Iron in Summary

Humans contain about 2-4g iron of which most is in hemoglobin and to a lesser extent myoglobin. Iron from diet is found in heme (animal foods) and nonheme (plant foods) forms. The heme iron needs to be hydrolyzed where as the nonheme is enzymatically freed.

Heme iron is absorbed intact accross the brushborder of the enterocyte whereas nonheme iron is released as ferric in the stomach, which may be reduced to ferrous. The ferric is absorbed across brush border by binding to transporters and the ferrous facilitated by chelators and membrane proteins.Chelators inhibit or enhance absorption of iron. Absorption is also regulated by hepcidin and ferroportin. Other iron-absorption enhancers are sugars, acids, animal meat, and mucin. Other inhibitors are polyphenols, oxalates, phytates, phosvitin and some minerals.Iron is stored in the liver, bone marrow and spleen. Uptake into tissues depends on transferrin.

Iron needs depend on its loss such as through menstrual losses and dietary intake. Deficiency mainly can affect infants and children, teenagers, menstruating females and pregnant women (whose iron needs expand due to increased blood volume). Iron deficiency can develop gradually into anemia. Toxicity may occur due to taking too much iron in supplements or if one has a genetic disorder called hemochromatosis. In the case of hemochromatosis, which is most prevalent among caucasian males, a diet with limited meat intake may be necessary.

Copper-zinc

A mineral supplement I've taken in the past includes 10mg zinc and 1mg of copper. Thus, the amount of zinc is not at the "higher than 50mg" level that can cause a copper deficiency because of interference with bioavailability (1). This is exactly the 10:1 ratio as suggested to avoid any copper deficiency (2). Someone did his/her homework.

1. http://lpi.oregonstate.edu/infocenter/minerals/zinc/
2. http://www.pccnaturalmarkets.com/health/2934002/

Top zinc-rich foods I eat frequently

1 chicken drumstick, broilers or fryers, meat and skin, cooked, roasted = 2.98mg
3 Eggs, whole, cooked, scrambled = 1.83mg
1 burrito, bean and cheese, microwaved = 1.33mg
1 cup milk, whole, 3.25% milkfat = .98mg
1 fish fillet, trout, rainbow, farmed = .32mg

Data found at: http://www.nal.usda.gov/fnic/foodcomp/

Zinc and copper not effective for acute diarrhea

Purpose of study: Zinc and copper are lost in significant amounts in acute diarrhea and zinc has been suggested as a therapy for its possible facilitation of water and electrolyte transport across intestinal mucosa to prevent villous atrophy and modulate immune response. This study evaluated whether or not zinc and copper supplementation had any beneficial effect on acute watery or bloody diarrhea when given with standard treatment.

Type of study: Randomized, double-blinded placebo-controlled trial

Method used to conduct study: Children ages 6-59 months with acute diarrhea were given standard treatment and randomized to placebo, zinc only (Zn 20mg/5ml elemental zinc), or zinc and copper (2mg/5ml of elemental copper) together via syrup. There were 808 children chosen for the study out of 1,200 screened over the period of Aug 2003 and Oct 2006. Each provided more than three stool samples in prior 24 hours, who had duration of diarrhea for up to 72 hours and who were able to orally accept fluid or food. Exclusions were those with positive HIV, kwashiorkor or participating in another study.

Summary: There was no observed impact on duration or total stool output in acute diarrhea found between the groups supplemented with zinc only, zinc and copper, or placebo. No serious adverse events were associated with the three syrups. Critique: Measures were taken in this study to ensure quality control and appropriate data analysis and interpretation. The quality of the study make its results valid given the amount of subjects and assessment of the data.

Nutritional implications and implications of future study: The researchers offered that the lack of effect would not have been due to low dose, poor adherence to treatment or failure to replenish zinc loss. They did offer that extent of zinc deficiency in study populations could be why other studies showed therapeutic benefits from zinc, but that not all therapeutic studies reported benefits of zinc in children with deficiency. Therapeutic supplementation with zinc may, in fact, depend on diarrhea etiology at different ages in populations. There may also have been interaction with zinc and the standard treatment, which included a multivitamin with vitamin A and B vitamins. Future study may need to evaluate zinc supplementation with different etiologies for diarrhea and separately with regards to multivitamin interaction.

Reference: Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Med 2009;7:22. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19416499

Armour Thyroid vs Synthroid

Armour thyroid is the "natural" therapy from dessicated porcine thyroid gland while Synthroid is produced synthetically as levothyroxine. Armour thyroid contains both T3 and T4 while Synthroid only contains T4. There is debate on whether or not use of both or one is better. Synthroid came into use because it was standardized unlike the natural kind, which varied a lot from batch to batch. But it turns out that patients often don't like T4 alone as much as the natural T3/T4. A new synthetic T3/T4 is now on the market as Liotrix, but is expensive.

Reference

http://www.netwellness.uc.edu/question.cfm/24516.htm

What Controls Basal Metabolic Rate

To regulate basal metabolic rate, the thyroid gland synthesizes hormones thyroxine, or triiodo-L-thyronine (T4), and the more active triiodo-L-tyronine (T3) (1).When secreted into the bloodstream, they associate with transport proteins (thyroxine-binding globulin, albumin, and transthyretin), which circulate the hormones (2). There is nearly 50 times T4 than there is T3, but T3 is more potent. T4 and T3 bind to nuclear receptors that affect gene expression. Increased mRNA and protein synthesis appear to lead to stimulation of oxygen consumption (when awake, at rest or fasting), heat production and also influences enzymes involved in carbohydrate metabolism (3;4).

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Pereira BM, Balasubramanian K, Govindarajulu P. Effect of thyroxine treatment on epididymal carbohydrate metabolism in the pubertal rat. Int J Androl 1983;6:283-93.
4. Hashimoto K, Ishida E, Matsumoto S et al. Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 2009;150:3417-24.

Iron Deficiency Symptoms

As iron deficiency develops gradually without anemia, symptoms can appear that can include pallor and problems of behavior, cognition, learning and attention span. These can particularly manifest themselves in children. Adults may witness problems related to work performance and productivity.

The effects may be related to impairment of the neurotransmitter gamma-aminobutyric acid (GABA) used to inhibit dopamine production in the brain and/or immune system impairment leading to more susceptibility to infection and inability to keep a normal body temperature.

The first stages of iron deficiency result in diminished liver, spleen and bone marrow iron stores and decreased plasma ferritin. Second stages begin when stores are low and iron transport decreases. Transferrin saturation decreases, which increases total iron-binding capacity, and there is limited iron for function in hemoglobin. This leads to a rise in protoporphyrin, the precursor to heme in hemoglobin. Finally, the anemia occurs.

Reference

Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009, pp. 485-87.

Hemochromatosis a Neolithic adaptation?

Hemochromatosis is a genetic disorder caused by one of several mutations related to double-than-normal iron absorption, which increases susceptibility to iron overload (1). Although the disorder affects about one in 200 in the U.S., it’s still largely unrecognized and can lead to deposits in organs—such as the liver—leading to organ damage and failure if not treated early enough (2-4).

Because the disorder is most prevalent in males of Northern European ancestry, particularly Celtic (5), it was hypothesized as recently as 2007 to be a possible Neolithic adaptation (6). The Neolithic period marked an early European dietary transition from high intake of meat to cereal grains (6).

Whether or not this hypothesis is correct, the state of the disorder suggests potential dietary management through eating primarily vegetarian foods such as the one eaten during the time of these early ancestors—cereal grains, little red meat, and limited vitamin C intake. This low-iron diet to prevent to iron overload, according to the Hemochromatosis Management Working Group, can help to “decrease the frequency and severity of iron overload,” thereby preventing many of the detrimental effects of the disorder (4).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Borgaonkar MR. Hemochromatosis. More common than you think. Can Fam Physician 2003;49:36-43.
3. Dolbey CH. Hemochromatosis: a review. Clin J Oncol Nurs 2001;5:257-60.
4. Barton JC, McDonnell SM, Adams PC et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998;129:932-9.
5. Pozzato G, Zorat F, Nascimben F et al. Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry. Eur J Hum Genet 2001;9:445-51.
6. Naugler C. Hemochromatosis: a Neolithic adaptation to cereal grain diets. Med Hypotheses 2008;70:691-2.

Korsakoff syndrome

Korsakoff’s syndrome, or Wernicke encephalopathy, is a serious neurological disorder occurring under conditions of thiamine deficiency. It’s usually caused by long-term abuse of alcohol, which breaks down thiamine in the body. It is characterized at autopsy by lesions in the brain stem.

Thiamine is necessary for proper glucose metabolism in the brain (1). As a B vitamin it acts as a cofactor for enzymes in the Krebs cycle including pyruvate dehydrogenase. Brain insults result when metabolism is inhibited, particularly where there is high demand for energy.

A cascade of injury to the brain occurs when neuronal death reduces production of succinate and GABA as well as neuron stimulation. Without functioning pyruvate dehydrogenase, lactic acid production increases. Nucleotide synthesis and NADPH production is reduced, which in turn reduces glutathione in blood cells.

Individuals carrying apolipoprotein E (ApoE) epsilon 4 (E4) allele are at higher risk of Korsakoff’s syndrome (2). Thus, the ApoE4 genotype is associated with higher risk of Alzheimer’s disease may also be at higher risk of “alcoholic dementia”. These apolipoproteins are protein moietys of a lipoprotein, which transport lipids in the blood.

Reference List

1. Salan, PN. Emedicine from WebMD. Wernicke Encephalopathy. 2009. Available at: http://emedicine.medscape.com/article/794583-overview.
2. Muramatsu T, Kato M, Matsui T et al. Apolipoprotein E epsilon 4 allele distribution in Wernicke-Korsakoff syndrome with or without global intellectual deficits. J Neural Transm 1997;104:913-20.3.

Diabetes: Women and Men

Type 2 diabetes mellitus is considered a major risk factor in cardiovascular disease (CVD) in both men and women, but CVD pathogenesis biochemistry can differ between the sexes.

Both sexes are affected by insulin resistance, which generally precedes the diabetes, and accompanying metabolic syndrome factors dyslipidemia and hypertension (1). The insulin resistance leads to elevated insulin levels, which stimulates sodium reabsorption. The sodium levels can induce prolonged hypertension. The hypertension leads to hardening of the arteries and eventual atherosclerosis. The chronic hyperglycemia leads to glycation of myocardial proteins and microvascular disease (1;2). Gradual nerve damage from abnormal signaling leads to autonomic neuropathy (2).

Although women have overall lower risk of heart disease than men before age 60 due in part because of estrogen, diabetes abolishes difference in CVD risk. In fact, diabetes in women is reported to increase risk of CVD three- to seven-fold whereas in men it increases risk two- to three-fold (3).

Diabetes is thought to affect women uniquely because of hormonal status. Diabetes appears to cancel benefits of estrogen, which “may be lost or hidden by diabetes” (3). With reduced estrogen, other CVD risk factors come into play in a pre-menopausal women just as it would for post-menopausal women (3).

Reference List
1. Grundy SM. Cardiovascular and metabolic risk factors: how can we improve outcomes in the high-risk patient? Am J Med 2007;120:S3-S8.
2. Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-46.
3. Bolego C, Cignarella A, Zancan V, Pinna C, Zanardo R, Puglisi L. Diabetes abolishes the vascular protective effects of estrogen in female rats. Life Sci 1999;64:741-9.

Post-menopausal estrogen therapy

Menopause is the eventual reduced production of sex hormones in women. Follicular cells in the ovaries appear to become exhausted by continual cycles of ovulation and atresia (1). The ovaries become less responsive to stimulation from gonadotropin—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—causing estrogens and progesterone levels to lower. The ovaries degenerate causing further diminished estrogen production until the hormone is only produced in limited amounts by other tissues (1).

The loss of estrogens production also reduces cardioprotective effects of this particular hormone. Estrogens, estradiol in particular, protects cardiovascular health because of its binding to estrogen receptors (ERs). ERs in absence of estrogen are associated with heat shock protein (HSP); estrogen binding promotes dissociation (2). Estrogen binding also changes gene transcription, altering levels and kinds of cellular proteins (2). The alterations directly affect myocardial, vascular smooth muscle and endothelial cells.

In vascular smooth muscle cells, estradiol has vasodilatory effects and functions in contractibility and growth. Its mechanisms may be related to effects on calcium channel currents, increases of Ca2+ and/or activation of K channels (2). In effect, estradiol leads to increased secretion of NO and cGMP production (2). These are thought to be estradiol’s primary antiatherogenic actions, although other mechanisms may exist such as promotion of endothelial cell regeneration and angiogenesis.

Because estrogen has been found to reduce risk of cardiovascular disease in postmenopausal women, future research on estrogen therapy is merited. Side risks involved, however, may be too serious for estrogen to be prescribed at this time.

Authors who analyzed Women’s Health Initiative (WHI) randomized trials from 1993-2004 on use of conjugated equine estrogens found that death from other hazards such as breast cancer did not favor use of estrogen therapy (3;4). Critics suggest that prescribers of estrogen therapy should have waited WHI results to have avoided cases of breast cancer (3). WHI trials, in fact, also found that hormone therapy, unfortunately, did little to reduce risk of coronary heart disease suggesting that more research is needed (5). The WHI data are related to both pre-menopause and post-menopause therapies with estrogen (4).

Reference List

1. Cohn RM, Roth KS. Biochemistry of Disease: Bridging Basic Science and Clinical Practice. Baltimore: Williams & Wilkins, 1996.
2. Skafar DF, Xu R, Morales J, Ram J, Sowers JR. Clinical review 91: Female sex hormones and cardiovascular disease in women. J Clin Endocrinol Metab 1997;82:3913-8. Available at: http://jcem.endojournals.org/cgi/content/full/82/12/3913
3. Postmenopausal hormone therapy and breast cancer. Prescrire Int 2009;18:66-7.
4. Prentice RL, Manson JE, Langer RD et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23.
5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.

Potassium Guards Against Sodium-induced Bone Loss

Reference: Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab 2002;87:2008-12. Available at: http://jcem.endojournals.org/cgi/content/full/87/5/2008?ijkey=b46c2855f83d19e380eb6674c66c94e884ed56a0

Purpose of study: To study effects of dietary potassium citrate added to diets high in sodium, as commonly found in industrialized nations, in postmenopausal women. Postmenopausal women are at higher risk of osteoporosis, especially if consuming a high-sodium diet.

Type of study: Randomized, double-blinded placebo-controlled trial

Method used to conduct study: After three weeks in which 60 post-menopausal women adhered to a low-salt diet, they were provided sodium chloride pills, salt packets (for sprinking on food) and one cup of bouillon per day. They were randomized and either take potassium citrate (90 mmol/d) or placebo. Twenty-four-hour urine samples were analyzed to determine compliance after 12 days. When compliance was compromised, subjects were contacted to enforce regimen. After four weeks, urine samples and fasting blood samples were collected. Fifty two of the women completed seven-week study of which 26 had taken placebo and 26 potassium citrate. Exclusions at the beginning of the study included women who were less than 2 years past menopause, on bone metabolism medications or who had past history of bone disease.

Summary: Calcium excretion increased by 42+-12 mg/d (33%) from low-salt to high-salt diet in the women on placebo. Calcium excretion decreased by 8+- 14mg (4%) in women on potassium citrate. The results suggest that potassium citrate prevented bone resorption in response to salt increase in the diet.

The method is thought to be the natriuretic and chloruretic effects of potassium alkaline salts. These potentially reduce extracellular volume expansion associated with higher salt intake. The alkaline salts also reduce endogenous acid, increase blood pH and bicarbonate. Calcium excretion in the urine can change depending on acid production.

Critique: Examining effects of potassium through a placebo-controlled trial goes far to point out the intracellular cations biological effects on calcium excretion. The results are significant. The researchers took appropriate measures in assuring that the postmenopausal women were compliant in their diets. A seven-week study, however, may not be long enough to determine whether or not potassium citrate will make a significant difference in reducing risk of bone loss and hip fracture.

Nutritional implications and implications of future study: Post-menopausal women at risk for osteoporosis, especially who eat a high-sodium diet, should consider increases of dietary sources of potassium, which are mainly fruits and vegetables. For the benefit of post-menopausal women who may dislike fruits and vegetables and eat mainly processed foods, it may be wise to add potassium to these processed foods. Similar trials should be conducted to determine effects of potassium-added, high-sodium processed foods.

Why Gatorade May Not Rehydrate You Any Faster Than Water

Research Summary Critique

Reference: Jeukendrup AE, Currell K, Clarke J, Cole J, Blannin AK. Effect of beverage glucose and sodium content on fluid delivery. Nutr Metab (Lond) 2009;6:9. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19232115

Purpose of study: The objective of many oral rehydration drinks is rapid fluid delivery to correct fluid balance in sports. This study investigated carbohydrate (CHO) and sodium (Na) effects on fluid delivery with a deuterium oxide (D20) tracer.

Previous research suggests Na concentration may increase delivery, but that CHO content is more important factor.

Type of study: Equivalence trial of eight different solutions.

Method used to conduct study: Two groups of 10 male subjects (ages 20 +- 1 y, weight: 81.2 +-7.5kg) were split into a CHO or NA group. The CHO group ingested four drinks, each with 20 mmol/L sodium, and with a stepped increase of 3% glucose from 0-9%. The Na group ingested four drinks, each with 6% glucose, with a stepped increase of 20 mmol/L from 0 mmol/L to 60 mmol/L. All drinks contained 3g of D20.

Each trial was performed in laboratory after overnight fast (7-9a.m.) and emptying of bladder. After ingesting drink, blood was taken every five minutes in the first hour and every 10 minutes in the second hour. Plasma D20 was analysed using isotope ratio mass spectrometry.

Summary: CHO concentration at 3% increased fluid delivery in comparison to 0%. Concentration above 6% led to fluid delivery that was slower than 0% and 3%. Sodium concentration in any amount did not show any increase in intestinal water absorption.

Critique: The researchers acknowledge that the investigation, which used the “triple lumen technique”, takes into account a section of the small intestine, but not gastric emptying. It may not represent total fluid availability in the body. However, D20 is useful to provide an integrative measure of gastric emptying and intestinal fluid absorption.

Nutritional implications and implications of future study: Because the study’s findings are that added sodium to oral rehydration drinks (sport drinks) has no effect on fluid delivery, it may change the way consumers choose these beverages. Sodium addition may not be preferred or it may still be for other reasons unrelated to fluid delivery such as for possible electrolyte replacement.

Boost brain health by living like an Indian

Getting plenty of sun and eating curry are integral parts of Indian culture. Now scientists have found that this combination also helps guard against Alzheimer's disease.

The biochemical mechanism by which the combination works is through immune system macrophages (1). Vitamin D was found to stimulate type I and II macrophages to break down and clear beta-amyloid plaques through genomic pathways. Curcuminoids, specifically bisdemethoxycurcumin, assisted with stimulating type 1 macrophages through non-geneomic pathways.

Immune therapies to clear beta-amyloid plaque are a new approach that health scientists hope will assist in prevention and treatment of AD.

Because vitamin D and curcumin work in different ways biochemically, both may be used in therapy for most promising effects.

Apart from hereditary implications, obesity, diabetes and hypertension are all risk factors in AD. Other promising dietary interventions are caloric reduction, antioxidant intake from fruits and vegetables, and increased intake of fish-derived omega-3 fatty acids.

Reference List

1. Masoumi A, Goldenson B, Ghirmai S et al. 1alpha,25-dihydroxyvitamin D_3 Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis 2009.

See Nutraingredients release.

Biochemistry of Metabolic Syndrome

Connecting the biochemical dots that lead to atherosclerosis is what is best attempted by the term metabolic syndrome (MS) (1). The term, of which is still under controversy, is used as a predictor of cardiovascular disease and type 2 diabetes mellitus (2-4).

MS can begin with abdominal obesity (MS dot 1), a consequence of overeating and a sedentary lifestyle (1;5). The additional adipose tissue can then reduce affinity of insulin receptors and/or create abnormal post-receptor responses resulting in insulin resistance (MS dot 2) (1).

Once insulin resistance overwhelms capacity to produce insulin to overcome it, then type 2 diabetes mellitus (T2DM) ensues (1). T2DM is accompanied by hyperglycemia and often by hyperlipidemia (MS dot 3) (1). The hyperlipidemia results because VLDL and chylomicrons are not cleared by the enzyme lipoprotein lipase of which is dependent on insulin (1). The high levels of free fatty acids then impair insulin action further (1). Plus, new research suggests that reduced secreition of adiponectin along with tumor necrosis factor alpha (TNFa) and a protein called resistin act to impair insulin receptor function (1). Poorly controlled glucose levels is then found along with hyperinsulinemia in cases (1).

Finally, the insulin resistance and hyperinsulinemia can stimulate salt reabsorption in the kidneys causing hypertension (MS dot 4) (5). Hypertension, or elevated blood pressure, and its force on artery walls makes them vulnerable to plaque build-up and narrowing that can ultimately lead to hardening of the arteries or atherosclerosis (6).

Clinically, the knowledge of progressing events in MS is what allows it to serve a valid purpose with patients (5;7). A doctor or nutritionist, for example, can use MS awareness to predict future risk factors and assist in treating obese patients with lower-calorie diet and other methods.

Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Lau DC. Metabolic syndrome: perception or reality? Curr Atheroscler Rep 2009;11:264-71.
3. Lien LF, Guyton JR. Metabolic syndrome. Dermatol Ther 2008;21:362-75.
4. Gallagher EJ, LeRoith D, Karnieli E. The metabolic syndrome--from insulin resistance to obesity and diabetes. Endocrinol Metab Clin North Am 2008;37:559-79, vii.
5. Ren J, Kelley RO. Cardiac health in women with metabolic syndrome: clinical aspects and pathophysiology. Obesity (Silver Spring) 2009;17:1114-23.
6. Takeuchi K. [Hypertension and metabolic syndrome/lifestyle diseases]. Rinsho Byori 2007;55:452-6.
7. de ZD, Bakker SJ. Does the metabolic syndrome add to the diagnosis and treatment of cardiovascular disease? Nat Clin Pract Cardiovasc Med 2008;5 Suppl 1:S10-S14.

Glycosylated Hemoglobin to Detect Diabetes

Glycosylated hemoglobin forms when prolonged hyperglycemia leads to glucose in the blood not used for energy to attach itself to hemoglobin (1;2). The reaction does not require an enzyme, but occurs spontaneously (1).

The concentration of glycosylated hemoglobin determined by an assay can be used to determine the status of a diabetic patient and effectiveness of treatment (1;2). The glycosylated hemoglobin assay has been found to be a more effective tests than others such as the oral glucose tolerance test for the detection of diabetes (3).

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4.
2. Diabetes and Hormone Center of the Pacific. Glycosylated hemoglobin testing. Available at: http://www.endocrinologist.com/Hemoglobin.htm
3. Dods RF, Bolmey C. Glycosylated Hemoglobin Assay and Oral Glucose Tolerance Test Compared for Detection of Diabetes Mellitus. Clin Chem 25/5, 764-768, 1979. Available at: http://www.clinchem.org/cgi/reprint/25/5/764

Metabolic Syndrome and Physicians

Despite controversy over the current definition of "metabolic syndrome", physicians are using it as a useful clinical tool. It can be used to help with counseling patients and to recommend treatments.

Metabolic syndrome is currently defined as a combination of several risk factors that ultimately lead to diabetes and cardiovascular disease. They include obesity, hypercholesterolemia, hyperlipidemia, hypertension, insulin resistance and inflamation (1).

Each of the several risk factors that makes up metabolic syndrome requires varying treatments, so physicians may find that lumping them together is not useful. In fact, controversy exists on if the term "metabolic syndrome" is even defined correctly (1).

But a 2007 Mayo Clinic meta-analysis found that metabolic syndrome is beginning to find development as a useful clinical tool (2). The review focused on heart disease factors and found that metabolic syndrome increased risk strongly (2).

Reference List

1. Cheng AY, Leiter LA. Metabolic syndrome under fire: weighing in on the truth. Can J Cardiol 2006;22:379-82.
2. Gami AS, Witt BJ, Howard DE et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403-14.

Personal magnesium intake

These are the foods I eat on a daily basis with highest magnesium intake:

Mixed Nuts - 308 mg per cup
Spinach - 150mg per cup
Yerba Mate - 90mg per cup
Chocolate Soymilk - 39mg per cup
Coffee (espresso) - 96mg per 4 oz

Total magnesium: 683mg

Luckily I'm meeting my recommended intake of 400mg per day.

Check your intake here: http://www.nal.usda.gov/fnic/foodcomp/search/

Is High Phosphorus Intake in the U.S. Diet Hazardous?

Controversy arises as to whether or not a high dietary intake of phosphorus is hazardous to health because in the U.S. the typical diet tends to be high in phosphorus and low in calcium (1). But although the need for increasing calcium for bone health has been clearly established, reducing phosphorus to re-balance the calcium:phosphorus ratio has not been shown to have any additional benefits (1;2).

Serum phosphate levels, for example, when high can reduce vitamin D formation in kidneys reducing serum calcium (2). But high phosphorus also appears to reduce urinary calcium indicating a reversal of the prior detriment (2). In addition, the kidney is effective in maintaining normal phosphorus balance by increasing excretion of phosphorus when necessary (1).

At this time no research including at least one controlled trial has not found any adverse effect from a diet high in phosphorus at levels common in the U.S. (1;2). The exception is in those with impaired excretion such as those with kidney dysfunction (2).

It is worth noting that because calcium interferes with phosphorus absorption, a higher calcium diet would lower phosphorus intake naturally (1). And when intake of phosphorus is in the form of phytate—which is plentiful in grains, legumes and nuts—it just might be detrimental because phytate can interfere with absorption of minerals such as calcium (1).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Linus Pauling Institute. Phosphorus. Micronutrient Information Center. Available at: http://lpi.oregonstate.edu/infocenter/minerals/phosphorus/

Calcium with or without vitamin D

Criteria for recommending calcium to a patient should not go without considering a patient’s vitamin D status. Vitamin D status is critical for improving intestinal absorption, for maintaining calcium homeostasis, for promoting reabsorption of calcium in the kidney and is involved in bone mineralization (1;2).

Calcium supplementation along with vitamin D has been subject of at least two randomized controlled trials in Australia. The first performed on 300 elderly women (77+/- 4.6 years) found no short-term benefit as to improving absorption or promoting bone health (3). But another, longer randomized controlled trial evaluated the effects of calcium with or without vitamin D over five years (4). The researchers studied hip bone mineral density and bone turnover in elderly women (ages 70-80) in a sunny climate (4).

Thus, while short-term benefits weren’t found, long-term benefits were, which where likely produced by reduced bone turnover rate over time (3;4). In response to the studies and other research, the Australian and New Zealand Bone and Mineral Society and Osteporosis Australia issued a joint statement explaining that while calcium intake above previously established recommended levels wasn’t likely to help prevent fractures in elderly men and women, the addition of vitamin D in supplements was supported by the evidence (5).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Cashman KD. Calcium and vitamin D. Novartis Found Symp 2007;282:123-38.
3. Zhu K, Bruce D, Austin N, Devine A, Ebeling PR, Prince RL. Randomized controlled trial of the effects of calcium with or without vitamin D on bone structure and bone-related chemistry in elderly women with vitamin D insufficiency. J Bone Miner Res 2008;23:1343-8.
4. Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab 2008;93:743-9.
5. Sanders KM, Nowson CA, Kotowicz MA, Briffa K, Devine A, Reid IR. Calcium and bone health: position statement for the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia and the Endocrine Society of Australia. Med J Aust 2009;190:316-20.

High-magnesium diet to beat colorectal cancer

At least three cohort studies have been published relating to the possible role of magnesium in reducing risk of colorectal cancer in women.

The first was prospective study from Sweden and reported in JAMA in which researchers found a reduced occurrence of colorectal cancer in women who had a higher dietary intake of magnesium (1).

Hanging on the coat-tails of the Swedish study, U.S. researchers assessed magnesium status of a cohort in Iowa women and found the similar results of reduced risk (2).

The latest was from the Netherlands, which found a few differences from the first two, indicating that there was no significant trend of lowering risk of colorectal cancer except in populations of overweight subjects (3).

According to the latest study, the method by which magnesium has a protective effect is thought to be through decrease of insulin resistance (3). However, as suggested by the U.S. researchers, more observational studies are necessary and, perhaps, clinical trials to assess whether or not the results can be attributed to magnesium or other factors in relation to a high-magnesium diet (2).

Could fiber in green leafy vegetables be a variable? I imagine so.

Reference List
1. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA 2005;293:86-9.
2. Folsom AR, Hong CP. Magnesium intake and reduced risk of colon cancer in a prospective study of women. Am J Epidemiol 2006;163:232-5.
3. van den Brandt PA, Smits KM, Goldbohm RA, Weijenberg MP. Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study. Br J Cancer 2007;96:510-3.

Is spinach a good source of magnesium?

Japanese researchers evaluated spinach’s magnesium bioavailability in rats in a study published in 1995 (1). Their conclusions were that spinach was a "one of the most promising" sources of magnesium and that oxalic acid in spinach after cooking (boil or fried) would not affect magnesium bioavailability.

Looking at their data, though, cooking did affect calcium absorption and, of course, oxalic acid had additional effects.

The researchers had divided rats into six groups, which led to this data:

• Mg-deficient diet
  o Serum magnesium decrease
  o Ca absorption 87.0%
  o Increase of calcium and phosphorus in liver and kidneys
  o Especially large calcium accumulation in kidneys
• Mg-deficient diet supplemented with raw powdered spinach
  o Mg absorption 88.9%
  o Ca absorption 84.1%
  o Large calcium accumulation in kidneys
  o Significantly higher liver and kidney Mg and phosphorus
• Mg-deficient diet with boiled powdered spinach
  o Mg absorption 88.4%
  o Ca absorption 57.3%
  o Large calcium accumulation in kidneys
  o Significantly higher liver and kidney Mg and phosphorus
• Mg-deficient diet with powdered fried spinach
  o Mg absorption 90.4%
  o Ca absorption 66.2%
  o Large calcium accumulation in kidneys
  o Significantly higher liver and kidney Mg and phosphorus
• Control diet with supplemented oxalic acid
  o Mg absorption 88.1%
  o Ca absorption 53.3%
  o Large calcium accumulation in kidneys
  o Significant decrease in weight
• Control diet
  o Mg absorption 87.7%
  o Ca absorption 83.5%o
  o Significant increase in weight gain in comparison to other groups
  

Reference List

1. Kikunaga S, Ishii H, Takahashi M. The bioavailability of magnesium in spinach and the effect of oxalic acid on magnesium utilization examined in diets of magnesium-deficient rats. J Nutr Sci Vitaminol (Tokyo) 1995;41:671-85.

Which exercise should I do to improve calcium status?

We’ve known for awhile that exercise improves bone health, but unsure what effects it has on calcium absorption and loss. There have been recent studies trying to find out more.

Just last April, researchers from San Diego State published a study in which they had investigated urinary calcium excretion in two groups of men—one sedentary and the other on a “high-impact and resistance-exercise program”—in a randomized crossover study of three weeks (1). The active men were found to have “significantly less” urinary calcium loss in comparison to week of restricted activity (1).

But, we should note, an earlier study in 2007 reported that exercise actually increased calcium losses through sweating (2). Quite different than the other study, this one which was evaluating effects of calcium supplementation, came to the conclusion that supplementation should be used to correct the negative calcium balance from dermal loss from exercise (2).

What’s the deal?

While the 2009 study used exercise that was high in impact and resistance, the type of exercise in the 2007 study was cycling, an aerobic exercise not high in impact or high in resistance. One could infer that the type of exercise could have much to do with the type of results researchers get. Could it also be that resistance training has a role in improving calcium absorption and reducing calcium excretion?

Reference List
1. Nemoseck T, Kern M. The effects of high-impact and resistance exercise on urinary calcium excretion. Int J Sport Nutr Exerc Metab 2009;19:162-71. 2. Martin BR, Davis S, Campbell WW, Weaver CM. Exercise and calcium supplementation: effects on calcium homeostasis in sportswomen. Med Sci Sports Exerc 2007;39:1481-6.

“No Single Universal Calcium Requirement”

In 2000, with a bit of an incendiary tone, professor Christopher Nordin of Australia called for a rational position on calcium requirements based on individual variances and culture. The matter was one of controversy, lacking human studies because of their difficulty, but despite plenty of evidence that low calcium causes osteoporosis in animals.

Modern human studies in which researchers deprive subjects of calcium for long periods would be immoral, Nordin points out, although there have been at least a couple in the past. One in particular was performed 50 years ago on Norwegian prisoners that showed deprivation led to negative calcium balance, which would result in osteoporosis.

We also know that diet higher in animal protein and sodium increase urinary calcium; thus, the implication would be that populations of the developed world would need more calcium intake. And status of vitamin D influences calcium absorption; thus, living at a higher latitude, darker skin color, and less exposure to sunlight should never be ignored.

Of course, periods of hormonal changes deserves special attention. According to Nordin in a 2001 interview, “very little work” had been done to determine calcium requirements in postmenopausal state despite that the lacking estrogen effects on the bone are profound.

Still, nine years later and despite the data, many doctors and nutritionists in the U.S.A. and other countries are recommending calcium in general terms of simply meeting RDA. Or, those who understand that certain individuals need more or less calcium, may not be educating patients on facts relating to animal protein, sodium and vitamin D.

A complete, holistic view of each individual patient is necessary and national guidelines should be more forthright in making this assertion. As Nordin states, there is “no single universal calcium requirement” and we need to make sure that our patients know the facts.

Allosteric enzymes

Allosteric enzymes are those that are controlled by the binding of an allosteric effector. The effector may be positive or negative in activating or inactivating the enzyme, respectively, and creates a conformational change of the enzyme. The product may be the allosteric effector in itself producing feedback or feedforward control.

There are two classes of allosteric enzymes based on the effect of the effector on Km and Vmax. If the effector alters Km it is in K class and if the effector alters Vmax it is in V class. There are also enzymes that have both Km and Vmax affected.
K class allosteric enzymes are affected by negative effector binding because it affects the affinity of the binding site for the substrate. V class allosteric enzymes are affective positively or negatively by effectors that increase or decrease rate of enzyme-substrate complex breakdown to products.

Given the conformational change and resulting activation and inactivation of an enzyme, catalysis of reactions would be unidirectional. Examples are hexokinase (or glucokinase), phosphofructokinase, and pyruvate kinase in the regulation of glycolysis. Glucokinase is activated by fructose-6-phosphate and inhibited by fructose-1-phosphate. Phosphofructokinase is activated by fructose 2,6 biphosphate and inhibited by ATP. Pyruvate kinase is activated by fructose-1-6-biphosphate (feedforward) and inhibited by ATP and alanine.

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4. p401-4; 587-89; 863-5
2. Stanford. Regulation of glycolysis. Available at: http://cmgm.stanford.edu/biochem200/regulation/

Why So Many Hormones?

Hormones are any substance in the body that carries a signal to regulate growth, differentiation and function of a variety of cells. The more signals needed, the more hormones in an organism. The big-brained human body is no different. In higher animals signal pathways of many hormonal systems originate in the brain. Because hormones are so specific in communicating between cells, we can expect yet more discovery of hormones in the future to add to the large number already found.

Their are major categories of hormones: peptide and protein, thyroid, catecholamine and steroid. The hormones are specific in targeting cognate receptors that are expressed for specific hormones (1). For example, catecholamine hormones epinephrine and norepinephrine as well as peptide hormones target specific cell surface receptors while steroid hormones target intracellular receptors.

Endocrine hormones are those synthesized in a gland and travels to reach distant target cells. Paracrine hormones are secreted by a cell and travel a short distance to reach a neighboring cell's receptors. Autocrine hormones are produced in a cell that functions as a target for the paracrine hormones.

Hormonal cascade systems may involve a number of hormones. A system may operate through a releasing hormone, anterioir pituitary tropic (or posteror pituitary) hormones and ultimate hormones (1). The posterior pituitary system branches off the right of the hypothalamus and is the system involving oxytocin and vasopressin.

A signal is generally transmitted first through the central nervous system, then innervate the hypothalamus secreting a releasing hormone and it begins the amplified cascade. Generally there is a feedback loop (ultra-short, short, or long) and a final hormone binds a cognate receptor to stop secretion or synthesis of releasing hormone.

If a hormone is not systemic, acting in an anatomically restricted site, it is said to be a local hormone. A hormone that functions locally as an autocrine and paracrine hormone is the neurotransmitter acetylcholine. Acetylcholine in neuron-neuron interaction acts as an excitatory transmitter. It is released after stimulation of a neuron, travels across the synapse and binds to specific nicotinic-acetylcholine receptor.

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4.

Can vitamin D prevent autoimmune diseases?

Vitamin D, apart from its role in calcium nutrition, has been recently studied for its surprising immunomodulation effects, which could have far implications (1). Not only does the hormone-like vitamin acts on vitamin D receptors, which are present on immune cells such as dentritic cells, but it has also been discovered that activated dentritic cells appear to produce vitamin D (2;3).

Because autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis have each been linked to low vitamin D status, vitamin D supplementation is thought to have potential use as a treatment (3-5). Its use for HIV infection and cancer are also being studied (6;7).

Prevention of autoimmune diseases are also associated with immunomodulation from vitamin D. A higher levels of vitamin D is associated with lower risk of multiple sclerosis (8) and with lower risk of type 1 diabetes mellitus (9;10). Vitamin D’s action for preventing type 1 diabetes and other autoimmune diseases is thought to be modulation of dentritic action and modifying T-cell differentiation (10).

Animal studies make the research more exciting. In an older study on mice, vitamin D was able to completely prevent the mouse model of multiple sclerosis (11). Others have also suggested use in preventing encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus (12). It should be noted that, in each case, a high-calcium diet was required (12).

Reference List

1. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008;4:80-90.
2. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol 2009;70:345-52.
3. Cutolo M, Otsa K. Review: vitamin D, immunity and lupus. Lupus 2008;17:6-10.
4. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008;47:840-8.
5. Vojinovic S, Vojinovic J, Cosic V, Savic V. [Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis]. Srp Arh Celok Lek 2005;133 Suppl 2:124-8.
6. Adorini L, Daniel KC, Penna G. Vitamin D receptor agonists, cancer and the immune system: an intricate relationship. Curr Top Med Chem 2006;6:1297-301.
7. Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006;64:226-33.
8. Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009;132:1146-60.
9. Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42.
10. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab 2005;16:261-6.
11. Hayes CE, Cantorna MT, Deluca HF. Vitamin D and multiple sclerosis. Proc Soc Exp Biol Med 1997;216:21-7.
12. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85.

Which Vitamin K for Heart Disease?

The most meaningful (and exciting) new data on vitamin K is on it’s relationship with coronary heart disease (CHD), but it’s a bit confusing.

A cross-sectional study published in Atherosclerosis in 2009 indicated menaquinone reduced coronary calcification, but maybe not phylloquinone (1). This supported a hypothesis made earlier that menaquinone, but not phylloquinone reduced risk of cardiovascular disease (2).

However, an intention-to-treat analysis in Am J Clin Nutr also published this year found phylloquinone supplementation appeared to slow coronary artery calcification (3). This study was performed on older adults with preexisting calcification (3).

One more piece of the puzzle is another not-yet-published September cohort study from Nutr Metab Cardiovasc Dis (4). The study followed 16,057 women ages 49-79 who did not have CHD at baseline (4). Questionnaires were used to determine estimation of vitamin K intake and multivariates were reduced as needed (4). According to its conclusions, menaquinones may have preventative effects against CHD, but not phylloquinone (4).

Eventually more studies will be needed to shed more light on the roles of both phylloquinone and menaquinone and, ultimately, the research will reveal best intake levels for CHD prevention.

Reference List

1. Beulens JW, Bots ML, Atsma F et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009;203:489-93.
2. Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19:39-42.
3. Shea MK, O'Donnell CJ, Hoffmann U et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009;89:1799-807.
4. Gast GC, de Roos NM, Sluijs I et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009;19:504-10.