Evidence for the Impermeability of the Human Placenta for Insulin

Wolf, Hans; Sabata, V; Frerichs, H.; Stubbe, P

doi:10.1055/s-0028-1095127

Cited by 38 publications

(9 citation statements)

References 2 publications

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“…The findings of Buse et al. (18), Wolf et al (19), and Spellacy et al (20) also indicate that the placenta represents a substantial barrier to the transport of insulin in humans. On the other hand, the possibility that the placenta may not be completely impermeable to insulin in the rat (21) as well as in other species (22)(23)(24) has been suggested by other investigators.…”

Section: Methodsmentioning

confidence: 93%

Peripheral metabolism of insulin, proinsulin, and C-peptide in the pregnant rat.

Katz¹,

Lindheimer²,

Mako³

et al. 1975

J. Clin. Invest.

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AB ST R A CT To clarify alterations in carbohydrate metabolismI whllich occuir in pregnancy, metabolic clearance rates of insulin, proinsulin, and C-peptide were measured by the constant infusion technique in term-pregnant rats and in virgin littermates. In addition, placental permeability to these peptides was evaluated by simultaneous determination of their conicentration in fetal blood, amniiotic fluid, and maternal arterial blood, and the renal extraction and excretion of insulin and C-peptide were determined duiring simuitiltaneotus studies of renal hemodynamics.The metabolic clearance rate (MICR) of insulin was higher (P <0.005) in pregnant animals (61.5±+1.7 ml/ min per kg nonconceptus body weiglht) than in virgin littermates (51.5±2.2 ml/nmin per kg). Insulin disappearance from the circulatioin after both single injection and discontinuance of a coinstant infusion Nas also faster in gravid animals. In contrast, the AICR of proinsulin and C-peptide, anid the disappearance of C-peptide from the circulation were siimilar in pregnanlt and cointrol rats. The placenta was virtually impermiieable to each of the three polypeptides since their mean levels in both fetal blood and amniotic fluid did not exceed 2.5 ng/ml and were only minimally iinflueinced by pharmacological concentrations as high as 60 ng,jml in the maternal circula- These results indicate that the peripheral metabolism of insulini is accelerated in pregnancy, while that of proinsulin and C-peptide is unaffected. Since transplacenital passage of insulin is negligible and its renal clearanice is not increased, the enhanced MCR of insulin in pregnancy is due to increased metabolism at an extrarenal site probably within the placenta itself.

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Section: Methodsmentioning

confidence: 93%

Peripheral metabolism of insulin, proinsulin, and C-peptide in the pregnant rat.

Katz¹,

Lindheimer²,

Mako³

et al. 1975

J. Clin. Invest.

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“…For example, insulin added to the culture of embryonic cells from 8.5-day-old embryo stimulates their proliferation (29). Because maternal insulin does not cross the placental barrier (34,35), synthesis of embryonic insulin might be necessary for cell growth and differentiation of neural and, possibly, other embryonic tissues before appearance of the endocrine pancreas.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo.

Deltour

Leduque

Blume

et al. 1993

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

187

146

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In the mouse, insulin is produced from two similar but nonallelic genes that encode proinsulins I and II. We have investigated expression of these two genes during mouse embryonic development, using a PCR to detect the two gene transcripts and immunocytochemistry to visualize the two corresponding proteins. At appearance of the dorsal pancreatic anlage at day 9.5 of gestation, both mRNAs could be detected in the embryos, and both proteins were present together in the same cells of the developing pancreas. At days 9.5 and 10.5, when the ventral anlage appears, there were fewer proinsulin H mRNAs than proinsulin I mRNAs. At day 12.5 this ratio was reversed. Proinsulin II mRNA, but not proinsulin I mRNA, could be detected at day 8.5 in the prepancreatic embryo. Proinsulin II mRNA, but not proinsulin I mRNA, was also found in the heads of embryos at day 9.5 and at all later stages studied. These results indicate that the two proinsulin genes are regulated independently, at least in part. They also suggest that insulin might play a role as a growth factor in the developing mouse brain.Insulin, a key hormone in metabolic homeostasis, is synthesized, stored, and secreted by beta cells of the pancreatic islets. The protein is synthetized in the form of a precursor, preproinsulin, which is highly conserved among animal species. Unlike most mammals, mice and rats express two nonallelic genes that encode proinsulins I and II. In the mouse these two proteins differ by two amino acids in the B chain and three amino acids in the C peptide. Mouse C peptide I also lacks the Gly-Ala residues present in positions 17 and 18 of C peptide 11(1, 2). The corresponding genes in mouse and rat are highly homologous, and their organization is similar, except that the preproinsulin I gene possesses only the first of two introns present in the preproinsulin II gene (1, 3).On previous studies concerning the regulation of these two nonallelic genes, mRNAs were reported to be present in nearly equal quantities in adult pancreas of mouse (1, 4), as well as of rat (5) Here we have investigated regulation of the expression of the two proinsulin genes during mouse development. In the mouse, the pancreas is derived from the duodenum as two evaginations evolving at days 9.5 (dorsal) and 10.5 (ventral) of the gestation. The evaginations coalesce at day 11, and insulin has been first detected in previous studies at day 11.5 (9, 10). We have used a reverse-transcriptase-PCR (RT-PCR) assay, which allows identification and estimation of the relative amounts of mRNA transcribed from each of the two proinsulin genes. This RT-PCR, using a single pair ofprimers and a single probe for the two transcripts, allowed comparison of the relative amounts of proinsulin I and II mRNAs in the samples (11). Immunocytochemistry with antibodies specific for each of the two proinsulins allowed us to distinguish the products of the two genes in embryo sections. We have, thus, been able to detect insulin mRNAs and proteins much earlier, to distinguish the two forms, ...

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“…Since insulin does not cross the placenta, 46 insulin is not acting in this third space during euglycemic insulin clamp studies. If significant amounts of glucose were being utilized in this space, glucose disposal rates would be increased during the clamp studies, whereas our findings were of decreased glucose disposal.…”

Section: Discussionmentioning

confidence: 99%

Insulin Action During Pregnancy: Studies with the Euglycemic Clamp Technique

Ryan

OʼSullivan²,

Skyler³

1985

Diabetes

281

116

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To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.

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Evidence for the Impermeability of the Human Placenta for Insulin

Cited by 38 publications

References 2 publications

Peripheral metabolism of insulin, proinsulin, and C-peptide in the pregnant rat.

Peripheral metabolism of insulin, proinsulin, and C-peptide in the pregnant rat.

Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo.

Insulin Action During Pregnancy: Studies with the Euglycemic Clamp Technique

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