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DOI: 10.1055/s-0030-1265163
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Sex Differences in the Development of Diabetes in Mice with Deleted Wolframin (Wfs1) Gene
Publikationsverlauf
received 24.07.2010
first decision 24.07.2010
accepted 26.08.2010
Publikationsdatum:
28. Oktober 2010 (online)

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 30th week and plasma insulin, c-peptide and proinsulin levels were measured at the 32nd week. At the 32nd 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
MissingFormLabel
- 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
MissingFormLabel
- 3
Barrett TG, Bundey SE.
Wolfram (DIDMOAD) syndrome.
J Med Genet.
1997;
34
838-841
MissingFormLabel
- 4
Barrett TG, Bundey SE, Macleod AF.
Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.
Lancet.
1995;
346
1458-1463
MissingFormLabel
- 5
Clark JB, Palmer CJ, Shaw WN.
The diabetic Zucker fatty rat.
Proc Soc Exp Biol Med.
1983;
173
68-75
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 18
Liu S, Mauvais-Jarvis F.
Minireview: Estrogenic protection of beta-cell failure in metabolic diseases.
Endocrinology.
2010;
151
859-864
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 22
Mittendorfer B.
Insulin resistance: sex matters.
Curr Opin Clin Nutr Metab Care.
2005;
8
367-372
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 28
Schalkwyk LC, Fernandes C, Nash MW. et al .
Interpretation of knockout experiments: the congenic footprint.
Genes Brain Behav.
2007;
6
299-303
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
Correspondence
V. Tillmann
Department of Paediatrics
University of Tartu
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Estonia
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eMail: Vallo.tillmann@kliinikum.ee