Chromium and Selenium

Question 1

History of selenium

Answer 1

• 1930s- Selenium (Se) thought to be responsible for toxicitiy in cattle eating ‘toxic’ plants.
• 1940s- High dose Se rodent study thought to cause frequency of ‘neoplasms’ in liver
• 1957- Se prevents liver necrosis in rodents (original cancer-forming study not reproducible)
• 1960-1970 Se demonstrated to be nutritionally essential and has anti-carcinogenic activity
• 25 ‘selenoproteins’ currently identified. Se is incorporated into the protein during co-translational synthesis of the target protein as Selenocysteine (Sec)

Question 2

How does selenium function

Answer 2

via ‘Selenoproteins’
* any protein that includes a selenocysteine (Sec, U, Se-Cys) amino acid residue

Question 3

Chief Biological Functions of Selenium via ‘Selenoproteins’

Answer 3

• Antioxidant
• Enzymic conversion T4 to T3

Question 4

Role of selenium as an antioxidant

Answer 4

Redox status regulation
* selenium is a part of the glutathione peroxidase which reduces hydrogen peroxide to water thus preventing oxidative stress

Question 5

Major Selenoproteins

Answer 5

• Glutathione Peroxidase-1 (GTX-1)
• Glutathione Peroxidase-2 (or GTX-GI)
• Glutathione Peroxidase-3 (GTX-3)
• Phospholipid hydroperoxide Glutathione Peroxidase (or GTX-4)
• Iodothyronine 5’-Deiodinase (DI-1)

Question 6

Glutathione Peroxidase-1 (GTX-1)

Answer 6

Specific for glutathione (GSH), in most cells and plasma. Not reactive for lipid or sterols. GTX-1 catalyses the following reaction:
* 2 x glutathione + ROOH > glutathione disulphide + ROH + H20

Question 7

Glutathione Peroxidase-2 (or GTX-GI)

Answer 7

Similar function that of GTX-1, but expression primarily in the intestine

Question 8

Glutathione Peroxidase-3 (GTX-3)

Answer 8

Similar functions, but found in the kidney and secreted into the plasma
* basis unclear.

Question 9

Phospholipid hydroperoxide Glutathione Peroxidase (or GTX-
4)

Answer 9

intracellular GPX activity, will reduce phospholipid and cholesterol hydroperoxides (not reduced by GPX-1). GPX-4 has ‘broader’ detoxifying capacity than GPX-1.
* k/o mice for GPX-4 embryonic lethal

Question 10

Iodothyronine 5’-Deiodinase (DI-1)

Answer 10

Major enzyme (90%) that converts T4 to T3, found primarily in ER of liver and kidney cells.
* DI-2: brain, skin, adipose
* DI-3: fetal liver, CNS, muscle

Question 11

What does dietary intake of Se depend on?

Answer 11

dependent on enrichment in soil.
* Se is derived primarily from volcanic reactions- hence large variations of enrichment in soil across the continents.
* Goes into air and eventually settles on ground so in plants and in animals; some can also go into water supply

Question 12

Se in animals and plants

Answer 12

• Se in animal products collects as selenocysteine and Se-proteins (variations due to supplementation of Se to animals)
• Some plants can ‘accumulate’ Se to toxic levels (>mg quantities)

Question 13

Se bioavailability

Answer 13

Hydrophyllic and highly absorbed (80-90%) efficient

Question 14

Se excretion

Answer 14

Kidney thought to regulate excretion and liver modulate excretion

Question 15

Se RDAs

Answer 15

• M/F = 55 ug/d
• ↑ with pregnancy and lactation

Question 16

Se intake in Canada

Answer 16

~100-150 ug/d

Question 17

Food sources of Se

Answer 17

Wide variety of foods
* nuts and seeds
* fish, meat, poulty
* grains and cereals
* dairy products

Question 18

Keshan Disease

Answer 18

Selenium deficiency
Endemic of cardiomyopathy until 1980s, in children younger than. 15 years of age.15 in every thousand affected (normally 1 or 2). All surrounding regions poor in Se- very regionally dependent. Intervention study with Se in 1974- reduced frequency to 5 in 1000. All
but not normalized
* Keshan province of China

Question 19

Se and TPN

Answer 19

1979- New Zealand case-study. Woman undergoing total parenteral nutrition (TNP). Within 20days TPN, dry flaking skin, after 30days muscle pain and wasting. Se plasma concentration was 9ug/L. Infused with 100ug/day Se, all symptoms gone by 1 week.

Question 20

Se toxicity

Answer 20

TUL: 400-1000ug/day - Symptoms (Long-term effects) of brittle hair and nails, garlic breath
* >2000ug/day (vomiting, diarrhea, fatigue)
* >grams/day (heart attack, kidney failure, death)

Question 21

Where might Se toxicity occur?

Answer 21

If no access to clean water; Se in water and food supply makes it difficult because cannot really control this

Question 22

Se impact on arsenic

Answer 22

Se binds arsenic (negatives binds positives) and can reduce the toxicity of arsenic and arsenic can reduce the toxicity of Se. And once they bind it is excreted. Want to get arsenic out of water but limited resources to do so in some places
* 100-200 million people have drinking water contaminated with Arsenic

Question 23

Properties of Cr?

Answer 23

• Chromium is an essential trace element
• multiple oxidative states

Question 24

oxidative states of Cr

Answer 24

• Cr3+ (active): form required for biological processes in humans; essential
• Cr6+: by-product of manufacturing processes

Question 25

Significance of Cr3+ to Humans

Answer 25

Required for biological processes * Carbohydrate metabolism * Lipid metabolism

Question 26

Cr absorption

Answer 26

Intestinal absorption mechanism remains unclear, no specific transporter identified

Question 27

Where is Cr concentrated in the body?

Answer 27

Upon absorption, Cr3+ is concentrated into three primary sites: kidney, muscle and liver

Question 28

How is Cr transported?

Answer 28

Principal carrier protein for chromium is transferrin moving Cr from blood to cellular chromodulin

Question 29

Describe chromodulin

Answer 29

Low Molecular Weight Chromium Binding Substance * Cr to its own protein binding factor within cells and serves as active way chromium behaves in the cell

Question 30

binding capacity of transferrin and chromodulin

Answer 30

* 1 transferrin binds 2 Cr3+ * 1 cellular chromodulin binds 4 Cr3+

Question 31

What might Cr improve?

Answer 31

insulin signalling * Cr is transported into cells and binds to chromodulin and helps to regulate the insulin signally cascade by facilitating autophosphorylation of IR and and inhibiting the phosphtyrosine phosphatase

Question 32

Postulated role of Cr3+

Answer 32

* Activates Tyrosine Kinase * Enhances Insulin Binding * Increases Insulin Receptor Number * Increases B- Cell Sensitivity * Inhibits Phosphotyrosine Phosphatase

Question 33

Evidence for how Cr may improve insulin signalling

Answer 33

Cr has impact on obese rats by reducing plasma glucose post meal more efficiently than those without Cr * normal response in lean either way

Question 34

Suggested mode of action of Cr with T2D

Answer 34

Supplemental chromium intake → increased insulin sensitivity * Canadian studies indicate up to 30% of patients with diabetes use complementary alternative management strategies * Chromium is commonly used to increase glycemic control in this population group

Question 35

Cr3+ food sources

Answer 35

Question 36

Estimated Cr 3+ absorption

Answer 36

ranges from 0.4% to 2.5% * (i.e. 35 ug= 0.1-0.63 ug/day)

Question 37

Cr3+ DRIs

Answer 37

Uses AIs * M - 35 ug/d * F - 25 ug/d * ↑ with pregnancy/ lactation

Question 38

Dietary insufficiency of Cr

Answer 38

* Impaired glucose tolerance * Elevated cholesterol and triglycerides, and decreased HDL concentrations * Nerve and brain disorders (Have been reported for patients on TPN diets without the inclusion of chromium)

Question 39

Measuring Cr status

Answer 39

Currently, no biological marker exists to accurately measure chromium status

Question 40

The most efficacious/bio-available form of supplemental chromium

Answer 40

Several trivalent forms have been studied for their ability to affect glycemic control in people with T2D * Chromium nicotinate * Chromium chloride * Chromium picolinate (CrPic)

Question 41

What Cr supplement is most studied?

Answer 41

Chromium picolinate (CrPic) * Most efficiently used form; its chemical structure enables optimal bio-availability * Virtually all experimental trials using CrPic supplementation for subjects with T2D have demonstrated beneficial effects

Question 42

What are some improved outcomes seen with CrPic?

Answer 42

13 of 15 clinical studies assessed in a review by Broadhurst et al. indicated significant improvements for at least one outcome measure for glycemic control: * Reduced blood glucose measures * Reduced insulin measures * Reduced glycemic medication requirements

Question 43

Cr3+ UL

Answer 43

No UL for Cr3+ * Consumption of excess Cr3+ through dietary food sources is highly unlikely * Supplements – controversial

Question 44

toxicity case of Cr

Answer 44

Patient consumed 600 ug/day over-the-counter oral chromium picolinate for six weeks to aid in weight reduction and developed renal failure * not seen in clinical trials

Question 45

Dietary excess of Cr6+

Answer 45

Classified as a human carcinogen - More about industry and water supply not our natural food supply * Possibility that Cr3+ is converted to Cr6+ in vivo? Has maybe been shown in animal studies, but unlikely for humans in normal conditions