Topic 12 and 13

What groups are at risk of iodine inadequacy?

-People living in regions with iodine-deficient soils -People with marginal iodine status who eat food containing goitrogens -Pregnant women -People who do not use iodized salts

What are minerals and how many are there?

90 natural elements, ~22 are essential for life Macroelements: >100mg/day --> calcium, phosphorus, magnesium, sodium, potassium, chloride Microelements: Trace: 1-100 mg/day --> iron, zinc, manganese, fluoride ultratrace: < 1 mg/day --> selenium, iodine, chromium

What is the selenocysteine insertion sequence?

Dictates the placement of selenocysteine into the selenoprotein; replaces the stop codon and allows selenocysteine to be placed instead of signifying the end of the AA chain

What are biologically active compounds made from selenium? What are the two selenoamino acids?

Selenoproteins --> biologically active compounds selenomethionine and selenocysteine are the amino acids

How is chromium transported and stored?

Transport is mediated by: transferrin (Tf), albumin, globulins and lipoproteins Chromium is thought to be delivered to tissues by transferrin and stored with iron in ferritin body contains 4-6 mg of chromium, mostly stored in kidney, muscle, spleen, heart, etc

Describe selenium excretion

50-60% urinary, 40-50% fecal --> homeostasis is though to be controlled by urinary excretion Se is excreted in urine as methylated metabolites; mainly as the selenosugar, 1B-methylseleno-N-acetyl-D-galactosamine In high Se intake, Di- and tri-methyl metabolites are also excreted

Where is iodine stored?

75-80% of body iodine (15-20 mg) is accumulated in the thyroid gland also can be found in the salivary glands, stomach, ovaries, and testis

How is chromium excreted?

95% in urine; some losses via desquamation of skin cells and fecal disposal

What is selenium's connection with disease states?

Abnormal selenium levels has been associated with: -Cancer; inverse relationship between Se intake and cancer mortality and incidence, no clear effects in clinical trials -Cognitive decline; marginal or deficient selenium levels might be linked to age-related declines in brain function, but clinical evidence is insufficient -Thyroid disease -CVD Selenium has a U shaped curve with disease states

What is the main metal buffer that plays an inhibitory role in mineral interactions?

An increase in metallothionein blocks the absorption of most minerals

How are F-, Ca2+, and PO4- connected?

Bone and teeth structure and regulation; all three are incorporated into forming stabilized hydroxyapatite

How are thyroid hormones activated?

By iodothyronine deiodinases (DI) --> contain selenium; produce T3 (activation) and reverse T3 and T2 (inactivation) DI1 --> thyroid, liver, kidney DI2 --> brain, pituitary, muscle, BAT, heart DI3 --> cerebral cortex, skin, placenta, pregnant uterus

How are Fe2+, Cu2+, Cr3+, and MN3+ connected?

By plasma transport, uptake, and storage Fe2+ is oxidized to Fe3+ by either hephaestin, ceruloplasmin, or GPI-ceruloplasmin; utilizes Cu2+ reduction Fe3+, Cr3+ and Mn3+ can all be transported via transferrin Cu also controls STEAP, which is responsible for Fe reduction Fe2+ and Cr3+ can be stored by ferritin

How are Ca2+ and Mg2+ connected?

Ca2+ activity can be inhibited by Mg2+ activity

Describe the absorption of iodine

Chemical forms in foods: -iodide (I-) --> bound to amino acids -Iodate (IO3-) --> breads or iodized salts absorbed efficiently in the stomach and intestine -in healthy adults, the absorption is greater than 90% Iodate needs to be reduced by glutathione, then is taken up by a Na+/I- symporter in the basolateral membrane of the thyroid gland (2 Na+ / 1 I-). The NA comes from the Na+/K+ ATPase that is co-localized in the small intestines NIS is inhibited by high concentrations of iodine

Where can we find chromium and in what form?

Chromium is an element present in air, water, and soils Trivalent chromium, Cr3+ is the most stable ionic form and is found attached to nitrogen, oxygen, or sulfur

What is Keshan disease?

Chronic selenium deficiency that leads to endemic cardiomyopathy main pathological features: -Focal myocardial necrosis -Heart insufficiency -Heart enlargement, dysrhythmia -Pulmonary edema Treatment --> 0.5mg/day selenium

What are some foods rich in goitrogens?

Cruciferous vegetables (broccoli,cauliflower, kale, cabbage, brussels sprouts, etc), cassava, and millet

How are Cu, Fe, I, and Se connected?

Cu plays a role in the oxidation state of Fe Oxidized Fe is utilized by TPO in order to form T4 and T3 from iodide Se plays a role in thyroid hormone activation

What is the transporter that can uptake all of the minerals in the brush border?

DMT1; is downregulated in the cases of high iron; can uptake Ca2+, Mg2+, Cu2+, and Zn2+

What are some of the physiological functions of selenoproteins?

Defensive mechanism against oxidative stress--> ex. glutathione peroxidases; Antioxidant -catalyzed the removal of H2O2 and organic hydroperoxides; mainly found in the cytosol -utilizes reduced glutathione to elicit its reaction Regulation of thyroid hormone activity --> 5'-deiodinases (DI); activation and deactivation of thyroid hormones --DI1: mostly active in the liver, produces most of circulating T3 --DI2: in the brain pituitary, placenta, and BAT --DI3: adult brain and fetal tissues, inactivates T3 Regulation of redox status --> Thioredoxin reductases; regulates intracellular redox state, participates in the synthesis of deoxynucleotides -helps to maintain the redox state by reducing oxidized thioredoxin and glutathione -Trx1 (cytosolic), Trx2 (mitochondria), Trx3 (testis)

What are the health concerns related to chromium?

Diabetes --> improvement of glucose control in T2DM with pharmacological doses of chromium; effectiveness remains controversial Weight loss/body composition changes --> supplements suggested to change body composition, weight and strength performance; studies showed no significant effects

Describe mineral interactions

Due to their diverse chemical nature, metabolism and functions of micronutrients are not as integrated as in macronutrients, but they have some key functions Absorption <---> Transport; metabolism and functions can be alter or can alter either absorption or transport

What are the enhancers and inhibitors of chromium absorption?

Enhancers --> amino acids; vitamin C; lipophilic compounds Inhibitors --> neutral or high pH (antacids); phytic acid

What are the physiological functions of chromium?

Enhances insulin action: The mechanism is thought to be mediated by a chromium-binding protein (chromodulin) which binds to insulin receptors and enhances its kinase activity -- functions to increase the kinase activity of the beta subunit of the insulin receptor --chromate may inhibit the activity of phosphotyrosine phosphatase to prolong insulin signaling Chromium binds to transferrin, which is subsequently uptaken by TfRs and undergoes endocytosis. When chromium is released by the lysosomes, it binds to apo-chromodulin and forms Cr4-chromodulin, which is believed to enhance kinase activity of the insulin receptor

What are some of the proposed roles of probiotics?

Fermented L. helveticus promotes a decrease in PTH and an increase in total calcium, ionized calcium, and phosphate in blood of post-menopasual women Probiotic yogurt containing L.acidophilus and B.lactis enables women in the third trimester of pregnancy to maintain their blood calcium at the correct level. No effect was observed on iron absorption

What is the main sign of iodine deficiency?

Goiter due to thyroid hyperplasia Cretinism --> severe iodine deficiency --> neurological alterations due to iodine deficiency during fetal development are irreversible Neurological --> mental retardation, deaf mutism, paralysis Myxedematous --> milder neurological symptoms, clinical hypothyroidism and growth retardation; selenium deficiency worsens symptoms Prevention --> iodination of salts, milk, oil capsules

What are the pending issues related to mineral interactions?

How is the interaction (enhancing and inhibiting) among the constellation of minerals in the gut? What is the role of gut microbes in mineral absorption?

What are some inhibiting and influencing factors for selenium absorption?

Influencing --> vitamins A,C,E and reduced glutathione inhibiting --> heavy metals and phytic acid

What is the biologically active form of iodine?

Iodide (I-) functional hormone --> triiodothyronine or T3

What are the dietary sources of chromium?

Mainly animal products: beef, fish, and poultry Meat and grains, some fruits and vegetables --> also found in spices, tea, and beer

What other roles does NIS play?

NIS is also present in thyroid gland (uptake), lactating mammary gland (secretion into milk), salivary glands and stomach cells (secretion into digestive tract)

What are some dietary sources of selenium?

Organ meats and seafoods have the highest concentration, followed by muscle meats, cereal and grains, eggs, milk and dairy products vegetables that are grown in selenium rich soils can provide selenium in the diet Plant proteins --> selenomethionine animal proteins --> selenocysteine animals are supplemented with inorganic forms --> sodium selenite or sodium selenate average US intake 93 and 134 micrograms/day for women and men

What is the universal mineral enhancer?

Organic acids; low pH, amino acids, and glutathione cane also serve as enhancers

What is the universal mineral inhibitor?

Phytic acid; oxalic acid and high pH can also serve as inhibitors

How can we assess selenium status?

Plasma GPx3, GPx1 in RBC, and selenoprotein P -GPx activity in RBC is thought to be marker for long term selenium status -levels of selenium in plasma (Short term) and urinary selenium metabolites (longer term) could also help determine selenium status

Describe selenium absorption in the gut

Rate of absorption --> 80-98%, absorption is not regulatory of Se homeostasis -- Se-Met is better absorbed than Se-Cys (97% compared to 80-90%) -- selenate is effectively absorbed (90%) -- Selenite is at 60% The selenoamino acids travel through either the sodium-dependent neutral amino acid transporter --> B(0) AT1 or through the basic amino acid transport --> rBAT Selenate and selenite travel through the solute carrier 26 (SLC 26) The liver uptakes ~50% of Se on the first pass from portal circulation

What are some of the physiological functions of thyroid hormones?

Regulation of basal metabolic rate: T3 increases O2 consumption Energy production: -induction of components of ETC -Increased activity of ADP translocator into mitochondria -Increase in mitochondria membrane area Energy-consuming processes: -increased heart rate (cardiac size, stroke volume and output) -increased cell membrane Na+/K+ ATPase: Regulation of macronutrient metabolism: T3 regulates the metabolism of all macronutrients Carbs: -increases glycolysis and gluconeogenesis -increase glycogenolysis Lipid: -increases synthesis of FAs and cholesterol -increases lipolysis and FA oxidation -Increases biliary excretion: reduce blood cholesterol Proteins: -increases protein synthesis in skeletal muscle and heart -increases skeletal muscle protein turnover Regulation of growth and development: T3 modulates brain development and body growth Brain development -neuronal axonal growth and synaptogenesis, glial cell production and myelinogenesis are T3-dependent processes -Requirements of T3 for brain development are met by fetal (from 3rd month) and maternal supply Body growth -T3 controls the secretion and receptor activation of growth hormone and IGF-1

Describe chromium absorption

Released from food by acid digestion --mechanisms for absorption in humans is unknown; likely by passive diffusion in the intestines --about 0.4-2.5% of Cr3+ is absorbed in the intestines, inversely proportional to concentration of chromium in the GI

Describe iodine's interactions with other nutrients

Selenium, iron and vitamin A deficiencies may magnify the effects of inadequate iodine: -5'-deoidinases are selenium-containing enzymes -iron is a component of the enzyme thyroperoxidase (TPO) (Heme iron). Iron also may be involved in the binding of T3 to nuclear receptors -vitamin A deficiency reduces iodine uptake by the thyroid gland, decreases the synthesis of thyroglobulin and the coupling of iodotyrosine residues to form T4

Describe the selenium metabolic pool

Selenoamino acids travel free to the liver and other tissues -selenite in portal blood is thought to be taken up by RBC and reduced to selenide (HSe), released back into portal blood bound to albumin Once it is metabolized, exists mainly as selenoprotein p

Describe selenium toxicity

Selenosis --> happens in miners and people who consume excess selenium from supplements; results in inhibition of protein synthesis signs and symptoms --> nausea, vomiting, diarrhea, hair and nail brittleness and loss, paresthesia, paralysis acute poisoning --> intake of grams of selenium is lethal, due to generalized organ damage

How can we assess iodine status?

Serum T3, T4 and, TSH, urinary iodine, thyroid gland size, and serum thyroglobulin

What are goitrogens?

Substances the inhibit iodine uptake and/or organification, and thyroid hormone release. These include goitrin, perchlorate, and lithium

How are thyroid hormones synthesized?

Takes place in the colloid Thyroglobulin --> acceptor protein; iodide is added to the tyrosine residue. Then undergoes conjugation, which removes some of the tyrosine residues from thyroglobulin and binds them together (utilizes the free -OH to make a bond). Then thyroglobulin is uptaken via endocytosis into the thyroid follicular cell. T3 and T4 are formed after proteolysis within the vesicle. They are released bound to thyroxine-binding globulin T4 --> greater in concentration; T3--> more potent

What is the purpose of selenium metabolism?

The creation of Se-Cys for protein use --> first need to create selenophosphate; controlled by selenophosphate synthase Se-Cys utilized in selenium dependent functions must be synthesized in the body from serine and selenophosphate

How is iodine excreted?

The kidneys have no major mechanism to regulate iodine reabsorption Mostly in the urine (~80-90%) Small amounts excreted the feces, milk, and sweat usually in functionally inactive metabolite form --> glucuronidation (T4), sulfation (T3), deamination, or decarboxylation

What is selenoprotein P?

The major plasma and extracellular Se-protein: synthesized and secreted by most tissues, but predominantly by the liver General function: Selenium transport and antioxidant (peroxynitrite (ONOO-) radical disposal in white cells)

How is thyroid hormone transported

Three main proteins: -thyroid hormone-binding globulin (lowest capacity, highest affinity) -thyroid-hormone prealbumin (transthyretin) -albumin 99.9% of plasma T3 and T4 are protein-bound forms

How are thyroid hormone levels regulated?

Through the HPT axis via TRH (thyrotropin releasing hormone) and TSH (thyroid-stimulating hormone)

Where can we find high concentrations of selenium?

Thyroid gland, kidneys, liver, heart, pancreas, and muscle

What is the main mechanism of action for thyroid hormones?

Thyroid hormone receptors belong to the family of nuclear acting proteins (steroid hormones, retinoic acid, vitamin D3, fatty acids) --> binding of T3 activates transcription of target genes effects of thyroid hormone are due to the hormone's occupancy of nuclear receptors, with subsequent effect on gene expression ex. RXR and TR are activated (the repressors are replaced by activators) by T3 binding through TRE (thyroid hormone response element), which results in the acetylation of histones

Describe iodine toxicity

UL --> 1,100 micrograms/day, including pregnant and lactating women Acute iodine poisoning is rare and are usually caused by doses of many grams. Symptoms include fever, abdominal pain, nausea, vomiting, diarrhea, weak pulse, and coma High intakes of iodine can cause: -iodine-induced hyperthyroidism -thyroiditis and thyroid papillary cancer -iodine deficiency-like abnormalities (goiter, elevated TSH levels, hypothyroidism, etc)

What are the potential effects of the gut microbiota?

When we compare germ-free animals and their conventionally-raised counterparts, gut microbiota can have: Beneficial effects --> i.e. enhanced iron uptake and storage or Detrimental effects --> i.e. increased mortality on vitamin A-deficieny diets and increased dietary zinc requirements

What is IDD

iodine deficiency disorder; it is the leading cause of mental development disorders in millions of children. It promotes: -impaired cognitive development, from mild forms to severe mental retardation (cretinism) -stunted growth -poor school performance -reduced work capacity is also implicated in still-birth, miscarriage, physical impairment, and thyroid dysfunction

What are some dietary sources of iodine?

it is abundant in soils; therefore its concentration in foods is highly variable and depends on the soil supplementation is the only reliable way to adequate dietary supply --> usually found in the form of iodized salts major dietary sources --> bread and milk

Describe iodine requirements during pregnancy

the requirement is sharply elevated because -an increase by 50% in maternal thyroxine (T4) production to maintain maternal euthyroidism and to transfer thyroid hormone to the fetus -iodine needs to be transferred to the fetus for fetal thyroid hormone production, particularly in later gestation -there's a probable increase in renal iodine clearance