High Variability of Insulin Sensitivity in Closely Related Obese Mouse Inbred Strains

Abstract

Obesity is one of several risk factors for insulin resistance and type 2 diabetes. Here we examined males of 6 obese mouse inbred lines derived from the Berlin Fat Mouse (BFM) outbred population with respect to insulin sensitivity and factors of the metabolic syndrome with focus on the skeletal muscle as a major target of insulin dependent glucose uptake.

Males were kept on a rodent standard diet and several approaches were carried out to address insulin sensitivity, adiposity and lipids in the serum. Transcript and protein levels of several genes in the insulin signalling pathway were measured. 2 of the lines, BFMI860-12 and in particular BFMI861-S1, showed a markedly reduced insulin sensitivity already at the age of 20 weeks. BFMI861-S1 mice also displayed elevated liver triglyceride levels as a sign of lipid overload and ectopic fat storage. The analysis of the insulin signalling pathway in skeletal muscle provided evidence for low insulin receptor (INSR) and normal glucose 4 transporter (GLUT4) protein amounts in BFMI861-S1 mice, while BFMI860-12 mice showed increased INSR and very low GLUT4 protein amounts. Interestingly, the sublines BFMI860-S2 and BFMI861-S2, which are highly related to the former 2 lines, respectively, were inconspicuously insulin sensitive. The expected few genetic differences among the BFMI lines facilitate the identification of causal genetic variation. This study identified 2 mouse lines with different impairments of insulin signalling. These lines resemble useful models for studying mechanisms leading to the pathophysiology of the metabolic syndrome, in particular insulin resistance.

Key words

adiposity - hyperinsulinemia - skeletal muscle - metabolic syndrome

• References

• 1 DeFronzo RA, Ferrannini E, Sato Y et al. Synergistic interaction between exercise and insulin on peripheral glucose uptake. J Clin Invest. 1981; 68: 1468-1474
• 2 Petersen KF, Shulman GI. Cellular mechanism of insulin resistance in skeletal muscle. J R Soc Med 2002; 95 (Suppl. 42) 8-13
• 3 Joost HG, Schurmann A. The genetic basis of obesity-associated type 2 diabetes (diabesity) in polygenic mouse models. Mamm Genome 2014; 25: 401-412
• 4 Koves TR, Ussher JR, Noland RC et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45-56
• 5 Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806
• 6 Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840-846
• 7 Sajan MP, Ivey 3rd RA, Farese RV. BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1alpha in livers of obese and type 2 diabetic humans. Metabolism 2015; 64: 1454-1465
• 8 Schafer N, Zhonghao Y, Wagener A et al. Changes in metabolite profiles caused by genetically determined obesity in mice. Metabolomics 2013;
• 9 Bandyopadhyay GK, Yu JG, Ofrecio J et al. Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 2006; 55: 2277-2285
• 10 Ruderman NB, Saha AK, Vavvas D et al. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 1999; 276 (1 Pt 1) E1-E18
• 11 Muoio DM, Newgard CB. Obesity-related derangements in metabolic regulation. Annu Rev Biochem 2006; 75: 367-401
• 12 Sinha R, Dufour S, Petersen KF et al. Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes 2002; 51: 1022-1027
• 13 Weiss R, Dufour S, Groszmann A et al. Low adiponectin levels in adolescent obesity: a marker of increased intramyocellular lipid accumulation. J Clin Endocrinol Metab 2003; 88: 2014-2018
• 14 Williams EG, Auwerx J. The Convergence of Systems and Reductionist Approaches in Complex Trait Analysis. Cell 2015; 162: 23-32
• 15 Neuschl C, Hantschel C, Wagener A et al. A unique genetic defect on chromosome 3 is responsible for juvenile obesity in the Berlin Fat Mouse. Int J Obes (Lond) 2010; 34: 1706-1714
• 16 Wagener A, Schmitt AO, Aksu S et al. Genetic, sex, and diet effects on body weight and obesity in the Berlin Fat Mouse Inbred lines. Physiol Genomics 2006; 27: 264-270
• 17 Vogel H, Mirhashemi F, Liehl B et al. Estrogen deficiency aggravates insulin resistance and induces beta-cell loss and diabetes in female New Zealand obese mice. Horm Metab Res 2013; 45: 430-435
• 18 Radikova Z, Koska J, Huckova M et al. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects. Exp Clin Endocrinol Diabetes 2006; 114: 249-256
• 19 Pisprasert V, Ingram KH, Lopez-Davila MF et al. Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans. Diabetes Care 2013; 36: 845-853
• 20 Gutch M, Kumar S, Razi SM et al. Assessment of insulin sensitivity/resistance. Indian journal of endocrinology and metabolism 2015; 19: 160-164
• 21 Karst S, Cheng R, Schmitt AO et al. Genetic determinants for intramuscular fat content and water-holding capacity in mice selected for high muscle mass. Mamm Genome 2011; 22: 530-543
• 22 Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000; 132: 365-386
• 23 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 24 Hesse D, Hommel A, Jaschke A et al. Altered GLUT4 trafficking in adipocytes in the absence of the GTPase Arfrp1. Biochemical and biophysical research communications 2010; 394: 896-903
• 25 Hommel A, Hesse D, Volker W et al. The ARF-like GTPase ARFRP1 is essential for lipid droplet growth and is involved in the regulation of lipolysis. Mol Cell Biol 2010; 30: 1231-1242
• 26 Zahn C, Jaschke A, Weiske J et al. ADP-ribosylation factor-like GTPase ARFRP1 is required for trans-Golgi to plasma membrane trafficking of E-cadherin. J Biol Chem 2008; 283: 27179-27188
• 27 Watanabe Y, Nakayama K, Taniuchi N et al. Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes. PLoS One 2015; 10: e0116851
• 28 Schafer N, Wagener A, Hantschel C et al. IGF-I contributes to glucose homeostasis in the Berlin Fat Mouse Inbred line. Growth Factors 2011; 29: 298-309