Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat.

Buchanan, Thomas A.; Schemmer, J K; Freinkel, Norbert

doi:10.1172/jci112622

Cited by 97 publications

(32 citation statements)

References 46 publications

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“…The potential consequences of placental transfer include the risk of neonatal hyperinsulinemia and hypoglycemia. Animal studies suggest that hypoglycemia may cause teratogenesis (12). There has been a recent report of congenital anomalies in the off-spring of two women taking insulin lispro throughout pregnancy, despite optimal glycemic control (13).…”

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confidence: 99%

Transfer of Insulin Lispro Across the Human Placenta

et al. 2003

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OBJECTIVE—Insulin lispro (Humalog), a human insulin analog, has a more rapid onset, earlier peak, and shorter duration of glucose lowering activity than regular human insulin. However, it is not known whether insulin lispro crosses the human placenta and reaches the fetus. Therefore, the objective of the present study was to examine whether insulin lispro crosses the placenta using the technique of perfusing a human placental lobule in vitro. RESEARCH DESIGN AND METHODS—Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. Insulin lispro, at concentrations ranging from 100 to 1000 μU/ml, was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of lispro insulin; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of insulin lispro in the fetal circulation was analyzed by a specific radioimmunoassay. RESULTS—No placental transfer of lispro could be detected during perfusion with 100 and 200 μU/ml. In contrast, there was a small concentration-dependent transfer to the fetus at concentrations of 580 μU/ml and higher, detectable after at least an hour of constant concentration of insulin lispro during perfusion. The rate of placental transfer was 0.019 μU · min−1 · g tissue−1 at maternal levels of 580 μU/ml and 0.045 μU · min−1 · g−1 tissue at maternal levels of 1000 μU/ml. Measuring lispro levels in 11 pregnant women revealed that a dose of 50 units may achieve serum concentrations >200 μU/ml with apparent linear correlation between dose and levels. CONCLUSIONS—Insulin lispro is not likely to cross the placenta at a single standard dose. This study suggests that insulin lispro is unlikely to reach or harm the unborn baby.

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confidence: 99%

Transfer of Insulin Lispro Across the Human Placenta

et al. 2003

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“…It has been suggested that this may explain why the incidence of macrosomia continues to be increased, despite excellent HbA 1c levels throughout pregnancy (5,6). From animal studies (in rodents), there is strong evidence that hypoglycemia occurring early in gestation might be teratogenic (7,8).…”

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confidence: 99%

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

et al. 2002

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OBJECTIVES -To investigate the frequency of severe hypoglycemia (SH) and hypoglycemic coma during the first trimester of type 1 diabetic pregnancy and in the 4 months before gestation and to identify risk indicators predicting first trimester SH in a nonselected nationwide cohort of pregnant women with type 1 diabetes.RESEARCH DESIGN AND METHODS -We conducted a longitudinal cohort survey in 278 pregnant type 1 diabetic women using questionnaires at inclusion and at 17 weeks of gestation, addressing the frequencies of SH (i.e., external help required) and hypoglycemic coma, general characteristics, hypoglycemia awareness, blood glucose symptom threshold, and the Hypoglycemia Fear Survey.RESULTS -The occurrence of SH (including hypoglycemic coma) rose from 0.9 Ϯ 2.4 episodes per 4 months before gestation to 2.6 Ϯ 6.3 episodes during the first trimester (P Ͻ 0.001), including an increase in episodes of coma from 0.3 Ϯ 1.3 to 0.7 Ϯ 3.7 (P ϭ 0.03). The proportion of women affected by SH rose from 25 to 41% (P Ͻ 0.001). First-trimester SH was independently related to a history of SH before gestation (odds ratio CONCLUSIONS -In type 1 diabetic pregnancy, the risk of SH is increased already before pregnancy and rises further during the first trimester. A history of SH before gestation, longer duration of diabetes, an HbA 1c level Յ6.5%, and a higher total daily insulin dose were risk indicators predictive for SH during the first trimester. Further research should aim to elucidate how the benefits of strict glycemic control balance with the markedly increased risk of SH early in pregnancy.[ Diabetes Care 25:554 -559, 2002

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“…Low maternal glucose levels, which can result from stringent metabolic control of pregnant diabetic women (23), have also been suggested, on the basis of studies with pregnant animals and embryo cultures (24,27), to adversely affect development. The results reported here show that low glucose levels, like high levels, directly impair the biosynthesis of sulfated proteoglycans in developing cartilage and are thus potentially teratogenic.…”

Section: Discussionmentioning

confidence: 99%

“…However, stringent metabolic control of insulin-treated diabetic women during pregnancy may expose patients to frequent hypoglycemia (23), which is also of concern as a risk factor in fetal development (15,24). Experimental studies of pregnant animals, and embryos in organ culture, indicate teratogenic consequences of both hyper- (10,25,26) and hypoglycemia (15,16,27,28).…”

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confidence: 99%

Abnormal ambient glucose levels inhibit proteoglycan core protein gene expression and reduce proteoglycan accumulation during chondrogenesis: possible mechanism for teratogenic effects of maternal diabetes.

Leonard

Bergman²,

Frenz³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Using a tissue culture system based on a nearly pure population of avian precartilage mesenchymal cells, we have found that ambient glucose levels as little as 50% lower, or 100% higher, than normally present in embryonic sera are deleterious to cartilage development, as measured by the accumulation of highly sulfated proteoglycan and the corresponding cartilage-specific chondroitin sulfate core protein mRNA. Abnormal glucose concentrations in the ranges studied did not selectively influence cell replication, and the effects on chondrogenesis were not due to differences in overall protein synthesis or glucose utilization in the treatment groups. Core protein gene expression was more severely affected than accumulation of extracellular product, suggesting the existence of posttranscriptional compensatory mechanisms. The sensitivity to ambient glucose levels of both expression of the cartilage-specific chondroitin sulfate core protein gene and the accumulation of the corresponding extracellular matrix macromolecules during chondrogenesis suggest a molecular mechanism for the well-known adverse effect of maternal diabetes on embryonic skeletogenesis. The results further suggest that hypoglycemia resulting from stringent control of diabetes may also be deleterious to skeletal development.

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Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat.

Cited by 97 publications

References 46 publications

Transfer of Insulin Lispro Across the Human Placenta

Transfer of Insulin Lispro Across the Human Placenta

Risk Indicators Predictive for Severe Hypoglycemia During the First Trimester of Type 1 Diabetic Pregnancy

Abnormal ambient glucose levels inhibit proteoglycan core protein gene expression and reduce proteoglycan accumulation during chondrogenesis: possible mechanism for teratogenic effects of maternal diabetes.

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