Skip to main content

Advertisement

SpringerLink
Log in

Approach to assessing determinants of glucose homeostasis in the conscious mouse

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Obesity and type 2 diabetes lessen the quality of life of those afflicted and place considerable burden on the healthcare system. Furthermore, the detrimental impact of these pathologies is expected to persist or even worsen. Diabetes is characterized by impaired insulin action and glucose homeostasis. This has led to a rapid increase in the number of mouse models of metabolic disease being used in the basic sciences to assist in facilitating a greater understanding of the metabolic dysregulation associated with obesity and diabetes, the identification of therapeutic targets, and the discovery of effective treatments. This review briefly describes the most frequently utilized models of metabolic disease. A presentation of standard methods and technologies on the horizon for assessing metabolic phenotypes in mice, with particular emphasis on glucose handling and energy balance, is provided. The article also addresses issues related to study design, selection and execution of metabolic tests of glucose metabolism, the presentation of data, and interpretation of results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ae Park S, Choi MS, Cho SY, Seo JS, Jung UJ, Kim MJ, Sung MK, Park YB, Lee MK (2006) Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice. Life Sci 79:1207–1213

    PubMed  Google Scholar 

  • Aigner B, Rathkolb B, Herbach N, Hrabe de Angelis M, Wanke R, Wolf E (2008) Diabetes models by screen for hyperglycemia in phenotype-driven ENU mouse mutagenesis projects. Am J Physiol Endocrinol Metab 294:E232–E240

    PubMed  CAS  Google Scholar 

  • Akinmokun A, Selby PL, Ramaiya K, Alberti KG (1992) The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycemic clamp. Diabet Med 9:432–437

    PubMed  CAS  Google Scholar 

  • Albarado DC, McClaine J, Stephens JM, Mynatt RL, Ye J, Bannon AW, Richards WG, Butler AA (2004) Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice. Endocrinology 145:243–252

    PubMed  CAS  Google Scholar 

  • Alexander J, Chang GQ, Dourmashkin JT, Leibowitz SF (2006) Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6J mice compared to control strains. Int J Obes 30:50–59

    CAS  Google Scholar 

  • Alonso LC, Watanabe Y, Stefanovski D, Lee EJ, Singamsetty S, Romano LC, Zou B, Garcia-Ocana A, Bergman RN, O’Donnell CP (2012) Simultaneous measurement of insulin sensitivity, insulin secretion, and the disposition index in conscious unhandled mice. Obes (Silver Spring) 20:1403–1412

    CAS  Google Scholar 

  • Anstee QM, Goldin RD (2006) Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 87:1–16

    PubMed  CAS  PubMed Central  Google Scholar 

  • Antoniewicz MR, Kelleher JK, Stephanopoulos G (2011) Measuring deuterium enrichment of glucose hydrogen atoms by gas chromatography/mass spectrometry. Anal Chem 83:3211–3216

    PubMed  CAS  PubMed Central  Google Scholar 

  • Araki E, Lipes MA, Patti ME, Bruning JC, Haag B 3rd, Johnson RS, Kahn CR (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190

    PubMed  CAS  Google Scholar 

  • Ayala JE, Bracy DP, McGuinness OP, Wasserman DH (2006) Considerations in the design of hyperinsulinemic-euglycemic clamps in the conscious mouse. Diabetes 55:390–397

    PubMed  CAS  Google Scholar 

  • Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP (2010) Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Models Mech 3:525–534

    CAS  Google Scholar 

  • Ayala JE, Bracy DP, Malabanan C, James FD, Ansari T, Fueger PT, McGuinness OP, Wasserman DH (2011) Hyperinsulinemic-euglycemic clamps in conscious, unrestrained mice. J Vis Exp 57:3188

  • Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB (2009) Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes 58:2429–2443

    PubMed  CAS  PubMed Central  Google Scholar 

  • Basciano H, Federico L, Adeli K (2005) Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab 2:5

    Google Scholar 

  • Berglund ED, Li CY, Poffenberger G, Ayala JE, Fueger PT, Willis SE, Jewell MM, Powers AC, Wasserman DH (2008) Glucose metabolism in vivo in four commonly used inbred mouse strains. Diabetes 57:1790–1799

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bergman RN, Phillips LS, Cobelli C (1981) Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Investig 68:1456–1467

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bigorgne AE, Bouchet-Delbos L, Naveau S, Dagher I, Prevot S, Durand-Gasselin I, Couderc J, Valet P, Emilie D, Perlemuter G (2008) Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice. Gastroenterology 134:1459–1469

    PubMed  Google Scholar 

  • Bonner JS, Lantier L, Hasenour CM, James FD, Bracy DP, Wasserman DH (2013) Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance. Diabetes 62:572–580

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79:537–543

    PubMed  CAS  Google Scholar 

  • Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561–572

    PubMed  CAS  Google Scholar 

  • Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2:559–569

    PubMed  CAS  Google Scholar 

  • Buettner R, Scholmerich J, Bollheimer LC (2007) High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity 15:798–808

    PubMed  CAS  Google Scholar 

  • Burgess SC, Jeffrey FM, Storey C, Milde A, Hausler N, Merritt ME, Mulder H, Holm C, Sherry AD, Malloy CR (2005) Effect of murine strain on metabolic pathways of glucose production after brief or prolonged fasting. Am J Physiol Endocrinol Metab 289:E53–E61

    PubMed  CAS  Google Scholar 

  • Butler AA, Kozak LP (2010) A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 59:323–329

    PubMed  CAS  PubMed Central  Google Scholar 

  • Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141:3518–3521

    PubMed  CAS  Google Scholar 

  • Camporez JP, Jornayvaz FR, Lee HY, Kanda S, Guigni BA, Kahn M, Samuel VT, Carvalho CR, Petersen KF, Jurczak MJ, Shulman GI (2013) Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. Endocrinology 154:1021–1028

    PubMed  CAS  PubMed Central  Google Scholar 

  • Castle AL, Fiehn O, Kaddurah-Daouk R, Lindon JC (2006) Metabolomics Standards Workshop and the development of international standards for reporting metabolomics experimental results. Brief Bioinform 7:159–165

    PubMed  CAS  Google Scholar 

  • Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:97–102

    PubMed  CAS  Google Scholar 

  • Chicco A, D’Alessandro ME, Karabatas L, Pastorale C, Basabe JC, Lombardo YB (2003) Muscle lipid metabolism and insulin secretion are altered in insulin-resistant rats fed a high sucrose diet. J Nutr 133:127–133

    PubMed  CAS  Google Scholar 

  • Coleman DL, Hummel KP (1973) The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia 9:287–293

    PubMed  CAS  Google Scholar 

  • Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578

    PubMed  CAS  Google Scholar 

  • Cresto JC, Lavine RL, Buchly ML, Penhos JC, Bhathena SJ, Recant L (1977) Half life of injected 125I-insulin in control and ob/ob mice. Acta Physiol Lat Am 27:7–15

    PubMed  CAS  Google Scholar 

  • Dickie MM (1969) Mutations at the agouti locus in the mouse. J Hered 60:20–25

    PubMed  CAS  Google Scholar 

  • Dobrzyn P, Dobrzyn A, Miyazaki M, Ntambi JM (2010) Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice. J Lipid Res 51:2202–2210

    PubMed  CAS  PubMed Central  Google Scholar 

  • Dong YF, Liu L, Kataoka K, Nakamura T, Fukuda M, Tokutomi Y, Nako H, Ogawa H, Kim-Mitsuyama S (2010) Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes. Diabetologia 53:180–191

    PubMed  CAS  Google Scholar 

  • Dubuc PU (1976) The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice. Metabolism 25:1567–1574

    PubMed  CAS  Google Scholar 

  • Ellacott KL, Murphy JG, Marks DL, Cone RD (2007) Obesity-induced inflammation in white adipose tissue is attenuated by loss of melanocortin-3 receptor signaling. Endocrinology 148:6186–6194

    PubMed  CAS  Google Scholar 

  • Enser M (1972) Clearing-factor lipase in obese hyperglycaemic mice (ob–ob). Biochem J 129:447–453

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165–168

    PubMed  CAS  Google Scholar 

  • Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O’Rahilly S (2003) Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New Engl J Med 348:1085–1095

    PubMed  CAS  Google Scholar 

  • Ge F, Zhou S, Hu C, Lobdell Ht, Berk PD (2010) Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice. American journal of physiology. Gastrointest Liv Physiol 299:G855–G866

    CAS  Google Scholar 

  • Goldsworthy M, Absalom NL, Schroter D, Matthews HC, Bogani D, Moir L, Long A, Church C, Hugill A, Anstee QM, Goldin R, Thursz M, Hollfelder F, Cox RD (2013) Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice. PLoS ONE 8:e61870

    PubMed  CAS  PubMed Central  Google Scholar 

  • Goren HJ, Kulkarni RN, Kahn CR (2004) Glucose homeostasis and tissue transcript content of insulin signaling intermediates in four inbred strains of mice: c57BL/6, C57BLKS/6, DBA/2, and 129X1. Endocrinology 145:3307–3323

    PubMed  CAS  Google Scholar 

  • Guo S (2014) Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 220:T1–T23

    PubMed  CAS  PubMed Central  Google Scholar 

  • Han BG, Hao CM, Tchekneva EE, Wang YY, Lee CA, Ebrahim B, Harris RC, Kern TS, Wasserman DH, Breyer MD, Qi Z (2008) Markers of glycemic control in the mouse: comparisons of 6-h- and overnight-fasted blood glucoses to Hb A1c. Am J Physiol Endocrinol Metab 295:E981–E986

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH (2014) 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J Biol Chem 289:5950–5959

    PubMed  CAS  Google Scholar 

  • Himms-Hagen J (1997) On raising energy expenditure in ob/ob mice. Science 276:1132–1133

    PubMed  CAS  Google Scholar 

  • Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J (1999) Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 84:1483–1486

    PubMed  CAS  Google Scholar 

  • Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV Jr, Alt FW, Kahn CR, Verdin E (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hong CJ, Tsai PJ, Cheng CY, Chou CK, Jheng HF, Chuang YC, Yang CN, Lin YT, Hsu CW, Cheng IH, Chen SY, Tsai SJ, Liou YJ, Tsai YS (2010) ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin. PLoS ONE 5:e15333

    PubMed  PubMed Central  Google Scholar 

  • Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

    PubMed  CAS  Google Scholar 

  • Humphreys MH, Ni XP, Pearce D (2011) Cardiovascular effects of melanocortins. Eur J Pharmacol 660:43–52

    PubMed  CAS  PubMed Central  Google Scholar 

  • Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141

    PubMed  CAS  Google Scholar 

  • Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687

    PubMed  CAS  Google Scholar 

  • Ikemoto S, Takahashi M, Tsunoda N, Maruyama K, Itakura H, Ezaki O (1996) High-fat diet-induced hyperglycemia and obesity in mice: differential effects of dietary oils. Metabolism 45:1539–1546

    PubMed  CAS  Google Scholar 

  • Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41:317–318

    PubMed  CAS  Google Scholar 

  • Inoue M, Sakuraba Y, Motegi H, Kubota N, Toki H, Matsui J, Toyoda Y, Miwa I, Terauchi Y, Kadowaki T, Shigeyama Y, Kasuga M, Adachi T, Fujimoto N, Matsumoto R, Tsuchihashi K, Kagami T, Inoue A, Kaneda H, Ishijima J, Masuya H, Suzuki T, Wakana S, Gondo Y, Minowa O, Shiroishi T, Noda T (2004) A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. Hum Mol Genet 13:1147–1157

    PubMed  CAS  Google Scholar 

  • Jackerott M, Baudry A, Lamothe B, Bucchini D, Jami J, Joshi RL (2001) Endocrine pancreas in insulin receptor-deficient mouse pups. Diabetes 50(Suppl 1):S146–S149

    PubMed  CAS  Google Scholar 

  • Jacobson L, Ansari T, McGuinness OP (2006a) Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice. American journal of physiology. Endocrinol Metab 290:E678–E684

    CAS  Google Scholar 

  • Jacobson L, Ansari T, Potts J, McGuinness OP (2006b) Glucocorticoid-deficient corticotropin-releasing hormone knockout mice maintain glucose requirements but not autonomic responses during repeated hypoglycemia. American journal of physiology. Endocrinol Metab 291:E15–E22

    CAS  Google Scholar 

  • James DE, Burleigh KM, Chisholm DJ, Kraegen EW (1985) In vivo dose response curves of insulin action in heart: anomalous effects at high insulin doses. J Mol Cell Cardiol 17:981–985

    PubMed  CAS  Google Scholar 

  • Jin ES, Jones JG, Merritt M, Burgess SC, Malloy CR, Sherry AD (2004) Glucose production, gluconeogenesis, and hepatic tricarboxylic acid cycle fluxes measured by nuclear magnetic resonance analysis of a single glucose derivative. Anal Biochem 327:149–155

    PubMed  CAS  Google Scholar 

  • Jin ES, Beddow SA, Malloy CR, Samuel VT (2013) Hepatic glucose production pathways after three days of a high-fat diet. Metabolism 62:152–162

    PubMed  CAS  PubMed Central  Google Scholar 

  • Jones JG, Naidoo R, Sherry AD, Jeffrey FM, Cottam GL, Malloy CR (1997) Measurement of gluconeogenesis and pyruvate recycling in the rat liver: a simple analysis of glucose and glutamate isotopomers during metabolism of [1,2,3-(13)C3]propionate. FEBS Lett 412:131–137

    PubMed  CAS  Google Scholar 

  • Jones JG, Solomon MA, Cole SM, Sherry AD, Malloy CR (2001) An integrated (2)H and (13)C NMR study of gluconeogenesis and TCA cycle flux in humans. Am J Physiol Endocrinol Metab 281:E848–E856

    PubMed  CAS  Google Scholar 

  • Jourdan T, Djaouti L, Demizieux L, Gresti J, Verges B, Degrace P (2009) Liver carbohydrate and lipid metabolism of insulin-deficient mice is altered by trans-10, cis-12 conjugated linoleic acid. J Nutr 139:1901–1907

    PubMed  CAS  Google Scholar 

  • Kaiyala KJ, Schwartz MW (2011) Toward a more complete (and less controversial) understanding of energy expenditure and its role in obesity pathogenesis. Diabetes 60:17–23

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kaiyala KJ, Morton GJ, Leroux BG, Ogimoto K, Wisse B, Schwartz MW (2010) Identification of body fat mass as a major determinant of metabolic rate in mice. Diabetes 59:1657–1666

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, Wasserman DH (2011) Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice. Diabetes 60:416–426

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kang L, Mayes WH, James FD, Bracy DP, Wasserman DH (2014) Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice. Diabetologia 57:603–613

    PubMed  CAS  PubMed Central  Google Scholar 

  • Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ (1995) Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377:151–155

    PubMed  CAS  Google Scholar 

  • Kennedy AJ, Ellacott KL, King VL, Hasty AH (2010) Mouse models of the metabolic syndrome. Dis Models Mech 3:156–166

    CAS  Google Scholar 

  • Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D (2000) Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Investig 105:199–205

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kobayasi R, Akamine EH, Davel AP, Rodrigues MA, Carvalho CR, Rossoni LV (2010) Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice. J Hypertens 28:2111–2119

    PubMed  CAS  Google Scholar 

  • Kraegen EW, James DE, Jenkins AB, Chisholm DJ (1985) Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. Am J Physiol 248:E353–E362

    PubMed  CAS  Google Scholar 

  • Kushner JA, Ye J, Schubert M, Burks DJ, Dow MA, Flint CL, Dutta S, Wright CV, Montminy MR, White MF (2002) Pdx1 restores beta cell function in Irs2 knockout mice. J Clin Investig 109:1193–1201

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lam TK, Gutierrez-Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L (2007) Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat Med 13:171–180

    PubMed  CAS  Google Scholar 

  • Laughlin MR, Lloyd KC, Cline GW, Wasserman DH (2012) NIH Mouse Metabolic Phenotyping Centers: the power of centralized phenotyping. Mamm Genome 23:623–631

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lee AW, Hengstler H, Schwald K, Berriel-Diaz M, Loreth D, Kirsch M, Kretz O, Haas CA, de Angelis MH, Herzig S, Brummendorf T, Klingenspor M, Rathjen FG, Rozman J, Nicholson G, Cox RD, Schafer MK (2012) Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype. PLoS ONE 7:e41537

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lee-Young RS, Ayala JE, Hunley CF, James FD, Bracy DP, Kang L, Wasserman DH (2010) Endothelial nitric oxide synthase is central to skeletal muscle metabolic regulation and enzymatic signaling during exercise in vivo. Am J Physiol Regul Integr Comp Physiol 298:R1399–R1408

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226

    PubMed  CAS  Google Scholar 

  • Leto D, Saltiel AR (2012) Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 13:383–396

    PubMed  CAS  Google Scholar 

  • Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH (2010) The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 7:251–264

    PubMed  CAS  Google Scholar 

  • Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO et al (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371:799–802

    PubMed  CAS  Google Scholar 

  • Mark AL, Shaffer RA, Correia ML, Morgan DA, Sigmund CD, Haynes WG (1999) Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens 17:1949–1953

    PubMed  CAS  Google Scholar 

  • Marti A, Corbalan MS, Forga L, Martinez JA, Hinney A, Hebebrand J (2003) A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord 27:385–388

    PubMed  CAS  Google Scholar 

  • Massiera F, Barbry P, Guesnet P, Joly A, Luquet S, Moreilhon-Brest C, Mohsen-Kanson T, Amri EZ, Ailhaud G (2010) A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations. J Lipid Res 51:2352–2361

    PubMed  CAS  PubMed Central  Google Scholar 

  • McGuinness OP, Ayala JE, Laughlin MR, Wasserman DH (2009) NIH experiment in centralized mouse phenotyping: the Vanderbilt experience and recommendations for evaluating glucose homeostasis in the mouse. American journal of physiology. Endocrinol Metab 297:E849–E855

    CAS  Google Scholar 

  • Mergen M, Mergen H, Ozata M, Oner R, Oner C (2001) A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. J Clin Endocrinol Metab 86:3448

    PubMed  CAS  Google Scholar 

  • Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S, Durand E, Vatin V, Degraeve F, Proenca C, Gaget S, Korner A, Kovacs P, Kiess W, Tichet J, Marre M, Hartikainen AL, Horber F, Potoczna N, Hercberg S, Levy-Marchal C, Pattou F, Heude B, Tauber M, McCarthy MI, Blakemore AI, Montpetit A, Polychronakos C, Weill J, Coin LJ, Asher J, Elliott P, Jarvelin MR, Visvikis-Siest S, Balkau B, Sladek R, Balding D, Walley A, Dina C, Froguel P (2009) Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet 41:157–159

    PubMed  CAS  Google Scholar 

  • Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, Bergman RN, Wasserman DH, Schwartz MW (2013) FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Investig 123:4799–4808

    PubMed  CAS  PubMed Central  Google Scholar 

  • Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573

    PubMed  CAS  Google Scholar 

  • Nagata R, Nishio Y, Sekine O, Nagai Y, Maeno Y, Ugi S, Maegawa H, Kashiwagi A (2004) Single nucleotide polymorphism (−468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis [corrected]. J Biol Chem 279:29031–29042

    PubMed  CAS  Google Scholar 

  • Nandi A, Kitamura Y, Kahn CR, Accili D (2004) Mouse models of insulin resistance. Physiol Rev 84:623–647

    PubMed  CAS  Google Scholar 

  • Nishina PM, Lowe S, Wang J, Paigen B (1994) Characterization of plasma lipids in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow. Metabolism 43:549–553

    PubMed  CAS  Google Scholar 

  • Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schurmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O’Rahilly S, Rohner-Jeanrenaud F, Tschop MH (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Investig 117:3475–3488

    PubMed  CAS  PubMed Central  Google Scholar 

  • Nunemaker CS, Zhang M, Wasserman DH, McGuinness OP, Powers AC, Bertram R, Sherman A, Satin LS (2005) Individual mice can be distinguished by the period of their islet calcium oscillations: is there an intrinsic islet period that is imprinted in vivo? Diabetes 54:3517–3522

    PubMed  CAS  Google Scholar 

  • Nunemaker CS, Wasserman DH, McGuinness OP, Sweet IR, Teague JC, Satin LS (2006) Insulin secretion in the conscious mouse is biphasic and pulsatile. American journal of physiology. Endocrinol Metab 290:E523–E529

    CAS  Google Scholar 

  • Oosterveer MH, Mataki C, Yamamoto H, Harach T, Moullan N, van Dijk TH, Ayuso E, Bosch F, Postic C, Groen AK, Auwerx J, Schoonjans K (2012) LRH-1-dependent glucose sensing determines intermediary metabolism in liver. J Clin Invest 122:2817–2826

    PubMed  CAS  PubMed Central  Google Scholar 

  • Osborn O, Sanchez-Alavez M, Brownell SE, Ross B, Klaus J, Dubins J, Beutler B, Conti B, Bartfai T (2010) Metabolic characterization of a mouse deficient in all known leptin receptor isoforms. Cell Mol Neurobiol 30:23–33

    PubMed  CAS  PubMed Central  Google Scholar 

  • Paik SG, Fleischer N, Shin SI (1980) Insulin-dependent diabetes mellitus induced by subdiabetogenic doses of streptozotocin: obligatory role of cell-mediated autoimmune processes. Proc Natl Acad Sci USA 77:6129–6133

    PubMed  CAS  PubMed Central  Google Scholar 

  • Palm F, Ortsater H, Hansell P, Liss P, Carlsson PO (2004) Differentiating between effects of streptozotocin per se and subsequent hyperglycemia on renal function and metabolism in the streptozotocin-diabetic rat model. Diabetes/Metab Res Rev 20:452–459

    Google Scholar 

  • Panchal SK, Brown L (2011) Rodent models for metabolic syndrome research. J Biomed Biotechnol 2011:351982

    PubMed  PubMed Central  Google Scholar 

  • Park HJ, DiNatale DA, Chung MY, Park YK, Lee JY, Koo SI, O’Connor M, Manautou JE, Bruno RS (2011) Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. J Nutr Biochem 22:393–400

    PubMed  CAS  Google Scholar 

  • Plumpton FS, Besser GM (1969) The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 56:216–219

    PubMed  CAS  Google Scholar 

  • Preitner F, Mody N, Graham TE, Peroni OD, Kahn BB (2009) Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am J Physiol Endocrinol Metab 297:E1420–E1429

    PubMed  CAS  PubMed Central  Google Scholar 

  • Previs SF, Fernandez CA, Yang D, Soloviev MV, David F, Brunengraber H (1995) Limitations of the mass isotopomer distribution analysis of glucose to study gluconeogenesis. Substrate cycling between glycerol and triose phosphates in liver. J Biol Chem 270:19806–19815

    PubMed  CAS  Google Scholar 

  • Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, Whitington PF (2004) Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. American journal of physiology. Gastrointest Liv Physiol 287:G1035–G1043

    CAS  Google Scholar 

  • Satapati S, Sunny NE, Kucejova B, Fu X, He TT, Mendez-Lucas A, Shelton JM, Perales JC, Browning JD, Burgess SC (2012) Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res 53:1080–1092

    PubMed  CAS  PubMed Central  Google Scholar 

  • Schein PS, Loftus S (1968) Streptozotocin: depression of mouse liver pyridine nucleotides. Cancer Res 28:1501–1506

    PubMed  CAS  Google Scholar 

  • Sharma K, Kohli P, Gulati M (2012) An update on exercise stress testing. Curr Probl Cardiol 37:177–202

    PubMed  Google Scholar 

  • Slot JW, Geuze HJ, Gigengack S, James DE, Lienhard GE (1991) Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. Proc Natl Acad Sci U S A 88:7815–7819

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

    PubMed  CAS  Google Scholar 

  • Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320

    PubMed  CAS  Google Scholar 

  • Ste Marie L, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD (2000) A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 97:12339–12344

    PubMed  CAS  PubMed Central  Google Scholar 

  • Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ (1997) GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 3:1096–1101

    PubMed  CAS  Google Scholar 

  • Sumiyoshi M, Sakanaka M, Kimura Y (2006) Chronic intake of high-fat and high-sucrose diets differentially affects glucose intolerance in mice. J Nutr 136:582–587

    PubMed  CAS  Google Scholar 

  • Sunny NE, Parks EJ, Browning JD, Burgess SC (2011) Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 14:804–810

    PubMed  CAS  PubMed Central  Google Scholar 

  • Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6 J mice. Diabetes 37:1163–1167

    PubMed  CAS  Google Scholar 

  • Sutton GM, Trevaskis JL, Hulver MW, McMillan RP, Markward NJ, Babin MJ, Meyer EA, Butler AA (2006) Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6 J mice lacking melanocortin-3 or -4 receptors. Endocrinology 147:2183–2196

    PubMed  CAS  PubMed Central  Google Scholar 

  • Svenson KL, Ahituv N, Durgin RS, Savage H, Magnani PA, Foreman O, Paigen B, Peters LL (2008) A new mouse mutant for the LDL receptor identified using ENU mutagenesis. J Lipid Res 49:2452–2462

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE (2005) Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension 46:326–332

    PubMed  CAS  Google Scholar 

  • Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S et al (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372:182–186

    PubMed  CAS  Google Scholar 

  • Tran LT, Yuen VG, McNeill JH (2009) The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 332:145–159

    PubMed  CAS  Google Scholar 

  • Trevaskis JL, Meyer EA, Galgani JE, Butler AA (2008) Counterintuitive effects of double-heterozygous null melanocortin-4 receptor and leptin genes on diet-induced obesity and insulin resistance in C57BL/6 J mice. Endocrinology 149:174–184

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tschop M, Heiman ML (2001) Rodent obesity models: an overview. Exp Clin Endocrinol Diabet 109, 307–319

  • Vaisse C, Clement K, Guy-Grand B, Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113–114

    PubMed  CAS  Google Scholar 

  • van Burck L, Blutke A, Kautz S, Rathkolb B, Klaften M, Wagner S, Kemter E, Hrabe de Angelis M, Wolf E, Aigner B, Wanke R, Herbach N (2010) Phenotypic and pathomorphological characteristics of a novel mutant mouse model for maturity-onset diabetes of the young type 2 (MODY 2). Am J Physiol Endocrinol Metab 298:E512–E523

    PubMed  Google Scholar 

  • Van den Bergh A, Vanderper A, Vangheluwe P, Desjardins F, Nevelsteen I, Verreth W, Wuytack F, Holvoet P, Flameng W, Balligand JL, Herijgers P (2008) Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness. Cardiovasc Res 77:371–379

    PubMed  Google Scholar 

  • Vella A, Rizza RA (2009) Application of isotopic techniques using constant specific activity or enrichment to the study of carbohydrate metabolism. Diabetes 58:2168–2174

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wang H, Storlien LH, Huang XF (2002) Effects of dietary fat types on body fatness, leptin, and ARC leptin receptor, NPY, and AgRP mRNA expression. Am J Physiol Endocrinol Metab 282:E1352–E1359

    PubMed  CAS  Google Scholar 

  • Wasserman DH (2009) Four grams of glucose. Am J Physiol Endocrinol Metab 296:E11–E21

    PubMed  CAS  PubMed Central  Google Scholar 

  • Wasserman DH, Ayala JE, McGuinness OP (2009) Lost in translation. Diabetes 58:1947–1950

    PubMed  CAS  PubMed Central  Google Scholar 

  • Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, Lettre G, Lim N, Lyon HN, McCarroll SA, Papadakis K, Qi L, Randall JC, Roccasecca RM, Sanna S, Scheet P, Weedon MN, Wheeler E, Zhao JH, Jacobs LC, Prokopenko I, Soranzo N, Tanaka T, Timpson NJ, Almgren P, Bennett A, Bergman RN, Bingham SA, Bonnycastle LL, Brown M, Burtt NP, Chines P, Coin L, Collins FS, Connell JM, Cooper C, Smith GD, Dennison EM, Deodhar P, Elliott P, Erdos MR, Estrada K, Evans DM, Gianniny L, Gieger C, Gillson CJ, Guiducci C, Hackett R, Hadley D, Hall AS, Havulinna AS, Hebebrand J, Hofman A, Isomaa B, Jacobs KB, Johnson T, Jousilahti P, Jovanovic Z, Khaw KT, Kraft P, Kuokkanen M, Kuusisto J, Laitinen J, Lakatta EG, Luan J, Luben RN, Mangino M, McArdle WL, Meitinger T, Mulas A, Munroe PB, Narisu N, Ness AR, Northstone K, O’Rahilly S, Purmann C, Rees MG, Ridderstrale M, Ring SM, Rivadeneira F, Ruokonen A, Sandhu MS, Saramies J, Scott LJ, Scuteri A, Silander K, Sims MA, Song K, Stephens J, Stevens S, Stringham HM, Tung YC, Valle TT, Van Duijn CM, Vimaleswaran KS, Vollenweider P, Waeber G, Wallace C, Watanabe RM, Waterworth DM, Watkins N, Witteman JC, Zeggini E, Zhai G, Zillikens MC, Altshuler D, Caulfield MJ, Chanock SJ, Farooqi IS, Ferrucci L, Guralnik JM, Hattersley AT, Hu FB, Jarvelin MR, Laakso M, Mooser V, Ong KK, Ouwehand WH, Salomaa V, Samani NJ, Spector TD, Tuomi T, Tuomilehto J, Uda M, Uitterlinden AG, Wareham NJ, Deloukas P, Frayling TM, Groop LC, Hayes RB, Hunter DJ, Mohlke KL, Peltonen L, Schlessinger D, Strachan DP, Wichmann HE, McCarthy MI, Boehnke M, Barroso I, Abecasis GR, Hirschhorn JN (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34

    PubMed  CAS  PubMed Central  Google Scholar 

  • Williams TD, Chambers JB, Gagnon SP, Roberts LM, Henderson RP, Overton JM (2003) Cardiovascular and metabolic responses to fasting and thermoneutrality in Ay mice. Physiol Behav 78:615–623

    PubMed  CAS  Google Scholar 

  • Winzell MS, Wulff EM, Olsen GS, Sauerberg P, Gotfredsen CF, Ahren B (2010) Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice. Eur J Pharmacol 626:297–305

    PubMed  CAS  Google Scholar 

  • Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23:32–40

    PubMed  CAS  Google Scholar 

  • Yamauchi R, Kobayashi M, Matsuda Y, Ojika M, Shigeoka S, Yamamoto Y, Tou Y, Inoue T, Katagiri T, Murai A, Horio F (2010) Coffee and caffeine ameliorate hyperglycemia, fatty liver, and inflammatory adipocytokine expression in spontaneously diabetic KK-Ay mice. J Agric Food Chem 58:5597–5603

    PubMed  CAS  Google Scholar 

  • Yen TT, Gill AM, Frigeri LG, Barsh GS, Wolff GL (1994) Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J 8:479–488

    PubMed  CAS  Google Scholar 

  • Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111–112

    PubMed  CAS  Google Scholar 

  • Zaman AK, Fujii S, Goto D, Furumoto T, Mishima T, Nakai Y, Dong J, Imagawa S, Sobel BE, Kitabatake A (2004) Salutary effects of attenuation of angiotensin II on coronary perivascular fibrosis associated with insulin resistance and obesity. J Mol Cell Cardiol 37:525–535

    PubMed  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Canadian Diabetes Association (CCH), and National Institutes of Health Grants DK059637 (Mouse Metabolic Phenotyping Center; DHW), DK050277 (DHW), and DK054902 (DHW).

Author information

Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, 823 Light Hall, 2215 Garland Ave, Nashville, TN, 37232, USA

    Curtis C. Hughey, David H. Wasserman & Louise Lantier

  2. Mouse Metabolic Phenotyping Center, School of Medicine, Vanderbilt University, 843 Light Hall, 2215 Garland Ave, Nashville, TN, 37232, USA

    David H. Wasserman & Louise Lantier

  3. Cellular and Molecular Metabolism Laboratory, Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004, Australia

    Robert S. Lee-Young

Authors
  1. Curtis C. Hughey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Wasserman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert S. Lee-Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louise Lantier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Curtis C. Hughey.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hughey, C.C., Wasserman, D.H., Lee-Young, R.S. et al. Approach to assessing determinants of glucose homeostasis in the conscious mouse. Mamm Genome 25, 522–538 (2014). https://doi.org/10.1007/s00335-014-9533-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-014-9533-z

Keywords

Search

Navigation