Skip to main content
SpringerLink
Log in

PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

PWD/PhJ (PWD) is a wild-derived inbred mouse strain unrelated to commonly studied strains, such as C57BL/6J (B6). A chromosome substitution panel with PWD chromosomes transferred into the B6 background is commercially available and will facilitate genetic analysis of this strain. We have previously shown that the PWD strain is a model of primary fasting hyperinsulinemia. To identify more specific phenotypes affected by the genetic variation in PWD compared to B6 mice, we examined physiological mechanisms that may contribute to their elevated insulin levels. PWD mice had increased nutrient-stimulated insulin secretion due to factors inherent to their pancreatic islets. Insulin secretion responses to glucose, palmitate, and the metabolic intermediate α-ketoisocaproate were increased ~2-fold in islets from PWD mice compared to B6 islets. In contrast, there were no strain differences in processes affecting insulin secretion downstream of β cell depolarization. PWD mice tended to have larger but fewer islets than B6 mice, resulting in similar insulin-staining areas and insulin content per unit of pancreatic tissue. However, pancreata of PWD mice were smaller, resulting in reduced total β cell mass and pancreatic insulin content compared to B6 mice. Combined, these data suggest that the elevated fasting insulin levels in PWD mice result from increased generation of metabolic signals leading to β cell depolarization and insulin secretion. Identification of the genetic differences underlying the enhanced nutrient-stimulated insulin secretion in this model may lead to new approaches to appropriately modulate insulin secretion for the treatment of obesity and type 2 diabetes.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alejandro EU, Lim GE, Mehran AE, Hu X, Taghizadeh F, Pelipeychenko D, Baccarini M, Johnson JD (2011) Pancreatic β-cell Raf-1 is required for glucose tolerance, insulin secretion, and insulin 2 transcription. FASEB J 25:3884–3895

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alemzadeh R, Jacobs W, Pitukcheewanont P (1996) Antiobesity effect of diazoxide in obese Zucker rats. Metabolism 45:334–341

    Article  CAS  PubMed  Google Scholar 

  • Chu KY, Lin Y, Hendel A, Kulpa JE, Brownsey RW, Johnson JD (2010) ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells. J Biol Chem 285:32606–32615

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Clee SM, Attie AD (2007) The genetic landscape of type 2 diabetes in mice. Endocr Rev 28:48–83

    Article  CAS  PubMed  Google Scholar 

  • Clee SM, Yandell BS, Schueler KM, Rabaglia ME, Richards OC, Raines SM, Kabara EA, Klass DM, Mui ET, Stapleton DS, Gray-Keller MP, Young MB, Stoehr JP, Lan H, Boronenkov I, Raess PW, Flowers MT, Attie AD (2006) Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38:688–693

    Article  CAS  PubMed  Google Scholar 

  • Dankner R, Chetrit A, Shanik MH, Raz I, Roth J (2009) Basal-state hyperinsulinemia in healthy normoglycemic adults is predictive of type 2 diabetes over a 24-year follow-up: a preliminary report. Diabetes Care 32:1464–1466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA (1994) Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia 37:1025–1035

    Article  CAS  PubMed  Google Scholar 

  • Didion JP, de Villena FP (2013) Deconstructing Mus gemischus: advances in understanding ancestry, structure, and variation in the genome of the laboratory mouse. Mamm Genome 24:1–20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dror V, Kalynyak TB, Bychkivska Y, Frey MH, Tee M, Jeffrey KD, Nguyen V, Luciani DS, Johnson JD (2008) Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells. J Biol Chem 283:9909–9916

    Article  CAS  PubMed  Google Scholar 

  • El-Azzouny M, Evans CR, Treutelaar MK, Kennedy RT, Burant CF (2014) Increased glucose metabolism and glycerolipid formation by fatty acids and GPR40 receptor signaling underlies the fatty acid potentiation of insulin secretion. J Biol Chem 289:13575–13588

    Article  CAS  PubMed  Google Scholar 

  • Frazer KA, Eskin E, Kang HM, Bogue MA, Hinds DA, Beilharz EJ, Gupta RV, Montgomery J, Morenzoni MM, Nilsen GB, Pethiyagoda CL, Stuve LL, Johnson FM, Daly MJ, Wade CM, Cox DR (2007) A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448:1050–1053

    Article  CAS  PubMed  Google Scholar 

  • Geraldes A, Basset P, Gibson B, Smith KL, Harr B, Yu HT, Bulatova N, Ziv Y, Nachman MW (2008) Inferring the history of speciation in house mice from autosomal, X-linked, Y-linked and mitochondrial genes. Mol Ecol 17:5349–5363

    Article  PubMed Central  PubMed  Google Scholar 

  • Gregorova S, Forejt J (2000) PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies—a valuable resource of phenotypic variations and genomic polymorphisms. Folia Biol (Praha) 46:31–41

    CAS  Google Scholar 

  • Gregorova S, Divina P, Storchova R, Trachtulec Z, Fotopulosova V, Svenson KL, Donahue LR, Paigen B, Forejt J (2008) Mouse consomic strains: exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies. Genome Res 18:509–515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Henquin JC (2011) The dual control of insulin secretion by glucose involves triggering and amplifying pathways in beta-cells. Diabetes Res Clin Pract 93(Suppl 1):S27–S31

    Article  CAS  PubMed  Google Scholar 

  • Henquin JC, Nenquin M, Ravier MA, Szollosi A (2009) Shortcomings of current models of glucose-induced insulin secretion. Diabetes Obes Metab 11(Suppl 4):168–179

    Article  CAS  PubMed  Google Scholar 

  • Ho MM, Hu X, Karunakaran S, Johnson JD, Clee SM (2014) Altered pancreatic growth and insulin secretion in WSB/EiJ Mice. PLoS ONE 9:e88352

    Article  PubMed Central  PubMed  Google Scholar 

  • Ishikawa M, Pruneda ML, Adams-Huet B, Raskin P (1998) Obesity-independent hyperinsulinemia in nondiabetic first-degree relatives of individuals with type 2 diabetes. Diabetes 47:788–792

    Article  CAS  PubMed  Google Scholar 

  • Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD (2008) Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci USA 105:8452–8457

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kanety H, Moshe S, Shafrir E, Lunenfeld B, Karasik A (1994) Hyperinsulinemia induces a reversible impairment in insulin receptor function leading to diabetes in the sand rat model of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 91:1853–1857

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furlotte NA, Eskin E, Nellaker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard TG, Oliver PL, McIntyre RE, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward CA, Bala S, Stalker J, Mott R, Durbin R, Jackson IJ, Czechanski A, Guerra-Assuncao JA, Donahue LR, Reinholdt LG, Payseur BA, Ponting CP, Birney E, Flint J, Adams DJ (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477:289–294

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Keller MP, Choi Y, Wang P, Davis DB, Rabaglia ME, Oler AT, Stapleton DS, Argmann C, Schueler KL, Edwards S, Steinberg HA, Chaibub Neto E, Kleinhanz R, Turner S, Hellerstein MK, Schadt EE, Yandell BS, Kendziorski C, Attie AD (2008) A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res 18:706–716

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Komatsu M, Takei M, Ishii H, Sato Y (2013) Glucose-stimulated insulin secretion: a newer perspective. J Diabetes Investig 4:511–516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laedtke T, Kjems L, Porksen N, Schmitz O, Veldhuis J, Kao PC, Butler PC (2000) Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes. Am J Physiol Endocrinol Metab 279:E520–E528

    CAS  PubMed  Google Scholar 

  • Lee KT, Karunakaran S, Ho MM, Clee SM (2011) PWD/PhJ and WSB/EiJ mice are resistant to diet-induced obesity but have abnormal insulin secretion. Endocrinology 152:3005–3017

    Article  CAS  PubMed  Google Scholar 

  • Matsuda M, Kawasaki F, Mikami Y, Takeuchi Y, Saito M, Eto M, Kaku K (2002) Rescue of beta-cell exhaustion by diazoxide after the development of diabetes mellitus in rats with streptozotocin-induced diabetes. Eur J Pharmacol 453:141–148

    Article  CAS  PubMed  Google Scholar 

  • Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, Botezelli JD, Asadi A, Hoffman BG, Kieffer TJ, Bamji SX, Clee SM, Johnson JD (2012) Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 16:723–737

    Article  CAS  PubMed  Google Scholar 

  • Misler S, Gee WM, Gillis KD, Scharp DW, Falke LC (1989) Metabolite-regulated ATP-sensitive K+ channel in human pancreatic islet cells. Diabetes 38:422–427

    Article  CAS  PubMed  Google Scholar 

  • Mott R (2007) A haplotype map for the laboratory mouse. Nat Genet 39:1054–1056

    Article  CAS  PubMed  Google Scholar 

  • Odeleye OE, de Courten M, Pettitt DJ, Ravussin E (1997) Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 46:1341–1345

    Article  CAS  PubMed  Google Scholar 

  • Petkov PM, Ding Y, Cassell MA, Zhang W, Wagner G, Sargent EE, Asquith S, Crew V, Johnson KA, Robinson P, Scott VE, Wiles MV (2004) An efficient SNP system for mouse genome scanning and elucidating strain relationships. Genome Res 14:1806–1811

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pratley RE, Weyer C (2001) The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus. Diabetologia 44:929–945

    Article  CAS  PubMed  Google Scholar 

  • Prentki M, Matschinsky FM, Madiraju SR (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18:162–185

    Article  CAS  PubMed  Google Scholar 

  • Rabaglia ME, Gray-Keller MP, Frey BL, Shortreed MR, Smith LM, Attie AD (2005) Alpha-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice. Am J Physiol Endocrinol Metab 289:E218–E224

    Article  CAS  PubMed  Google Scholar 

  • Salvalaggio PR, Deng S, Ariyan CE, Millet I, Zawalich WS, Basadonna GP, Rothstein DM (2002) Islet filtration: a simple and rapid new purification procedure that avoids ficoll and improves islet mass and function. Transplantation 74:877–879

    Article  CAS  PubMed  Google Scholar 

  • Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J (2008) Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care 31(Suppl 2):S262–S268

    Article  CAS  PubMed  Google Scholar 

  • Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR, O’Brien W, Courtland HW, Jepsen KJ, Kirby A, Kulbokas EJ, Daly MJ, Broman KW, Lander ES, Nadeau JH (2008) Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA 105:19910–19914

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O’Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304:445–448

    Article  CAS  PubMed  Google Scholar 

  • Sudbery I, Stalker J, Simpson JT, Keane T, Rust AG, Hurles ME, Walter K, Lynch D, Teboul L, Brown SD, Li H, Ning Z, Nadeau JH, Croniger CM, Durbin R, Adams DJ (2009) Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels. Genome Biol 10:R112

    Article  PubMed Central  PubMed  Google Scholar 

  • Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta-cells. Pflug Arch 407:493–499

    Article  CAS  Google Scholar 

  • Utzschneider KM, Prigeon RL, Carr DB, Hull RL, Tong J, Shofer JB, Retzlaff BM, Knopp RH, Kahn SE (2006) Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care 29:356–362

    Article  PubMed  Google Scholar 

  • van Boekel G, Loves S, van Sorge A, Ruinemans-Koerts J, Rijnders T, de Boer H (2008) Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression. Diabetes Obes Metab 10:1195–1203

    PubMed  Google Scholar 

  • Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53(Suppl 3):S16–S21

    Article  CAS  PubMed  Google Scholar 

  • Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE (2000) A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 49:2094–2101

    Article  CAS  PubMed  Google Scholar 

  • Zavaroni I, Bonini L, Gasparini P, Barilli AL, Zuccarelli A, Dall’Aglio E, Delsignore R, Reaven GM (1999) Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited. Metabolism 48:989–994

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Jetton TL, Goshorn S, Lynch CJ, She P (2010) Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion. J Biol Chem 285:33718–33726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Xiaoke Hu for her assistance with the perifusion studies and Subashini Karunakaran for assistance with maintaining the animal colony. Funding for these studies was provided by the Heart and Stroke Foundation of BC and the Yukon. SMC is a Michael Smith Foundation for Health Research Career Investigator and Canada Research Chair in the Genetics of Obesity and Diabetes.

Author information

Authors and Affiliations

  1. Diabetes Research Group, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    Maggie M. Ho, James D. Johnson & Susanne M. Clee

  2. Diabetes Research Group, Department of Surgery, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada

    James D. Johnson

Authors
  1. Maggie M. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James D. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanne M. Clee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susanne M. Clee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ho, M.M., Johnson, J.D. & Clee, S.M. PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion. Mamm Genome 26, 131–141 (2015). https://doi.org/10.1007/s00335-015-9554-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-015-9554-2

Keywords

Search

Navigation