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Margaret K Hahn Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Banting & Best Diabetes Centre, Toronto, Ontario, Canada

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Adria Giacca Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Banting & Best Diabetes Centre, Toronto, Ontario, Canada
Department of Physiology, University of Toronto, Toronto, Ontario, Canada

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Sandra Pereira Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Department of Physiology, University of Toronto, Toronto, Ontario, Canada

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Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests.

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Neehar Gupta
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Edward Park
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Harmanjit Sandhu
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Tracy Goh
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Vaja Tchipashvili
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Adria Giacca
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Insulin suppresses glucose production (GP) via both extrahepatic (indirect) and hepatic (direct) effects. We have shown that the direct effect, undetectable in moderately hyperglycemic diabetic dogs, is restored by insulin-induced euglycemia. The first aim of the present study was to determine whether euglycemia per se, and not the excess insulin needed to obtain it, restores the direct effect of insulin on GP. Basal insulin was given portally in depancreatized dogs to attain only moderate hyperglycemia, then an additional insulin was given portally or peripherally to match the peripheral insulin levels and thus to obtain a greater hepatic insulinization with portal delivery. Plasma glucose was allowed to fall to euglycemia before a euglycemic clamp was performed. During euglycemia, there was a tendency (P=0.075) for greater suppression of GP by portal than peripheral insulin. Also, there was a significantly different effect of time (P=0.01) on GP in the two groups, with greater suppression over time in the portal group. The second aim was to test the hypothesis that because of inadequate hepatic insulinization and consequent lack of direct inhibition of GP, peripheral insulin replacement requires peripheral hyperinsulinemia to achieve euglycemia. Portal or peripheral insulin was given to achieve euglycemia and basal GP, and insulin levels were measured. More peripheral insulinemia was required with peripheral than portal insulin replacement to maintain similar euglycemia and GP. Our conclusions are as follows: (1) euglycemia per se is sufficient to acutely restore the direct effect of insulin on GP and (2) at euglycemia, peripheral replacement of insulin, as in insulin-treated diabetes, results in peripheral hyperinsulinemia but unchanged basal GP.

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Edward Park
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Victor Wong
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Xinyu Guan
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Andrei I Oprescu
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Adria Giacca
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Recent evidence indicates that inflammatory pathways are causally involved in insulin resistance. In particular, Iκ Bα kinase β (IKKβ ), which can impair insulin signaling directly via serine phosphorylation of insulin receptor substrates (IRS) and/or indirectly via induction of transcription of proinflammatory mediators, has been implicated in free fatty acid (FFA)-induced insulin resistance in skeletal muscle. However, it is unclear whether liver IKKβ activation plays a causal role in hepatic insulin resistance caused by acutely elevated FFA. In the present study, we wished to test the hypothesis that sodium salicylate, which inhibits IKKβ , prevents hepatic insulin resistance caused by short-term elevation of FFA. To do this, overnight-fasted Wistar rats were subject to 7-h i.v. infusion of either saline or Intralipid plus 20 U/ml heparin (IH; triglyceride emulsion that elevates FFA levels in vivo) with or without salicylate. Hyperinsulinemic–euglycemic clamp with tracer infusion was performed to assess insulin-induced stimulation of peripheral glucose utilization and suppression of endogenous glucose production (EGP). Infusion of IH markedly decreased (P < 0.05) insulin-induced stimulation of peripheral glucose utilization and suppression of EGP, which were completely prevented by salicylate co-infusion. Furthermore, salicylate reversed IH-induced 1) decrease in Iκ Bα content; 2) increase in serine phosphorylation of IRS-1 (Ser 307) and IRS-2 (Ser 233); 3) decrease in tyrosine phosphorylation of IRS-1 and IRS-2; and 4) decrease in serine 473-phosphorylated Akt in the liver. These results demonstrate that inhibition of IKKβ prevents FFA-induced impairment of hepatic insulin signaling, thus implicating IKKβ as a causal mediator of hepatic insulin resistance caused by acutely elevated plasma FFA.

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Sandra Pereira Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Anu Shah Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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I George Fantus Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Jamie W Joseph Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Adria Giacca Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, Department of Medicine, Toronto General Research Institute, Banting and Best Diabetes Centre, Institute of Medical Science, School of Pharmacy, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic–euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.

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Gary J Remington Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Celine Teo Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Virginia Wilson Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Araba Chintoh Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Melanie Guenette Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Zohra Ahsan Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Adria Giacca Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Margaret K Hahn Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8
Centre for Addiction and Mental Health, Institute of Medical Science, Department of Psychiatry, Department of Physiology, 250 College Street, Toronto, Ontario, Canada M5T 1R8

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Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

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Sandra Pereira Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Wen Qin Yu Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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María E Frigolet Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Jacqueline L Beaudry Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Yaniv Shpilberg Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Edward Park Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Cristina Dirlea Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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B L Grégoire Nyomba Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Michael C Riddell Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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I George Fantus Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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Adria Giacca Department of Physiology, University of Toronto, Department of Medicine, Mount Sinai Hospital, Toronto General Research Institute and Banting and Best Diabetes Centre, University Health Network, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, Faculty of Health, School of Kinesiology and Health Science, York University, Department of Internal Medicine, University of Manitoba, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8

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We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

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