Early Hepatic Insulin Resistance Precedes the Onset of Diabetes in Obese C57BLKS-db/db Mice

Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Diabetes (Impact Factor: 8.47). 07/2010; 59(7):1616-25. DOI: 10.2337/db09-0878
Source: PubMed

ABSTRACT To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db) mouse strain.
Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains.
Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities.
Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of beta-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.

Download full-text


Available from: Jason K Kim, Jul 04, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of new therapies for the treatment of type 2 diabetes requires robust, reproducible and well validated in vivo experimental systems. Mice provide the most ideal animal model for studies of potential therapies. Unlike larger animals, mice have a short gestational period, are genetically similar, often give birth to many offspring at once and can be housed as multiple groups in a single cage. The mouse model has been extensively metabolically characterized using different tests. This report summarizes how these tests can be executed and how arising data are analyzed to confidently determine changes in insulin resistance and insulin secretion with high reproducibility. The main tests for metabolic assessment in the mouse reviewed here are the glucose clamp, the intravenous and the oral glucose tolerance tests. For all these experiments, including some commonly adopted variants, we describe: (i) their performance; (ii) their advantages and limitations; (iii) the empirical formulas and mathematical models implemented for the analysis of the data arising from the experimental procedures to obtain reliable measurements of peripheral insulin sensitivity and beta cell function. Finally, a list of previous applications of these methods and analytical techniques is provided to better comprehend their use and the evidences that these studies yielded.
    Journal of Diabetes Research 05/2013; 2013:986906. DOI:10.1155/2013/986906 · 3.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper deals with one of the key problems when interacting with virtual environments (VE): finger force feedback during manipulation of virtual objects. In the real world, control of haptic interactions with objects is achieved using the kinesthetic/tactile information. In a VE, the presentation of such information requires a dextrous hand master that provides force feedback to different fingers. The presence of friction and/or time delays and the lack of tactile information in such devices reduce operator performance. In those cases, other sensory channels such as vision and audition could be used to replace (sensory substitution) or to supplement (information redundancy) the haptic channel. In this paper, we present the result of an experimental study aimed at investigating human performance during interactions with virtual objects through different sensory channels. This study was performed using the Rutgers VR distributed system. This system enable the users to receive force informations through the haptic, visual, or auditive channel. The experiment was performed using both partially immersive monoscopic and stereoscopic visual displays. Results indicate that redundant presentation of haptic information greatly increases performance and reduce error rates as compared to the open-loop case (with no force feedback). The best results were obtained where both direct haptic and redundant sound feedback were provided. Increment of task completion time when using visual force feedback suggest an overload of the visual channel
    Robot and Human Communication, 1995. RO-MAN'95 TOKYO, Proceedings., 4th IEEE International Workshop on; 08/1995
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases.
    Lipids in Health and Disease 01/2011; 10:20. DOI:10.1186/1476-511X-10-20 · 2.31 Impact Factor