Sex Differences in the Development of Diabetes in Mice with Deleted Wolframin (Wfs1) Gene

Abstract

Wolfram syndrome, caused by mutations in the wolframin (Wfs1) gene, is characterised by juvenile-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus and deafness. Diabetes tend to start earlier in boys. This study investigated sex differences in longitudinal changes in blood glucose concentration (BGC) in wolframin-deficient mice (Wfs1KO) and compared their plasma proinsulin and insulin levels with those of wild-type (wt) mice. Non-fasting BGC was measured weekly in 42 (21 males) mice from both groups at nine weeks of age. An intraperitoneal glucose tolerance test (IPGTT) was conducted at the 30^th week and plasma insulin, c-peptide and proinsulin levels were measured at the 32^nd week. At the 32^nd week, Wfs1KO males had increased BGC compared to wt males (9.40±0.60 mmol/l vs. 7.91±0.20 mmol/l; p<0.05). The opposite tendency was seen in females. Both male and female Wfs1KO mice had impaired glucose tolerance on IPGTT. Wfs1KO males had significantly lower mean plasma insulin levels than wt males (57.78±1.80 ng/ml vs. 69.42±3.06 ng/ml; p<0.01) and Wfs1KO females (70.30±4.42 ng/ml; p<0.05). Wfs1KO males had a higher proinsulin/insulin ratio than wt males (0.09±0.02 vs. 0.05±0.01; p=0.05) and Wfs1KO females (0.04±0.01; p<0.05). Plasma c-peptide levels in males were lower in Wfs1KO males (mean 55.3±14.0 pg/ml vs. 112.7±21.9 pg/ml; p<0.05). Male Wfs1KO mice had a greater risk of developing diabetes than female Wfs1KO mice. Low plasma insulin concentration with an increased proinsulin/insulin ratio in Wfs1KO males indicates possible disturbances in converting proinsulin to insulin which in long-term may lead to insulin deficiency. Further investigation is needed to clarify the mechanism for the sex differences in the development of diabetes in Wolfram syndrome.

Key words

Wolfram syndrome - diabetes - Wfs1 - proinsulin

References

• 1 Akiyama M, Hatanaka M, Ohta Y. et al . Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice.  Diabetologia. 2009;  52 653-663
• 2 Alonso-Magdalena P, Ropero AB, Carrera MP. et al . Pancreatic insulin content regulation by the estrogen receptor ER alpha.  PLoS One. 2008;  3 e2069
• 3 Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome.  J Med Genet. 1997;  34 838-841
• 4 Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.  Lancet. 1995;  346 1458-1463
• 5 Clark JB, Palmer CJ, Shaw WN. The diabetic Zucker fatty rat.  Proc Soc Exp Biol Med. 1983;  173 68-75
• 6 Contreras JL, Smyth CA, Bilbao G. et al . 17Beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality.  Transplantation. 2002;  74 1252-1259
• 7 Eckhoff DE, Eckstein C, Smyth CA. et al . Enhanced isolated pancreatic islet recovery and functionality in rats by 17beta-estradiol treatment of brain death donors.  Surgery. 2004;  136 336-345
• 8 Eckhoff DE, Smyth CA, Eckstein C. et al . Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction.  Surgery. 2003;  134 169-179
• 9 Franks PW, Rolandsson O, Debenham SL. et al . Replication of the association between variants in WFS1 and risk of type 2 diabetes in European populations.  Diabetologia. 2008;  51 458-463
• 10 Gabreels BA, Swaab DF, de Kleijn DP. et al . The vasopressin precursor is not processed in the hypothalamus of Wolfram syndrome patients with diabetes insipidus: evidence for the involvement of PC2 and 7B2.  J Clin Endocrinol Metab. 1998;  83 4026-4033
• 11 Hardy C, Khanim F, Torres R. et al . Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.  Am J Hum Genet. 1999;  65 1279-1290
• 12 Ishihara H, Takeda S, Tamura A. et al . Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion.  Hum Mol Genet. 2004;  13 1159-1170
• 13 Koks S, Soomets U, Paya-Cano JL. et al . Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway.  Physiol Genomics. 2009;  37 249-259
• 14 Kuhl J, Hilding A, Ostenson CG. et al . Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm Diabetes Prevention Programme: the impact of sex and type 2 diabetes heredity.  Diabetologia. 2005;  48 35-40
• 15 Le May C, Chu K, Hu M. et al . Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice.  Proc Natl Acad Sci USA. 2006;  103 9232-9237
• 16 Li AC, Brown KK, Silvestre MJ. et al . Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice.  J Clin Invest. 2000;  106 523-531
• 17 Liu S, Le May C, Wong WP. et al . Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival.  Diabetes. 2009;  58 2292-2302
• 18 Liu S, Mauvais-Jarvis F. Minireview: Estrogenic protection of beta-cell failure in metabolic diseases.  Endocrinology. 2010;  151 859-864
• 19 Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models.  Curr Atheroscler Rep. 2004;  6 180-185
• 20 Macotela Y, Boucher J, Tran TT. et al . Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism.  Diabetes. 2009;  58 803-812
• 21 Medlej R, Wasson J, Baz P. et al . Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population.  J Clin Endocrinol Metab. 2004;  89 1656-1661
• 22 Mittendorfer B. Insulin resistance: sex matters.  Curr Opin Clin Nutr Metab Care. 2005;  8 367-372
• 23 Noormets K, Koks S, Kavak A. et al . Male mice with deleted Wolframin (Wfs1) gene have reduced fertility.  Reprod Biol Endocrinol. 2009;  7 82
• 24 Peden NR, Gay JD, Jung RT. et al . Wolfram (DIDMOAD) syndrome: a complex long-term problem in management.  Q J Med. 1986;  58 167-180
• 25 Pick A, Clark J, Kubstrup C. et al . Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat.  Diabetes. 1998;  47 358-364
• 26 Riggs AC, Bernal-Mizrachi E, Ohsugi M. et al . Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis.  Diabetologia. 2005;  48 2313-2321
• 27 Sandhu MS, Weedon MN, Fawcett KA. et al . Common variants in WFS1 confer risk of type 2 diabetes.  Nat Genet. 2007;  39 951-953
• 28 Schalkwyk LC, Fernandes C, Nash MW. et al . Interpretation of knockout experiments: the congenic footprint.  Genes Brain Behav. 2007;  6 299-303
• 29 Smith CJ, Crock PA, King BR. et al . Phenotype-genotype correlations in a series of wolfram syndrome families.  Diabetes Care. 2004;  27 2003-2009
• 30 Soliman AT, Bappal B, Darwish A. et al . Growth hormone deficiency and empty sella in DIDMOAD syndrome: an endocrine study.  Arch Dis Child. 1995;  73 251-253
• 31 Sparso T, Andersen G, Albrechtsen A. et al . Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation.  Diabetologia. 2008;  51 1646-1652
• 32 Zhu M, Mizuno A, Kuwajima M. et al . Ovarian hormone-induced beta-cell hypertrophy contributes to the homeostatic control of beta-cell mass in OLETF female rat, a model of Type II diabetes.  Diabetologia. 1998;  41 799-805
• 33 Zierath JR, Houseknecht KL, Gnudi L. et al . High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect.  Diabetes. 1997;  46 215-223

Correspondence