Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...

https://www.thyca.org/download/document/486/PregnancyandPostpartum.pdf

2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

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Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum

Amyloid β peptide (Aβ), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate Aβ-degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered Aβ and in the metabolic suppression of the endogenous Aβ levels in a gene dose-dependent manner. The regional levels of Aβ in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest level and cerebellum the lowest, correlating with the vulnerability to Aβ deposition in brains of humans with AD. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Aβ accumulation.

http://science.sciencemag.org/content/sci/292/5521/1550.full.pdf

Metabolic Regulation of Brain Aβ by Neprilysin

Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

/pdf/insulin-and-neurodegenerative-disease-shared-and-specific-4gan2n2hye.pdf

Insulin and neurodegenerative disease: shared and specific mechanisms

Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid beta protein precursor (AbetaPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.

Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine.

Insulin degrading enzyme (IDE) is a metalloprotease that has been involved in amyloid β peptide (Aβ) degradation in the brain. We analyzed the ability of human brain soluble fraction to degrade Aβ analogs 1–40, 1–42 and the Dutch variant 1–40Q at physiological concentrations (1 nM). The rate of synthetic 125I-Aβ degradation was similar among the Aβ analogs, as demonstrated by trichloroacetic acid precipitation and SDS-PAGE. A 110 kDa protein, corresponding to the molecular mass of IDE, was affinity labeled with either 125I-insulin, 125I-Aβ 1–40 or 125I-Aβ 1–42 and both Aβ degradation and cross-linking were specifically inhibited by an excess of each peptide. Sensitivity to inhibitors was consistent with the reported inhibitor profile of IDE. Taken together, these results suggested that the degradation of Aβ analogs was due to IDE or a closely related protease. The apparent Km, as determined using partially purified IDE from rat liver, were 2.2 ± 0.4, 2.0 ± 0.1 and 2.3 ± 0.3 μM for Aβ 1–40, Aβ 1–42 and Aβ 1–40Q, respectively. Comparison of IDE activity from seven AD brain cytosolic fractions and six age-matched controls revealed a significant decrease in Aβ degrading activity in the first group, supporting the hypothesis that a reduced IDE activity may contribute to Aβ accumulation in the brain.

Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains.

We studied the ability of ATP to inhibit in vitro the degrading activity of insulin-degrading enzyme. The enzyme was purified from rat skeletal muscle by successive chromatographic steps. The last purification step showed two bands at 110 and 60 kDa in polyacrylamide gel. The enzyme was characterized by its insulin degradation activity, the substrate competition of unlabeled to labeled insulin, the profile of enzyme inhibitors, and the recognition by a specific antibody. One to 5 mM ATP induced a dose-dependent inhibition of insulin degradation (determined by trichloroacetic acid precipitation and insulin antibody binding). Inhibition by 3 mM adenosine 5'-diphosphate, adenosine 5'-monophosphate, guanosine 5'-triphosphate, pyrophosphate, beta-gamma-methyleneadenosine 5'-triphosphate, adenosine 5'-O-(3 thiotriphosphate), and dibutiryl cyclic adenosine 5'-monophosphate was 74%, 4%, 38%, 46%, 65%, 36%, and 0%, respectively, of that produced by 3 mM ATP. Kinetic analysis of ATP inhibition suggested an allosteric effect as the plot of 1/v (insulin degradation) versus ATP concentration was not linear and the Hill coefficient was more than 1 (1.51 and 2.44). The binding constant for allosteric inhibition was KiT = 1.5 x 10(-7) M showing a decrease of enzyme affinity induced by ATP. We conclude that ATP has an inhibitory effect on the insulin degradation activity of the enzyme.

ATP inhibits insulin-degrading enzyme activity.

Innumerous data support the fact that insulin-degrading enzyme (IDE) is the primary enzymatic mechanism for initiating and controlling cellular insulin degradation. Nevertheless, insulin degradation is unlikely to be the only cellular function of IDE, because it appears that some cellular effects of insulin are mediated by IDE as a regulatory protein. Insulin-degrading enzyme shows a significant correlation with various cellular functions, such as cellular growth and differentiation, and the expression of IDE is developmentally regulated. Besides insulin, other substrates are also degraded by IDE, including various growth-promoting peptides. It has also been shown that IDE enhances the binding of androgen to DNA in the nuclear compartment. It is also known that the androgen hormones have a stimulatory effect on prostate growth, and that estradiol stimulates uterine growth. To establish whether IDE is regulated by a cellular prostate/uterine growth stimulus, the present study assessed whether IDE was modified in quantity and activity during proliferative conditions (castration + testosterone in the male rat, or castration + estradiol or the proestrus phase of the estrous cycle in the female rat) and autolysis (castration or the metestrus phase of the estrous cycle) using cytosolic and nuclear fractions of rat prostate and cytosolic fractions of rat uterus. The activity and amount of IDE decreased in the cytosolic fraction with castration and during metestrus, and increased with testosterone or estradiol treatment and during proestrus. In the nuclear fraction, the quantity of the IDE followed the same pattern observed in the cytosolic fraction, although without degradative activity. The data presented here suggest that IDE may participate in prostatic and uterine growth and that the testosterone or estradiol and/or prostate and uterus insulin-like growth factors may be important factors for the expression and regulation of IDE in the prostate and uterus.

Androgen- and Estrogen-Dependent Regulation of Insulin-Degrading Enzyme in Subcellular Fractions of Rat Prostate and Uterus

Introduction: Iodine is considered to be an essential micronutrient in pregnant women. Iodine placental transport to the embryo---fetus is essential for hormone synthesis and is crucial for nervous system development. However, the relationship between iodine intake and placental weight and its potential implications for the newborn have not been studied. Material and methods: Iodine intake was analyzed in 77 pregnant women based on urinary iodine excretion (UIE) levels, measured using Pino’s modified method (normal value, ≥150 g/L). Placental weight was measured (PW: normal, ≥500 g). In the newborn, weight, height, and head perimeter (HP) were also measured. Placental index (PI: placental weight/newborn weight) was calculated, and was considered normal if ≥0.15. Results: UIE was normal in 50 pregnant women (mean ± SD, 279 ± 70.22 g/L) and decreased in 27 (94 ± 31.49 g/L). Newborns of mothers with low UIE had a similar weight (3357 ± 416.30 g; n: 27) to those of mothers with normal UIE (3489 ± 560.59 g; n: 50). Forty-four percent of mothers with low UIE had PW <500 g, and statistically lower HPs were found in newborns of mothers with low PW (PW 3 500 g: 36.05 ± 0.55 cm, n: 54; PW < 500 g: 33.93 ± 15 cm, n: 23, p < 0.019). Similar results were found with PI, but they did not reach statistical significance (0.17 ± 0.04; p = 0.066). No differences were seen in all other parameters. Conclusion: The study suggests the existence of a relationship between PW and HP. This finding may be related to iodine intake during pregnancy.

Low iodine intake during pregnancy: relationship to placental development and head circumference in newborn.

The effect of somatostatin on insulin release by incubated slices of rat pancreas was studied. Somatostatin inhibited insulin release induced by arginine/glucose (A/G), glucagon, glibenclamide, pentoxifyllin, 3′,5′-adenosine monophosphate (cAMP), phentolamine, and KC1. When A/G was used as a stimulus, the quantal inhibitory effect of somatostatin was not neutralized by progressively increasing glucose concentrations. The alpha adrenergic blocking agent phentolamine, the phosphodiesterase inhibitors theophylline (10 HIM) or pentoxifyllin (10 niM), and KC1 partially reversed the inhibitory effect of somatostatin on A/G stimulation. The maximal reversal of somatostatin inhibition was obtained when the slices of pancreas were stimulated with A/G in the presence of the calcium ionophore A23187 plus ATP. These results suggest that the inhibitory effect of somatostatin on insulin secretion could result from calcium translocation in pancreatic beta cells.

Juan C. Cresto

Papers

Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains.

ATP inhibits insulin-degrading enzyme activity.

Androgen- and Estrogen-Dependent Regulation of Insulin-Degrading Enzyme in Subcellular Fractions of Rat Prostate and Uterus

Low iodine intake during pregnancy: relationship to placental development and head circumference in newborn.

Studies on the mode of action of somatostatin on insulin secretion.