Glucose Metabolism In Vivo in Four Commonly Used Inbred Mouse Strains

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Diabetes (Impact Factor: 8.1). 08/2008; 57(7):1790-9. DOI: 10.2337/db07-1615
Source: PubMed


To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains.
Hyperinsulinemic-euglycemic (approximately 8.5 mmol/l) and -hypoglycemic (approximately 3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (approximately 15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets.
Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets.
Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments.

Download full-text


Available from: Patrick T Fueger, Oct 06, 2015
28 Reads
  • Source
    • "Fasting blood glucose was measured immediately prior to sacrifice via handheld glucometer. HOMA-IR was calculated using the following formula: fasting serum insulin (mU/ml) Â fasting blood glucose (mg/dl)/405 (Berglund et al., 2008). Serum insulin (Mercodia Mouse Insulin ELISA) and adiponectin (SPI Bio Mouse Adiponectin) were measured by ELISA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus is a highly prevalent metabolic disease affecting 29.1 million people or 9.3% of the population of the United States. The most prevalent form of diabetes is type 2 diabetes (T2D) which comprises 90-95% of all reported cases of diabetes. While the exact cause of T2D remains an enigma, known risk factors include age, weight, sedentary lifestyle, poor dietary habits, and genetic predisposition. However, these risk factors can not sufficiently explain the increasing prevalence of T2D. Recently, environmental exposures have been explored as potential risk factors. Indeed, epidemiological and limited empirical studies have revealed elevated serum concentrations of certain persistent organic pollutants (POPs), including the bioaccumulative metabolite of p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), are positively correlated with increased T2D prevalence. The goal of the present study is to determine if chronic exposure to DDE promotes T2D in a widely used in vivo model, the high saturated fat-fed mouse. Male C57BL/6H mice were exposed to DDE (2.0mg/kg) or vehicle (corn oil; 1ml/kg) via gavage for 5 consecutive days, then every 7 days for the duration of the study. One week following the 5 day consecutive DDE dosing, animals were placed on either a low fat (10%kcal from lard) or high fat (45%kcal from lard) diet (HFD) for 13 weeks. Chronic exposure to DDE promoted fasting hyperglycemia after 4 and 8 weeks on the HFD diet and normalized fasting blood glucose levels at week 13. This DDE-mediated decrease in fasting hyperglycemia was preceded by improved glucose tolerance at week 12. In addition to normalizing fasting hyperglycemia at the end of high fat feeding, DDE exposure decreased HFD-induced fasting hyperinsulinemia, homeostasis model assessment of insulin resistance (HOMA-IR) values, and hepatic steatosis. Therefore, based on the current data, chronic DDE exposure appears to have a biphasic effect on HFD-induced hyperglycemia in the male C57BL/6H mouse characterized by elevated fasting blood glucose at weeks 4 and 8 of HFD intake followed by normoglycemia upon sacrifice. In addition, chronic DDE exposure reduced HFD-induced hepatic steatosis upon sacrifice. These results indicate chronic exposure to DDE can directly affect systemic glucose and hepatic lipid metabolism and that these effects can be diet dependent. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Toxicology 12/2014; 328. DOI:10.1016/j.tox.2014.12.017 · 3.62 Impact Factor
  • Source
    • "Glucose tolerance testing was performed as we have described [21], in mice at 16 weeks of study diet following a 12-h overnight fast. Insulin sensitivity was estimated using the HOmeostatic Model Assessment of Insulin Resistance (HOMA-IR) method [22], calculated using the formula: basal insulin ð "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.
    Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.024 · 11.34 Impact Factor
  • Source
    • "females, providing further evidence of a more pronounced penetrance of phenotype on the C57BL/6 background. The influence of genetic strain on phenotype has been well documented in mice (Berglund et al., 2008; Goren et al., 2004). This difference might be attributed to the effect that the host genome can have on numerous metabolic factors, such as insulin secretion or peripheral and hepatic sensitivity (Doetschman, 2009; Kahle et al., 2013), particularly in the C57BL/6J mouse model, which serves as a common in-bred strain of diet-induced T2D (Freeman et al., 2006; Toye et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: PANcreatic-DERived Factor (PANDER, FAM3B) is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and serve a potential role in the onset or progression of type 2 diabetes. Despite having a potential pleiotropic pivotal role in glycemic regulation and T2D, there has been limited generation of stable animal models for PANDER investigation, with none on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure bred PANDER C57BL/6 knockout model (PANKO-C57) was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 exhibited an enhanced metabolic phenotype particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and c-peptide levels, whereas leptin levels were increased as compared to matched C57BL/6J WT mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions as demonstrated by increased phosphorylation of hepatic Akt and AMPK along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared to C57BL/6 WT. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D.
    Disease Models and Mechanisms 09/2014; 7(11). DOI:10.1242/dmm.016402 · 4.97 Impact Factor
Show more

Similar Publications