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Metabolic disorders of cattle
Medical Hypotheses hfeda Hvporhrur0993) 40,29b-3m 0 LongmanGroup UK Ltd 1993
Metabolic Disorders of Cattle G. REID 25 Gilchtist St, Te Aloha, New Zealand
Abstract - Goldberger (1) discovered human pellagra was a non-infectious disease, affecting mostly the small and the timid in overcrowded institutions. Symptoms were diarrhoea, dermatitis and dementia. The staff and older children escaped the disease. They ate the meat and left the small and timid with the gravy. The ‘Goldberger syndrome’ is observed during competitive feeding of livestock, in ketotic animals and in the zinc depleted which are lethargic and pick all day at their feed (6,9). The pellagra preventative factor was later found to be nicotinic acid, derived from the amino acid tryptophan. Deficiencies of copper, magnesium, vitamin B6 (activated by a zinc kinase) inhibit the conversion of tryptophan to nicotinic acid (2,3,4). Stresses, including liver diseases, malabsorption, iron overload, porphyria, marasmus, cold stress, pregnancy, lactation, antibiotics and sulfa drugs, all increase dietary needs of nicotinic acid (3). Elevated free fatty acids and ketone bodies in the blood are associated with ketosis, zinc depletion and the prediabetic state (6,7). There is a diminished uptake of glucose by the tissues, a condition also found in parturient paresis of dairy cows when elevated hydrocortisone promotes insulin resistance and hyperglycaemia (8). This defect in insulin response leads to a diabetidike state. The major predisposing factor in parturient paresis of dairy cows is hypocalcaemia. Gut absorption of dietary calcium may not meet the primary demands of lactation initiation until bone calcium mobilisation is established (8).
Introduction
In experimental nicotinic acid deficiency iu the diet of the young calf, acute lethal scours developed in the first few days of life (5). On the other hand nicotinic acid therapy for ketosis in lactating cows reduced the free fatty acids and ketone bodies in the blood plasma. It also reduced the Date received 6 July 1992 Date accepted 28 August 1992
rate of glucose removal following glucose loading (6). The nicotinic acid effect reduces hypoglycaemia, whereas insulin and zinc reduce hyperglycaemia. High tiee fatty acids in the blood diminish glucose uptake by the tissues, a state found iu zinc defiiient rats, in the pte-diabetic state (7) and in hydrocortisone induced insulin n&stance (8). In parturient paresis of dairy cows, as plasma Cal296
METABOLIC
cium declined, plasma hydrocortisone levels rose (8). Hydrocortisone promoted insulin resistance and elevated blood glucose (8). Lamond (9) observed that the zinc deficient could not compete in mob feeding at the feedlot The Fit sign was a modification of appetite, then depressed appetite and weight loss, similar to animals with ketosis (6). The zinc deficient animals also became less active and were apathetic. Skin lesions, hair loss and dermatitis developed. Ketotic cows am also zinc deficient (14). When lactating cows were starved for 2 days, plasma tryptophan levels fell to a quarter of the level in fully fed cows (10).
Dlscussiou Oral nicotinic acid and zinc therapies both have an anti-lipolytic effect High fatty acid levels in blood plasma diminish the uptake of glucose by the tissues, a situation found in the pre-diabetic state and in zinc deficient rats (7). Low birthweight babies have high blood glucose values (11) as do patients on Total Parenteral Nutrition (TPN) (12). The elevated glucose and insulin levels in TPN patients lead to failure to mobilise body stores of linoleic acid (12). There are differences in glucose tolerance between oral glucose dosing and intravenous glucose injections (7). The periparturient dairy cow has a declining calcium level in plasma which promotes elevated hydrocortisane, insulin resistance and hyperglycaemia (8). New Zealand dairy cows had low zinc levels in the periparturient period (13). There is a reduced glucose tolerance in zinc deficiency (7). Zinc levels fall during physiological stress, coinciding with rising glucocorticoid levels (14). There is increasing alimentary stasis in preparturient dairy cows, leading to a decline in calcium absorption from the gut (8.15). Hypocalcaemia leads to increased release of hydrocortisone and elevated glucose (8) when plasma zinc levels are also low lketosis, elevated hydrocortisone (14)l. Glucose uptake by the tissues is impaired by insulin resistance. Linoleic acid
Both zinc and nicotinic acid inhibit adipose tissue degradation and hence the production of ketones (6, 7).
297
DISORDERS OF CATIU
In zinc deficiency, fat pads fi-om zinc deficient rats took up glucose mom slowly than did fat pads from control animals (16). Horrobin has noted that prostaglandin synthesis may be blocked by high blood glucose levels and low zinc levels (17). He states that high glucose and insulin levels create an essential fatty acid deficiency attributed to failure to mob&e body stores of linoleic acid (12). The effect of insulin and zinc in siphoning off glucose into the fat cell is crucial to reducing the glucose load and mobilising linoleic acid. Linoleic acid is then available for elongation, desaturation and prostaglandin synthesis. It is hypotbesised that the initial zinc-essential fatty acid interaction is indirect It is suggested that the action of zinc on glucose metabolism leads to mobilisation of linoleic acid and inhibits adipose tissue release of free fatty acids which compete with essential fatty acids (17). Enhrphins
The hormone lipotrophin is involved in the mobilisation of fatly acids from body stores (18). (Is lipotrophin inhibited by zinc and insulin?) B-endorphin is one of the neuropeptide fragments of the hormone lipotmphin. The endorphins mimic opiates and the catatonic effect of B-endorphin resembles the apathy observed in zinc deficient rats (21), in ketotic cows (6) and in animals observed by Reid after subjection to the ‘Golberger syndrome’. In these situations fatty acids are mobilised from adipose tissue. Horrobin describes possible roles of prostaglandins in mediating opioid actions (19). Opiates, inducing apnoea and a lo-fold increase in the incidence of Sudden Infant Death, have been associated with maternal addiction to methadone (20). Calf diarhoea
The production and study of an acute nicotinic acid deficiency in the calf suggested that nicotinic acid synthesis depended on colonisation by intestinal gut flora on the first few days after birth (5). The symptoms of induced nutritional scours exhibited by these calves were loss of appetite, severe scouring, dehydration, weakness and sudden death by the second or third day on the deficient diet Post mortem studies found no disease producing organisms and only slight congestion of the lungs. Young calves born during storms die suddenly from
298
MEDICAL HYPOTHESES
0
6
12
16
24
-
Fig. 1 Comparison of semm zinc, plasma corticoids, and rectal temperature in hyperthermal stressed cows. From (1411.
scours in a similar manner. Cold stress increases the dietary need for nicotinic acid (3).
Conclusion Physiological stress lowered serum zinc in ketotic cows, in cows subjected to hyperthermal stress (14), in peri-parttnient cows (13) during parturition and in animals suffering from dystocia (26). Cows approaching parturition and developing uegative calcium balance developed elevated glucocorticoids and elevated glucose (8). The cows subjected to hyperthermal stress recorded declining zinc levels coinciding with increasing levels of corticosteroids (14) (Fig. 1). Glucose levels and corticosteroids were not recorded for the New Zealand periparturient cows with low serumzinc, nor for the cows with dystocia and low serum zinc during labour (Fig. 2). It is suggested that the hyperthermic animals with low serum zinc and elevated corticoids would also have elevated glucose levels and insulin resistance. It is suggested that the cows approaching parturition in negative calcium balance, with elevated corticoids and glucose would also register low serum zinc levels. It is suggested that the cows with dystocia and low serum zinc would also have elevated corticoids and elevated glucose and hypocalcaemia. It is suggested that the peri-parturieut cows with low serum zinc levels also had elevated corticoids and elevated glucose and hypocalcaemia. It is suggested that all 3 parameters (glucocorticoids, glucose, zinc) am biochemical markers for increasing
the diabetic-like state described by Littledyke (8). He concluded that hypoglycaemia of parturient paresis was associated with a defect in the insulin response to hyperglycaemia and increased adrenal corticoid activity, which combine to produce a diabetic-like state (29). The role of oral zinc in the duodenal mucosamay be crucial to the production of hormones which stimulate the release of insulin-like substances from the salivary glands and the exocrine cells of the pancreas (7). Corticosteroid stimulatiou of plasma glucose elevation would mimic the elevation of plasma glucose by the intravenous route. Zinc deficiency reduced glucose tolerance iu intravenous glucose challenge but not in oral glucose challenge (7). The insulin-like substances secreted in saliva and pancreatic secretions into the gut have non-suppressible insulin-like activity in contrast to the insulin suppression activity of elevated corticoid hormones (7). Stimulation of this nonsuppressible insulin-like activity may even be life saving during suppression of insulin release from the pancreas and during suppression of insulin activity. High blood glucose and corticoid induced insulin resistance set the stage for essential fatty acid deficiency. A failure to mobilise body stores of linoleic acid (12) leads to pathology analogous with zinc deficiency at parturition in the rat (21) and with aspirin toxicity (22). Skin lesions typical of essential fatty acid deficiency develop in zinc deficiency (23). [High levels of saturated fatty acids inhibit metabolism of essential fatty acids (17).] Deficiency of essential fatty acids leads to failure of prostaglaudin synthesis. [Note the alimentary stasis associated with hypocalcaemia and elevated blood glucose (8)) The salivary glands, exocriue cells of the pancreas and intestinal mucosa absorb zinc rapidly.
05 Sampling Period - Days -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4
5 6
7
Fig. 2 h&an blood plasma zinc 1eveIs of dairy cows in peripartwient period. prom (13)].
MFXABOLJC
DISORDERS
299
OF CATEE
In 1973 Reid treated a prostrate comatose cow with oral zinc sulphate (dry as she could not swallow). The cow was professionally diagnosed as moribund and in a coma. She had not responded to calcium borogluconate. Reid observed the animal had sunken eyes, a completely dry mouth devoid of saliva and mminal stasis. The cow was unconscious. She fitted the description of patients administered large doses of corticosteroids for bum stress and surgical stress presenting low-cardiac-output syndrome resulting in rapid depression in serum zinc [see Flynn et al in (14)]. Reid considers the visceral distension and ascites were typical of venous stagnation and low cardiac-output syndrome. An hour or so after oral zinc treatment the cow had left the barn and was located beside a hedge chewing the cud. There was a resumption of salivary flow and ruminal motility. The muzzle was moist. There was a reversal of venous stagnation and an increase in arterial blood flow as evidence of reduction in dehydration_
insulin release, apart from calcium (29). In the skin l,25(OI-I)& said to influence cellular growth and differentiation (29). The hormone induces changes in keratinocytes (29) and VDR protein has been found in the nuclei of cells in the root sheath of the hair follicle (28). The VDR protein with its repetitive zinc motifs may be sensitive to zinc availability. If this is so, the defective insulin response which produces a diabeticlike state in parturient paresis in diary cows may involve metabolic vitamin D resistance and hypocalcaemia. zinc deficiency has been attributed to a failure to fold the steroid receptors properly, for mcognition of the gene (30). A primary lesion of zinc deficiency in the skin, intestine and hair follicle may involve the hormone 1,25(OI-QDs and its hormone receptor protein. Zinc hormone receptors appear to be essential for vitamin D altered cell function, such as blocking or inducing transcription of specific proteins (29).
The steroid and thyroidhormonereceptor super&amReferences ily (27) This superfamily of hormone receptor proteins are zinc binding structures of amino acid loops or fingers formed around a zinc atom These hormone receptors fold into a zinc repeating motif for nucleic acid binding and activation of gene expression (27). These hormone receptors bind to thyroid hormone, adrenal and sex hormones and the hormone active version of vitamin D (1,25(OH)~Ds). The levels of these hormones rise during parturition of dairy cows, coinciding with the fall in plasma zinc (13, 21). High doses of calcium or vitamin D are preventive measures in hypocalcaemia of the dairy cow. Cortisone and glucose levels rise in hypocalcaemia and insulin levels fall (8). Apgar found an exogenous source of zinc was required during parturition in the rat (21). Hypocalcaemia at parturition of dairy cows appears to resemble the genetic disorder of vitamin D resistant rickets in children. These children have a defect in the protein chain of the zinc finger steroid receptor - the vitamin D receptor (VDR) protein (28). The children develop hypocalcaemia and alopecia (28). The defect in the VDR protein may account for similar lesions in zinc deficiency and vitamin D resistance. The classic lesions of zinc deficiency in animals and in human acrodermatitis enteropathica are anorexia, skin lesions and alopecia. In the pancreas 1,25(OH)aDs is essential for normal
1. Roe DA. A plague of corn. Ithaca: Cornell University Press, 1973. 2. VanEys J. Nicotinic acid. In: MachlinLJ,ed Handbookof vitamins, 2nd ed. New Yorkz Marcel Dekkcr, 1991: 326. 3. Hat&es V. In: Machlin LJ, ed. Handbook of vitamins, 1st ed. New YoI1E:Marcel Dekker, 1984: 356. 4. Leklem JE. Vitamin 86. Itr Machlin LJ, ed. Handbook of vitamins, 2nd ed. New York: Marcel Dekker, 1991: 352. 5. Hopper JH. Johnson BC. The production and study of an acute nicotinic acid deficiency in the young calf. J Nutr 1955.56: 303-3 10. 6. Fmnk TJ, Schultz LH. Oral nicotinic acid as a treatment for ketosis. J Dairy Sci 197% 62: 1804-l 807. 7. Roth HP, Rirchgessner M. Review zinc and insulin mechanism. Biol Trace EIem Rev 1981; 3: 13-32. 8. Littledyke ET, Wbipp SC, Schroeder L. Studies of patturient paresis. J AmVetMed Assoc 1969; 155(12): 1955-1962. 9. Lamond M. Zinc deficiency in ruminants. Irish Vet J 1984; 38: 40-47. 10. Davis SR, Huchson GA, McLay LM. Blood plasma tryptophan concentmtion- A potentially useful indicator of feed intake in pasture fed animals. Proc N 2 Sot Anim Pmd 1982; 42: 165-166. Il. Charlton V. Neonatal specialist, University of California, San Francisco, qorted in New Zealand Herald, August 1,198s. 12. Honobin DF, Cunnane SC. Interactions between zinc, essential fatty acids and prostagIandins. Med Hypoth 1980; 6: 277-296. 13. Pryor WJ. Plasma zinc status of dairy cattle in the periparturient period. N ZVet J 1976; 24: 57-58. 14. Wegner TN, Ray DE, Cox CD, Stott GH. Effect of stress in serum zinc and plasma corticoids in dairy cattle. J Dairy Sci
300 1973; 56(6): 748-752. 15. Moodie EW, Robertz.on A. Some aspects of calcium metabolism in the dairy cow. Res Vet Sci 1962.3: 470-484. 16. Quarterman J. The metabolic role of zinc with special reference to carbohydrate and lipid metabolism. Rowett Res Inst, Annualreport 1968; 24: 100-108. 17. Hozmbin DF. The nutritional regulation of T lymphocyte function. Med Hypoth 197% 5: 969-985. 18. de Weid D. Neuropeptides and psychopathology. Endeavor New Series No. 4. Pergamon Press, 1980. 19. Hormbin DF. Possible roles of prostaglandins in mediating opioid actions in endotphins. In: Shaw NS, Donald AG, eds. Plenem Press, 1991. 20. Becker LE. Neural maturation delay as a risk in the chain of events leading to SIDS. Can J Neural Sci 1970; 17: 361-371. 21. Apgac J. Effect of zinc deficiency on parturition in the rat. Am J Physiol 1968; 215 (1): 160-163. 22. O’Dell BL, Reynolds G, Reeves PG. Analogous effects of zinc deficiency and aspirin toxicity in the pregnantrat. J Nutr 1977; 107: 1222-1228.
MEDICALBYFQTfIEsEs 23. Bettger WJ, Reeves PG. Moscatelli ER, Reynolds G. O’Dell BL. Interaction of zinc and essential fatty acids in the rat. J Nutr 1979; 109: 480-488. 24. Hove E, Elvehjem CR, Hart EB. The physiology of zinc in the nutrition of the rat. Am J Physioll937; 119: 768-775. 25. McKim~?yJM, Felig P. The metabolic response to injury and infection. In: De Gmot L, ed. Endocrinology 3. New Yoric Grune & Stratton, 1979: 1966. 26. Dufty J. CSIRO: Div Anim Health, Australia. Personal communication, 1974. 27. Evans M. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-895. 28. Anon. Zinc fmgen snd vitamin D resistance. Lancet, 4 March, 1989: 478. 29. Collins ED, Norman AW. Vitamin D. In: Machlin LJ, ed. Handbook of vitamins 2nd ed. New York: Marcel Dekker, 1990: 59-98. 30. Klug A, Rhodes D. ‘Zinc fingers’: A novel protein motif for nucleic acid recognition. Trends Biochem Sci 1987; 12: 464 469.
Metabolic Disorders of Cattle G. REID 25 Gilchtist St, Te Aloha, New Zealand
Abstract - Goldberger (1) discovered human pellagra was a non-infectious disease, affecting mostly the small and the timid in overcrowded institutions. Symptoms were diarrhoea, dermatitis and dementia. The staff and older children escaped the disease. They ate the meat and left the small and timid with the gravy. The ‘Goldberger syndrome’ is observed during competitive feeding of livestock, in ketotic animals and in the zinc depleted which are lethargic and pick all day at their feed (6,9). The pellagra preventative factor was later found to be nicotinic acid, derived from the amino acid tryptophan. Deficiencies of copper, magnesium, vitamin B6 (activated by a zinc kinase) inhibit the conversion of tryptophan to nicotinic acid (2,3,4). Stresses, including liver diseases, malabsorption, iron overload, porphyria, marasmus, cold stress, pregnancy, lactation, antibiotics and sulfa drugs, all increase dietary needs of nicotinic acid (3). Elevated free fatty acids and ketone bodies in the blood are associated with ketosis, zinc depletion and the prediabetic state (6,7). There is a diminished uptake of glucose by the tissues, a condition also found in parturient paresis of dairy cows when elevated hydrocortisone promotes insulin resistance and hyperglycaemia (8). This defect in insulin response leads to a diabetidike state. The major predisposing factor in parturient paresis of dairy cows is hypocalcaemia. Gut absorption of dietary calcium may not meet the primary demands of lactation initiation until bone calcium mobilisation is established (8).
Introduction
In experimental nicotinic acid deficiency iu the diet of the young calf, acute lethal scours developed in the first few days of life (5). On the other hand nicotinic acid therapy for ketosis in lactating cows reduced the free fatty acids and ketone bodies in the blood plasma. It also reduced the Date received 6 July 1992 Date accepted 28 August 1992
rate of glucose removal following glucose loading (6). The nicotinic acid effect reduces hypoglycaemia, whereas insulin and zinc reduce hyperglycaemia. High tiee fatty acids in the blood diminish glucose uptake by the tissues, a state found iu zinc defiiient rats, in the pte-diabetic state (7) and in hydrocortisone induced insulin n&stance (8). In parturient paresis of dairy cows, as plasma Cal296
METABOLIC
cium declined, plasma hydrocortisone levels rose (8). Hydrocortisone promoted insulin resistance and elevated blood glucose (8). Lamond (9) observed that the zinc deficient could not compete in mob feeding at the feedlot The Fit sign was a modification of appetite, then depressed appetite and weight loss, similar to animals with ketosis (6). The zinc deficient animals also became less active and were apathetic. Skin lesions, hair loss and dermatitis developed. Ketotic cows am also zinc deficient (14). When lactating cows were starved for 2 days, plasma tryptophan levels fell to a quarter of the level in fully fed cows (10).
Dlscussiou Oral nicotinic acid and zinc therapies both have an anti-lipolytic effect High fatty acid levels in blood plasma diminish the uptake of glucose by the tissues, a situation found in the pre-diabetic state and in zinc deficient rats (7). Low birthweight babies have high blood glucose values (11) as do patients on Total Parenteral Nutrition (TPN) (12). The elevated glucose and insulin levels in TPN patients lead to failure to mobilise body stores of linoleic acid (12). There are differences in glucose tolerance between oral glucose dosing and intravenous glucose injections (7). The periparturient dairy cow has a declining calcium level in plasma which promotes elevated hydrocortisane, insulin resistance and hyperglycaemia (8). New Zealand dairy cows had low zinc levels in the periparturient period (13). There is a reduced glucose tolerance in zinc deficiency (7). Zinc levels fall during physiological stress, coinciding with rising glucocorticoid levels (14). There is increasing alimentary stasis in preparturient dairy cows, leading to a decline in calcium absorption from the gut (8.15). Hypocalcaemia leads to increased release of hydrocortisone and elevated glucose (8) when plasma zinc levels are also low lketosis, elevated hydrocortisone (14)l. Glucose uptake by the tissues is impaired by insulin resistance. Linoleic acid
Both zinc and nicotinic acid inhibit adipose tissue degradation and hence the production of ketones (6, 7).
297
DISORDERS OF CATIU
In zinc deficiency, fat pads fi-om zinc deficient rats took up glucose mom slowly than did fat pads from control animals (16). Horrobin has noted that prostaglandin synthesis may be blocked by high blood glucose levels and low zinc levels (17). He states that high glucose and insulin levels create an essential fatty acid deficiency attributed to failure to mob&e body stores of linoleic acid (12). The effect of insulin and zinc in siphoning off glucose into the fat cell is crucial to reducing the glucose load and mobilising linoleic acid. Linoleic acid is then available for elongation, desaturation and prostaglandin synthesis. It is hypotbesised that the initial zinc-essential fatty acid interaction is indirect It is suggested that the action of zinc on glucose metabolism leads to mobilisation of linoleic acid and inhibits adipose tissue release of free fatty acids which compete with essential fatty acids (17). Enhrphins
The hormone lipotrophin is involved in the mobilisation of fatly acids from body stores (18). (Is lipotrophin inhibited by zinc and insulin?) B-endorphin is one of the neuropeptide fragments of the hormone lipotmphin. The endorphins mimic opiates and the catatonic effect of B-endorphin resembles the apathy observed in zinc deficient rats (21), in ketotic cows (6) and in animals observed by Reid after subjection to the ‘Golberger syndrome’. In these situations fatty acids are mobilised from adipose tissue. Horrobin describes possible roles of prostaglandins in mediating opioid actions (19). Opiates, inducing apnoea and a lo-fold increase in the incidence of Sudden Infant Death, have been associated with maternal addiction to methadone (20). Calf diarhoea
The production and study of an acute nicotinic acid deficiency in the calf suggested that nicotinic acid synthesis depended on colonisation by intestinal gut flora on the first few days after birth (5). The symptoms of induced nutritional scours exhibited by these calves were loss of appetite, severe scouring, dehydration, weakness and sudden death by the second or third day on the deficient diet Post mortem studies found no disease producing organisms and only slight congestion of the lungs. Young calves born during storms die suddenly from
298
MEDICAL HYPOTHESES
0
6
12
16
24
-
Fig. 1 Comparison of semm zinc, plasma corticoids, and rectal temperature in hyperthermal stressed cows. From (1411.
scours in a similar manner. Cold stress increases the dietary need for nicotinic acid (3).
Conclusion Physiological stress lowered serum zinc in ketotic cows, in cows subjected to hyperthermal stress (14), in peri-parttnient cows (13) during parturition and in animals suffering from dystocia (26). Cows approaching parturition and developing uegative calcium balance developed elevated glucocorticoids and elevated glucose (8). The cows subjected to hyperthermal stress recorded declining zinc levels coinciding with increasing levels of corticosteroids (14) (Fig. 1). Glucose levels and corticosteroids were not recorded for the New Zealand periparturient cows with low serumzinc, nor for the cows with dystocia and low serum zinc during labour (Fig. 2). It is suggested that the hyperthermic animals with low serum zinc and elevated corticoids would also have elevated glucose levels and insulin resistance. It is suggested that the cows approaching parturition in negative calcium balance, with elevated corticoids and glucose would also register low serum zinc levels. It is suggested that the cows with dystocia and low serum zinc would also have elevated corticoids and elevated glucose and hypocalcaemia. It is suggested that the peri-parturieut cows with low serum zinc levels also had elevated corticoids and elevated glucose and hypocalcaemia. It is suggested that all 3 parameters (glucocorticoids, glucose, zinc) am biochemical markers for increasing
the diabetic-like state described by Littledyke (8). He concluded that hypoglycaemia of parturient paresis was associated with a defect in the insulin response to hyperglycaemia and increased adrenal corticoid activity, which combine to produce a diabetic-like state (29). The role of oral zinc in the duodenal mucosamay be crucial to the production of hormones which stimulate the release of insulin-like substances from the salivary glands and the exocrine cells of the pancreas (7). Corticosteroid stimulatiou of plasma glucose elevation would mimic the elevation of plasma glucose by the intravenous route. Zinc deficiency reduced glucose tolerance iu intravenous glucose challenge but not in oral glucose challenge (7). The insulin-like substances secreted in saliva and pancreatic secretions into the gut have non-suppressible insulin-like activity in contrast to the insulin suppression activity of elevated corticoid hormones (7). Stimulation of this nonsuppressible insulin-like activity may even be life saving during suppression of insulin release from the pancreas and during suppression of insulin activity. High blood glucose and corticoid induced insulin resistance set the stage for essential fatty acid deficiency. A failure to mobilise body stores of linoleic acid (12) leads to pathology analogous with zinc deficiency at parturition in the rat (21) and with aspirin toxicity (22). Skin lesions typical of essential fatty acid deficiency develop in zinc deficiency (23). [High levels of saturated fatty acids inhibit metabolism of essential fatty acids (17).] Deficiency of essential fatty acids leads to failure of prostaglaudin synthesis. [Note the alimentary stasis associated with hypocalcaemia and elevated blood glucose (8)) The salivary glands, exocriue cells of the pancreas and intestinal mucosa absorb zinc rapidly.
05 Sampling Period - Days -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4
5 6
7
Fig. 2 h&an blood plasma zinc 1eveIs of dairy cows in peripartwient period. prom (13)].
MFXABOLJC
DISORDERS
299
OF CATEE
In 1973 Reid treated a prostrate comatose cow with oral zinc sulphate (dry as she could not swallow). The cow was professionally diagnosed as moribund and in a coma. She had not responded to calcium borogluconate. Reid observed the animal had sunken eyes, a completely dry mouth devoid of saliva and mminal stasis. The cow was unconscious. She fitted the description of patients administered large doses of corticosteroids for bum stress and surgical stress presenting low-cardiac-output syndrome resulting in rapid depression in serum zinc [see Flynn et al in (14)]. Reid considers the visceral distension and ascites were typical of venous stagnation and low cardiac-output syndrome. An hour or so after oral zinc treatment the cow had left the barn and was located beside a hedge chewing the cud. There was a resumption of salivary flow and ruminal motility. The muzzle was moist. There was a reversal of venous stagnation and an increase in arterial blood flow as evidence of reduction in dehydration_
insulin release, apart from calcium (29). In the skin l,25(OI-I)& said to influence cellular growth and differentiation (29). The hormone induces changes in keratinocytes (29) and VDR protein has been found in the nuclei of cells in the root sheath of the hair follicle (28). The VDR protein with its repetitive zinc motifs may be sensitive to zinc availability. If this is so, the defective insulin response which produces a diabeticlike state in parturient paresis in diary cows may involve metabolic vitamin D resistance and hypocalcaemia. zinc deficiency has been attributed to a failure to fold the steroid receptors properly, for mcognition of the gene (30). A primary lesion of zinc deficiency in the skin, intestine and hair follicle may involve the hormone 1,25(OI-QDs and its hormone receptor protein. Zinc hormone receptors appear to be essential for vitamin D altered cell function, such as blocking or inducing transcription of specific proteins (29).
The steroid and thyroidhormonereceptor super&amReferences ily (27) This superfamily of hormone receptor proteins are zinc binding structures of amino acid loops or fingers formed around a zinc atom These hormone receptors fold into a zinc repeating motif for nucleic acid binding and activation of gene expression (27). These hormone receptors bind to thyroid hormone, adrenal and sex hormones and the hormone active version of vitamin D (1,25(OH)~Ds). The levels of these hormones rise during parturition of dairy cows, coinciding with the fall in plasma zinc (13, 21). High doses of calcium or vitamin D are preventive measures in hypocalcaemia of the dairy cow. Cortisone and glucose levels rise in hypocalcaemia and insulin levels fall (8). Apgar found an exogenous source of zinc was required during parturition in the rat (21). Hypocalcaemia at parturition of dairy cows appears to resemble the genetic disorder of vitamin D resistant rickets in children. These children have a defect in the protein chain of the zinc finger steroid receptor - the vitamin D receptor (VDR) protein (28). The children develop hypocalcaemia and alopecia (28). The defect in the VDR protein may account for similar lesions in zinc deficiency and vitamin D resistance. The classic lesions of zinc deficiency in animals and in human acrodermatitis enteropathica are anorexia, skin lesions and alopecia. In the pancreas 1,25(OH)aDs is essential for normal
1. Roe DA. A plague of corn. Ithaca: Cornell University Press, 1973. 2. VanEys J. Nicotinic acid. In: MachlinLJ,ed Handbookof vitamins, 2nd ed. New Yorkz Marcel Dekkcr, 1991: 326. 3. Hat&es V. In: Machlin LJ, ed. Handbook of vitamins, 1st ed. New YoI1E:Marcel Dekker, 1984: 356. 4. Leklem JE. Vitamin 86. Itr Machlin LJ, ed. Handbook of vitamins, 2nd ed. New York: Marcel Dekker, 1991: 352. 5. Hopper JH. Johnson BC. The production and study of an acute nicotinic acid deficiency in the young calf. J Nutr 1955.56: 303-3 10. 6. Fmnk TJ, Schultz LH. Oral nicotinic acid as a treatment for ketosis. J Dairy Sci 197% 62: 1804-l 807. 7. Roth HP, Rirchgessner M. Review zinc and insulin mechanism. Biol Trace EIem Rev 1981; 3: 13-32. 8. Littledyke ET, Wbipp SC, Schroeder L. Studies of patturient paresis. J AmVetMed Assoc 1969; 155(12): 1955-1962. 9. Lamond M. Zinc deficiency in ruminants. Irish Vet J 1984; 38: 40-47. 10. Davis SR, Huchson GA, McLay LM. Blood plasma tryptophan concentmtion- A potentially useful indicator of feed intake in pasture fed animals. Proc N 2 Sot Anim Pmd 1982; 42: 165-166. Il. Charlton V. Neonatal specialist, University of California, San Francisco, qorted in New Zealand Herald, August 1,198s. 12. Honobin DF, Cunnane SC. Interactions between zinc, essential fatty acids and prostagIandins. Med Hypoth 1980; 6: 277-296. 13. Pryor WJ. Plasma zinc status of dairy cattle in the periparturient period. N ZVet J 1976; 24: 57-58. 14. Wegner TN, Ray DE, Cox CD, Stott GH. Effect of stress in serum zinc and plasma corticoids in dairy cattle. J Dairy Sci
300 1973; 56(6): 748-752. 15. Moodie EW, Robertz.on A. Some aspects of calcium metabolism in the dairy cow. Res Vet Sci 1962.3: 470-484. 16. Quarterman J. The metabolic role of zinc with special reference to carbohydrate and lipid metabolism. Rowett Res Inst, Annualreport 1968; 24: 100-108. 17. Hozmbin DF. The nutritional regulation of T lymphocyte function. Med Hypoth 197% 5: 969-985. 18. de Weid D. Neuropeptides and psychopathology. Endeavor New Series No. 4. Pergamon Press, 1980. 19. Hormbin DF. Possible roles of prostaglandins in mediating opioid actions in endotphins. In: Shaw NS, Donald AG, eds. Plenem Press, 1991. 20. Becker LE. Neural maturation delay as a risk in the chain of events leading to SIDS. Can J Neural Sci 1970; 17: 361-371. 21. Apgac J. Effect of zinc deficiency on parturition in the rat. Am J Physiol 1968; 215 (1): 160-163. 22. O’Dell BL, Reynolds G, Reeves PG. Analogous effects of zinc deficiency and aspirin toxicity in the pregnantrat. J Nutr 1977; 107: 1222-1228.
MEDICALBYFQTfIEsEs 23. Bettger WJ, Reeves PG. Moscatelli ER, Reynolds G. O’Dell BL. Interaction of zinc and essential fatty acids in the rat. J Nutr 1979; 109: 480-488. 24. Hove E, Elvehjem CR, Hart EB. The physiology of zinc in the nutrition of the rat. Am J Physioll937; 119: 768-775. 25. McKim~?yJM, Felig P. The metabolic response to injury and infection. In: De Gmot L, ed. Endocrinology 3. New Yoric Grune & Stratton, 1979: 1966. 26. Dufty J. CSIRO: Div Anim Health, Australia. Personal communication, 1974. 27. Evans M. The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889-895. 28. Anon. Zinc fmgen snd vitamin D resistance. Lancet, 4 March, 1989: 478. 29. Collins ED, Norman AW. Vitamin D. In: Machlin LJ, ed. Handbook of vitamins 2nd ed. New York: Marcel Dekker, 1990: 59-98. 30. Klug A, Rhodes D. ‘Zinc fingers’: A novel protein motif for nucleic acid recognition. Trends Biochem Sci 1987; 12: 464 469.