Am J Clin Nutr 1987 Mooradian 877 95

Review
Article
Micronutrient
Arshag D Mooradian,
status
MD
in diabetes
E Morley, MB,
mellitus12
BCh
and John
ABSTRACT Diabetes mellitus is a chronic metabolic disorder, which can alter the nutritional status of the individual. Some micronutrients, in particular zinc and chromium, have been implicated in the pathogenesis of carbohydrate intolerance. This review evaluates the available published data on the status of 10 mineral elements and seven vitamins in diabetic patients and experimental animal models of diabetes. The role of these micronutrients in insulin secretion and carbohydrate metabolism is discussed in an attempt to determine whether the reported alterations in serum or tissue content of minerals or vitamins contribute to the carbohydrate intolerance of diabetic patients. It is concluded that both Type I and Type II diabetes mellitus can result in changes in certain micronutrients. However, adequately controlled studies to establish the role of trace elements in the pathogenesis of diabetes mellitus are not available. Am J C/in Nutr 1987;45:877-95. KEY WORDS
pyridoxine,
Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013
ascorbate,
Diabetes mellitus, osteopenia
micronutrient, minerals, vitamins,
zinc,
chromium,
magnesium,
Introduction The intricate relationship between nutrition and diabetes mellitus was suspected as early as 1674 when Sir Thomas Willis suggested that patients with diabetes mellitus should be advised to have gummy and starchy food. Since then a variety of dietary recommendations have been made by different diabetologists (14). Despite the large literature on the role of dietary composition in control of diabetes mellitus, there are relatively few studies on the effect of diabetes mellitus on nutrient status of the individual. It is generally accepted that chronic insulin deficiency is equivalent to starvation in the sense that both conditions are catabolic states and will lead ultimately to cachexia. This catabolic state of uncontrolled diabetes mellitus is readily reversed with insulin therapy, and the reader is referred to previous excellent reviews on the role of insulin in treatment of diabetes mellitus and prevention of major nutrient wastage (5-8). Malnutrition has been suggested as a cause of diabetes mellitus in certain geographic areas (9, 10). However, the exact pathogenetic role of malnutrition in diabetes mellitus has been disputed.
Am J Clin Nutr 1987:45:877-95. Printed in USA.
Over the last 20 yr, numerous studies have found alterations in micronutrient status of patients with diabetes mellitus, and in some studies deficiency of certain minerals or vitamins has been correlated with presence of diabetic complications. Methodological uncertainties and differences in patient populations studied have led to contradictory findings and controversial conclusions. In addition, severely restricted diets prescribed for obese diabetics and impact of recently recommended high fiber diets on mineral and vitamin absorption are of concern (11, 12). These findings have not been comprehensively evaluated in critical reviews. In this communication, we review the available studies on the vitamin and mineral status of patients with diabetes mellitus and the possible role of these substances in the pathogenesis of diabetes mellitus. Table 1
From the Geriatric Research Education and Clinical Center (ADM), Sepulveda VA Medical Center, Sepulveda, CA, and the Department of Medicine (ADM, JEM), University of California, Los Angeles, CA. 2Ad(fr reprint requests to Arshag D Mooradian, MD, VA Medical Center (lIE),16111 Plummer St.Sepulveda, CA 91343. Received March 26, 1986. Accepted for publication August 5, 1986. Society for Clinical Nutrition 877
1987 American
878 TABLE
Micronutrient
MOORADIAN 1
status of diabetic patients
Status in dia betic patients Micronutrient Type I Type II
AND
MORLEY
I. Trace
Zinc
elements (Zn)
4 4 4 4
NL or NL NL
4
NL NL
Chromium (Cr) Calcium (Ca) Magnesium (Mg) Copper (Cu) Manganese (Mn) Iron (Fe) Selenium (Se) II. Vitamins A Thiamin 3-6 3-12 C 1,25-dihydroxycholecalciferol E
*
4
NL or t NL ? NL NLt NLor4 NL NLor4 NL
? NL NLor4 NLor4 NLor4
4 t
t f
NL = neither increased or decreased. Type of diabetes not specified. Increased in Japanese diabetics.
summarizes tients with Trace Zinc
the micronutrient diabetes mellitus.
status
of pa-
minerals
Since the original finding in 1934 by Scott (13) that crystalline insulin contains --0.5% zinc (Zn), many studies have investigated the role of Zn nutriture in insulin secretion and metabolism. In 1937, Hove et al (14) found minor differences in response to oral glucose between Zn-deficient and ad libitum-fed control rats. Subsequent studies in Zn-deficient rats suggested that these animals were unable to clear glucose adequately (15-18). A similar finding was reported in Chinese hamsters (19). This impaired clearance was still present when Zn-deficient animals were compared with pairfed control animals (19). It needs to be pointed out that others have failed to demonstrate impaired glucose tolerance after oral (20) or parenteral administration (21) of glucose. In a well-controlled study in rats by Brown et al (22), Zn deficiency had no apparent effect on oral glucose tolerance or pancreatic insulin concentration. Clearly, impaired glucose tolerance is present to a greater degree after parenteral than after oral administration and this
could well be due to the greater stimulation of insulin secretion seen following enteral administration of glucose. The effect of Zn deficiency on insulin secretion from the pancreas is controversial. Basal serum insulin values have been reported either to be the same as or lower than pair-fed and ad-libitum control animals (15-18, 20, 22, 23). Overall these studies suggest that there may be a minor impairment of insulin secrelion in response to some secretagogues. This would be compatible with the report that stimulation of insulin secretion is accompanied by reduction of Zn content in $ cells of pancreas (24) and the demonstration that insulin is stored in complexes with varying ratios of Zn in pancreatic cells (25, 26). In addition to decreased insulin secretion in Zn-deficient animals, it has been suggested that Zn deficiency may lead to increased insulin resistance. In 1966, Quarterman et al (15) found decreased sensitivity to coma and convulsions following insulin administration in Zn-deficient animals. Huber and Gershoff(17) reported reduction in bioassayable serum insulin-like activity using an in vitro adipose tissue assay. Antigenic properties of insulin were altered by varying the Zn to insulin ratio (27). Further, a number of more recent studies have suggested that Zn plays a role in insulin action. These studies have shown that Zn can enhance the binding of insulin to hepatocyte membranes (28) and that it has an additive effect to that of insulin on lipogenesis in rat adipocytes (29). May and Contoreggi (30) suggested that the insulin-like effects of Zn ions in adipocytes involve the ability of Zn to modulate hydrogen peroxide generation. Zn supplementation in the obese (ob/ob) mouse resulted in a lower fasting plasma glucose level and a decrease in hyperinsulinemia normally present in these animals (31). However, responsiveness to a glucose load remained impaired in ob/ob mice after Zn supplementation, and insulin response was markedly impaired. These findings are compatible with the reports demonstrating that pharmacological concentrations of Zn, in vitro, inhibit glucoseinduced insulin secretion from islets of Langerhans (32-34) and demonstrating that acute administration of Zn to normal animals produced a transient elevation in plasma glucose with a decrease in circulating insulin and an
MICRONUTRIENT
STATUS
IN
DIABETES
879
increase in glucagon (35). In our preliminary studies we have failed to show a correlation between serum and urine Zn and severity of glucose intolerance in patients with Type II diabetes mellitus (36). Further, in a pilot study we found no significant effect of pharmacological Zn supplementation on the glycosylated hemoglobin (HbA1) levels in patients with Type II diabetes mellitus (37). In summary, although there are a number of tantalizing suggestions that Zn deficiency may play a role in the development of some forms of glucose intolerance, presently available data lead us to conclude that the role of Zn deficiency in pathogenesis of diabetes mellitus is not proven. Further, it appears that effects of Zn on insulin secretion are biphasic with higher concentrations impairing insulin release. There is accumulating evidence that development of diabetes mellitus may lead to Zn deficiency. Tissue Zn deficiency (including low femur Zn) has been reported in genetically diabetic (db/db) mice (38). This is in contrast to findings in animal models of Type I diabetes mellitus (streptozotocinand alloxan-induced) where Zn concentrations appear to be normal (38). Low serum and blood-clot Zn and hyperzincuria have been reported in initial stages of Type I diabetes mellitus (39). In our studies we found low serum Zn levels (<70 zg/dL) in 9% of 180 subjects with Type II diabetes mellitus (37) and hyperzincuria (>800 tg/24 h) in 100% of 25 subjects with Type II diabetes mellitus (36). Zn absorption was mildly impaired in these subjects despite the hyperzincuria (36). Studies in dogs receiving a 7-d continuous intravenous infusion of glucose (7.1 g/kg body wt/d) showed that glucose per se could produce hyperzincuria (36). These studies led us to conclude that hyperzincuria, which results from a glucosemediated process, interacts with impaired Zn absorption to produce borderline Zn deficiency in patients with Type II diabetes mellitus. Major causes of morbidity and mortality in older diabetic patients relate to impaired immune function (40, 41), which leads to increased infections and to diabetic foot ulcers and cellulitis and/or osteomyelitis, which result in amputations. Zn was demonstrated to be necessary for adequate function of T-cell
lymphocytes (42). We found that in patients with Type II diabetes mellitus and Zn deficiency there was improvement in the Tlymphocyte response to phytohemagglutinin and no consistent change in natural-killer (NK)-cell activity following Zn supplementation (37). We found a similar dichotomy in the effects of Zn supplementation on NK-cell activity and phytohemagglutinin-induced responses in Zn-deficient patients with lung cancer (43). Zn is well established as playing a role in wound healing (44-47). Zn supplementation was shown to accelerate healing of leg ulcers in elderly subjects in two double-blind trials (44,45). This is in keeping with findings from animal studies (46, 47). There are no reported double-blind studies on effects of Zn replacement on diabetic ulcers. Clearly, evaluation of the potential role of Zn in accelerating healing of diabetic foot ulcers is important therapeutically. Zn is recognized to be associated with altered taste perception (48). Although diabetics have poor taste perception, Zn supplementation (220 mg zinc sulfate three times a day for 3 mo) failed to improve taste recognition in diabetics with decreased serum Zn levels (37). One potentially toxic effect of Zn supplementation in patients with diabetes mellitus is that high doses of Zn in normal adults increase lowdensity lipoprotein (LDL) and decrease highdensity lipoprotein (HDL) cholesterol (49). The mechanism of this effect appears to be secondary to the impairment of copper metabolism produced by megadoses of Zn (vide infra). However, in a recent long-term study in patients with Wilsons disease, oral Zn therapy did not lower the HDL-cholesterol level (50). Overall, available studies on Zn and diabetes suggest that Zn deficiency, which occurs in some diabetics, may well play an important role in impaired T-cell function and in the pathogenesis of diabetic foot ulcers. Further studies are necessary to delineate more clearly the role of Zn in the pathogenesis of Type II diabetes mellitus. Chromium Chromium that has been (Cr) is an essential trace metal suggested to have an important
880
MOORADIAN
AND
MORLEY
role in normal glucose homeostasis (51-53). Deficiency of Cr or its biologically active form, the glucose-tolerance factor (GTF), has been implicated in the pathogenesis of some forms of glucose intolerance and diabetes mellitus (54-56). GTF is a naturally occurring low molecular weight (400-600 daltons) organic compound (57). It is water soluble and stable against wet heat, acid, and alkali treatments. The exact chemical structure is still unknown, but it appears to be a complex of nicotinic acid, amino acid components, and Cr. Glycine, cysteine, and glutamic acid appear to be the amino acid components of this compound (51, 52). Several synthetic GTFs have been found to have chemical and biological properties similar to naturally occurring GTF (52, 58, 59). Richest sources of GTF include brewers yeast, liver, and kidney. Experiments in rats (54, 60) and squirrel monkeys (61) demonstrated that dietary deficiency of Cr can result in elevated blood glucose, triglycerides, and cholesterol levels. These metabolic abnormalities were readily reversed by the administration of inorganic Cr. In mice a single intraperitoneal injection of GTF reduced the nonfasting plasma glucose level by 38% in nondiabetic and by 14-29% in diabetic animals (62). The combination treatment of diabetic mice with GTF and exogenous insulin was significantly more effective in reducing plasma glucose than either treatment alone. Similarly, in two patients Cr deficiency secondary to prolonged total parenteral nutrition was associated with glucose intolerance that is responsive to Cr supplementation (55, 56). In healthy adults, Cr supplementation either as inorganic Cr chloride or brewers yeast did not result in significant improvement in glucose tolerance (63-66). A double-blind cross-over study in 76 normal free-living subjects concluded that inorganic Cr supplementation improves glucose tolerance in individuals with blood glucose values 100 mg/dL at 90 mm during an oral glucosetolerance test (67). It is tempting to speculate that one factor contributing to the decline of carbohydrate tolerance in the elderly is the documented decrease of tissue Cr levels with age (68-70), particularly in Western societies that eat refined foods that are somewhat deficient in Cr (71). In a group of aged volunteers, supplementa-
tion of inorganic Cr or GTF in the form of brewers yeast improved glucose tolerance and insulin sensitivity in up to 50% of subjects (7274). However, a recently conducted study in 23 healthy well-nourished elderly volunteers did not find any significant changes in glucose tolerance, insulin, cholesterol, or triglycerides after supplementation with Cr or brewers yeast (75). Several limited clinical trials in small numbers of patients have reported that Cr or GTF supplementation may improve glucose intolerance in some patients with abnormal oral glucose-tolerance tests or overt diabetes (6466, 73, 74, 76). However, three double-blind cross-over studies failed to demonstrate any beneficial effects of Cr supplementation on blood glucose levels (77-79). In men with Type I or Type II diabetes, Cr supplementation with either the organic or the inorganic form did not alter fasting plasma glucose or glucose response to either a standard meal or to tolbutamide (78). Conversely, Cr supplementation in six Type II diabetic patients improved insulin sensitivity measured by a closed-loop insulin delivery system (80). In another study of 37 Type II diabetic patients, small amounts of Cr supplements (brewers yeast 1.6 g/d) resulted in a 17% decrease in glycosylated hemoglobin levels and a 36% increase in HDL levels with no change in fasting blood glucose (76). The discrepancies in these reported findings are probably secondary to the fact that experimental subjects studied are heterogenous for Cr status and ability to metabolize the inorganic Cr salt into the biologically active GTF. It has been suggested that Cr supplementation will improve glucose tolerance only in those with Cr deficiency. At present there are no reliable methods to evaluate marginal Cr deficiency. A trial of Cr supplementation may be worthwhile in relatively healthy individuals with mild glucose intolerance and elevated plasma insulin levels. Whether the organic form of Cr (GTF) is superior to the inorganic form in its ability to enhance insulin sensitivity is not known. Although some animal models of diabetes respond preferentially to GTF rather than to inorganic Cr (62, 81), evidence suggests that in humans biological activities of these two forms are similar. A recent preliminary study in healthy elderly volunteers showed that a corn-
MICRONUTRIENT
STATUS
IN
DIABETES
881
bination of Cr and nicotinic acid improved glucose tolerance, while Cr and nicotinic acid by themselves were ineffective (82). The exact mechanism by which GTF improves glucose tolerance is not known. It is suggested that GTF enhances the binding of insulin to its specific receptors possibly through initiating disulfide linkages between insulin and cell membrane (51, 52). In vitro experiments have shown that GTF can bind insulin and that these complexes of insulin and GTF exhibit greater biological activity than either insulin or GTF alone (83). The physiological significance of this observation is not clear. However, there is a 4-h lag period between administration of GTF and optimal effects on insulin action in vivo, which suggests that mechanisms other than enhanced insulin binding to its receptors, such as conversion to another active form or transport to specific intracellular sites, are involved in the action of GTF (62). Cr and/or GTF appears to have an important role in lipid metabolism. Cr deficiency in rats is associated with elevated serum cholesterol levels (54, 60). In genetically diabetic mice, GTF administration lowers the elevated plasma triglyceride and cholesterol levels by 47% and 35%, respectively (62). Several clinical trials in adults with or without glucose intolerance found that Cr supplementation may decrease serum total cholesterol and increase HDL-cholesterol levels (63, 64, 74, 76, 84). These findings could not be confirmed in subsequent placebo-controlled studies in diabetic men (78, 79) and healthy subjects (67, 75). Overall, it appears that Cr supplementations may reduce total cholesterol levels by 5-12%, increase HDL levels by 8-36%, but have no effect on serum triglyceride levels (63, 64, 74, 76, 84). The biological significance of these alterations in blood lipid levels secondary to Cr deficiency is not clear. Epidemiological and experimental data suggest that Cr deficiency may be a factor in the pathogenesis of atherosclerosis (85-87). It is not known if Cr supplementation can have beneficial effects on lipid metabolism and atherosclerosis in a subgroup of patients with marginal Cr deficiency. Prevalence of Cr deficiency among diabetic patients is not well established. Basal plasma Cr levels in Type I diabetic patients were found
to be increased, whereas plasma levels in Type II diabetic patients were similar to those in healthy controls (78). To evaluate the status of body Cr stores, plasma Cr response to oral glucose load was studied; relative plasma Cr response to a glucose load has been suggested as a potential test to assess Cr status of individuals. Plasma Cr in women with abnormal oral glucose-tolerance test decreased in response to an oral glucose load (64). When these subjects diets were supplemented with brewers yeast, ingestion of glucose resulted in an increase in plasma Cr concentration. A subsequent study in a group of patients with Type I or Type II diabetes found an increase in plasma Cr level in response to a test meal (88). Urinary Cr excretion tends to be increased in diabetics (88, 89) although only one study reported statistically significant differences between the nonobese Type II diabetic patients and control subjects (88). Increased urinary excretion of Cr in insulin-requiring diabetic patients is counterbalanced by enhanced gastrointestinal absorption of Cr (90). As a group, diabetic children have reduced hair Cr compared with control children (91). Hair Cr content in adult insulin-dependent diabetic patients was decreased only in female patients (92). In a study of adult male Type I and Type II diabetic patients, there were no differences in hair or red blood cell Cr levels when compared with control subjects (88). A wide variation in Cr levels was found in various samples from both diabetic and healthy individuals. Although differences in Cr level between diabetic patients as a group and nondiabetic subjects did not reach statistical significance, the lowest values of Cr were seen in certain individual diabetic patients, which suggests that there might be a subgroup of diabetic patients with Cr deficiency (88). It is possible that differences in patient population studied as well as differences in body pools of Cr evaluated can account in part for discrepancies in reported findings. Methodological problems in measurements of Cr in the majority of the studies reported make the conclusions drawn uncertain. Furthermore, measurements of elemental Cr level may not reflect the functional Cr status in diabetic patients. Screening for GTF deficiency using appropriate bioassay techniques may yield physiologically more relevant information.
882
MOORADIAN
AND
MORLEY
Overall it appears that although Cr deficiency can lead to glucose intolerance, it rarely plays a role in the pathogenesis of diabetes mellitus and most diabetic patients are not Cr deficient. However, at present, the major technical problems associated with the demonstration of Cr deficiency do not allow an accurate assessment of Cr status. Inconsistency of responses to Cr supplementation in diabetic patients may be in part secondary to heterogeneity of diabetic patients with regard to micronutrient status. It is possible that response to Cr supplementation is determined by Cr status of the patient such that only those with Cr deficiency will respond favorably to supplementation. The potential role of Cr deficiency in the glucose intolerance associated with aging deserves further investigation. Magnesium Magnesium (Mg) is an essential ion involved in glucose homeostasis at multiple levels. It is a cofactor in the glucose transport system of plasma membranes, has an important role in activity of various enzymes involved in glucose oxidation, may play a role in release of insulin, and can modulate the mechanisms of energy transfer from highenergy phosphate bonds (93-96). Human and animal studies have indicated that diabetes mellitus is associated with increased urinary loss of Mg especially when hyperglycemia is poorly controlled (97-101). Thus, it is not surprising that in a survey of patients attending a general medical clinic, diabetes mellitus was found to be the most frequent chronic disease associated with hypomagnesemia (102). Although studies in small groups of patients have yielded conificting results (103, 104), overwhelming evidence indicates that plasma Mg concentration in diabetic patients is reduced. In a study of 582 unselected diabetic outpatients, the mean plasma Mg level was significantly lower than the level in control subjects (105). Moreover, 25% of diabetic patients had values below those of all control subjects except one. An inverse correlation between plasma concentrations of Mg and glucose was found in a study of diurnal profile of diabetic patients and control subjects (106). Similarly, an inverse
correlation between serum Mg level and duration of diabetes was found in a study of diabetic children in Sweden (107). Insulindependent diabetic patients had a 30% decrease in trabecular bone Mg content of iliac crest biopsies (107); Mg content of erythrocytes, leukocytes, and muscle was normal (108-112), which suggests that the effect of diabetes or insulin treatment on different tissue pools of Mg can be variable. In rats, hypomagnesemia was found in experimentally induced diabetes mellitus (100, 101), and depletion of Mg in bone occurred when the Mg intake was restricted to the physiologic requirement of control animals (101). The underlying cause of hypomagnesemia in diabetes is not totally clear. It appears to be, at least in part, secondary to urinary Mg loss (97-10 1). In a study of 215 insulin-treated diabetic patients, 39% had hypomagnesemia and 55% had hypermagnesiuria (98). Residual insulin secretory status in insulin-dependent diabetes had no influence on serum Mg level (67) although insulin caused a shift of Mg from extracellular space into hepatocytes and muscle cells (113). Of particular concern was the large urinary Mg loss during diabetic ketoacidosis (77). The resultant hypomagnesemia can have lifethreatening effects on myocardium and skeletal muscles. Furthermore, hypomagnesemia was implicated in insulin resistance following diabetic ketoacidosis (114). Biological sequelae of mild hypomagnesemia in diabetic patients are not completely defined. Yajnik et al (96) found that the direct relation of plasma Mg concentrations with glucose disposal rate was secondary to the alterations in tissue sensitivity to insulin. It is possible that Mg may be an important determinant of insulin sensitivity in noninsulin dependent diabetes mellitus. Mg deficiency has been linked to two common complications of diabetes, namely retinopathy (115) and ischemic heart disease (116, 117). Patients with severe diabetic retinopathy have lower plasma Mg levels than do diabetic patients with minimal retinal changes, which suggests that hypomagnesemia may be a risk factor in development of diabetic retinopathy (115). Whether the accelerated atherosclerosis of diabetes is in part related to depleted body-pool Mg remains totally conjectural.
MICRONUTRIENT
STATUS
IN
DIABETES
883
Copper The role of copper (Cu) in glucose homeostasis is not well defined. Experimental data suggest that impairment of glucose tolerance can be secondary to Cu deficiency (118-121). Cu deficiency in rats fed sucrose or fructose, but not those fed starch, significantly increased glucose response and decreased insulin response to an oral glucose load (121). In Cudeficient rats with streptozotocin-induced diabetes, glucose intolerance is improved by Cu supplementation. The combined effect of Cu and insulin on lowering peak blood glucose following intraperitoneal injection of 4C glucose and incorporation of glucose into lipid was much greater than either insulin or Cu alone (120). In vitro experiments have shown that Cu has insulin-like activity in promoting lipogenesis (118, 122). The mechanism underlying the Cu-enhanced glucose utilization is unknown. In addition, experimentallyinduced Cu deficiency in a healthy man was associated with elevated total-cholesterol level, which contributes to atherosclerosis (123). Conversely, elevated serum Cu concentrations have been found in diabetic and nondiabetic arteriosclerosis (124-127); the role of Cu in arteriosclerosis is not understood. With the exception of two clinical studies (128, 129) and one study in alloxan-induced diabetic rats (130), human studies and experiments in diabetic animals have found either normal or increased serum and tissue Cu concentrations (127, 131-138). In insulindeficient diabetic rats, concentrations of Cu and (Cu, Zn)-metallothionein in the liver and kidney are markedly elevated (136, 137). The tissue Cu content was normalized by insulin treatment, which suggests that hormonal imbalance may be related to altered tissue Cu content (136). Moreover, intestinal Cu absorption in diabetic rats is markedly enhanced (139); this may contribute to increased tissue Cu content. Pair feeding of Cu to diabetic and control rats did not demonstrate that enhanced food consumption by the diabetic rat had a significant impact on accumulation of Cu (136). Urinary excretion of Cu was fivefold higher in streptozotocin-induced diabetic rats than in control rats, insulin treatment significantly reduced the urinary losses of Cu (140).
In humans there was a weak correlation between fasting blood glucose and serum Cu (132, 133). Generally, serum concentrations of Cu and ceruloplasmin are elevated in Type II diabetic patients (133). Elevated serum Cu levels were not correlated with duration of diabetes, but levels were higher in older patients and in those with complications (127). Increased urinary Cu excretion was found in Russian diabetic patients (141); blood Cu content was also increased in Russian diabetics with gangrene in contrast to those without gangrene, in whom the Cu levels were reduced (129). The pathophysiological implications of these observations are not known. Whether increased renal Cu content contributes to the nephropathy of diabetes mellitus is not known. Mean erythrocyte Cu-Zn superoxide dismutase was lower in insulin-dependent diabetic patients than in healthy control subjects (142). However, the small differences found probably have no biological significance. Manganese Experimental evidence suggests that manganese (Mn) deficiency in guinea pigs can cause impaired glucose utilization and Mn supplementation can reverse glucose intolerance induced by Mn deficiency (143). Intrauterine Mn deficiency resulted in atrophy of islet cells (144), and hepatic Mn content in rats with streptozotocin-induced diabetes was significantly elevated (136, 145). Similarly, excessive accumulation of Mn was found in fetuses and livers of diabetic dams (146, 147). In the liver, each mole of activated arginase, a Mn-dependent enzyme, contained 4 mol Mn (148). It is possible that increased rates of hepatic amino acid metabolism and urea synthesis, which characterize insulin deficiency, are related to increased arginase activity in liver of streptozotocin-induced diabetic rats. Mn status in human diabetics is controversial. Kosenko reported Mn blood levels to be approximately one-half of the normal values (128). In contrast, Lisun-Lobanova found elevated Mn levels in diabetic patients aged 6170 yr (131). In a study of serum Mn levels in patients with various diseases, 62% of diabetic patients (type not specified) had elevated Mn levels> 1.6 tg/100 mL. Levels < 1 zg/100 mL
884
MOORADIAN
AND
MORLEY
were observed in 7% of diabetic patients studied (132). Although serum Mn levels reported in the older literature are high according to modern standards, inclusion of control subjects in each study allows a valid comparison between serum Mn concentrations of diabetic patients and that of control subjects. It is noteworthy that elevated serum Mn levels were reported in patients with myocardial infarction (132, 149) and with atherosclerosis (150). Whether the elevated serum Mn levels in a subgroup of diabetic patients are an independent risk factor for cardiovascular disease remains to be seen. Iron Iron (Fe) overload, as in hemochromatosis, can cause glucose intolerance secondary to pancreatic tissue injury (151, 152). Conversely, Fe deficiency does not seem to have a significant effect on glucose homeostasis but is associated with increased serum triglyceride level (153). Fe status of diabetic patients has not been well studied, but Fe mobilization or uptake and utilization appear to be delayed (154). In experimental streptozotocin-induced diabetic rats, tissue Fe content in liver, kidney, and femur was increased (138). In a similar study, streptozotocin-induced diabetic rats and control rats were fed equivalent quantities of Fe, and the diabetic rats had Fe content increased in liver and muscle and reduced in duodenum (136). In another study streptozotocin-induced diabetes was associated with 4.9-fold increase in urinary Fe excretion without reduction in plasma, liver, and kidney Fe content (140). Overall, diabetic state is not associated with Fe deficiency and there appears to be no evidence of major alterations in Fe status of diabetic patients who do not have renal failure or gastrointestinal neuropathy with malabsorption (154). Further studies in human and experimental diabetes are clearly warranted. Selenium In recent years, there has been a growing understanding of the role of selenium (Se) in human and animal nutrition. Se, being an integral part of glutathione peroxidase, has a protective role against tissue damage caused
by peroxides produced from lipid metabolism (155). Se deficiency in humans causes decreased glutathione peroxidase activity and cardiomyopathy (156-158). In Se-deficient rats, insulin secretory reserve was significantly reduced, and glucose intolerance developed in rats maintained on Se and vitamin E-deficient diets (159). The literature on Se status in diabetic populations is meager. In a study of 27 children with insulin-dependent diabetes, the mean serum Se level was higher than that in healthy control subjects (160). There was no correlation between Se concentrations and childrens age, sex, weight, height, fasting plasma glucose levels, or glycosylated hemoglobin levels. Although serum Se levels may not necessarily reflect tissue levels, it appears that diabetic children do not have Se deficiency contributing to the known complications of diabetes mellitus. Aluminum, titanium, and silicon
In one study from Russia (129), diabetic patients had reduced blood levels of titanium and silicon. In patients with gangrene, plasma aluminum was increased but aluminum content of cellular elements of blood was reduced.
Vitamins Vitamin A
Vitamin A is a surface-membrane-active agent, which has a diphasic concentrationdependent effect on insulin release (161, 162). At low concentrations, vitamin A stimulates insulin release while at high concentrations it has an inhibitory effect which may be mediated in part by impairment of intracellular glucose oxidation (162). The status of vitamin A in diabetic patients is not well studied. In rats with streptozotocininduced diabetes, 12-fold increase in vitamin A intake did not affect the degree of hyperglycemia and glycosuria, but wound healing was significantly enhanced (163). At present, there is no evidence to suggest that diabetic patients may have vitamin A deficiency that may be contributing to impaired wound healing. Although hypercarotenemia has been found in some diabetics (164), overwhelming evi-
MICRONUTRIENT
STATUS
IN DIABETES
885
dence suggests that serum levels of carotene and vitamin A in Type II diabetic patients are normal (165, 166). The rise in serum vitamin A level following oral administration of f3 carotene was similar to that seen in healthy controls and indicates that Type II diabetic patients do not have any defects in absorption or conversion of carotene to vitamin A (166). However, high postabsorptive serum levels of vitamin A have been observed in diabetic patients with increased serum 3-lipoprotein 1evels (167, 168). Group B Vitamins
Of the group B vitamins, thiamin, vitamin B-6, and vitamin B-l2 have been associated with carbohydrate intolerance or diabetes mellitus. The daily requirement of thiamin is dependent on the amount of carbohydrate consumed. However, the high-carbohydrate, highfiber diet currently recommended to diabetic patients appears to provide sufficient thiamin to meet the metabolic needs of the individual (169). Thiamin status of diabetic patients is controversial. Haugen reported a significantly low blood thiamin level in insulin-dependent diabetic patients (170). Conversely, elderly patients with noninsulin-dependent diabetes had normal blood levels of thiamin (170). Erythrocyte transketolase (ETK) activity, an indirect measure of thiamin status, was found to be reduced in Type I and Type II diabetic patients (171), but the reduced ETK activity could not be corrected by the addition of thiamm pyrophosphate, which suggests that the low ETK activity in diabetic patients was due to a reduced apoenzyme level rather than to deficiency of the cofactor for ETK activity, namely, thiamin (171). In a group of Japanese diabetics (type unspecified), plasma thiamin levels were elevated (172), and thefe was a statistically significant though weak correlation between plasma glucose and thiamin levels. Similar correlations were found in rabbits with alloxan-induced diabetes (172). The elevated thiamin levels were attributed by the authors to impaired tissue transport (173). However, this speculation is not supported by conclusive experimental evidence. At present there are no data to suggest that thiamin supplementation should be recommended for diabetic
patients. The occasional patient with diabetic neuropathy may respond to thiamin administration (174). Plasma vitamin B-6 and pyridoxal 5phosphate concentrations were significantly reduced in patients with diabetes mellitus (169, 175-177). Sebastian et al found vitamin B-6 deficiency in one-third of the diabetic patients studied (175); those with poor control of blood glucose had more pronounced deficiency. Insulin-treated patients had lower plasma vitamin B-6 levels than those treated with oral hypoglycemic agents (175). The reason for vitamin B-6 deficiency in diabetic patients is not known. Of interest is the observation that plasma levels of vitamin B-6 gradually decline following an oral glucose load (178). Insulin response to an oral glucose load is significantly impaired in pyridoxine-deficient rats, and in vitro pancreas perfusion experiments showed that secretion of both insulin and glucagon was impaired in pyridoxine deficiency (179). Pyridoxine deficiency in experimental animals and humans has been associated with glucose intolerance (180-184). The role for vitamin B-6 in glucose homeostasis has been suggested by its effect on tryptophan metabolism (185). In vitro experiments have shown that the metabolites of tryptophan degradation, quinolinic acid and hydroxyanthranilic acid, have inhibitory effects on enzymes regulating carbohydrate metabolism (186, 187). Interestingly, diabetic patients were found to have abnormalities in tryptophan metabolism such as increased formation of hydroxykynurenine and xanthurenic acid (188); xanthurenic acid binds insulin and reduces its biological activity (189). Similar changes in tryptophan metabolism were reported in two other clinical states characterized by carbohydrate intolerance: glucocorticoid therapy and oral contraceptive agent use (190). Pharmacological doses of vitamin B-6 can reverse the abnormalities of tryptophan metabolism and may improve carbohydrate tolerance in pregnancy (191, 192) and in women taking oral contraceptive agents (193). However, two studies in pregnant women failed to show beneficial effects of vitamin B-6 on gestational diabetes (194, 195). At present it is not known if improvement of glucose tolerance secondary to vitamin 8-6 administration is related to the role of this vi-
886
MOORADIAN
AND
MORLEY
tamin in tryptophan metabolism. In a study of women on oral contraceptive steroids, vitamin 8-6 normalized tryptophan metabolism in all, yet carbohydrate tolerance improved only in those with evidence of vitamin B-6 deficiency (196). Hence, the effect of vitamin B-6 on carbohydrate metabolism is not solely mediated by its effect on tryptophan metabolism. Vitamin 8-6 administration had no effect on glucose homeostasis in diabetic patients with vitamin B-6 deficiency (197). As is the case with thiamin, supplementation of the diabetic diet with vitamin 8-6 cannot be justified except for those with severe neuropathy where a trial of pharmacological doses of vitamin 8-6 may be useful in the occasional patient (174). Vitamin B-l2 deficiency is associated particularly with insulin-dependent diabetes mellitus. Pernicious anemia and diabetes mellitus can occur in the same individual as part of polyglandular autoimmune syndromes (198). In Type I polyglandular failure, the incidence of diabetes mellitus is 2-4% and the incidence of pernicious anemia is 13-15%. Diabetes mellitus occurs more often in Type II polyglandular failure, but the incidence of pernicious anemia in this syndrome is <1%. In Type III polyglandular failure, both diabetes mellitus and pernicious anemia have been described in association with thyroid disease. Vitamin C
Numerous reports have suggested an intimate interrelationship between vitamin C and glucose homeostasis (199-2 14). Guinea pigs maintained on a low-protein diet and large doses of vitamin C develop hyperglycemia (204). Dehydroascorbic acid (DHAA), an oxidative metabolite of ascorbic acid (vitamin C), is a diabetogenic agent (200-203). Administration of DHAA to rats causes degranulation of cells of pancreas and hyperglycemia (201, 202). Pre-injection of rats with reduced glutathione or cysteine prevents development of hyperglycemia, which suggests that the diabetogenic effect of DHAA is mediated through its interaction with the sulffiydryl groups essential for islet cell integrity (215). The clinical implication of these observations is unclear: it is not known if large doses of vitamin C will induce overt diabetes in a predisposed individual.
Clinical studies from India have indicated that plasma ascorbate concentrations were lower and dehydroascorbate concentrations were higher in diabetic patients irrespective of age, sex, duration of the disease, type of treatment, and glycemic control (207-209). Subsequent studies from Leeds in the United Kingdom (214) and Portland in the United States (213) did not confirm elevated plasma DHAA levels in Type I or Type II diabetic patients. Racial differences or marginal dietary ascorbate deficiency in Asian patients may account for this discrepant finding. Type II diabetic patients have higher turnover of ascorbic acid. Within 7 d after discontinuing vitamin C supplements in diabetic patients, the plasma ascorbate level fell to presupplementation levels in contrast to the control nondiabetic subjects who retained the high levels of plasma ascorbate (208). Diabetes mellitus appears to influence tissue content of ascorbic acid. In rats with streptozotocin-induced diabetes, liver and kidney content of ascorbate was significantly reduced (210). In Type II diabetic subjects, the mean leukocyte ascorbate concentration was not reduced in spite of lower plasma levels (208). However, in vivo studies have clearly demonstrated that hyperglycemia can induce intracellular depletion of ascorbic acid in mononuclear leukocytes, probably by competitive inhibition of cellular ascorbate transport since ascorbate and glucose appear to have a common transport mechanism (212). Similarly, insulin-dependent diabetics have reduced platelet vitamin C content, which may contribute to the enhanced aggregation of platelets in diabetic subjects (216). Otherwise, the biological significance of low plasma and possibly low tissue vitamin C levels in diabetic patients is not known. In Type II diabetic patients vitamin C supplementation at a dose of 500 mg/d for 15 d resulted in an increase in the plasma ascorbate level but did not alter blood glucose control (213). In a subgroup of Type II diabetic patients with poor dietary vitamin C intake, low leukocyte ascorbate concentrations, and hypercholesterolemia, vitamin C therapy normalized the vitamin C levels and corrected the hypercholesterolemia, probably by activating the ascorbate-dependent cholesterol 7a-
MICRONUTRIENT
STATUS
IN
DIABETES
887
hydroxylase enzyme (206). Moreover, the cutaneous capillary fragility in diabetes was corrected by 1 g daily supplements of vitamin C (217). At present, minimum daily vitamin C requirement for the diabetic population is not known. In the absence of poor dietary vitamin C intake or decreased leukocyte content of vitamin C, there seems to be no justification for high-dose vitamin C therapy in diabetic patients. Animal experiments have suggested that pharmacological doses of ascorbic acid and dehydroascorbic acid are neurotoxic and diabetogenic (200-203, 218). Although the relevance of these findings to diabetic patient is not known, caution should be exercised in recommending high doses of vitamin C supplements. Vitamin C in large doses can interfere with glucose measurements (219) and thus hamper the monitoring of diabetes control. Vitamin E
In rats maintained on vitamin E-deficient diets, insulin secretory capacity is reduced and glucose intolerance develops in those with combined deficiency of vitamin E and selenium (159). However, clinical studies have indicated that vitamin E deficiency is not a feature of diabetes mellitus. Darby et al (220) reported that human diabetics had higher plasma tocopherol levels than did normal subjects. In confirming these results we found that both plasma a- and total, but not y-, tocopherols were elevated (221). a- and total tocopherols were also increased in platelets from diabetics. The normal decrease in platelet tocopherol levels that occurs with aging is not present in patients with diabetes. There is a tendency for plasma and platelet tocopherol levels to be higher in patients with Type II diabetes mellitus than those with Type I diabetes. Tocopherol levels are higher in adipose tissue of Type II diabetes than of normal controls (222). Elevated atocopherol levels have been found in serum and tissues from spontaneously diabetic BB rats but not in nondiabetic control rats (223). Tissue y-tocophero1 levels were reduced in these animals. These defects were returned to normal by insulin treatment, which suggests that excess accumulation of tocopherols in di-
abetics is a metabolic consequence of the insulin deficiency. In view of the known ability of vitamin E to inhibit platelet aggregation (224) and the enhanced platelet aggregation in patients with diabetes (225), it seems likely that the reported increase in vitamin E in diabetics may be an attempt to compensate for the increased adhesiveness of diabetic platelets. Unfortunately, in the single study done to examine the relationship of vitamin E to platelet aggregation in Type II diabetes mellitus, numbers of patients were small and vitamin E levels in the platelets were found not to be increased but rather to be reduced (226). In this study Vitamin E content in the platelets was inversely correlated with adenosine diphosphate-induced platelet aggregability and platelet thromboxane production. This finding is compatible with the hypothesis that vitamin E excess in some diabetics plays a protective role against the tendency for increased platelet aggregability in diabetics. Further studies on the relationship between vitamin E and platelet aggregability in diabetes mellitus are indicated. Diabetic osteopenia
It is generally accepted that young Type I diabetic patients have reduced bone mass (227-232). The reduction in bone mass in children with diabetes mellitus has been attributed to reduced rate of accretion of bone during the growth period. In older insulindependent Type I diabetic patients, bone mineral loss appears to be an important factor in the development of osteopenia (233, 234). It is not clear whether the osteopenia is more severe among females than among males (227-230). In the growing-adolescent patient population, it appears that females have greater deficit of bone mass than do males (228). Effects of diabetes mellitus on bone mass in adult onset Type II diabetes is not well studied (227, 235). Levin et al found minimal changes of bone mass in a group of Type II diabetic patients (227). In a rat model of Type II diabetes, bone turnover and metabolic balance studies of calcium and phosphate were normal (236). The underlying etiology of osteopenia in diabetic patients is not known; altered metabolic
888
MOORADIAN
AND
MORLEY
milieu or diabetic microangiopathy have both been proposed as possible causes. Diabetic microangiopathy appears to have a minor role, if any, because rate of bone loss is highest in the first 2 years of diabetes onset, a lime before significant microangiopathy develops (230, 234, 237). The various metabolic abnormalities in juvenile diabetic patients that may contribute to the low bone mass include low serum magnesium and ionized calcium, low serum immunoreactive parathyroid hormone (PTH), and low serum 1,25-dihydroxycholecalciferol. Serum levels of 24,25-dihydroxycholecalciferol are normal. In addition, these patients have hypercalciuria, hypermagnesuria, and increased intestinal calcium absorption (98, 231, 238, 239). These findings were not documented in a study of adult Type I or Type II diabetic subjects (240). Increased intestinal calcium absorption in juvenile diabetic patients can be attributed to the increase in absorptive capacity of intestinal mucosa of diabetic subjects (241) and may not necessarily be in conflict with the finding of reduced
serum 1,25-dihydroxycholecalciferol in these patients. In alloxan-induced diabetic rats the net calcium absorption per gram dry weight of intestine was significantly reduced (242). The blood glucose level has been shown to modulate the activity of Ca2-ATPase (calcium pump) (243), and we have found that white blood cell calmodulin (a regulator of cakium pump) is significantly lower in diabetic patients than in age-matched control subjects (244). It is possible that these alterations may contribute to the abnormalities of calcium and bone metabolism observed in some diabetic patients. Based on the available data, a likely scenario for the pathogenesis of the osteopenia of diabetes mellitus is that urinary loss of magnesium leads to hypomagnesemia. Hypomagnesemia leads to decreased PTH secretion and action (245), which results in decreased formation of 1,25-dihydroxycholecalciferol (246). The insulin deficiency state will further impair formation of 1,25-dihydroxycholecalciferol (247). This results in inability to enhance in-
l PTH 2#{176}toMg
Altered bone metabolism 20 to
o)PTH
bJMg
++
ci lionized Co
f Ca in the urine
FIG 1. Schematic representation of the alterations
in calcium
metabolism
which
may contribute
to diabetic
osteopenia.
MICRONUTRIENT
STATUS
IN
DIABETES
889
testinal calcium absorption in the face of marked hypercalciuria, leading to calcium depletion. Bouts of hypophosphatemia associated with poor diabetic control (4) will further aggravate calcium loss from bone (Fig 1). Conclusion Experimental evidence has suggested that deficiencies in many of the trace elements including zinc, chromium, magnesium, copper, and manganese as well as vitamin B-6 deficiency may lead to glucose intolerance. However, adequately controlled studies that establish the role of trace elements in the pathogenesis of carbohydrate intolerance are not available. Although the majority of diabetic patients do not have micronutrient deficiencies, zinc, chromium, and magnesium deficiencies have been identified in a subgroup of patients. The trace-metal urinary losses are accentuated during uncontrolled hyperglycemia and glycosuria. Serum or tissue content of certain elements such as copper, manganese, iron, and selenium can be higher in diabetic patients than in nondiabetic controls. Serum ascorbic acid, group B vitamins (thiamin, 8-6, and 8-12) and possibly 1,25-dihydroxycholecalciferol concentrations may be low in diabetic patients. Vitamin A and vitamin E levels are normal or increased. These alterations may contribute to some of the complications of diabetes, and there is a place for judicious replacement of micronutrients in diabetic patients with demonstrated deficiencies. The inconsistency of responses of diabetic patients to mineral or vitamin supplementation may be secondary to the heterogeneity of this patient population with regard to the micronutrient status. It is likely that the response of patients to supplements is determined by nutritional state so that only those with micronutrient deficiencies will respond to the supplements favorably. Patients who are maintained on high-fiber diet or those who are acidotic or glycosuric are at particular risk of developing profound deficiency of certain micronutrients such as zinc and magnesium. Adequacy of mineral and vitamin intake should be established when severely restricted diets are prescribed to diabetic patients. Most studies reviewed in this manuscript do not distinguish what may be secondary effects of chronic mal-
nutrition from the disease process of diabetes mellitus per se. Further studies are needed in which diabetic patients are compared with control subjects with matched nutritional status. C]
References
1. Ernest I, Linner E, Svanborg A. Carbohydrate-rich, fat-poor diet in diabetes. Am J Med 1965;39:594600. 2. Anderson JW. Effect of carbohydrate restrictions and high carbohydrate diets on men with chemical diabetes. Am J Clin Nutr l977;30:402-8. 3. Nuttall FQ, Mooradian AD, Gannon MC, Bilhington C, Krezowski P. Effect of protein ingestion on the glucose and insulin response to a standardized oral glucose load. Diabetes Care l984;7:465-70. 4. Nuttali FQ. Diet and the diabetic patient. Diabetes Care 1983;6: 197-207. 5. Fritz IR. Insulin actions on carbohydrate and lipid metabolism. Biochem Action Horm l972;2:165214. 6. Pilkis SJ, Park CR. Mechanism of action of insulin. Ann Rev Pharmacoi 1974;l4:365-88. 7. Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med l978;88:681-95. 8. Denton RM, Brownsey RW, Belsham GJ. A partial view of the mechanism of insulin action. Diabetologia 1981;21:347-62. 9. Golden BE, Golden MHN. Malnutrition and diabetes mellitus: a case study. Wis Med J l983;32: 24 1-7. 10. Oh JM. Diabetes mehhitus in Africans. J R Coil Physicians Lond 1983;l7:224-7. 11. Jenkins DJA. Dietary fibre, diabetes and hyperhipidemia. Lancet l979;2: 1287-90. 12. Anderson JW, Ferguson SK, Karounos D, OMalley L, Seiling B, Den WJL. Mineral and vitamin status on high-fiber diets: long-term studies of diabetic patients. Diabetes Care i980;3:38-40. 13. Scott DA. Crystalline insulin. Biochem J 1934;28: 1592-602. 14. Hove E, Elvehjem CA, Hart EB. The physiology of zinc in the nutrition of the rat. Am J Physiol l937;l 19:768-75. 15. Quarterman J, Mills CF, Humphnes WR. The reduced secretion of and sensitivity to insulin in zinc
deficient rats. 1966;25:356-8. Biochem Biophys Res Commun
16. Hendricks DG, Mahoney AW. Glucose tolerance in zinc deficient rats. J Nutr 1972;l02:i079-84. 17. Huber AM, Gershoff SN. Effect of zinc deficiency in rats on insulin release from the pancreas. J Nutr l973;l03: 1739-44. 18. Kirchgessner M, Roth HP, Weigand E. Biochemical changes in zinc deficiency. In: Prasad AS, Oberleas D, eds. Trace elements in human health and disease. Vol 1. Zinc and copper. New York: Academic Press, 1976:189-266.
890
MOORADIAN
AND
MORLEY abetic and streptozotocin-induced diabetic mice. Am J Clin Nutr 1983;37:382-6. Hagglof B, Hallmans G, Hohmgren G, Ludvigsson J, Falkmer S. Prospective and retrospective studies of zinc concentrations in serum, blood clots, hair and urine in young patients with insulin-dependent diabetes mehlitus. Acta Endocrinol (Copenh) 1983; 102:88-95. Herold KC, Huen A, Gould L, Traisman H, Rubenstein AH. Alterations in lymphocyte subpopulationsin Type I (insulin-dependent) diabetes mellitus: exploration of possible mechanisms and relationships to autoimmune phenomena. Diabetologia 1984;27: 102-5. Galluzzo A, Giordano C, Rubino G, Bompiani GD. Immunoregulatory T-lymphocyte subset deficiency in newly diagnosed Type I (insulin-dependent) diabetes melhitus. Diabetologia l984;26:426-30. Blazsek I, Mathe G. Zinc and immunity. Biomed Pharmacother l984;38: 187-93. Allen JI, Bell E, Boosalis MA, et al. The association between urinary zinc excretion and lymphocyte dysfunction in patients with lung cancer. Am J Med 1985;79:209-l5. Haeger K, Lanner E, Magnusson P0. Oral zinc sulfate in the treatment of venous leg ulcer. In: Pories WJ, Strain WH, Hsu JM, Woosley RL, eds. Clinical applications of zinc metabolism. Springfield, IL: Charles C Thomas, 1974:158-67. Hailbook T, Lanner E. Serum-zinc and healing of venous leg ulcers.Lancet l972;2:780-2. Sandstead HH, Lanier VC, Jr, Shepard GH. Zinc and wound healing. Effects of zinc deficiency and zinc supplementation. Am J Clin Nutr 1970;23: 5 14-9. Quantrillo EP. Effect of supplemental zinc on wound healing in rats. Am J Surg 197 l;12l:661-4. Henkin RI, Schecter PJ, Friedwald WT, Demits DL, Raff M. A double blind study of the effects of zinc sulfateon taste and smell dysfunction. Am J Med Sci l976;272:285-99. Hooper FL, Visconti L, Garry PJ, Johnson GE. Zinc lowers high-density lipoprotein-cholesterol levels. JAMA 1980;244: 1960-1. Hill GM, Brewer GJ, Block WD, McGinnis MM, Prasad AS. Lipid parameters in Wilsons disease patients on zinc therapy. Fed Proc l986;355(abstract). Mertz W. Chromium occurrence and function in biological systems. Physiol Rev l969;49:l63-239. Mertz W, Toepfer EW, Roginski EE, Polansky MM. Present knowledge of a role of chromium. Fed Proc 1974;33:2275-80. Wallach S. Clinical and biochemical aspects of chromium deficiency. J Am Coll Nutr 1985;4:107-20. Schroeder HA. Chromium deficiency in rats: a syndrome simulating diabetes melhitus with retarded growth. J Nutr 1966;88:439-45. Jeejeeboy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Chin Nutr l977;30: 531-8. Freund H, Atamian S, Fischer JE. Chromium defi-
19. Boquist L, Lernmark A. Effects on the endocrine pancreas in Chinese hamsters fed zinc-deficient diets. Arch Pathol Microbiol Scand 1969;76:2l 5-28. 20. Quarterman J, Florence E. Observations on glucose tolerance and plasma levels of free fatty acids and insulin in the zinc deficient rat. Br J Nutr 1972;28: 75-9. 21. Macapinlac MP, Pearson WN, Darby WJ. Some characteristics of zinc deficiency in the albino rat. In: Prasad AS, ed. Zinc metabolism. SpringfIeld, IL: Charles C Thomas, 1966:142-66. 22. Brown ED, Penhos JC, Recant L, Smith JC, Jr.Glucose tolerance, plasma and pancreatic insulin levels in zinc deficient rats. Proc Soc Exp Biol Med h975;l 50:557-60. 23. Roth MP, Kirchgessner M. Insuhin-gehalte in serum bzu. Plasma von zinkimangelratten vor und nach glucosestimulierung. mt J Vitam Nutr Res 1975;45: 202-8. 24. Engelbart K, Kief M. Uber das funktionelle Verhatten von Zink und Insulin in den i9-Zellendes rattenPankreas. Virchows Arch [Cell Pathol] l970;4: 294-302. 25. Coombs TL, Grant PT, Frank BT. Differences in the binding of zinc ion by insulin and proinsulin. Biochem J 197 l;l25:62(abstr). 26. Scott DA, Fisher AM. The insulin and zinc content of normal and diabetic pancreas. J Din Invest l938;l 7:725-8. 27. Arquilla E, Thiene P, Brugman T, Ruess W, Sugiyama R. Effects of Zn on the conformation of antigenic determinants of insulin.Biochem J 1978;l75: 289-97. 28. Arquilla ER, PackerS, Tarmas W, Miyamoto S. The effect of zinc on insulin metabolism. Endocrinology 1978; 103:1440-9. 29. Coulston L, Dandona P. Insulin-like effect of zinc on adipocytes. Diabetes l980;29:665-7. 30. May JM, Contoreggi CS. The mechanism of the insulin-hike effects of ionic zinc. J Biol Chem 1982;257:4362-8. 31. Herck NB, Dalpe-Scott M, Rowe J, Heick HMC. Zinc supplementation attenuates insulin secretory activity in pancreatic islets of the ob/ob mouse. Diabetes l985;36:l79-86. 32. Ghalghazi T, Ludvigsen CW, McDaniel ML, Lacy PE. The inhibitory effect of zinc on insulin secretion. IRCS J Med Sci 1979;7:122. 33. Figlewicz DP, Formby B, Hodgson AT, Schmid FG, Grodsky GM. Kinetics of zinc uptake and distribution in fractions from cultured rat islets of Langerhans. Diabetes 1979;29:767-73. 34. Figlewicz DP, Heldt A, Forhan SE, Grodsky GM. Effect of exogenous zinc on insulin secretion in vivo. Endocrinology l980;108:730-2. 35. Etzel KR, Cousins RJ. Hyperglycemic action of zinc in rats. J Nutr 1983;113:l657-63. 36. Kinlaw WB, Levine AS, Morley JE, Silvis SE, McClain CJ. Abnormal zinc metabolism in type II diabetes mellitus. Am J Med 1983;75:273-7. 37. Niewoehner CB, Allen JI, Bcosalis M, Levine AS, Morley JE. The role of zinc supplementation in Type II diabetes mehlitus. Am J Med 1986;8 1:63-8. 38. Levine AS, McClain CJ, Handwerger BS, Brown DM, Morley JE. Tissue zinc status of genetically di-
39.
40.
41.
42. 43.
44.
45. 46.
47. 48.
49.
50.
51. 52.
53. 54.
55.
56.
MICRONUTRIENT ciency during total parenteral nutrition. JAMA 1979;24l :496-8. Mertz W. Effects and metabolism of glucose tolerance factor.Nutr Rev l975;33:l29-35. Toepfer EW, Mertz W, Polansky MM, Roginski EE, Wolf WR. Preparation of chromium-containing material of glucose tolerance factor activity from brewers yeast extracts and by synthesis. J Agric Food Chem l977;25:162-6. Tuman RW, Bilbo JT, Doisy RJ. Comparison and effects of natural and synthetic glucose tolerance factor in normal and genetically diabetic mice. Diabetes l978;27:49-56. Wolliscroft J, Barbosa J. Analysis of chromium induced carbohydrate intolerance in the rat. J Nutr l977;l07: 1702-6. Davidson IWF, Blackwell WL. Changes in carbohydrate metabolism of squirrel monkeys with chromium dietary supplementation. Proc Soc Exp Biol Med l968;127:66-72. Tuman RW, Doisy RJ. Metabolic effects of the glucose tolerance factor (GTF) in normal and genetically diabetic mice. Diabetes 1977;26:820-6. Riales R, Albrink MJ. Effects of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoproteins of adult men. Am J Chin Nutr 198 l;34:2670-8. Liu VJK, Morris JS. Relative chromium response as an indicator of chromium status. Am J Clin Nutr 1978;3l:972-6. Polansky MM, Anderson RA, Bryden NA, Roginski EE, Mertz W, Ghinsmann WH. Chromium supplementation of free living subjects-effect on glucose tolerance and insulin. Fed Proc 198 l;40:885(abstr). Polansky MM, Anderson RA, Bryden NA, Ghinsmann WH. Chromium (Cr) and brewers yeast supphementation of human subjects. Effect on glucose tolerance, serum glucose, insulin and lipid parameters. Fed Proc l982;41:391(abstr). Anderson RA, Polansky MM, Bryden NA, Roginski EE, Mertz W, Ghinsmann WH. Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables. Metabolism h983;32: 894-9. Schroeder HA, Bahassa JJ, Tipton IH. Abnormal trace elements in man. J Chronic Dis 1962;l5:94l64. Schroeder HA, Nason AP, Tipton IH. Chromium deficiency as a factor in atherosclerosis. J Chronic Dis l970;23: 123-42. Barry PSI. A comparison of concentrations of lead in human tissues. Br J md Med 1975;32:l 19-39. Pi-Sunyer FX, Offenbacher EG. Chromium. Present knowledge in nutrition. In: Hegsted DM, Chichester CO, Darby WJ, McNutt KW, Stalvey RM, Stotz EH, eds. Nutrition reviews. New York, NY: Nutrition Foundation, 1976:571-86. Ghinsmann WH, Mertz W. Effect of trivalent chromium on glucose tolerance. Metab Clin Exp l966;15: 510-20. Levine RA, Streeten DHP, Doisy RS. Effect of oral chromium supplementation on the glucose tolerance of elderly subjects. Metab Din Exp 1968;l 7:1 14-25. Offenbacher EG, Pi-Sunyer FX. Beneficial effect of
STATUS
IN
DIABETES yeast on glucose
891 tolerance and blood 1980;29:9l9-25. CI, Pi-Sunyer FX. The efchromium and brewers yeast on plasma lipids, and plasma chrosubjects. Am J Clin Nutr 1985;42:
Diabetes
chromium-rich
75.
57. 58.
lipids in elderly subjects. Offenbacher EG, Rinko
fects of inorganic glucose tolerance,

mium in elderly
454-61. 76. Grant AP, McMullen

containing glucose
59.
60.
61.
62.
JK. The effect ofbrewers yeast factor on the response to treatment in type 2 diabetics. A short controlled study. Ulster Med J l982;5l:l 10-4. 77. Sherman L, Glennon JA, Brech Wi, Klomberg GH, Gordon ES. Failure of trivalent chromium to improve hyperglycemia in diabetes mellitus. Metabolism 1968; 17:439-42. 78. Rabinowitz MB, Gonick HC, Levin SR, Davidson MB. Effects of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men. Diabetes Care 1983;6:319-27. 79. Uusitupa Mu, Kumpulainen iT, Voutilainen E, et al. Effect of inorganic chromium supplementation
tolerance on glucose tolerance, insulin response and serum
63.
80.
64.
81.
65.
82.
66.
83.
67.
84.
85.
68.
86.
69.
87.
70.
71.
88.
89.
72.
90.
73.
91.
74.
lipids in noninsuhin-dependent diabetics. Am J Clin Nutr 1983;38:404-l0. Elias AN, Grossman MK, Valenta LI. Use of the artificial beta cell (ABC) in the assessment of peripheral insulin sensitivity: effect of chromium supplementation in diabetic patients. Gen Pharmacol 1984;l5:535-9. Steele N, Frobish L. Biologjcal activity of glucose tolerance factor in swine. J Anim Sci l977;45: 1341-5. Urberg M, Parent M, Hill D, Zemel M. Evidence for synergism between chromium and nicotinic acid in normalizing glucose tolerance. Diabetes 1986; 35(suppl 1): 147A(abstr). Evans GW, Roginski EE, Mertz W. Interaction of the glucose tolerance factor (GTF) with insulin. Biochem Biophys Res Commun l974;50:718-22. Elwood JC, Nash DT, Streeten DHP. Effect of high chromium brewers yeast on human serum lipids. J Am Coll Nutr 1982;l:263-74. Schroeder HA. Serum cholesterol and glucose levels in rats fed refined and less refined sugars and chromium. J Nutr l969;97:237-42. Schroeder HA, Nason AP, Tipton IH. Chromium deficiency as a factor in atherosclerosis. J Chronic Dis l970;23:l23-42. Punsar 5, Erametsa 0, Karvonen Mi, Ryhanen A, Hilska P, Vornamo H. Coronary heart disease and drinking water. J Chronic Dis l975;28:259-87. Rabinowitz MB, Levin SR, Gonick HC. Comparisons of chromium status in diabetic and normal men. Metabolism l980;29:355-64. Gurson CT, Saner G. The effect of glucose loading on urinary excretion of chromium in normal adults, in individuals from diabetic families and in diabetics. Am J Clin Nutr l978;31:l 158-61. Doisy Ri, Streeten DH, Frieberg JM, Schneider AJ. Chromium metabolism in man and biochemical effects. In: Prasad AS, ed. Trace elements in human health and disease. Vol 2. New York: Academic Press, 1976:97-104. Hambidge KM, Rodgerson DO, OBrien D. Concentration of chromium in the hair of normal chil-
892
MOORADIAN dren and children with juvenile diabetes melhitus. Diabetes l968;17:5 17-9. Rosson JW, Foster KJ, Walton Ri, Monro PP, Taylor TG, Alberti KGMM. Hair chromium concentrations in adult insulin treated diabetics. Clin Chim Acta 1979;93:299-304. Lehninger AS. Role of metal ions in enzyme systems. Physiol Rev 1950;30:393-429. Aikawa JK. Magnesium: its biologicsignificance. Fort Lauderdale: CRC Press Inc, 1981. Goldman J, Fisher V. Magnesium is required in addition to calcium for insulin stimulation of glucose transport. Endocrinology l983;l 12(suppl): 27 1(abstr). Yajnik CS, Smith RF, Hockaday TDR, Ward NI. Fasting plasma magnesium concentrations and glucose disposalin diabetes.Br Med J l984,288:l032-4. Fujii 5, Takemura T, Wada M, Akai T, Okuda K. Magnesium levelsin plasma, erythrocyte and urine in patientswith diabetes mellitus. Horm Metab Res l982;l4:l6l-2. McNair P. Christensen MS, ChristiansenC, Madsbad S, Transboh lB. Renal hypomagnesaemia in human diabetes mellitus:itsrelationto glucose homeostasis. Euri Din Invest l982;12:8h-5. Butler AM. Diabetic coma. N Engl J Med 1950;1243: 648-59. Fort P, LifshitzF, Wapnir IL, Wapnir RA. Magnesium metabolism in experimental diabetes mellitus. Diabetes 1977;26:882-6. Schneider LE, Schedl HP. Effects of alloxan diabetes on magnesium metabolism in the rat.Proc Soc Exp Biol Med l974;h47:494-7. Jackson ECH, Meier DW. Routine serum magnesium analysis. Ann Intern Med l968;69:743-8. Becketi AG, Lewis JG. Serum magnesium in diabetes melhitus. Chin Sci 1959;l8:597-604. De Leeuw I, Vertommen J, Abs R. The magnesium content of the trabecular bone in diabetic subjects. Biomedicine l978;29: 16-7. Mather HM, Nisbet JA, Burton GH, et al. Hypomagnesaemia in diabetes. Din Chim Acta 1979;95: 235-42. Mather HM, Levin GE, Nisbet JA, Hadley LA-A, Oakley NW, Pilkington TRE. Diurnal profilesof plasma magnesium and blood glucose in diabetes. Diabetologia 1982;22: 180-3. Ewald U, Gebre-Medhin M, Tuvemo T. Hypomagnesemia in diabetic children. Acta Paediatr Scand 1983;72:367-7 1. Rosner F, Gorfien PC. Zinc and magnesium levels in diabetes.JAMA 1970;2h 1:2156. Jam AP, Gupta NN, Kumar A. Some metabolic facts of magnesium in diabetes mehhitus. J Assoc Physicians India l976;24:827-3 1. Milewicz A, Stepien-Dobrowlska M, Szklarz E, Glebowska H, Gladysz A, Czarnowska J. Behaviour of the magnesium level in the serum, whole blood and erythrocytes in juvenile diabetes. Wiad Lek l976;29:
599-601.
AND
MORLEY
92.
93. 94. 95.
96.
97.
98.
99. 100.
101.
102. 103. 104.
105.
106.
107.
108. 109.
110.
Ill.
112.
Levin GE, Mather HM, Pilkington TRE. Tissue magnesium status in diabetes mellitus. Diabetologia 1981 ;2 1:131-4. Menzel R, Pusch H, Ratzmann GW, et al. Serum magnesium in insulin-dependent diabetics and
healthy subjects in relation to insulin secretion and glycemia during glucose-glucagon test. Exp Din Endocrinol l985;85:81-8. 113. Mellerup El. Insulineffects on calcium, magnesium, and phosphate metabolism in rats. Acta Endocrinol 1974;75:748-55. 114. Moles KW, McMullen JK. Insulin resistance and hypomagnesaemia: case report. Br Med J l982;285: 262. 115. McNair P, Christiansen C, Madsbad 5, et al. Hypomagnesaemia, a risk factor in diabetic retinopathy. Diabetes 1978;27: 1075-7. 116. Seelig MS, Heggtveit HA. Magnesium interrelationships in ischemic heart disease: a review. Am J Din Nutr 1974;27:59-79. 117. Marier JR. Cardio-protective contribution of hard waters to magnesium intake. Rev Can Biol l978;37: 115-25. 118. Cohen AM, leitelbaum A, Miller E, Ben-br V. Hirt R, Fields M. The effect of copper on carbohydrate metabolism. Isr J Med Sci l982;18:840-4. 119. Hassel CA, Allen DA, Marchello JA, Lei KY. Impaired glucose tolerance in copper-deficient rats. Fed Proc 1982;41:39l(abstr). 120. Fields M, Reiser S, Smith JC, Jr. Effect of copper or insulin in diabetic copper-deficientrats Proc Soc Exp Biol Med 1983;173:137-9. 121. Reiser 5, Ferretti Ri, Fields M, Smith JC, Jr. Role of dietary fructose in the enhancement of mortality and biochemical changes associated with copper deficiency in rats. Am J Clin Nutr 1983;38:214-22. 122. Saggerson ED, Sooranna SR. Evans Ci. Insulin-like actions of nickel and other transition-metal ions in rat fat cells. Biochem J 1976;l 54:349-57. 123. Klevay LM, Inman L, Johnson LK, et al. Increased cholesterol in plasma in a young man during experimental copper depletion. Metabolism l984;33: 11 12-8. 124. Carnes WH. Copper and connective tissue metabolism. lnt Rev Connect lissue Res l968;4:197-232. 125. Schroeder HA. The role of trace elements in cardiovascular diseases. Med Chin North Am l974;58:38l96. 126. Jarrett RI, Keen H. Diabetes and atherosclerosis. In: Jarrett RI, Keen H, eds. Complications of diabetes. London: Edward Arnold, 1975:179-204. 127. Noto R, Ahicata R, Sfogliano L, Neri S. Bifarella M. A study of cupremia in a group of elderly diabetics. Acta Diabetol Lat l983;20:8l-5. 128. Kosenko LG. Concentration of trace elements in blood of patients with diabetes mellitus. Fed Proc bransl (Suppl) 1965;24:237-8. 129. Kuheshova I. Content of blood microelements in diabetes melhitus and diabetic gangrene. Vrach Delo 1973;8:l 12-4. 130. Kovtunyak NA, Isapok P1. Level of trace elements in the pancreas and its histophysiology during alloxan diabetes. Mikroelem Med l973;4:91-4. 131. Lisun-Lobanova VP. brace elements (manganese, copper and zinc) in patients with diabetes mehlitus. Zdravookhr Beloruss l963;9:49-53. 132. Kanabrocki EL, Case LF, Graham L, et al. Nondialyzable manganese and copper levels in serum of patients with various diseases. J Nucl Med l967;8: 166-72.
MICRONUTRIENT 133. Martin Mateo MC, Bustamante Bustamante J, Gonzalez Cantalapiedra MA. Serum zinc, copper and insulin in diabetes mellitus. Biomedicine l978;29: 56-8. Lahey ME, Gubler CI, Cartwright GE, Wintrobe MM. Studies on copper metabolism. VI Blood copper in normal human subjects. J Din Invest 1953;32: 322-8. Pidduck BS, Wren MD. Plasma zinc and copper in diabetes melhitus. Diabetes 1970;19:234-9. Failla ML, Kiser RA. Altered tissue content and cytosol distribution of trace metals in experimental diabetes. J Nutr 1981;l 11:1900-9. Failla ML, Kiser RA. Hepatic and renal metabolism of copper and zinc in the diabetic rat. Am J Physiol 1983;244:El 15-21. Johnson WT, Evans GW. Effects of the interrelationship between dietary protein and minerals on tissue content of trace metals in streptozotocindiabetic rats. J Nutr 1984;l 14:180-90. Craft NE, Failla ML. Zinc, iron, and copper absorption in the streptozotocin-diabetic rat. Am J Physiol l983;244:E122-8. Lau AL, Failla ML Urinary excretion of zinc, copper and iron in the streptozotocin-diabetic rat. J Nutr l984;l 14:224-33. Radbil OS, Grigoryev Y. Blood and urinary zinc and copper content in patients with diabetes. Vrach Delo l974;l0:95-7. Hagglof B, Marklund SL, Holmgren G. CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase in lymphocytes and erythrocytes in insulin-dependent diabetic children. Acta Endocrinol 1983;l02:235-9. Everson GJ, Shrader RE. Abnormal glucose tolerance in manganese deficient guinea pigs. J Nutr 1968;94: 89-94. Shrader RE, Everson GJ. Pancreatic pathology in manganese-deficient guinea pigs. J Nutr l968;94: 209-81. Bond JS, Fade ML, Unger DF. Elevated manganese concentration and arginase activity in livers of streptozotocin-induced diabetic rats. J Biol Chem 1983; 258:8004-9. Eriksson UJ. Diabetes in pregnancy: retarded fetal growth, congenital malformations and feto maternal concentrations of zinc, copper and manganese in the rat. J Nutr 1984;l 14:477-84. Uriu-Hare JY, Stern JS, Reaven GM, Kee CL. The effect of maternal diabetes on trace element status and fetal development in the rat. Diabetes 1985;34: 1031-40. Hirsch-Kohb H, Kolb Hi, Greenberg DM. Nuclear magnetic resonance studies of manganese binding of rat liver arginase. J Biol Chem 197 h;246:395-401. Hegde B, Griffith GC, Butt EM. Tissue and serum manganese levels in evaluation of heart muscle damage. A comparison with SOOT. Proc Soc Exp Biol Med 1961;107:734-7. Volkov NF. Cobalt, manganese and zinc content in the blood of atherosclerosis patients. Fed Proc 1963;22:897-9. Milder MS, Cook JD, StrayS, Finch CA. Idiopathic hemochromatosis, an interim report. Medicine 1980; 59:34-49.
STATUS 152.
IN
DIABETES
893
153.
134.
154.
135. 136.
155.
156.
137.
157.
138.
158.
139.
159.
140.
141.
160.
142.
161.
162.
143.
163.
144.
145.
164. 165.
146.
166. 167.
147.
Dandona P. Hussain MA, Varghese Z, Politis D, Flynn DM, Hofibrand AV. Insulin resistance and iron overload. Ann Din Biochem 1983;20:77-9. Mertz W. Trace minerals and atherosclerosis. Fed Proc 1982;41 :2807-12. Bern MM, Busick El. Disorders of blood and diabetes. In: Marble A, Krall LP, Bradley RF, Christlieb AR, Soehdner JS, eds. Joshins diabetes mehlitus. Philadelphia, PA: Lea and Febiger, 1985:748-52. Sunde RA, Hoekstra WG. Structure, synthesis and functions of glutathione peroxidase. Nutr Rev l980;38;265-73. Van Rij AM, Thomson CD, McKenzie JM, Robinson MF. Selenium deficiency in total parenteral nutrition. Am J Din Nutr h979;32:2076-85. Chen X, Yang G, Chen J, Chen X, Wen Z, Ge K. Studies on the relations of selenium and keshan disease. Biol Trace Element Res 1980;2:9l-107. Johnson RA, Baker SS, Fallon JT, et al. An occidental case of cardiomyopathy and selenium efficiency. N Engl J Med 198 l;304:l2lO-2. Asayama K, Kooy NW, Burr IM. Effect of vitamin E deficiency and selenium deficiency on insulin secretory reserve and free radical scavenging systems in islets: decrease of isletmanganosuperoxide dismutase. J Lab Din Med 1986;107:459-64. Gebre-Medhin M, Ewald V, Phantin LO, Tuvemo I. Elevated serum selenium in diabetic children. Acta Paediatr Scand h984;73:109-l4. Chertow BS, Baker GR. The effects of vitamin A on insulin release and glucose oxidation in isolated rat islets. Endocrinology l978;103: 1562-72. Chertow BS, Buschmann RI, Kaplan RL. Cellular mechanisms of insulin release. Effects of retinol on insulin release and islet ultrastructure. Diabetes 1979;28:754-61. Seifter E, Rettura G, Padawer J, Stratford F, Kambosos D, Levenson SM. Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A. Ann Surg 198 l;194:42-50. Cohen H. Observations on carotenemia. Ann Intern Med h958;48:2h9-27. Kimble MS. Germek OA, Servinghaus EL. Vitamin A and carotene metabolism in the diabetic as reflected by blood levels. Am J Med Sd l946;212:57485. Ramachandran K. Beta carotene metabolism in diabetes. Indian J Med Res 1973;61:183l-4. Beaumont JL, Beaumont V. Vitamin A tolerance test, fat metabolism disturbances and antihipidemic drugs. In: Grattini 5, Paleotti R, eds. Drugs affecting
lipid metabolism. Amsterdam: Elsevier Publishing
148.
149.
150.
151.
Co, 1961:361-72. 168. Kahan J. The vitamin A absorption test. I Studies on children and adults without disorders in the alimentary tract. Scand J Gastroenterol h969;4:31324. 169. Hollenbeck CB, Leklem JE, Riddle MC, Connor WE. The composition and nutritional adequacy of subject-selectedhigh carbohydrate, how fat diets in insulin-dependent diabetes mellitus. Am J Din Nutr l983;38:4 1-51. 170. Haugen HN. The blood concentration of thiamine in diabetes. Scand J Chin Lab Invest l964;16:260-6. 171. Kjosen MS. Seim SH. The transketolase assay of
894
MOORADIAN thiamine in some diseases. Am J Din Nutr 1977;30: 159 1-6. Hobara R, Ozawa K, Okazaki M, Yasuhara H. Relationship between thiamine and glucose levels in diabetes melhitus. Jpn J Pharmacol 1981 ;3 1:1098100. Chen CP. Active transport of thiamine by freshly isolated rat hepatocytes. J Nutr Sci Vitaminol (Tokyo) 1978;24:35 1-62. Kaplan WE, Abourizk NN. Diabetic peripheral neuropathies affecting the lower extremity. J Am Podiatry Assoc 1981;7l:356-62. Sebastian HM, de Castro Del Pozo 5, De La Fuente Gomez L, Caro-Paton Gomez T. Estudio sobre carencia de piridoxima en los diabeticos. Rev Din Esp 1963;9 1:99-103. Davis RE, Calder JS, Curhow DH. Serum pyridoxal and folate concentrations in diabetics. Pathology 1976;8: 151-9. Wilson RG, Davis RE. Serum pyridoxal concentrations in children with diabetes mehlitus. Pathology 1977;9:95-8. Leklem JE, Hatcher LF, Pendleton C, Hollenbeck CB. Decreased pyridoxal 5!phosphate following oral glucose. Fed Proc l982;4l:277(abstr). Toyota T, Kai Y, Kakizaki M, Ohtsuka H, Shibata Y, Goto Y. The endocrine pancreas in pyridoxine deficient rats. Tohuku J Exp Med 1981 ;l 34:331-6. Wedell J, Jahnke K, Daweke H, Zimmermann H. Untersuchungen zur Bedeutung des Pyridoxins beim diabetes mellitus. Khin Wochenschr l963;4h:45l-7. Schlutz GO. Uber das Vorkommen von Pyridoxinmangeldiabetes in nord Sumatra. Int Z Vitaminforsch l963;33:150-3. Tezuka I, Makino K. Hyperglycemia in pyridoxine deficient rats. J Vitaminol (Kyoto) 1959;5:304-6. Makris A, Gershoff SN. Insulin sensitivity in vitamin B6 deficient rats. Effects of acute and chronic growth hormone treatment. Nutr Metab 16:337-51. Emerson GA, Kishi HS, Morrill BJ, Snipes JW, Walker JB. Effects of how intakes of vitamin B6 upon diabetic and control rats. Vitam Horm l964;22:64353. Editorial: Vitamin B6 and diabetes. Lancet l976;l: 788. Quagliariello E, PapaS, Saccone C, Alifano A. Effect of 3-hydroxyanthranilic acid on the mitochondrial respiratory system. Biochem J l964;9l:h37-46. Veneziale CM, Walter P, Kneer N, Lardy HA. Influence of L-tryptophan and its metabohites on gluconeogenesis in the isolated perfused liver. Biochemistry 1967;6:2 129-38. Kotake Y, Jr, Inada I. Studies on xanthurenic acid; preliminary report on xanthurenic acid diabetes. J Biochem (Tokyo) h953;40:291-4. Kotake Y, Sotokawa I, Murakami E, Hisatake A, Abe M, Ideka Y. Studies on the xanthurenic acidinsulin complex. II Physiological activities. J Biochem (Tokyo) 1968;63:578-8l. Rose DP. Aspects of tryptophan metabolism in health and disease: a review. J Din Pathol h972;25:l7-25. Benninka HJTC, Schreurs WHP. Improvement of oral glucose tolerance in gestational diabetes by pyridoxine. Br Med J 1975;3:l3-5. Spellacy WN, Buhi WC, Birk SA. Vitamin B6 treatment of gestational diabetes mellitus. Studies of blood
AND
MORLEY glucose and plasma insulin. Am J Obstet Gynecol 1977; 127:599-602. Spellacy WN, Buhi WC, Birk SA. The effect of vitamin B6 on carbohydrate metabolism in women taking steroid contraceptives: preliminary report. Contraception 1972;6:265-73. Perkins RP. Failure of pyridoxine to improve glucose tolerance in gestational diabetes mellitus. Obstet Gynecol l977;50:370-2. Gillmer MDG, Mazibuku D. Pyridoxine treatment of chemical diabetes in pregnancy. Am J Obstet Gynecol l979;l 33:499-502. Adams PW, Wynn V, Folkard J, Seed M. Influence of oral contraceptives, pyridoxine (vitamin B6) and tryptophan on carbohydrate metabolism. Lancet 1976;l:759-64. Rao RH, Vigg BL, Jaya Rao KS. Failure of pyridoxine to improve glucose tolerance in diabetics. J Din Endocrinol Metab l980;50: 198-200. Trence DL, Morley JE, Handwerger BS. Polyglanduhar autoimmune syndromes. Am J Med 1984;77: 107-16. Owens LB. Wright J, Brown E. Vitamin C survey in diabetes.N Engl J Med 194l;224:3l9-23. Patterson JW. The diabetogenic effect of dehydroascorbic and dehydroisoascorbic acid. J Biol Chem 1950;183:81-8. MacDonald MK, Bhattacharya SK. Histological changes in rats rendered hyperglycemic by injection of dehydroascorbic acid. Q J Exp Physiol 1956;41: 153-61. Merlini D, Caramia F. Effect of dehydroascorbic acid on the islets of Langerhans of the rat pancreas. J Cell Biol 1965;26:245-6 1. Massina A, Brucchieri A, Gasso G. Experimental diabetes induced by dehydroascorbic acid. Bull Soc Ital Biol Sper 1968;44:l 138-41. Nandi BK, Majumder AK, Subramanian N, Chatterjee lB. Effects of large doses of vitamin C in guinea pigs and rats. J Nutr l973;l03:1688-95. Majumder AK, Banerjee SK, Nandi BK, Chatteijee lB. Cause of diabetes mehlitus in guinea pigs and human beings: accumulation of dehydroascorbic acid in blood. Sci Cult l974;40:328-31. Ginter E, Zdichynec B, Holzerova 0, et al. Hypochohesterolemic effect of ascorbic acid in maturityonset diabetes melhitus. Int J Vitam Nutr Res h978;48:368-73. Chauerjee IB, Baneijee A. Estimation of dehydroascorbic acid in blood of diabetic patients. Anal Biochem h979;98:368-74. Som 5, Basu 5, Mukherjee D, et al. Ascorbic acid metabolism in diabetes melhitus. Metabolism 1981; 30:572-7. Baneijee A. Blood dehydroascorbic acid and diabetes melhitus in human beings. Ann Clin Biochem 1982;19:65-70. Yew MS. Effect of streptozotocin diabetes on tissue ascorbic acid and dehydroascorbic acid. Horm Metab Res l983;h5:h58. Bigley R, Wirth M, Layman D, Riddle M, Stankova L. Interaction between glucose dehydroascorbate transport in human neutrophils and fibroblasts. Diabetes l983;32:545-8. Chen MS, Hutchinson ML, Pecoraro RE, Lee WYL, Labbe RF. Hyperglycemia-induced intracellular de-
172.
193.
173.
194.
174.
195.
175.
196.
176.
197.
177.
198.
178.
199. 200.
179.
201.
180.
181.
202.
182. 183.
203.
204.
184.
205.
185. 186.
206.
187.
207.
208.
188.
209.
189.
210.
190. 191.
211.
192.
212.
MICRONUTRIENT pletion of ascorbic acid in human mononuclear heukocytes. Diabetes 1983;32:1078-81. Stankova L, Riddle M, Lamed J, et al. Plasma ascorbate concentrations and blood cell dehydroascorbate transport in patients with diabetes mellitus. Metabolism l984;33:347-53. Newill A, Habibzadeh N, Bishop N, Schorah Ci. Plasma levels of vitamin C components in normal and diabetic subjects. Ann Clin Biochem l984;21: 488-90. Patterson JW, Lazarow A. Sulfhydryl protection against dehydroascorbic acid diabetes. J Biol Chem 1950;186:l41-4. Sarji KE, Kleinfehder J, Brewington P, Gonzalez J, Hempling H, Colwell JA. Decreased platelet vitamin C in diabetes mellitus: possible role in hyperaggregation. Thromb Res l979;15:639-50. Cox BD, Butterfield WJH. Vitamin C supplements and diabetic cutaneous capillary fragility. Br Med J 1975;2:205. Sjostrand SE. Pharmacological properties of dehydroascorbic add and ascorbic acid: effects on the central and peripheral nervous systems in experimental animals. Acta Physiol Scand (Suppl) 1970; 358: 1-79. Marble A, Ferguson BD. Diagnosis and classification of diabetes mehhitus and the non-diabetic melhituria. In: Marble A, Krall LP, Bradley RF, Christhieb AR, Soehdner AR, eds. Joshins diabetes mellitus. Philadelphia, PA: Lea and Febiger, 1985:332-52. Darby Wi, Ferguson ME, Furman RH, Lemley JM, Ball CT, Meneely GR. Plasma tocopherols in health and disease. Ann NY Acad Sci l949;52:328-33. Vatassery GT, Morley JE, Kuskowski MA. Vitamin E in plasma and platelets of human diabetic patients and control subjects. Am J Chin Nutr 1983;37: 641-4. McMasters V, Howard T, Kinsell LW, Van Der Veen J, Olcott MS. Tocopherol storage and depletion in adipose tissue and plasma of normal and diabetic human subjects. Am J Din Nutr 1967;20:622-6. Behrens WA, Scott FW, Madere R, Trick KD. Increased plasma and tissue levels of Vitamin E in the spontaneously diabetic BB rat. Life Sci 1984;35: 199206. Steiner M, Anastasi J. Vitamin E: an inhibitor of the platelet release reaction. J Din Invest l976;57: 732-7. Cohwell JA, Winocour PD, Holushka PV. Do platelets have anything to do with microvascuhar disease? Diabetes 1983;32(suppl 2):14-9. Watanabe J, Umeda F, Wakasugi H, Ibayashi H. Effect of vitamin Eon platelet aggregation in diabetes melhitus. Thromb Haemost l984;51:313-6. Levin ME, Boisseau VC, Avioli LV. Effects of diabetes mellitus on bone mass in juvenile and adultonset diabetes. N Engl J Med l976;294:241-5. Santiago JV, McAhister WH, Ratzan SK, et al. Decreased cortical thickness and osteopenia in children with diabetes mellitus. J Clin Endocrinol Metab l977;45:845-8. Rosenbboom AL, Lezotte DC, Weber FT, et al. Diminution of bone mass in childhood diabetes. Diabetes l977;26: 1052-5. MacNair P, Madsbad S, Christiansen C, Faber OK,
STATUS
IN
DIABETES I, Binder
mellitus:
895 C. Osteopenia
its relation
Transbol
diabetes
in insulin-treated
sex and
to age at onset,
213.
231.
214.
232.
233.
215.
216.
234.
217.
235.
218.
236.
219.
237.
238.
220.
duration of disease. Diabetologia 1978;l5:87-90. Wiske PS, Wentworth SM, Norton JA, Epstein 5, Johnston CC. Evaluation of bone mass and growth in young diabetics. Metabolism l982;3h:848-54. Hui SL, Epstein 5, Johnston CC, Jr. A prospective study ofbone mass in patients with Type I diabetes. i Din Endocrinol Metab 1985;60:74-80. McNair P, Madsbad 5, Christensen MS, et al. Bone mineral loss in insulin-treated diabetes melhitus; studies on pathogenesis. Acta Endocrinol 1970;90: 463-72. McNair P, Christiansen C, Christensen MS, et al. Development of bone mineral loss in insulin-treated diabetes: a one-and-a-half year follow-up study in sixty patients. Eur i Clin Invest 1981;l 1:55-9. De-Leeuw I, Abs R. Bone mass density in maturitytype diabetics measured by the 1251 photon absorption technique. Diabetes 1977;26: 1130-5. Levy J, Teitelbaum SL, Gavin JR, Fausto A, Kurose H, Aviohi IS. Bone calcification and calcium homeostasis in rats with non-insulin dependent diabetes induced by streptozotocin. Diabetes l985;34:36572. McNair P, Christensen MS, Christiansen C, Madsbad 5, Transboh I. Is diabetic osteoporosis due to microangiopathy? Lancet l981;l:l27l. Frazer TE, White NH, Hough 5, et al. Alterations in circulating vitamin D metabohites in the young insulin-dependent diabetic. J Chin Endocrinol Metab
N, Madsbad 5, Christensen MS. Decreased serum concentration of ionized calcium in insulin-dependent human diabetes mellitus. Eur J Clin Invest 1983;l3:267-70. Heath H III, Lambert PW, Service FJ, Amnaud SB. Calcium homeostasis in diabetes melhitus. J Chin Endocrinol Metab l979;49:462-6. Karasov WH, Diamond JM. Adaptive regulation of sugar and amino acid transport by vertebrate intestine. Am J Physiol h983;245:G443-62. Schneider LE, SchedI HP. Diabetes and intestinal calcium absorption in the rat. Am J Physiol 1972;223: 13 19-23. Davis FB, Davis PJ, Nat G, et al. The effect of in vivo glucose administration on human erythrocyte Ca2-ATPase activity and on enzyme responsiveness in vitro to thyroid hormone and calmoduhin. Diabetes l985;34:639-46. Morley JE, Levine AS, Beyer HS, Mooradian AD, Kaiser FE, Brown DM. The effects of aging and diabetes mellitus on human red and white cell calmoduhin levels. Diabetes 1984;33:77-80. Rude RK, Ohdham SB, Sharp CF. Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 1978;47:800-6. Haussler MR, McCain TA. Basic and clinical concepts related to Vitamin D metabolism and action. N Engl J Med 1977;297:974-83. Wongsurawat N, Azmbrecht Hi, Zenser TV, Davis BB, Thomas ML, Forte LR. 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 production by isolated renal slices is modulated by diabetes and insulin in the rat. Diabetes l983;32:302-6. 198 l;53:h 154-9. McNair P, Fogh-Anderson
239.
221.
240.
222.
241.
223.
242.
224.
243.
225.
244.
226.
227.
245.
228.
246.
247.
229.
230.

Am J Clin Nutr 1987 Mooradian 877 95

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Am J Clin Nutr 1987 Mooradian 877 95

Uploaded by

Copyright:

Available Formats

Review

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Diabetes mellitus, osteopenia

micronutrient, minerals, vitamins,

? NL NLor4 NLor4 NLor4

summarizes tients with Trace Zinc

the micronutrient diabetes mellitus.

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Altered bone metabolism 20 to

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

DIABETES yeast on glucose

lipids in elderly subjects. Offenbacher EG, Rinko

fects of inorganic glucose tolerance,

454-61. 76. Grant AP, McMullen

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

93. 94. 95.

102. 103. 104.

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

Downloaded from ajcn.nutrition.org at Bangladesh: ASNA Sponsored on August 16, 2013

You might also like