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Home , Chromium, Chromium deficiency

The Nutritional Relationships of David L. Watts, Ph.D., F.A.C.E.P.1

In 1959 a physiological role for chromium was determined. It is known that chromium is a 1. Trace Elements, Inc., P.O. Box 514, Addison. Texas 75001. constituent of the glucose tolerance factor urine.10 Doisy and co-workers reported that both the (GTF) and is synergistic with in liver and hair levels of chromium in diabetics were promoting cellular glucose uptake. Chromium decreased proportionately.11 The chromium content deficiency produces an increase in the found in the hair is apparently related to and requirement for insulin. Chromium facilitates reflective of chromium nutritional status.12 An insulin at intracellular sites including the increase in TMA chromium levels have been ribosomes, and is known to stimulate some reported in patients receiving chromium enzymes in vitro. Chromium is important for supplementation.13 Thus TMA is a useful tool for the structure and of nucleic acids.1 evaluating chromium and tissue storage, 2 3 particularly since biological GTF is significantly active in hair follicles.14 Body Content and Requirements The total body content of chromium in the Conditions Associated with Chromium adult is estimated at 5 to 6 milligrams. Animal Deficiency studies have shown that chromium A number of physiological and disease concentrations are high in the spleen, testes, conditions are related to chromium status and have epididymis, and bone marrow. Tissue shown a correlate with TMA chromium levels. chromium levels are highest at birth and decline with age. The daily requirement for Diabetes chromium based upon urinary excretion studies Hambidge, et al, reported that children with has been estimated at 1 microgram per day. juvenile diabetes as a had lower hair Dietary requirements range from 30 to 200 chromium levels than found in a normal control micrograms in order to compensate for its poor group.15 In adult diabetics the TMA chromium 4 absorption. levels were found low only in female patients.16 In the plasma, chromium is transported by its Some studies have reported conflicting results of attachment to transferrin. Hexavalent TMA chromium levels and suggest its usefulness chromium is better absorbed than the trivalent for determining the chromium status of groups form.5 rather than individuals. However, this may only be due to interpretive differences of TMA results. The Assessment of Chromium Status — Serum interpretive and therapeutic usefulness of TMA on A reliable range for serum chromium is individuals will be discussed later. lacking.6 At this time, serum determination is not a good indicator of body status since the Peripheral Neuropathy 7 serum is not in equilibrium with tissue stores. A case of peripheral neuropathy was reported in Studies report that serum and urinary chromium a patient on long term TPN. The patient developed are not affected significantly by chromium glucose intolerance, , and other 8 9 supplementation. metabolic disturbances that did not respond to increased insulin. After chromium supplementation, Tissue Analysis her metabolic dysfunctions improved along with Tissue mineral analysis (TMA) of human improvement in glucose tolerance and peripheral hair is a good method of assessing chromium neuropathy. Insulin requirements were also status. TMA is known to relate to body stores reduced.17 better than either serum or

17 Journal of Orthomolecular Medicine Vol. 4, No. 1, 1989

Cardiovascular Heart Disease (CHD) TMA levels. This is perhaps due to a similarity Experimental animal studies have revealed developing in higher intake of refined that chromium may be associated with the carbohydrates by Europeans. High glucose or development of atherosclerosis.18 19 Chromium sucrose intake results in chromium losses.27 Mertz deficiency has been noted with stated that animal protein is the best source of hypercholesterolemia,20 aortic plaques, and available chromium, and that insufficient protein corneal opacity.21 Schroeder, et al, found intake would be expected to to a low chromium levels in the aorta of subjects who chromium status,28 a condition observed in died of CHD to be lower than in those who died malnourished children. Spices are also substantially of accidental causes.22 Chromium high in chromium. supplementation has resulted in improved cholesterol levels and an increase in high Hormonal Factors Contributing to Chromium lipoproteins (HDL). Stout presented evidence Deficiency — Insulin that insulin itself may be related to the patho- Like glucose, insulin also contributes to genesis of atherosclerosis.23 Studies have shown . Insulin injection is known to a close relationship between insulin levels and increase chromium excretion.29 Since many patients cardiovascular disease. Serum insulin has been with adult onset diabetes have excessive insulin found to be elevated in myocardial infarct production,30 chromium deficiency would be patients as well as those who have expected in this group. Since both insulin and atherosclerosis, cerebral vascular disease, and glucose increase the excretion of chromium, it is peripheral vascular disease. Stout further important to consider the effects of food emphasized that "although diabetes is often consumption on serum insulin and glucose levels. regarded as a disease of insulin deficiency, Studies of the effects of different foods on serum insulin concentrations are commonly above glucose and insulin response (termed the glycemic normal in non-insulin-dependent diabetics who index (GI) have revealed surprising results. Foods are obese, as well as in patients using insulin." are categorized as percent (%) of GI. The higher the Insulin in high concentrations is known to GI%, the higher the insulin and glucose response. stimulate cholesterol synthesis in smooth muscle As an example, glucose is listed as 100%. High GI and synthesis in the arterial wall. Low foods include carrots 92%; parsnips 98%; honey insulin levels have the opposite effect. Other 87%; cornflakes 80%; and white potato, 70%. Low endocrine factors are probably involved as well GI foods include lentils, 29%; and peanuts 13%.31 32 and will be discussed later. 33 Consumption of foods with a high GI may make Other conditions associated with human chromium replacement difficult. chromium deficiency include impaired growth, negative nitrogen balance, and decreased Estrogen respiratory quotient.24 Chromium stores often become depleted during pregnancy.34 Pregnancy produces a diabetogenic Factors Contributing to CR Deficiency — state characterized by insulin resistance.35 This Dietary results in excessive endogenous insulin secretion,36 The chromium content of foods is markedly thereby contributing to chromium excretion or reduced by processing and refining. Losses are transfer to the fetus. It is likely that excess estrogen as high as 90 percent in some foods. Earlier contributes to the hyperinsulinism during studies that compared autopsied tissue in the pregnancy. Insulin levels are found to be highest in U.S. with those of other countries found that the the last trimester. Estrogen also contributes average tissue chromium content was 2 to 12 to the same metabolic effect of increased insulin times higher than those of the U.S.25 26 production,37 38 either directly or indirectly.39 However, TMA studies of over two thousand Europeans at Trace Elements, Inc. over the past Thyroid two years do not show a major difference in The thyroid hormone and insulin are 18 The Nutritional Relationships of Chromium mutually competitive.40 41 42 43 Thyroid activity Obviously emotional changes trigger hormonal may directly or indirectly affect chromium status. responses. In clinical practice one often sees Low thyroid function may allow increased prediabetic patients who develop manifestations of insulin secretion resulting in chromium loss, or glucose intolerance following stressful or increased insulin production may suppress traumatic events. These patients may become thyroid function or expression. At this time the emotionally stressed following an auto accident, thyroid-insulin relationship remains speculative. for example. Their insulin and glucose levels may However a prevalence of thyroid failure develop severe swings, resulting in instability and occurring in diabetics has been reported.44 thus poor response to therapy. This type of trauma results in the syndrome termed post traumatic Hyper-Parathyroidism (HPTH) dysinsulinism. It is not uncommon for predisposed HPTH may contribute to chromium deficiency individuals to develop diabetes following this type due to hyperinsulinism. HPTH has been of stress episode. associated with hyperinsulinism due to tumours of the pancreatic islets, pituitary, or other organs. Minerals Symptoms of HPTH are not unlike those of Figure 1 shows the minerals that are diabetes.45 antagonistic to chromium.48 49 The lines indicate a direct antagonism either on a metabolic Stress or absorptive level. The broken lines indicate an Physiological or emotional stress is known to indirect antagonistic relationship. A patient with affect chromium status. The stress of infections increased tissue retention of any one or increases chromium excretion. Patients suffering combination of these essential and toxic elements from myocardial infarction commonly develop can be expected to have increased chromium hyperglycemia and glucose intolerance without requirements. Depending upon the individual, an exogenous glucose load. It has been proposed supplementation of these trace elements, that the cardiac event can itself produce individually or in combination, can contribute to diabetes.46 Emotional instability of insulin chromium losses or decreased absorption. dependent diabetic patients (those with anxiety, Minerals that are considered synergistic to depression, and other psychiatric symptoms), chromium include: results in poor glucose control compared to diabetic patients without psychiatric symptoms.47 Potassium Phosphorus

Figure 2.

Figure 1.

19 Journal of Orthomolecular Medicine Vol. 4, No. 1, 1989

NOTE: Some minerals may appear as both associated with the different types of diabetes. In synergistic and antagonistic — a common review of the prevalence of these different types phenomena among trace elements. In 85-90% of patients have the less severe adult- physiological quantities a mineral can be onset form, or Type II. Type I (juvenile-onset) synergistic, but at pharmacological or toxic levels affects approximately 10-15%. A true type I it becomes antagonistic. diabetic condition is characterized by a lack of Many of the synergistic are insulin production or secretion from the pancreas. frequently found to be deficient in diabetic The islets may be atrophied or completely patients.50 A nutritional deficiency of these trace destroyed. On the other had, insulin production in elements can also contribute to chromium type II diabetes in many cases is actually normal deficiency. or higher than normal.55 As mentioned previously, both glucose and insulin increases chromium excretion; therefore, chromium deficiency would Figure 2 represents the vitamins that are be expected in both groups. Response to considered antagonistic to chromium. Chronic chromium supplementation may vary con- high intake can contribute to chromium siderably between the two groups. deficiency and/or increased requirements. A deficiency of the synergistic vitamins may TMA Indications of Chromium Requirements also lead to poor chromium status in some The antagonistic minerals (figure 1) and the individuals. The following list of vitamins are synergistic minerals to chromium should be considered synergistic to chromium.51 evaluated in conjunction with TMA chromium Thiamin (B1) E levels. An elevation above the ideal of the (B2) antagonistic minerals would indicate increased Pyridoxine (B6) (B3) chromium requirements. Synergistic minerals below the ideal TMA level may also indicate Assessing Chromium Status and Therapy increased requirements. The ideal levels From TMA Patterns of Individuals established at TEI are: Presently there are conflicting views on the 42 Mg% essentiality of chromium in , due Phosphorus 16 Mg% to the variation in clinical and biochemical Potassium 10 Mg% response of diabetic patients to chromium Iron 2.8 Mg% supplementation.52 There is also uncertainty 2.5 Mg% surrounding the use of TMA in evaluating Manganese 0.15 Mg% chromium status and therapy in individuals. Zinc 20 Mg% Much of this confusion can be cleared up in light Lead <0.5 Mg% of the many factors that can affect chromium Magnesium 6 Mg% status and function. It is important to note that The significant ratio that should be considered diabetes is not a singularly caused disease but a with chromium is calcium to magnesium. The series of related metabolic, endocrine,53 and TEI ideal calcium/magnesium ratio is 7.1:1. nutritional54 disorders that lead to poor glucose TMA chromium levels in type II diabetic control and abnormal insulin production or patients are usually found below the ideal. action. Frequently the calcium/magnesium ratio is The ideal TMA chromium level established at disturbed. An elevated calcium/magnesium ratio TEI is 0.08 Mg%. However, indications of (greater than 15:1) may be used as an indicator of functional chromium requirements should not be insulin production. The mechanism of the based upon the TMA chromium level alone, but disturbed calcium/magnesium relationship is in relation to other nutritional factors known to based upon the mediation of insulin secretion by affect chromium status, with serological glucose calcium.56 57 TMA calcium levels usually exceed and insulin tests as an adjunct. the ideal in patients with a type II condition, and TMA results have revealed patterns indicate other endocrine influences that occur concomitantly with type II diabetes. Any factor that contributes to increased calcium absorption or 20 The Nutritional Relationships of Chromium retention can be considered a chromium results in the inability to store insulin antagonist, resulting in increased insulin secretion adequately. Poor insulin production is due to due to decreased tissue sensitivity. increased catabolic glandular activity.,65 Increased requirements for the synergistic Vitamin D nutrients to calcium and particularly zinc66 Vitamin D is considered a chromium would be expected to be increased in type I antagonist due to its multiple effects. Vitamin D diabetics, since increased adrenal and thyroid activity is similar to parathyroid activity, which activity increases calcium and magnesium 58 67 68 69 increases serum vitamin D3 metabolites, thereby excretion from the body, as well as copper. increasing calcium absorption and retention. This The increase in catabolic glandular activity results in a relative .59 would also decrease vitamin D metabolism70 and Since vitamin D enhances the synthesis of lower insulin production and PTH activity.71 72 73 insulin, and insulin enhances the synthesis of Elevated blood glucose contributes to chromium vitamin D,60 61 we can readily see that PTH, loss in type I diabetes, which is due to increased vitamin D, calcium, and insulin can individually gluconeogenesis precipitated by excessive or collectively contribute to chromium catabolic glandular activity. deficiency, especially in type II diabetic conditions. Together these related factors produce Conclusion a vicious cycle, resulting in chromium depletion In summary, TMA can be useful for and thereby increasing insulin production in order determining chromium status in individuals to compensate for decreasing tissue insulin when evaluated with its other synergistic and sensitivity. These combined factors can result in antagonistic co-factors. The calcium to elevated TMA calcium levels and magnesium ratio is as important as the calcium/magnesium ratios. evaluation of the chromium level alone and can be used as an indicator of functional chromium , regardless of the chromium level Copper is considered an indirect chromium itself. antagonist due to its close relationship with It has been found that the GTF activity of estrogen and diabetogenic effects.62 It is well chromium consists of the combination of known that serum copper increases during chromium with glycine, glutamic acid, cysteine, pregnancy, estrogen therapy, and oral and niacin. Chromium supplementation may contraceptive use. Plasma insulin elevates during produce little response without these co-factors. pregnancy along with estrogen63 and in Presently this combination is provided by Trace conjunction with estrogen therapy.64 This again Nutrients, professional products. to the cycle of insulin enhanced vitamin D synthesis, which enhances parathyroid activity Footnote — The TMA results (mineral levels and increases intestinal calcium absorption, and and ratios) discussed in this article are based renal reabsorption. This relationship contributes upon atomic absorption spectro-photometric to decreased insulin sensitivity as a result of analysis and laboratory procedures utilized by induced chromium deficiency. Copper Trace Elements, Inc., and may not apply as well can eventually lead to adult-onset diabetes. to different laboratory techniques and These interrelated factors can also be involved preparatory procedures. in the incidence of arteriosclerosis found in diabetic patients. Type I diabetic patients may or may not show References markedly low TMA chromium levels, and may 1. Whitney EN, Cataldo CB: Understanding Normal not respond as remarkably to chromium and Clinical Nutrition. West Pub., St. Paul, supplementation. Type I patients do, however, Minn., 1983. show extremely low tissue zinc levels (usually 2. Mertz W: Chromium occurrence and function in below 50% of the ideal) along with low TMA biological systems. Physiol. Rev. 49, 1969.' calcium and magnesium levels. A [ 21 Journal of Orthomolecular Medicine Vol. 4, No. 1, 1989

3. Wacker WE, Vallee BL: Chromium, manganese, 21. Saner G: Chromium in Nutrition and Disease. iron, and other in ribonucleic acid from Alan R. Liss, Inc., N.Y., 1980. diverse biological sources. /. Biol. Chem. 234, 22. Schroeder HA, Nason AP, Tipton IH: Chromium 1959. deficiency as a factor in atherosclerosis. /. Chron. 4. Alpers DH, Clouse RE, Stenson WF: Manual of Dis. 23, 1970. Nutritional Therapeutics. Little, Brown Co., 23. Stout RW: Insulin and atheroma — An update. Boston, 1983. Lancet, I, 1987. 5. Underwood EJ: Trace Elements in Human and 24. Saner G: Chromium in Nutrition and Disease. Animal Nutrition. Academic Press, N.Y., 1977. Alan R. Liss, Inc., N.Y., 1980. . 6. Sauberlich HE, Dowdy RP, Skala JH: Laboratory 25. Tipton IH, Cook MJ: Trace elements in human Tests for the Assessment of Nutritional Status. tissue II: Adult subjects from the U.S. Health CRC Press, Fl., 1984. Phys. 9, 1963. 7. Underwood EJ: Trace Elements in Human and 26. Tipton IH, Schroeder HA, Perry HM, Cook MJ: Animal Nutrition. Academic Press, N.Y., 1977. Trace elements in human tissues III: Subjects from 8. Anderson, et al. Urinary chromium excretion of , the Near and Far East ad Europe. Health human subjects: effects of chromium Phys. 11, 1965. supplementation and glucose loading. Am. J. Clin. 27. Mertz W, Wolf WR, Roginski EE: Relation of Nutr. 36, 1982. chromium excretion to glucose metabolism in 9. Polansky MM, Bryden NA, Anderson RA: Serum human subjects. Fed. Proc. 36,1977. chromium as an indicator of chromium status of 28. Mertz W: Chromium and its relation to humans. Fed. Proc. 43,1984. carbohydrate metabolism. The Medical Clinics of 10. Alpers DH, Clouse RE, Stenson WF: Manual of North America, Vol. 60. W.B. Saunders Co., Phil., Nutritional Therapeutics. Little, Brown Co., 1976. Boston, 1983. 29. Alpers DH, Clouse RE, Stenson WF: Manual of 11. Doisy RJ, Streeten D, Freiberg JM, Schnieder AJ: Nutritional Therapeutics. Little, Brown Co., Chromium metabolism in man and biochemical Boston, 1983. effects. Trace Elements in Human Health and 30. Brown JHU: Integration and Coordination of Disease Vol. II. Prasad, A.S., Ed. Academic Press, Metabolic Processes, A Systems Approach to N.Y., 1976. Endocrinology. Van Nostrand Reinhold Co., N.Y., 12. Mertz W: Chromium occurrence and function in 1978. biological systems. Phys. Rev. 49, 1969. 31. Crapo P, et al: Postprandial plasma glucose and 13. Hunt AE, Allen KGD, Smith BA: Effect of insulin responses to different complex chromium supplementation on hair chromium carbohydrates. Diabet. Vol. 26, 12, 1978. concentration and diabetic status. Fed. Proc. 42, 32.Coulston AM, et al: Effect of source of dietary 1983. carbohydrate on plasma glucose, insulin, and 14. Hambidge KM: Chromium nutrition in man. A. J. gastric inhibitory polypeptide responses to test Clin. Nutr. 27, 1974. meals in subjects with noninsulin-dependent 15. Hambidge KM, Rodgerson DO, O'Brien D: The diabetes mellitus. Am. J. Clin. Nutr. 40, 1984. concentration of chromium in the hair of normal 33. David JA, Jenkins DM, et al: Glycemic index of and children with juvenile diabetes mellitus. foods: a physiological basis for carbohydrate Diabet., 17, 1968. exchange. Am. J. Clin. Nutr. 34, 1981. 16. Rosson JW, et al: Hair chromium concentrations in 34. Hambidge KM, Rodgerson DO: Comparison of adult insulin treated diabetes. Clin. Chim. Acta. 93, hair chromium levels of nulliparous and parous 1979. women. Am. J. Ob. Gyn. 103, 1969. 17. Jeejeebhoy KN, Chu RC, Marliss EB: Chromium 35. Felig P: Body fuel metabolism and diabetes deficiency, glucose intolerance, and neuropathy mellitus in pregnancy. The Medical Clinics of reversed by chromium supplementation, in a North America, Vol. 61. W.B. Saunders Co., Phil . patient receiving long-term . 1977. Am. J. Clin. Nutr. 30, 1977. 36. Spellacy WN, Goetz FC: Plasma insulin in normal 18. Schroeder HA: Serum cholesterol and glucose in and late pregnancy. N.E.J.M., 268, 1963. rats fed refined and less refined and 37. Gershberg H, et al: Glucose tolerance in women chromium. /. Nutr. 97, 1969. receiving an ovulatory suppressant. Diabet., 13, 19. Schroeder HA, Nason AP, Tipton IH: Chromium 1964. deficiency as a factor in atherosclerosis. /. Chron. 38. Javier Z, et al: Ovulatory suppressants, estrogen, Dis. 23, 1970. and carbohydrate metabolism. Metabol. 17, 1968. 20. Wolliscroft J, Barbosa J: Analysis of chromium in 39. Watts DL: Nutritional relationships — copper, induced carbohydrate intolerance in the rat. /. Nutr. (unpub) Trace Elements, Inc. Dallas, Tx., 1988. 1977.

22 The Nutritional Relationships of Chromium

40. Ibid. modulation of circulating hormone levels. 41. Watts DL, HeiseTN: Balancing Body Chemistry. Endocrinol. 5, 1976. Trace Elements, Inc., Dallas, Tx., 1987. 59. Watts DL: Nutritional Interrelationships — 42. Watts DL: Nutritional interrelationships — Magnesium. Trace Elements, Inc., Dallas, Tx., minerals — vitamins — endocrines. Trace 1988. (unpub) Elements, Inc., Dallas, Tx. 1988 (unpub). 60. Cross HS, Peterlik M: Hormonal and ionic control 43.Rubel LL: The GP and the Endocrine Glands. of transport in the differentiating Rubel, 111. 1959. enterocyte. Progress in Clinical and Biological 44. Gray RS, Smith AF, Clarke BF: Hypercho- Research Vol. 168. Epithelial Calcium and lesterolemia in diabetics with clinically un- Phosphate Transport Molecular and Cellular recognized primary thyroid failure. Horm. Metab. Aspects. Bronner, F., Peterlik, M., Eds. Alan R. Res. 13, 1981. Liss, Inc., N.Y., 1984. 45. The Merck Manual. Holvey, D.N., Ed. Merck and 61. Vitamin D and insulin secretion. Nutr. Rev. 44, 11, Co., Inc., N.Y., 1972. 1986. 46. Husband DJ, Alberti KGMM: "Stress" hy- 62. Watts DL: Nutritional interrelationships — perglycaemia during acute myocardial infarction: Copper. Trace Elements, Inc., Dallas, Tx., 1988. An indication of pre-existing diabetes. Lancet, Jul. (unpub) 1983. 63. Spellacy WN, Goetz FC: Plasma insulin in normal 47. Lustermazn PJ, et al: Stress and diabetic control. and late pregnancy. N.E.J.M. 268, 1963. Lancet Mar., 1983. 64. Gershberg H, et al: Glucose tolerance in women 48. Saner G: Chromium in Nutrition and Disease. Alan receiving an ovulatory suppressant. Diabet. 13, R. Liss, Inc., N.Y., 1980. 1964. 49. Kutsky RJ: Handbook of Vitamins, Minerals and 65. Prasad AS: Zinc deficiency in human subjects. Hormones. 2nd. Ed. Van Norstrand Reinhold Co., Clinical, Biochemical, and Nutritional Aspects of N.Y., 1981. Trace Elements. Prasad, A.S., Ed. Alan R. Liss, 50. Mooradian AD, morley JE: Micronutrient status in Inc., N.Y., 1982. diabetes mellitus. Am. J. Clin. Nutr. 45, 5, 1987. 66. Watts DL: The nutritional relationship of zinc. /. 51. Ibid. Ortho. Med. 3,2, 1988. 52. Is Chromium essential for humans? Nutr. Rev. 67. Clark I, Goeffroy RF, Bowers W: Effects of 46,1, 1988. adrenal cortical steroids on calcium metabolism. 53. Levine R: Glandular and metabolic disorders. Endocrinol. 64, 1959. Medical and Health Annual. Encyl. Brit., Inc., 68. Kleeman CR, Levi J, Better O: and 111., 1983. adrenocortical hormones. Nephron. 25, 1975. 54. Mooradian AD, et al. Micronutrient status in 69. Evans G W, et al. Biliary copper excretion in the diabetes mellitus. Am. J. Clin. Nutr. 45,5, 1987. rat. Proc. Soc. Exp. Bio. Med. 136, 1971. 55. Brown JHU: Integration and Coordination of 70. KlimRG, et al: Intestinal calcium absorption in Metabolic Processes: A Systems Approach to exogenous hyper-corticism. Role of 25 (OH) D Endocrinology. Van Nostrand Reinhold Co., N.Y., and corticosteroid dose. /. Clin. Invest. 60, 1977. 1978. 71. Watts DL: Determining osteroporotic tendencies 56. Leclerq-Meyer V, et al: Effect of calcium and from tissue mineral analysis of human hair, type I magnesium on glucagon secretion. Endocrinol, 93, and type II. Townsend letter for Drs. Oct. 1986. 1977. 72. Stoerk HC: The blood calcium lowering effect of 57. Malaisse WJ, et al: The stimulus-secretion hydrocortisone in parathyroid-ectomized rats. coupling of glucose-induced insulin release. /. Lab. Proc. Soc. Exp. Biol. Med. 68, 1961. Clin. Med. 76, 1970. 73. Margargal LE, et al: Effects of steroid hormones 58. Haussler MR, et al: The assay of 1-alpha 25 on the parathyroid hormone dose-response curve. dihydroxy vitamin D3; physiologic and pathologic /. Pharm. Exp. Ther. 169, 1969.

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