Long-term consequences in offspring of diabetes in pregnancy: studies with syngeneic islet-transplanted streptozotocin-diabetic rats

Abstract

To study the long-term effects of exposure to maternal hyperglycemia and insulin deficiency in utero, we used the syngeneic islet transplanted streptozotocin-diabetic rat model of diabetes in pregnancy and examined insulin secretion and action in 6-month-old offspring. Female rats were rendered diabetic with streptozotocin and then transplanted with 2500, 750, or 500 islets. Control animals were also studied, and one group whose islet transplants failed remained diabetic. During pregnancy, plasma glucose levels in the diabetic rats and the groups receiving 500 and 750 islets were 24.7 +/- 1.0, 15.3 +/- 1.4, and 7.9 +/- 0.5 mmol/liter, respectively, all significantly greater than the control value (5.6 +/- 0.3 mmol/liter; P < 0.05). The plasma glucose level in the 2500 islet group was 6.2 +/- 0.2 mmol/liter, which was not significantly higher than the control value. When the offspring were studied at 6 months, there was no significant difference between groups in either glucose or insulin levels after iv glucose, although acute insulin secretion tended to be higher in the offspring of the diabetic animals. A study of insulin action with the euglycemic clamp at two insulin levels showed that insulin sensitivity was reduced in the offspring of diabetic animals vs. controls (1.97 +/- 0.24 vs. 7.58 +/- 0.95 mumol/liter x 100/kg/min.pmol/liter; P < 0.05). Insulin sensitivity was also significantly reduced in the 2500, 750, and 500 islet group offspring (4.81 +/- 0.57, 4.82 +/- 0.64, and 4.01 +/- 0.63 mumol/liter x 100/kg/min.pmol/liter; P < 0.05) compared to that in the control. There were no differences in insulin sensitivity between male and female animals. In summary, animals displaying maternal insulin deficiency have offspring who are insulin resistant without any evidence of iv glucose intolerance or diminished insulin secretion.

Anti-Islet Autoantibodies Trigger Autoimmune Diabetes in the Presence of an Increased Frequency of Islet-Reactive CD4 T Cells

“…New data have raised the question of whether the epigenetic factor is islet-specific autoantibody transmitted from mother to offspring or altered colonization of the offspring by microbial commensals whose interaction with the innate immune system influences diabetes incidence in NOD mice (44). Furthermore, maternal hyperglycemia can perturb fetal islet development (45), which could affect tolerance to the islets. Evidence against a role for antibodies came from the observation that fortnightly injections of 70 μg purified Ig from diabetic NOD mice could not induce diabetes in B cell–deficient NOD.…”

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

“…The ␤-cell mass is normal, and plasma insulin concentrations are either normal or elevated at 3 mo of age (7,214,217). In vivo and in vitro stimulation of ␤-cells results in an enhanced insulin secretion (7), and these rats are markedly resistant to the actions of insulin (184,214,459). The insulin resistance in the offspring of STZ-induced diabetic rats can be partially restored by near normalization of maternal glycemia with islet transplantation during pregnancy (459).…”

“…In vivo and in vitro stimulation of ␤-cells results in an enhanced insulin secretion (7), and these rats are markedly resistant to the actions of insulin (184,214,459). The insulin resistance in the offspring of STZ-induced diabetic rats can be partially restored by near normalization of maternal glycemia with islet transplantation during pregnancy (459). As in perinatal protein-restricted offspring, the offspring of severely diabetic rats develop signs of glucose intolerance during pregnancy with higher glucose and lower insulin concentrations than normal pregnant rats (214).…”

Early-Life Origins of Type 2 Diabetes: Fetal Programming of the Beta-Cell Mass

“…The multiple lipid and protein abnormalities associated with diabetes may be as important in the induction of fetal abnormalities as hyperglycemia, but they are not replicated by the maternal glucose infusion model. A concern of studies using STZ during pregnancy is the possibility that the toxin might cross the placenta and be directly harmful to the fetal pancreas and other fetal tissues, and thus make any analysis of the long-term effects of hyperglycemia in utero difficult [39]. The problem may be circumvented by giving STZ to female neonates who will later become pregnant: this will result in moderate gestational hyperglycemia [40].…”