Maternal Factors in a Model of Type 1 Diabetes Differentially Affect the Development of Insulitis and Overt Diabetes in Offspring

Abstract

Type 1 diabetes, a multifactorial disease involving genetic and environmental factors, results from the destruction of pancreatic ␤-cells. The maternal environment has been suggested to be important in the development of diabetes. To assess the role of maternal factors in the development of insulitis and overt diabetes, we transplanted pre-implantation stage embryos of nonobese diabetic (NOD) mice, a model of type 1 diabetes, into the uterus of each recipient. Recipients were ICR and DBA/2J mice without diabetic genetic predisposition and NOD mice not exhibiting overt diabetes during the experiment; offspring were designated as NOD/ICR, NOD/DBA, and NOD/NOD, respectively; unmanipulated NOD offspring were also examined. NOD/ICR and NOD/ DBA offspring developed insulitis significantly earlier than NOD/NOD offspring. However, overt diabetes was significantly suppressed in NOD/ICR and NOD/DBA offspring in comparison with NOD/NOD offspring. Insulin autoantibodies (IAAs) were undetectable in ICR and DBA/2J surrogate mothers and in NOD/ICR and NOD/ DBA offspring at the onset of insulitis, suggesting that maternal factors other than transmitted IAAs induced the earlier onset. The present study indicates that altered maternal factors modify the immune response to islets, which in turn might affect the pathogenic course from insulitis to overt diabetes. Diabetes 54:2026 -2031, 2005 H uman type 1 diabetes is characterized by the establishment of autoimmune insulitis, which precedes ␤-cell destruction, culminating in hypoinsulinemia and hyperglycemia. Human type 1 diabetic patients spontaneously develop a diabetic syndrome that is controlled by both genetic and environmental factors (1,2). The environmental triggers of islet autoimmunity and type 1 diabetes are essentially unknown but are considered likely to operate early in life, possibly even in utero (3). Previous studies have linked the risk of type 1 diabetes to congenital rubella infection, but noncongenital infection does not appear to convey this risk, indicating the importance of pre-or perinatal events as triggers of islet autoimmunity (4 -6). It has been suggested that maternal environment and maternally transmitted insulin autoantibodies (IAAs) in particular modify the risk of the development of autoimmune diabetes in offspring (7); however, it was recently reported (8) that fetal exposure to IAAs did not increase the risk of diabetes development in nonobese diabetic (NOD) mice. The exact role of maternal environmental factors and their relationship in the initiation and modification of the pathogenesis of diabetes in each diabetic individual remain largely unknown. In our previous study (9), by transplanting NOD embryos into the uterus of a recipient ICR mouse, we analyzed genetic predisposition versus diabetic environment and the interaction between these two factors in NOD embryos as causes of congenital malformation.In the present study, using the same experimental strategy, the onset and incidence of insulitis and overt diabetes were examined in offspring ...

In utero undernutrition reduces diabetes incidence in non-obese diabetic mice

“…Restriction of energy intake increases circulating corticosterone levels, which in turn enhances negative selection of potentially autoreactive CD4-CD8 cells in thymus [48]. Maternal undernutrition during gestation may also decrease transplacental transmission of islet antibodies, a process which can also contribute to diabetes in NOD mice [49]. While our experiment showed a significant effect of intrauterine undernutrition on the degree of insulitis in NOD mice, suggesting that immune responses are altered in our low-birthweight model, we did not measure anti-islet antibodies, corticosterone, lymphocyte numbers or activity, or cytokines.…”

Can maternal microchimeric cells influence the fetal response toward self antigens?

“…This was not the case when another maternal background like DBA/2 or ICR non-diabetes prone mice was used. 38 Moreover, NOD progeny from NOD mothers deficient in B cells or in B and/or T cells failed to develop diabetes supporting the possibility that maternal T and potentially B cells acquired during pregnancy and lactation might play a role in the development of auto-immune diabetes. 39 These data suggest that the maternal environment during fetal life can play a role in offspring's immunity later in life.…”

Phenotypes of IRS-2 Deficient Mice Produced by Reproductive Technology are Stable

“…It was reported that the change in immune response brought about by maternal environment involving pseudo-pregnant recipients and surrogate mothers induced this difference of progression to diabetes [6]. In addition, Greeley et al (2002) reported that NOD offspring implanted in mothers of a nonautoimmune strain were protected from spontaneous diabetes [4].…”

“…Onset of diabetes in non-obese diabetic (NOD) mice produced by embryonic transfer and surrogate nursing by ICR and DBA/2J strain mice was significantly suppressed in comparison with mice produced from pseudo-pregnant recipients and surrogate mothers using NOD mice [6]. It was reported that the change in immune response brought about by maternal environment involving pseudo-pregnant recipients and surrogate mothers induced this difference of progression to diabetes [6].…”

“…The B6J-Irs2 -/-mice in this case were produced by IVF -ET [5]. Phenotypes of NOD/shi mice, a type 1 diabetes model, were affected by pseudo-pregnant recipients and surrogate mothers used in reproductive technology [6]. It has been suggested that adiponectin improves the insulin resistance of IRS-1 in muscles and IRS-2 in liver via PPARα or AMP kinase [22,23].…”