Metformin Prevents the Development of Acute Lipid-Induced Insulin Resistance in the Rat Through Altered Hepatic Signaling Mechanisms

Abstract

Metformin reduces the incidence of progression to type 2 diabetes in humans with obesity or impaired glucose tolerance. We used an animal model to investigate whether metformin could prevent acute lipid-induced insulin resistance and the mechanisms involved. Metformin or vehicle was administered to rats daily for 1 week. Rats were studied basally, after 3.75 h of intralipid-heparin or glycerol infusion, or after 5 h of infusion with a hyperinsulinemic-euglycemic clamp between 3 and 5 h. Metformin had no effect on plasma triacylglycerol or nonesterified fatty acid concentrations and did not alter glucose turnover or gluconeogenic enzyme mRNA after lipid infusion. However, metformin normalized hepatic glucose output and increased liver glycogen during lipid infusion and clamp. Basal liver (but not muscle or fat) AMP-activated protein kinase activity was increased by metformin (by 310%; P < 0.01), associated with increased phosphorylation of acetyl CoA carboxylase. Postclamp liver but not muscle phosphorylated/total Akt protein was increased, whereas basal c-Jun NH 2 -terminal kinase-1 and -2 protein expression were reduced (by 39 and 53%, respectively; P < 0.05). Metformin also increased hepatic basal IB␣ levels (by 260%; P < 0.001) but had no effect on tyrosine phosphorylation or expression of insulin receptor substrate-1 (IRS-1). In summary, metformin opposes the development of acute lipid-induced insulin resistance in the liver through alterations in multiple signaling pathways. Diabetes 53:3258 -3266, 2004

Acute Bidirectional Manipulation of Muscle Glucose Uptake by In Vivo Electrotransfer of Constructs Targeting Glucose Transporter Genes

“…Proteins were resolved by SDS-PAGE electrophoresis and electrotransferred as previously described (25). Immunoblotting and quantitation were also as previously described (25). Green fluorescent protein (GFP) antibody was purchased from Molecular Probes, ␤-actin antibody from Sigma (St. Louis, MO), and Akt and HSP-70 antibodies from Cell Signaling Technology (Beverley, MA).…”

“…Protein content of supernatants was quantified using the Bradford method (Protein Assay kit; Bio-Rad laboratories, New South Wales, Australia), and aliquots containing 10 -25 g protein were denatured in Laemmli buffer for 5 min at 95°C or 30 min at 37°C. Proteins were resolved by SDS-PAGE electrophoresis and electrotransferred as previously described (25). Immunoblotting and quantitation were also as previously described (25).…”

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

“…All other animals received Ola at the 90 min time point (Met 400/Ola, nZ11; Met 150/Ola, nZ13; Veh/Ola; nZ11). The lower dose of Met (150 mg/kg!two doses, administered 15-16 h apart) was based on evidence that similar doses improve measures of glucose metabolism in rat models of diabetes (Matthaei et al 1993, Borst et al 2000, Cleasby et al 2004, Yasuda et al 2004. We also examined a higher dose (400 mg/kg!two doses) based on the possibility of dose-dependent effects on metabolic indices (Suzuki et al 2002, Hauton 2011.…”

Study of antioxidant potential of malotilate in ethanol induced hepatic dysfunction in Sprague Dawley rats

“…The cell homogenate then was centrifuged at 3000× g for 10 min at 4 o C (Remi Industries Ltd, Remi Laboratory Instruments, Cooling Centrifuge, C-24 BL is low volume high speed model in table top design) to remove debris and nuclei. The supernatant which consists of cytosolic and mitochondrial fractions was stored at -80 o C. They were used for determination of MDA, 9 SOD, 10 and CAT 11 activities using UV Visible spectrophotometer, Model Lambda 35, Manufactured by Perkin Elmer Inc. USA.…”