Maternal diabetes impairs gastrulation and insulin and IGF-I receptor expression in rabbit blastocysts.
Women with type 1 diabetes are subfertile. Diabetes negatively affects pregnancy by causing early miscarriage and poor prenatal outcomes. In this study we examine consequences of maternal type 1 diabetes on early embryo development, metabolic gene expression, and the pattern of insulin receptor (IR) and IGF-I receptor (IGF-IR) distribution in rabbit blastocysts. In female rabbits, type 1 diabetes was induced by alloxan treatment. Six-day-old blastocysts were recovered and assessed for receptor distribution and metabolic gene expression. In vitro culture of blastocysts was performed in medium containing 1 mm, 10 mm, or 25 mm glucose, simulating normo- and hyperglycemic developmental condition in vitro. The fertility rate of the diabetic rabbits clearly mirrored subfertility with a drop in blastocyst numbers by 40% (13.3 blastocysts in diabetic vs. 21.9 in control females). In blastocysts onset and progression of gastrulation was delayed and expression of IR and IGF-IR and their metabolic target genes (hexokinase, phosphoenolpyruvate carboxykinase), both in vivo and in vitro, was down-regulated. The amount of apoptotic cells in the embryonic disc was increased, correlating closely with the reduced transcription of the bcl-x(L) gene. Blastocyst development is clearly impaired by type 1 diabetes during early pregnancy. Insulin-stimulated metabolic genes and IR and IGF-IR are down-regulated, resulting in reduced insulin and IGF sensitivity and a delay in development. Dysregulation of the IGF system and embryonic glucose metabolism are potential reasons for diabetogenous subfertility and embryopathies and start as soon as during the first days of life.
Ramin
Nicole
N
Department of Anatomy and Cell Biology, Martin Luther University Faculty of Medicine, Grosse Steinstrasse 52, D-06097 Halle (Saale), Germany.
Thieme
René
R
Fischer
Sünje
S
Schindler
Maria
M
Schmidt
Thomas
T
Fischer
Bernd
B
Navarrete Santos
Anne
A
D000496:Alloxan; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D054262:Gastrulation / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000097:blood / Q000503:physiopathology; D011817:Rabbits; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D007328:Insulin; D000496:Alloxan; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019764:Phosphoenolpyruvate Carboxykinase (ATP)