of endogenous glucose production (EGP). Diabetes 52 [Suppl 1]:A59
Arora P, Basu R, Zangeneh F, Schwenk W, Rizza R (2003) The ability of insulin to stimulate incorporation of extracellular glucose into hepatic glycogen is impaired in type 2 diabetes. Diabetes 52 [Suppl 1]:A59
Basu A, Basu R, Shah P et al. (2000) Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism. Evidence for a defect in hepatic glucokinase activity. Diabetes 49:272–283
Basu A, Basu R, Shah P et al. (2001) Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. Diabetes 50:1351–1362
Iozzo P, Hallsten K, Oikonen V et al. (2003) Insulin-mediated hepatic glucose uptake is impaired in type 2 diabetes: evidence for a relationship with glycaemic control. J Clin Endocrinol Metab 88:2055–2060
Caro JF, Triester S, Patel VK, Tapscott EB, Frazier NL, Dohm GL (1995) Liver glucokinase: decreased activity in patients with type II diabetes. Horm Metab Res 27:19–22
Boden G (1999) Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 111:241–248
Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283
Nuutila P, Koivisto VA, Knuuti J et al. (1992) Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest 89:1767–1774
Iozzo P, Hallsten K, Oikonen V et al. (2003) Effects of metformin and rosiglitazone monotherapy on insulin-mediated hepatic glucose uptake and their relation to visceral fat in type 2 diabetes. Diabetes Care 26:2069–2074
Sindelar DK, Chu CA, Rohlie M, Neal DW, Swift LL, Cherrington AD (1997) The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. Diabetes 46:187–196
Moore MC, Satake S, Lautz M et al. (2004) Nonesterified fatty acids and hepatic glucose metabolism in the conscious dog. Diabetes 53:32–40
Tonelli J, Kishore P, Stein D, Schubart U, Hawkins M (2003) Time-dependent effects of free fatty acids (FFA) on glucose effectiveness (GE) in type 2 diabetes mellitus (T2DM). Diabetes 52 [Suppl 1]:A59
Bajaj M, Pratipanawatr T, Berria R et al. (2002) Free fatty acids reduce splanchnic and peripheral glucose uptake in patients with type 2 diabetes. Diabetes 51:3043–3048
Shah P, Vella A, Basu A et al. (2002) Effects of free fatty acids and glycerol on splanchnic glucose metabolism and insulin extraction in nondiabetic humans. Diabetes 51:301–310
Bajaj M, Berria R, Pratipanawatr T et al. (2002) Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans. Am J Physiol Endocrinol Metab 283:E346–E352
DeFronzo RA (1987) Use of the splanchnic/hepatic balance technique in the study of glucose metabolism. Baillieres Clin Endocrinol Metab 1:837–862
Tippett PS, Neet KE (1982) Specific inhibition of glucokinase by long chain acyl coenzymes A below the critical micelle concentration. J Biol Chem 257:12839–12845
Tippett PS, Neet KE (1982) An allosteric model for the inhibition of glucokinase by long chain acyl coenzyme A. J Biol Chem 257:12846–12852
Lam TK, Werve G van de, Giacca A (2003) Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab 284:E281–E290
Massillon D, Barzilai N, Hawkins M, Prus-Wertheimer D, Rossetti L (1997) Induction of hepatic glucose-6-phosphatase gene expression by lipid infusion. Diabetes 46:153–157
Stingl H, Krssak M, Krebs M et al. (2001) Lipid-dependent control of hepatic glycogen stores in healthy humans. Diabetologia 44:48–54
Wiesenthal SR, Sandhu H, McCall RH et al. (1999) Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 48:766–774
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
Hamacher K, Coenen HH, Stocklin G (1986) Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 27:235–238
van den Hoff J, Burchert W, Muller-Schauenburg W, Meyer GJ, Hundeshagen H (1993) Accurate local blood flow measurements with dynamic PET: fast determination of input function delay and dispersion by multilinear minimization. J Nucl Med 34:1770–1777
Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7
Munk OL, Bass L, Roelsgaard K, Bender D, Hansen SB, Keiding S (2001) Liver kinetics of glucose analogs measured in pigs by PET: importance of dual-input blood sampling. J Nucl Med 42:795–801
Keiding S, Hansen SB, Rasmussen HH et al. (1998) Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology 28:700–706
Keiding S, Munk OL, Schiott KM, Hansen SB (2000) Dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography of liver tumours without blood sampling. Eur J Nucl Med 27:407–412
Sokoloff L, Reivich M, Kennedy C et al. (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916
Sweet IR, Peterson L, Kroll K, Goodner CJ, Berry M, Graham MM (1996) Effect of glucose on uptake of radiolabeled glucose, 2-DG, and 3-O-MG by the perfused rat liver. Am J Physiol 271:E384–E396
Bender D, Munk OL, Feng HQ, Keiding S (2001) Metabolites of (18)F-FDG and 3-O-(11)C-methylglucose in pig liver. J Nucl Med 42:1673–1678
Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–590
Lammertsma AA, Brooks DJ, Frackowiak RS et al. (1987) Measurement of glucose utilisation with [18F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical methods. J Cereb Blood Flow Metab 7:161–172
Choi Y, Hawkins RA, Huang SC et al. (1994) Evaluation of the effect of glucose ingestion and kinetic model configurations of FDG in the normal liver. J Nucl Med 35:818–823
Satake S, Moore MC, Igawa K et al. (2002) Direct and indirect effects of insulin on glucose uptake and storage by the liver. Diabetes 51:1663–1671
Halimi S, Assimacopoulos-Jeannet F, Terrettaz J, Jeanrenaud B (1987) Differential effect of steady-state hyperinsulinaemia and hyperglycaemia on hepatic glycogenolysis and glycolysis in rats. Diabetologia 30:268–272
Minassian C, Tarpin S, Mithieux G (1998) Role of glucose-6 phosphatase, glucokinase, and glucose-6 phosphate in liver insulin resistance and its correction by metformin. Biochem Pharmacol 55:1213–1219
Hue L, Maisin L, Rider MH (1988) Palmitate inhibits liver glycolysis. Involvement of fructose 2,6-bisphosphate in the glucose/fatty acid cycle. Biochem J 251:541–545
Ferrannini E, DeFronzo RA (1997) Insulin actions in vivo: glucose metabolism. In: Alberti KGGM, Zimmet P, DeFronzo RA (eds) International textbook of diabetes. Wiley, Chichester, pp 505–530
Gustafson LA, Neeft M, Reijngoud DJ et al. (2001) Fatty acid and amino acid modulation of glucose cycling in isolated rat hepatocytes. Biochem J 358:665–671
Chu CA, Sherck SM, Igawa K et al. (2002) Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs. Am J Physiol Endocrinol Metab 282:E402–E411