Role of free fatty acids in hepatic insulin resistance during late pregnancy in conscious rabbits

1991 ◽  
Vol 260 (6) ◽  
pp. E938-E945 ◽  
Author(s):  
M. Gilbert ◽  
M. C. Pere ◽  
A. Baudelin ◽  
F. C. Battaglia
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Uptake ◽  
Hepatic Insulin Resistance ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Lipid Infusion ◽  
Hepatic Glucose

This study addresses whether elevated free fatty acids (FFA) contribute to the hepatic insulin resistance of pregnancy. We applied a euglycemic hyperinsulinemic clamp with or without Intralipid plus heparin infusion in conscious virgin and pregnant rabbits after an 18-h fast coupled with chronic catheterization of the hepatic and portal veins and femoral artery. A primed constant infusion of [3-3H]glucose was used to determine glucose fluxes. Insulin was infused into a mesenteric vein for 140 min. In pregnant rabbits, basal net hepatic uptake of lactate was almost two times that of nonpregnant rabbits. During a euglycemic hyperinsulinemic clamp there was a decline of approximately 65% in hepatic lactate uptake in nonpregnant rabbits at 80 min, whereas a similar decrease was observed only at 140 min in pregnant rabbits. This effect was blocked by lipid infusion. In the basal state the hepatic uptake of FFA was greater in pregnant than in nonpregnant animals. During the hyperinsulinemic clamp the hepatic uptake dropped by approximately 70 and approximately 30% in nonpregnant and pregnant females, respectively. Lipid infusion did not prevent the hepatic FFA uptake and hepatic ketone body output from decreasing. Hepatic glucose production was totally suppressed in the control period in nonpregnant animals but not during lipid infusion (approximately 65%). Hepatic glucose production was not significantly different between pregnant and nonpregnant rabbits during lipid infusion. Glucose utilization was markedly reduced in nonpregnant animals during lipid infusion to levels comparable with that in pregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on mechanisms of hepatic insulin resistance in cafeteria-fed rats

1993 ◽  
Vol 264 (1) ◽  
pp. E18-E23 ◽  
Author(s):  
M. B. Davidson ◽  
D. Garvey
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Insulin Response ◽  
Glucose Production ◽  
Insulin Binding ◽  
Hepatic Insulin Resistance ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Glucose Levels ◽  
Hepatic Glucose ◽  
Fat Stores

Whether hyperinsulinemia causes insulin resistance or vice versa is controversial. The development of hyperinsulinemia and insulin resistance was tracked in the cafeteria-fed rat to determine which occurred first. After 3 days of cafeteria feeding the rats were obese, manifested a small but significant decrease in fasting glucose levels, and showed no change in fasting insulin levels, basal hepatic glucose production (HGP), insulin binding to hepatic membranes, and glucose utilization during a euglycemic hyperinsulinemic clamp, but the rats did demonstrate an increased glucose disappearance rate associated with an enhanced insulin response to intra-arterial glucose and hepatic insulin resistance during the clamp. After 7 days of cafeteria feeding, the results were similar except that fasting hyperglycemia and hyperinsulinemia, an enhanced basal HGP, and decreased insulin binding developed. After 6 wk of cafeteria feeding, both hepatic and peripheral insulin resistances were present. After 7 days of cafeteria feeding in rats given streptozotocin or etomoxir, an inhibitor of free fatty acid (FFA) oxidation, hepatic insulin resistance persisted despite elimination of hyperinsulinemia and reduction of FFA oxidation. These data do not support a causal role for either hyperinsulinemia or enhanced lipolysis of hypertrophied fat stores and subsequent FFA oxidation in the liver in the development of hepatic insulin resistance in this animal model of obesity.

Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

2006 ◽  
Vol 291 (3) ◽  
pp. E536-E543 ◽  
Author(s):  
Chaodong Wu ◽  
Salmaan A. Khan ◽  
Li-Jen Peng ◽  
Honggui Li ◽  
Steven G. Carmella ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Flux ◽  
Hepatic Glucose

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P2), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P2 level, hepatic F26P2 levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P2 levels were much lower than those of the control. The decrease in F26P2 leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P2 states, increases in both gluconeogenesis and glycogenolysis in the liver are responsible for elevations of hepatic glucose production and thereby contribute to the development of hyperglycemia. Additionally, the increased hepatic gluconeogenesis was associated with the elevated mRNA levels of peroxisome proliferator-activated receptor-γ coactivator-1α and phospho enolpyruvate carboxykinase. This study provides the first in vivo demonstration showing that decreasing hepatic F26P2 levels leads to increased gluconeogenesis in the liver. Taken together, the present study demonstrates that perturbation of glucose flux in the liver plays a predominant role in the development of a diabetic phenotype, as characterized by hepatic insulin resistance.

scholarly journals Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

2015 ◽  
Vol 308 (11) ◽  
pp. E1001-E1009 ◽  
Author(s):  
Cathryn M. Kolka ◽  
Joyce M. Richey ◽  
Ana Valeria B. Castro ◽  
Josiane L. Broussard ◽  
Viorica Ionut ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Fold Increase ◽  
Canine Model ◽  
Hepatic Insulin Resistance ◽  
Lipid Infusion ◽  
Peripheral Insulin Resistance ◽  
Induce Insulin Resistance

Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance.

Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites

2003 ◽  
Vol 284 (2) ◽  
pp. E281-E290 ◽  
Author(s):  
Tony K. T. Lam ◽  
Gérald Van de Werve ◽  
Adria Giacca
Keyword(s):  
Insulin Resistance ◽  
Phosphatase Activity ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Fatty Acyl ◽  
Hepatic Insulin Resistance ◽  
P Content ◽  
Hepatic Glucose ◽  
Fasted Rats

To investigate the sites of the free fatty acid (FFA) effects to increase basal hepatic glucose production and to impair hepatic insulin action, we performed 2-h and 7-h Intralipid + heparin (IH) and saline infusions in the basal fasting state and during hyperinsulinemic clamps in overnight-fasted rats. We measured endogenous glucose production (EGP), total glucose output (TGO, the flux through glucose-6-phosphatase), glucose cycling (GC, index of flux through glucokinase = TGO − EGP), hepatic glucose 6-phosphate (G-6- P) content, and hepatic glucose-6-phosphatase and glucokinase activities. Plasma FFA levels were elevated about threefold by IH. In the basal state, IH increased TGO, in vivo glucose-6-phosphatase activity (TGO/G-6- P), and EGP ( P < 0.001). During the clamp compared with the basal experiments, 2-h insulin infusion increased GC and in vivo glucokinase activity (GC/TGO; P < 0.05) and suppressed EGP ( P< 0.05) but failed to significantly affect TGO and in vivo glucose-6-phosphatase activity. IH decreased the ability of insulin to increase GC and in vivo glucokinase activity ( P < 0.01), and at 7 h, it also decreased the ability of insulin to suppress EGP ( P < 0.001). G-6- P content was comparable in all groups. In vivo glucose-6-phosphatase and glucokinase activities did not correspond to their in vitro activities as determined in liver tissue, suggesting that stable changes in enzyme activity were not responsible for the FFA effects. The data suggest that, in overnight-fasted rats, FFA increased basal EGP and induced hepatic insulin resistance at different sites. 1) FFA increased basal EGP through an increase in TGO and in vivo glucose-6-phosphatase activity, presumably due to a stimulatory allosteric effect of fatty acyl-CoA on glucose-6-phosphatase. 2) FFA induced hepatic insulin resistance (decreased the ability of insulin to suppress EGP) through an impairment of insulin's ability to increase GC and in vivo glucokinase activity, presumably due to an inhibitory allosteric effect of fatty acyl-CoA on glucokinase and/or an impairment in glucokinase translocation.

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

2002 ◽  
Vol 282 (1) ◽  
pp. E38-E45 ◽  
Author(s):  
Chaodong Wu ◽  
David A. Okar ◽  
Christopher B. Newgard ◽  
Alex J. Lange
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Kk Mice ◽  
Hepatic Glucose

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

scholarly journals Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21

2015 ◽  
Vol 226 (3) ◽  
pp. 207-217 ◽  
Author(s):  
João Paulo G Camporez ◽  
Mohamed Asrih ◽  
Dongyan Zhang ◽  
Mario Kahn ◽  
Varman T Samuel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Glucose And Lipid Metabolism ◽  
Hepatic Glucose

Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance.

scholarly journals Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

2009 ◽  
Vol 297 (6) ◽  
pp. R1785-R1794 ◽  
Author(s):  
Elisabeth L. Raab ◽  
Patricia M. Vuguin ◽  
Doris A. Stoffers ◽  
Rebecca A. Simmons
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Intrauterine Growth ◽  
Hepatic Glucose ◽  
Neonatal Hepatocytes

Intrauterine growth retardation (IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagon-like-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1–6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance.

Effect of a mixed meal on hepatic lactate and gluconeogenic precursor metabolism in dogs

1984 ◽  
Vol 247 (3) ◽  
pp. E362-E369 ◽  
Author(s):  
M. A. Davis ◽  
P. E. Williams ◽  
A. D. Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Lactate Production ◽  
Glucose Production ◽  
Hepatic Uptake ◽  
Mixed Meal ◽  
Arterial Lactate ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
Arterial Glucose ◽  
Arterial Lactate Level

The present experiments were undertaken to assess lactate and gluconeogenic precursor metabolism in the 30 h following consumption of a mixed meal by the overnight-fasted, conscious dog. The arterial glucose level rose by a maximum of 13 mg/dl 4 h after the meal and had returned to control levels by 12 h. Hepatic glucose production was suppressed for 12 h after feeding, but net hepatic glucose uptake did not occur. The arterial lactate level rose from 0.55 +/- 0.10 to 1.28 +/- 0.14 mM within 1 h of feeding and remained elevated for 12 h. Net hepatic lactate production, measured with an A-V difference technique, rose from 3.5 +/- 2.8 to 19.4 +/- 3.1 mumol X kg-1 X min-1 h after the meal and declined slowly over the next 22 h. The liver then began to consume lactate so that at 30 h net hepatic uptake was 5.7 +/- 0.5 mumol X kg-1 X min-1. The total hepatic uptake of the gluconeogenic amino acids (alanine, glycine, serine, threonine) increased from 5.3 +/- 0.8 to 11.5 +/- 2.5 mumol X kg-1 X min-1 at 1 h and remained elevated for 4 h. The arterial alanine level rose from 0.36 +/- 0.03 to 0.51 +/- 0.04 mM at 2 h and remained elevated for 18 h. Insulin increased from 11 +/- 2 microU/ml to a maximum of 44 +/- 5 4 h after the meal, and the glucagon level rose from 59 +/- 8 pg/ml to a maximum of 150 +/- 22 1 h after feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

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