Hepatic insulin resistance resuIting in increased endogenous glucose production (EGP) is a major factor in the pathogenesis of type 2 diabetes (T2DM) Increased plasma levels of free fatty acids (FFAs) which are characteristically seen in obese individuals, have been established to cause peripheral (muscle) as well as hepatic insulin resistance. Most of the research efforts in recent years have focused on peripheral insulin resistance. Mainly due to methodological problems, hepatic insulin resistance has not received much attention. Recently, however, several methods have become available which allow non-invasive measurement of in vivo rates of gluconeogenesis (GNG) and glycogenolysis (GL), the two components of EGP. Using the 2H2O method, we have recently shown in healthy volunteers that acute elevations of plasma FFAs cause hepatic insulin resistance through inhibition of insulin suppression of GL. In the current application, we plan to expand these findings.
In Specific Aim 1, we propose to assess dose dependency, duration and possible gender differences of the effects of acute elevation of plasma FFAs on insulin suppression of GL/EGP in healthy subjects and in patients with mild and severe T2DM. These studies will involve measurements of rates of GL, GNG and EGP during euglycemic-hyperinsulinemic clamping (in normal controls) or during isoglycemic-hyperinsulinemic clamping (in patients with T2DM) with and without simultaneous infusion of heparinized lipid (at different rates of infusion) to acutely raise plasma FFAs to different levels.
In Specific Aim 2, we propose to evaluate effects of prolonged elevation of plasma FFAs on hepatic insulin sensitivity. The experimental approach will be to lower plasma FFAs overnight (12 h) with Niaspan (a nicotinic acid analog) and to measure insulin suppression of GL/EGP the next morning (during hyperinsulinemic clamping) in obese patients with mild or severe T2DM.
In Specific Aim 3, we will address the mechanism by which elevated FFAs cause hepatic insulin resistance. Specifically, we will test the hypothesis that FFA mediated hepatic insulin resistance is associated with intrahepatic accumulation of diacylglycerol (DAG), activation of protein kinase C (PKC), with increased serine and decreased tyrosine phosphorylation of IRS-1/2, and a decrease in PI3 kinase responses to insulin. The experimental approach will be to sacrifice rats at various time intervals during hyperinsulinemic-euglycemic clamping performed with and without lipid/heparin infusions and determine hepatic concentrations of DAG, PKC activity and isoforms, IRS-1/2, tyrosine phosphorylation and PI3 kinase activity. These studies will hopefully provide much needed information relative to important details and mechanisms of FFA induced hepatic insulin resistance. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK066003-01
Application #
6708458
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2004-02-15
Project End
2008-01-31
Budget Start
2004-02-15
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$331,100
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Boden, Guenther; Salehi, Sajad; Cheung, Peter et al. (2013) Comparison of in vivo effects of insulin on SREBP-1c activation and INSIG-1/2 in rat liver and human and rat adipose tissue. Obesity (Silver Spring) 21:1208-14
Singh, Anamika; Boden, Guenther; Homko, Carol et al. (2012) Whole-blood tissue factor procoagulant activity is elevated in type 1 diabetes: effects of hyperglycemia and hyperinsulinemia. Diabetes Care 35:1322-7
Boden, Guenther; Song, Weiwei; Duan, Xunbao et al. (2011) Infusion of glucose and lipids at physiological rates causes acute endoplasmic reticulum stress in rat liver. Obesity (Silver Spring) 19:1366-73
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Boden, Guenther (2009) High- or low-carbohydrate diets: which is better for weight loss, insulin resistance, and fatty livers? Gastroenterology 136:1490-2
Boden, Guenther; Duan, Xunbao; Homko, Carol et al. (2008) Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 57:2438-44
Boden, Guenther (2008) Obesity and free fatty acids. Endocrinol Metab Clin North Am 37:635-46, viii-ix
Boden, Guenther; Song, Weiwei; Kresge, Karen et al. (2008) Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors. Am J Physiol Endocrinol Metab 295:E692-7
Boden, Guenther; Song, Wei Wei (2008) Effects of insulin and free fatty acids on matrix metalloproteinases. Curr Diab Rep 8:239-42
Chen, W-W; Li, L; Yang, G-Y et al. (2008) Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 116:65-8

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