A possible hepatic factor in the control of plasma free fatty acid levels (original) (raw)
Related papers
Diabetes, 1997
We investigated the mechanism by which a selective increase in arterial insulin can suppress hepatic glucose production in vivo. Isotopic (3-3 H-glucose) and arteriovenous difference methods were used in overnight-fasted, conscious dogs. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon infusions) was used to control the endocrine pancreas. Equilibration (100 min) and basal (40 min) periods were followed by a 180-min test period. In control dogs (/i = 5), basal insulin delivery was continued throughout the study. In the other two groups, peripheral insulin was selectively increased at the beginning of the test period by stopping the portal insulin infusion and infusing insulin peripherally at twice the basal portal rate. One group (INS + FAT; n = 6) received an infusion of 20% intralipid + heparin (0.5 U • kg" 1 • min" 1) to clamp the nonesterified fatty acid (NEFA) levels during hyperinsulinemia; the other group (INS; n = 7) received only saline during the experimental period. In the INS group, a selective increase in peripheral insulin of 84 pmol/L was achieved (36 ± 6 to 120 ± 24 pmol/1, last 30 min) while portal insulin was unaltered (84 ± 18 pmol/1). In the INS + FAT group, a similar increase in peripheral insulin was achieved (36 ± 6 to 114 ± 6 pmol/1, last 30 min); again, portal insulin was unaltered (96 ± 12 pmol/1). In the control group, basal insulin did not change. Glucagon and glucose remained near basal values in all protocols. In the INS group, NEFA levels dropped from 700 ± 90 (basal) to 230 ± 65 umol/1 (last 30 min; P > 0.05), but in the INS + FAT group changed minimally (723 ± 115 [basal] to 782 ± 125 umol/1 [last 30 min]). In the INS group, net hepatic glucose output dropped by 6.7 umol • kg" 1 • min" 1 (P < 0.05), whereas in the INS + FAT group it dropped by 3.9 umol • kg' 1 • min" 1 (P < 0.05). When insulin levels were not increased (i.e., in the control group), net hepatic glucose output dropped 1.7 umol • kg • min" 1 (P < 0.05). In all groups, the net hepatic glucose output data were confirmed by the tracer-determined glucose production data. In the INS group, net hepatic gluconeogenic substrate uptake (ala-From the Departments of Molecular Physiology and Biophysics (D.
Free fatty acids impair hepatic insulin extraction in vivo
Diabetes, 1999
Hyperinsulinemia is a common finding in obesity and results from insulin hypersecretion and impaired hepatic insulin extraction. In vitro studies have shown that free fatty acids (FFAs), which are often elevated in obesity, can impair insulin binding and degradation in isolated rat hepatocytes. To investigate whether F FAs impair hepatic insulin extraction (E H ) in vivo, either saline (SAL) or 10% Intralipid (0.03 ml · kg -1 · m i n -1 ) plus heparin (0.44 U · kg -1 · min -1 ) (IH) was infused into normal dogs to elevate FFA levels. Insulin was infused intraportally at 18 pmol · kg -1 · min -1 for 150 min (period A, high insulin dose), and then at 2.4 pmol · kg -1 · min -1 for another 150 min (period B, low insulin dose). After the low portal insulin dose, additional insulin was infused peripherally at 8.4 pmol · k g -1 · min -1 for 120 min (period C) to assess the clearance of insulin from the peripheral plasma. In 16 paired experiments, FFA levels were 1,085 ± 167, 1,491 ± 240, 1,159 ± 221 µmol/l (IH) and 221 ± 44, 329 ± 72, 176 ± 44 µmol/l (SAL) in periods A, B, and C, respectively. Peripheral insulin levels were greater with IH (P < 0.001) than with SAL in all periods (1,620 ± 114, 126 ± 12, 1,050 ± 72 pmol/l for IH vs. 1,344 ± 168, 96 ± 4.2, 882 ± 60 pmol/l for SAL). Glucose clearance was impaired by IH in all periods (P < 0.05), whereas glucose production was slightly increased by IH during period B. Peripheral insulin clearance (Cl) and E H were calculated from the insulin infusion rate and insulin concentration data in each period by taking into account the nonlinearity of insulin kinetics. Cl was lower (P < 0.01) with IH (9.6 ± 0.6, 12.0 ± 0.9, 10.2 ± 0.6 ml · kg -1 · min -1 ) than with SAL (11.2 ± 1, 13.6 ± 0.7, 11.9 ± 0.9 ml · kg -1 · min -1 ) in periods A, B, and C. E H was also lower (P < 0.05) with IH (25 ± 4, 40 ± 5, 32 ± 5%) than with SAL (30 ± 2.8, 47 ± 3, 38 ± 3%). We conclude that FFAs can impair hepatic insulin extraction in vivo at high and low insulin levels, an effect that may contribute to the peripheral hyperinsulinemia of obesity. Diabetes 48:766-774, 1999
Journal of Clinical Investigation, 1996
Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, suggesting that insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs ( n ϭ 8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 g/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg. Two additional experiments were performed at the 0.5 mU/min/kg insulin dose: a double Liposyn infusion (2 ϫ LI; 1.0 ml/min 20% Liposyn, heparin as above), and a glycerol infusion (19 mg/min). With the 0.125 mU/min/kg insulin infusion, FFA fell 40% and HGO fell 33%; preventing the fall in FFA with LI entirely prevented this decline in HGO. With 0.5 mU/ min/kg insulin infusion, FFA levels fell 64% while HGO declined 62%. Preventing the fall in FFA at this higher insulin dose largely prevented the fall in HGO; however, steady state HGO still declined by 18%. Doubling the LI infusion did not further affect HGO, suggesting that the effect of FFA on HGO is saturable. Elevating plasma glycerol levels did not alter insulin's ability to suppress HGO. These data directly support the concept that insulin suppression of HGO is not direct, but rather is mediated via insulin suppression of adipose tissue lipolysis. Thus, resistance to insulin control of hepatic glucose production in obesity and/or non-insulin-dependent diabetes mellitus may reflect resistance of the adipocyte to insulin suppression of lipolysis. ( J. Clin. Invest. 1996. 98:741-749.) Key words: adipose tissue • insulin action • hepatic glucose output • free fatty acids • lipolysis 1. Abbreviations used in this paper: HGO, hepatic glucose output; LI, liposyn ϩ heparin; NIDDM, non-insulin-dependent diabetes mellitus; R d , whole body glucose uptake.
Nonesterified Fatty Acids and Hepatic Glucose Metabolism in the Conscious Dog
Diabetes, 2004
We used tracer and arteriovenous difference techniques in conscious dogs to determine the effect of nonesterified fatty acids (NEFAs) on net hepatic glucose uptake (NHGU). The protocol included equilibration ([3-3 H]glucose), basal, and two experimental periods (؊120 to ؊30, ؊30 to 0, 0 -120 [period 1], and 120 -240 min [period 2], respectively). During periods 1 and 2, somatostatin, basal intraportal insulin and glucagon, portal glucose (21.3 mol ⅐ kg ؊1 ⅐ min ؊1 ), peripheral glucose (to double the hepatic glucose load), and peripheral nicotinic acid (1.5 mg ⅐ kg ؊1 ⅐ min ؊1 ) were infused. During period 2, saline (nicotinic acid [NA], n ؍ 7), lipid emulsion (NA plus lipid emulsion [NAL], n ؍ 8), or glycerol (NA plus glycerol [NAG], n ؍ 3) was infused peripherally. During period 2, the NA and NAL groups differed (P < 0.05) in rates of NHGU (10.5 ؎ 2.08 and 4.7 ؎ 1.9 mol ⅐ kg ؊1 ⅐ min ؊1 ), respectively, endogenous glucose R a (2.3 ؎ 1.4 and 10.6 ؎ 1.0 mol ⅐ kg ؊1 ⅐ min ؊1 ), net hepatic NEFA uptakes (0.1 ؎ 0.1 and 1.8 ؎ 0.2 mol ⅐ kg ؊1 ⅐ min ؊1 ), net hepatic -hydroxybutyrate output (0.1 ؎ 0.0 and 0.4 ؎ 0.1 mol ⅐ kg ؊1 ⅐ min ؊1 ), and net hepatic lactate output (6.5 ؎ 1.7 vs. ؊2.3 ؎ 1.2 mol ⅐ kg ؊1 ⅐ min ؊1 ). Hepatic glucose uptake and release were 2.6 mol ⅐ kg ؊1 ⅐ min ؊1 less and 3.5 mol ⅐ kg ؊1 ⅐ min ؊1 greater, respectively, in the NAL than NA group (NS). The NAG group did not differ significantly from the NA group in any of the parameters listed above. In the presence of hyperglycemia and relative insulin deficiency, elevated NEFAs reduce NHGU by stimulating hepatic glucose release and suppressing hepatic glucose uptake.
Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects
Metabolism, 1987
Raised levels of free fatty acids (FFA) compete with glucose for utilization by insulin-sensitive tissues, and, therefore, they may induce insulin resistance in the normal subject. The influence of experimental elevations in FFA levels on glucose metabolism in native insulin-resistant states is not known. We studied seven women with moderate obesity (63% above their ideal body weight) but normal glucose tolerance with the use of the insulin clamp technique with or without an infusion of lntralipid + heparin. Upon raising plasma insulin levels to-60 pU/mL while maintaining euglycemia, whole body glucose utilization ('H-3-glucose) rose similarly without (from 66 ? 7 to 113 + 11 mg/min m', P-C .02) or with (from 70 + 7 to 137 ? 19 mg/min m*, P < .02) concomitant lipid infusion. In contrast, endogenous glucose production was considerably (73%) suppressed (from 66 c 7 to 15 + 6 mg/min m*, P < .OOl) during the clamp without lipid, but declined only marginally (from 70 & 7 to 46 + 7 mg/min ma; NS) with lipid administration. The difference between the control and the lipid study was highly significant (P-C .02), and amounted to an average of 3.6 g of relative glucose overproduction during the second hour of the clamp. Blood levels of lactate rose by 34 + 15% (.l > P > .05) in the control study but only by 17 ? 10% (NS) during lipid infusion. Blood pyruvate concentrations fell in both sets of experiments (by-45% at the end of the study) with similar time courses. In contrast, blood alanine levels did not change from baseline during the control clamp (181 f 1 B v 185 + 14 I.rmol/L) whereas they fell slightly (11 + 3%) but consistently (175 + 15 Y 196 f 14 I.rmol/L, P-C .02) during lipid infusion. Furthermore, a positive correlation was found to exist in the pooled data between the decrease in blood alanine concentrations and the corresponding increase in endogenous glucose production (r = .59. P < .02). We conclude that in the obese subject an increased supply of fatty fuels fails to inhibit insulin-mediated glucose disposal but induces hepatic insulin resistance. The greater availability of exogenous glucose precursors (glycerol) and the lower circulating levels of endogenous precursors (lactate and alanine) suggest that the observed increase in endogenous glucose production is sustained by hepatic gluconeogenesis.
Stimulation of insulin secretion by infusion of free fatty acids
Journal of Clinical Investigation, 1969
slow in two dogs infused under pentobarbital anesthesia. As glucose levels fell during oleate infusion, plasma insulin often declined somewhat from initial peak levels. At the end of each FFA infusion (duration: 45-150 min), plasma FFA and insulin rapidly dropped to preinfusion levels, and plasma glucose rose toward normal. Although in most experiments the maximum rise in insulin and fall in glucose occurred at 15 and 45 min after onset of the oleate infusion, respectively, some variation in the time of maximum response was apparent.
Mechanisms of fatty acid-induced inhibition of glucose uptake
Journal of Clinical Investigation, 1994
Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels ( -50, -550, -750 MuM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from -50 to -750 gM) decreased glucose uptake in a dose-dependent fashion (from -9 to -4 mg/kg per min). The decrease was caused mainly (-2/3) by a reduction in glycogen synthesis and to a lesser extent ( 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration ( -750MM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium ( -550MM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by -50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level. (J. Clin. Invest. 1994. 93:2438-2446 Subjects 14 healthy, normal weight volunteers (13 men and 1 woman) were studied. We were unable to recruit more women, largely because ofthe 1. Abbreviations used in this paper: CHO, carbohydrate; FFM, fat free mass; G-6-P, glucose-6-phosphate; GRd, glucose rate ofdisappearance; GS, glycogen synthase; HGO, hepatic glucose output; NIDDM, noninsulin-dependent diabetes mellitus; npRQ, nonprotein respiratory quotient; PDH, pyruvate dehydrogenase; UDPG, uridine-diphosphate-glucose.
American Journal of Physiology - Endocrinology And Metabolism, 2003
To determine the effects of an increase in lipolysis on the glycogenolytic effect of epinephrine (EPI), the catecholamine was infused portally into 18-h-fasted conscious dogs maintained on a pancreatic clamp in the presence [portal (Po)-EPI+FFA, n = 6] and absence (Po-EPI+SAL, n = 6) of peripheral Intralipid infusion. Control groups with high glucose (70% increase) and free fatty acid (FFA; 200% increase; HG+FFA, n = 6) and high glucose alone (HG+SAL, n = 6) were also included. Hepatic sinusoidal EPI levels were elevated (Δ568 ± 77 and Δ527 ± 37 pg/ml, respectively) in Po-EPI+SAL and EPI+FFA but remained basal in HG+FFA and HG+SAL. Arterial plasma FFA increased from 613 ± 73 to 1,633 ± 101 and 746 ± 112 to 1,898 ± 237 μmol/l in Po-EPI+FFA and HG+FFA but did not change in EPI+SAL or HG+SAL. Net hepatic glycogenolysis increased from 1.5 ± 0.3 to 3.1 ± 0.4 mg · kg−1 · min−1( P < 0.05) by 30 min in response to portal EPI but did not rise (1.8 ± 0.2 to 2.1 ± 0.3 mg · kg−1 · min−1) in ...
AJP: Endocrinology and Metabolism, 2008
Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [11C]acetate and [11C]palmitate to quantify liver FFA metabolism ( n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content ( n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs ( P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% ( P = 0....
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2007
Alterations of free fatty acid (FA) metabolism in several organs are implicated in the pathogenesis of chronic disorders. The aim of this study was to investigate the biodistribution and partitioning of the FA analog, 14(R,S)-(18)F-fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), across different lipid pools in plasma and in metabolically important organs and its response to insulin. Eight anesthetized pigs were studied during fasting or euglycemic insulin stimulation. Plasma samples from the carotid artery, hepatic vein, and portal vein were collected at 10 and 40 min after (18)F-FTHA injection via indwelling catheters. The animals were then sacrificed and tissue biopsies rapidly obtained from the heart, brain, liver, subcutaneous and visceral fat, pancreas, intestine, and skeletal muscle. Radioactivity was assessed in the FA, phospholipid, and triglyceride or glycerol ester pools. The tissue-to-plasma intact (18)F-FTHA ratio was high in all tissues, with the highest values being in ...