Am J Clin Nutr 1987 Mooradian 877 95

Am J Clin Nutr 1987:45:877-95. Printed in USA. © 1987 American Society for Clinical Nutrition 877

Micronutrient status in diabetes mellitus1’2

Arshag D Mooradian, MD and John E Morley, MB, BCh

Review Article

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 dataon 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 concludedthat 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 Diabetes mellitus, micronutrient, minerals, vitamins, zinc, chromium, magnesium,

pyridoxine, ascorbate, osteopenia

Introduction

The intricate relationship between nutritionand diabetes mellitus was suspected as earlyas 1674 when Sir Thomas Willis suggested thatpatients with diabetes mellitus should be ad-vised to have gummy and starchy food. Sincethen a variety of dietary recommendationshave been made by different diabetologists (1-4). Despite the large literature on the role ofdietary composition in control of diabetesmellitus, there are relatively few studies on theeffect of diabetes mellitus on nutrient statusof the individual. It is generally accepted thatchronic insulin deficiency is equivalent tostarvation in the sense that both conditionsare catabolic states and will lead ultimately tocachexia. This catabolic state of uncontrolleddiabetes mellitus is readily reversed with in-sulin therapy, and the reader is referred to pre-vious excellent reviews on the role of insulinin treatment of diabetes mellitus and preven-tion of major nutrient wastage (5-8). Mal-nutrition has been suggested as a cause of di-abetes mellitus in certain geographic areas (9,10). However, the exact pathogenetic role ofmalnutrition in diabetes mellitus has beendisputed.

Over the last 20 yr, numerous studies havefound alterations in micronutrient status ofpatients with diabetes mellitus, and in somestudies deficiency of certain minerals or vita-mins has been correlated with presence of di-abetic complications. Methodological uncer-tainties and differences in patient populationsstudied have led to contradictory findings andcontroversial conclusions. In addition, severelyrestricted diets prescribed for obese diabeticsand impact of recently recommended high fi-ber diets on mineral and vitamin absorptionare of concern (11, 12). These findings havenot been comprehensively evaluated in criticalreviews. In this communication, we review theavailable studies on the vitamin and mineralstatus of patients with diabetes mellitus andthe possible role of these substances in thepathogenesis of diabetes mellitus. Table 1

‘From the Geriatric Research Education and ClinicalCenter (ADM), Sepulveda VA Medical Center, Sepulveda,CA, and the Department of Medicine (ADM, JEM), Uni-versity 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.

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878 MOORADIAN AND MORLEY

TABLE 1Micronutrient status of diabetic patients

Status in dia

Micronutrient Type I

betic patients

Type II

I. Trace elements

Zinc (Zn) 4 4Chromium (Cr) NLCalcium (Ca) 4 NLMagnesium (Mg) 4 4Copper (Cu) NL NL or fManganese (Mn) 4 or NL �tIron (Fe) NL NLSelenium (Se) ?

II. VitaminsA ? NLThiamin NL NLt3-6 NLor4 NLor43-12 NLor4 NLC NLor4 NLor41,25-dihydroxycholecalciferol 4 NLE t f

* NL = neither increased or decreased.

t Type of diabetes not specified.f Increased in Japanese diabetics.

summarizes the micronutrient status of pa-tients with diabetes mellitus.

Trace minerals

Zinc

Since the original finding in 1934 by Scott(13) that crystalline insulin contains ‘-�-0.5%zinc (Zn), many studies have investigated therole of Zn nutriture in insulin secretion andmetabolism. In 1937, Hove et al (14) foundminor differences in response to oral glucosebetween Zn-deficient and ad libitum-fed con-trol rats. Subsequent studies in Zn-deficientrats suggested that these animals were unableto clear glucose adequately (15-18). A similarfinding was reported in Chinese hamsters (19).This impaired clearance was still present whenZn-deficient animals were compared with pair-fed control animals (19). It needs to be pointedout that others have failed to demonstrate im-paired glucose tolerance after oral (20) or par-enteral administration (21) of glucose. In awell-controlled study in rats by Brown et al(22), Zn deficiency had no apparent effect onoral glucose tolerance or pancreatic insulinconcentration. Clearly, impaired glucose tol-erance is present to a greater degree after par-enteral than after oral administration and this

could well be due to the greater stimulationof insulin secretion seen following enteral ad-ministration of glucose.

The effect of Zn deficiency on insulin se-cretion from the pancreas is controversial.Basal serum insulin values have been reportedeither to be the same as or lower than pair-fedand ad-libitum control animals (15-18, 20, 22,23). Overall these studies suggest that theremay be a minor impairment of insulin secre-lion in response to some secretagogues. Thiswould be compatible with the report thatstimulation of insulin secretion is accompa-nied by reduction of Zn content in $ cells ofpancreas (24) and the demonstration that in-sulin is stored in complexes with varying ratiosof Zn in pancreatic � cells (25, 26).

In addition to decreased insulin secretionin Zn-deficient animals, it has been suggestedthat Zn deficiency may lead to increased in-sulin resistance. In 1966, Quarterman et al (15)found decreased sensitivity to coma and con-vulsions following insulin administration inZn-deficient animals. Huber and Gershoff(17)reported reduction in bioassayable seruminsulin-like activity using an in vitro adiposetissue assay. Antigenic properties of insulinwere altered by varying the Zn to insulin ratio(27). Further, a number of more recent studieshave suggested that Zn plays a role in insulinaction. These studies have shown that Zn canenhance the binding of insulin to hepatocytemembranes (28) and that it has an additiveeffect to that of insulin on lipogenesis in ratadipocytes (29). May and Contoreggi (30) sug-gested that the insulin-like effects of Zn ionsin adipocytes involve the ability of Zn tomodulate hydrogen peroxide generation. Znsupplementation in the obese (ob/ob) mouseresulted in a lower fasting plasma glucose leveland a decrease in hyperinsulinemia normallypresent in these animals (31). However, re-sponsiveness to a glucose load remained im-paired in ob/ob mice after Zn supplementa-tion, and insulin response was markedly im-paired. These findings are compatible with thereports demonstrating that pharmacologicalconcentrations of Zn, in vitro, inhibit glucose-induced insulin secretion from islets of Lan-gerhans (32-34) and demonstrating that acuteadministration of Zn to normal animals pro-duced a transient elevation in plasma glucosewith a decrease in circulating insulin and an

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MICRONUTRIENT STATUS IN DIABETES 879

increase in glucagon (35). In our preliminarystudies we have failed to show a correlationbetween serum and urine Zn and severity ofglucose intolerance in patients with Type IIdiabetes mellitus (36). Further, in a pilot studywe found no significant effect of pharmaco-logical Zn supplementation on the glycosyl-ated hemoglobin (HbA1�) levels in patientswith Type II diabetes mellitus (37).

In summary, although there are a numberof tantalizing suggestions that Zn deficiencymay play a role in the development of someforms of glucose intolerance, presently avail-able data lead us to conclude that the role ofZn deficiency in pathogenesis of diabetes mel-litus is not proven. Further, it appears that ef-fects of Zn on insulin secretion are biphasicwith higher concentrations impairing insulinrelease.

There is accumulating evidence that devel-opment of diabetes mellitus may lead to Zndeficiency. Tissue Zn deficiency (including lowfemur Zn) has been reported in genetically di-abetic (db/db) mice (38). This is in contrast tofindings in animal models of Type I diabetesmellitus (streptozotocin- and alloxan-induced)where Zn concentrations appear to be normal(38). Low serum and blood-clot Zn and hy-perzincuria have been reported in initial stagesof Type I diabetes mellitus (39).

In our studies we found low serum Zn levels(<70 zg/dL) in 9% of 180 subjects with TypeII diabetes mellitus (37) and hyperzincuria(>800 �tg/24 h) in 100% of 25 subjects withType II diabetes mellitus (36). Zn absorptionwas mildly impaired in these subjects despitethe hyperzincuria (36). Studies in dogs receiv-ing a 7-d continuous intravenous infusion ofglucose (7.1 g/kg body wt/d) showed that glu-cose per se could produce hyperzincuria (36).These studies led us to conclude that hy-perzincuria, which results from a glucose-mediated process, interacts with impaired Znabsorption to produce borderline Zn defi-ciency in patients with Type II diabetes mel-litus.

Major causes of morbidity and mortality inolder diabetic patients relate to impaired im-mune function (40, 41), which leads to in-creased infections and to diabetic foot ulcersand cellulitis and/or osteomyelitis, which re-sult in amputations. Zn was demonstrated tobe necessary for adequate function of T-cell

lymphocytes (42). We found that in patientswith Type II diabetes mellitus and Zn defi-ciency there was improvement in the T-lymphocyte response to phytohemagglutininand no consistent change in natural-killer(NK)-cell activity following Zn supplemen-tation (37). We found a similar dichotomy inthe effects of Zn supplementation on NK-cellactivity and phytohemagglutinin-induced re-sponses in Zn-deficient patients with lungcancer (43).

Zn is well established as playing a role inwound healing (44-47). Zn supplementationwas shown to accelerate healing of leg ulcersin elderly subjects in two double-blind trials(44,45). This is in keeping with findings fromanimal studies (46, 47). There are no reporteddouble-blind studies on effects of Zn replace-ment on diabetic ulcers. Clearly, evaluation ofthe potential role of Zn in accelerating healingof diabetic foot ulcers is important therapeu-tically.

Zn is recognized to be associated with al-tered taste perception (48). Although diabeticshave poor taste perception, Zn supplementa-tion (220 mg zinc sulfate three times a day for3 mo) failed to improve taste recognition indiabetics with decreased serum Zn levels (37).One potentially toxic effect of Zn supplemen-tation in patients with diabetes mellitus is thathigh doses of Zn in normal adults increase low-density lipoprotein (LDL) and decrease high-density lipoprotein (HDL) cholesterol (49).The mechanism of this effect appears to besecondary to the impairment of copper me-tabolism produced by megadoses of Zn (videinfra). However, in a recent long-term studyin patients with Wilson’s disease, oral Zntherapy did not lower the HDL-cholesterollevel (50).

Overall, available studies on Zn and diabetessuggest that Zn deficiency, which occurs insome diabetics, may well play an importantrole in impaired T-cell function and in thepathogenesis of diabetic foot ulcers. Furtherstudies are necessary to delineate more clearlythe role of Zn in the pathogenesis of Type IIdiabetes mellitus.

Chromium

Chromium (Cr) is an essential trace metalthat has been suggested to have an important

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role in normal glucose homeostasis (51-53).Deficiency of Cr or its biologically active form,the glucose-tolerance factor (GTF), has beenimplicated in the pathogenesis of some formsof glucose intolerance and diabetes mellitus(54-56). GTF is a naturally occurring lowmolecular weight (400-600 daltons) organiccompound (57). It is water soluble and stableagainst wet heat, acid, and alkali treatments.The exact chemical structure is still unknown,but it appears to be a complex of nicotinicacid, amino acid components, and Cr. Gly-cine, cysteine, and glutamic acid appear to bethe amino acid components of this compound(51, 52). Several synthetic GTF’s have beenfound to have chemical and biological prop-erties similar to naturally occurring GTF (52,58, 59). Richest sources of GTF include brew-er’s yeast, liver, and kidney.

Experiments in rats (54, 60) and squirrelmonkeys (61) demonstrated that dietary de-ficiency of Cr can result in elevated blood glu-cose, triglycerides, and cholesterol levels.These metabolic abnormalities were readilyreversed by the administration of inorganic Cr.In mice a single intraperitoneal injection ofGTF reduced the nonfasting plasma glucoselevel by 38% in nondiabetic and by 14-29%in diabetic animals (62). The combinationtreatment of diabetic mice with GTF and ex-ogenous insulin was significantly more effec-tive in reducing plasma glucose than eithertreatment alone. Similarly, in two patients Crdeficiency secondary to prolonged total par-enteral nutrition was associated with glucoseintolerance that is responsive to Cr supple-mentation (55, 56). In healthy adults, Cr sup-plementation either as inorganic Cr chlorideor brewer’s yeast did not result in significantimprovement in glucose tolerance (63-66). Adouble-blind cross-over study in 76 normalfree-living subjects concluded that inorganicCr supplementation improves glucose toler-ance in individuals with blood glucose values� 100 mg/dL at 90 mm during an oral glucose-tolerance test (67).

It is tempting to speculate that one factorcontributing to the decline of carbohydratetolerance in the elderly is the documented de-crease of tissue Cr levels with age (68-70), par-ticularly in Western societies that eat refinedfoods that are somewhat deficient in Cr (71).In a group of aged volunteers, supplementa-

tion of inorganic Cr or GTF in the form ofbrewer’s yeast improved glucose tolerance andinsulin sensitivity in up to 50% of subjects (72-74). However, a recently conducted study in23 healthy well-nourished elderly volunteersdid not find any significant changes in glucosetolerance, insulin, cholesterol, or triglyceridesafter supplementation with Cr or brewer’syeast (75).

Several limited clinical trials in small num-bers of patients have reported that Cr or GTFsupplementation may improve glucose intol-erance in some patients with abnormal oralglucose-tolerance tests or overt diabetes (64-66, 73, 74, 76). However, three double-blindcross-over studies failed to demonstrate anybeneficial effects of Cr supplementation onblood glucose levels (77-79). In men with TypeI or Type II diabetes, Cr supplementation witheither the organic or the inorganic form didnot alter fasting plasma glucose or glucose re-sponse to either a standard meal or to tolbu-tamide (78). Conversely, Cr supplementationin six Type II diabetic patients improved in-sulin sensitivity measured by a closed-loop in-sulin delivery system (80). In another study of37 Type II diabetic patients, small amounts ofCr supplements (brewer’s yeast 1.6 g/d) re-sulted in a 17% decrease in glycosylated he-moglobin levels and a 36% increase in HDLlevels with no change in fasting blood glucose(76). The discrepancies in these reported find-ings are probably secondary to the fact thatexperimental subjects studied are heteroge-nous for Cr status and ability to metabolizethe inorganic Cr salt into the biologically activeGTF. It has been suggested that Cr supple-mentation will improve glucose tolerance onlyin those with Cr deficiency.

At present there are no reliable methods toevaluate marginal Cr deficiency. A trial of Crsupplementation may be worthwhile in rela-tively healthy individuals with mild glucoseintolerance and elevated plasma insulin levels.Whether the organic form of Cr (GTF) is su-perior to the inorganic form in its ability toenhance insulin sensitivity is not known. Al-though some animal models of diabetes re-spond preferentially to GTF rather than to in-organic Cr (62, 81), evidence suggests that inhumans biological activities of these two formsare similar. A recent preliminary study inhealthy elderly volunteers showed that a corn-

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bination of Cr and nicotinic acid improvedglucose tolerance, while Cr and nicotinic acidby themselves were ineffective (82).

The exact mechanism by which GTF im-proves glucose tolerance is not known. It issuggested that GTF enhances the binding ofinsulin to its specific receptors possibly throughinitiating disulfide linkages between insulinand cell membrane (51, 52). In vitro experi-ments have shown that GTF can bind insulinand that these complexes of insulin and GTFexhibit greater biological activity than eitherinsulin or GTF alone (83). The physiologicalsignificance of this observation is not clear.However, there is a 4-h lag period betweenadministration of GTF and optimal effects oninsulin action in vivo, which suggests thatmechanisms other than enhanced insulinbinding to its receptors, such as conversion toanother active form or transport to specificintracellular sites, are involved in the actionof GTF (62).

Cr and/or GTF appears to have an impor-tant role in lipid metabolism. Cr deficiency inrats is associated with elevated serum choles-terol levels (54, 60). In genetically diabeticmice, GTF administration lowers the elevatedplasma triglyceride and cholesterol levels by47% and 35%, respectively (62). Several clin-ical trials in adults with or without glucose in-tolerance found that Cr supplementation maydecrease serum total cholesterol and increaseHDL-cholesterol levels (63, 64, 74, 76, 84).These findings could not be confirmed in sub-sequent placebo-controlled studies in diabeticmen (78, 79) and healthy subjects (67, 75).Overall, it appears that Cr supplementationsmay reduce total cholesterol levels by 5-12%,increase HDL levels by 8-36%, but have noeffect on serum triglyceride levels (63, 64, 74,76, 84). The biological significance of thesealterations in blood lipid levels secondary toCr deficiency is not clear. Epidemiological andexperimental data suggest that Cr deficiencymay be a factor in the pathogenesis of athero-sclerosis (85-87). It is not known if Cr sup-plementation can have beneficial effects onlipid metabolism and atherosclerosis in asubgroup of patients with marginal Cr defi-ciency.

Prevalence of Cr deficiency among diabeticpatients is not well established. Basal plasmaCr levels in Type I diabetic patients were found

to be increased, whereas plasma levels in TypeII diabetic patients were similar to those inhealthy controls (78). To evaluate the statusof body Cr stores, plasma Cr response to oralglucose load was studied; relative plasma Crresponse to a glucose load has been suggestedas a potential test to assess Cr status of indi-viduals. Plasma Cr in women with abnormaloral glucose-tolerance test decreased in re-sponse to an oral glucose load (64). When thesesubjects’ diets were supplemented with brew-er’s yeast, ingestion of glucose resulted in anincrease in plasma Cr concentration. A sub-sequent study in a group of patients with TypeI or Type II diabetes found an increase inplasma Cr level in response to a test meal (88).Urinary Cr excretion tends to be increased indiabetics (88, 89) although only one study re-ported statistically significant differences be-tween the nonobese Type II diabetic patientsand control subjects (88). Increased urinaryexcretion of Cr in insulin-requiring diabeticpatients is counterbalanced by enhanced gas-trointestinal absorption of Cr (90). As a group,diabetic children have reduced hair Cr com-pared with control children (91). Hair Cr con-tent in adult insulin-dependent diabetic pa-tients was decreased only in female patients(92). In a study of adult male Type I and TypeII diabetic patients, there were no differencesin hair or red blood cell Cr levels when com-pared with control subjects (88). A wide vari-ation in Cr levels was found in various samplesfrom both diabetic and healthy individuals.Although differences in Cr level between di-abetic patients as a group and nondiabeticsubjects did not reach statistical significance,the lowest values of Cr were seen in certainindividual diabetic patients, which suggeststhat there might be a subgroup of diabetic pa-tients with Cr deficiency (88). It is possible thatdifferences in patient population studied aswell as differences in body pools of Cr evalu-ated can account in part for discrepancies inreported findings. Methodological problems inmeasurements of Cr in the majority of thestudies reported make the conclusions drawnuncertain. Furthermore, measurements of el-emental Cr level may not reflect the functionalCr status in diabetic patients. Screening forGTF deficiency using appropriate bioassaytechniques may yield physiologically morerelevant information.

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Overall it appears that although Cr defi-ciency can lead to glucose intolerance, it rarelyplays a role in the pathogenesis of diabetesmellitus and most diabetic patients are not Crdeficient. However, at present, the majortechnical problems associated with the dem-onstration of Cr deficiency do not allow anaccurate assessment of Cr status. Inconsistencyof responses to Cr supplementation in diabeticpatients may be in part secondary to hetero-geneity of diabetic patients with regard to mi-cronutrient status. It is possible that responseto Cr supplementation is determined by Crstatus of the patient such that only those withCr deficiency will respond favorably to sup-plementation. The potential role of Cr defi-ciency in the glucose intolerance associatedwith aging deserves further investigation.

Magnesium

Magnesium (Mg) is an essential ion in-volved in glucose homeostasis at multiple lev-els. It is a cofactor in the glucose transportsystem of plasma membranes, has an impor-tant role in activity of various enzymes in-volved in glucose oxidation, may play a rolein release of insulin, and can modulate themechanisms of energy transfer from high-energy phosphate bonds (93-96).

Human and animal studies have indicatedthat diabetes mellitus is associated with in-creased urinary loss of Mg especially when hy-perglycemia is poorly controlled (97-101).Thus, it is not surprising that in a survey ofpatients attending a general medical clinic, di-abetes mellitus was found to be the most fre-quent chronic disease associated with hypo-magnesemia (102). Although studies in smallgroups of patients have yielded conificting re-sults (103, 104), overwhelming evidence in-dicates that plasma Mg concentration in dia-betic patients is reduced. In a study of 582unselected diabetic outpatients, the meanplasma Mg level was significantly lower thanthe level in control subjects (105). Moreover,25% of diabetic patients had values belowthose of all control subjects except one. Aninverse correlation between plasma concen-trations of Mg and glucose was found in astudy of diurnal profile of diabetic patients andcontrol subjects (106). Similarly, an inverse

correlation between serum Mg level and du-ration of diabetes was found in a study of di-abetic children in Sweden (107). Insulin-dependent diabetic patients had a 30% de-crease in trabecular bone Mg content of iliaccrest biopsies (107); Mg content of erythro-cytes, leukocytes, and muscle was normal(108-112), which suggests that the effect of di-abetes or insulin treatment on different tissuepools of Mg can be variable. In rats, hypomag-nesemia was found in experimentally induceddiabetes mellitus (100, 101), and depletionof Mg in bone occurred when the Mg intakewas restricted to the physiologic requirementof control animals (101). The underlying causeof hypomagnesemia in diabetes is not totallyclear. It appears to be, at least in part, second-ary to urinary Mg loss (97-10 1). In a study of215 insulin-treated diabetic patients, 39% hadhypomagnesemia and 55% had hypermagne-siuria (98). Residual insulin secretory statusin insulin-dependent diabetes had no influenceon serum Mg level (67) although insulincaused a shift of Mg from extracellular spaceinto hepatocytes and muscle cells (113). Ofparticular concern was the large urinary Mgloss during diabetic ketoacidosis (77). The re-sultant hypomagnesemia can have lifethreat-ening effects on myocardium and skeletalmuscles. Furthermore, hypomagnesemia wasimplicated in insulin resistance following di-abetic ketoacidosis (114).

Biological sequelae of mild hypomagnese-mia in diabetic patients are not completelydefined. Yajnik et al (96) found that the directrelation of plasma Mg concentrations withglucose disposal rate was secondary to the al-terations in tissue sensitivity to insulin. It ispossible that Mg may be an important deter-minant of insulin sensitivity in noninsulin de-pendent diabetes mellitus. Mg deficiency hasbeen linked to two common complications ofdiabetes, namely retinopathy (115) and isch-emic heart disease (116, 117). Patients withsevere diabetic retinopathy have lower plasmaMg levels than do diabetic patients with min-imal retinal changes, which suggests that hy-pomagnesemia may be a risk factor in devel-opment of diabetic retinopathy (115). Whetherthe accelerated atherosclerosis of diabetes is inpart related to depleted body-pool Mg remainstotally conjectural.

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Copper

The role of copper (Cu) in glucose homeo-stasis is not well defined. Experimental datasuggest that impairment of glucose tolerancecan be secondary to Cu deficiency (118-121).Cu deficiency in rats fed sucrose or fructose,but not those fed starch, significantly increasedglucose response and decreased insulin re-sponse to an oral glucose load (121). In Cu-deficient rats with streptozotocin-induced di-abetes, glucose intolerance is improved by Cusupplementation. The combined effect of Cuand insulin on lowering peak blood glucosefollowing intraperitoneal injection of ‘4C glu-cose and incorporation of glucose into lipidwas much greater than either insulin or Cualone (120). In vitro experiments have shownthat Cu has insulin-like activity in promotinglipogenesis (118, 122). The mechanism un-derlying the Cu-enhanced glucose utilizationis unknown. In addition, experimentally-induced Cu deficiency in a healthy man wasassociated with elevated total-cholesterol level,which contributes to atherosclerosis (123).Conversely, elevated serum Cu concentrationshave been found in diabetic and nondiabeticarteriosclerosis (124-127); the role of Cu inarteriosclerosis is not understood.

With the exception of two clinical studies(128, 129) and one study in alloxan-induceddiabetic rats (130), human studies and exper-iments in diabetic animals have found eithernormal or increased serum and tissue Cuconcentrations (127, 131-138). In insulin-deficient diabetic rats, concentrations of Cuand (Cu, Zn)-metallothionein in the liver andkidney are markedly elevated (136, 137). Thetissue Cu content was normalized by insulintreatment, which suggests that hormonal im-balance may be related to altered tissue Cucontent (136). Moreover, intestinal Cu ab-sorption in diabetic rats is markedly enhanced(139); this may contribute to increased tissueCu content. Pair feeding of Cu to diabetic andcontrol rats did not demonstrate that enhancedfood consumption by the diabetic rat had asignificant impact on accumulation of Cu(136). Urinary excretion of Cu was fivefoldhigher in streptozotocin-induced diabetic ratsthan in control rats, insulin treatment signif-icantly reduced the urinary losses of Cu (140).

In humans there was a weak correlation be-tween fasting blood glucose and serum Cu(132, 133). Generally, serum concentrationsof Cu and ceruloplasmin are elevated in TypeII diabetic patients (133). Elevated serum Culevels were not correlated with duration of di-abetes, but levels were higher in older patientsand in those with complications (127). In-creased urinary Cu excretion was found inRussian diabetic patients (141); blood Cucontent was also increased in Russian diabeticswith gangrene in contrast to those withoutgangrene, in whom the Cu levels were re-duced (129).

The pathophysiological implications ofthese observations are not known. Whetherincreased renal Cu content contributes to thenephropathy of diabetes mellitus is not known.Mean erythrocyte Cu-Zn superoxide dismu-tase was lower in insulin-dependent diabeticpatients than in healthy control subjects (142).However, the small differences found probablyhave no biological significance.

Manganese

Experimental evidence suggests that man-ganese (Mn) deficiency in guinea pigs cancause impaired glucose utilization and Mnsupplementation can reverse glucose intoler-ance induced by Mn deficiency (143). Intra-uterine Mn deficiency resulted in atrophy ofislet cells (144), and hepatic Mn content inrats with streptozotocin-induced diabetes wassignificantly elevated (136, 145). Similarly,excessive accumulation of Mn was found infetuses 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 he-patic amino acid metabolism and urea syn-thesis, which characterize insulin deficiency,are related to increased arginase activity inliver of streptozotocin-induced diabetic rats.

Mn status in human diabetics is controver-sial. Kosenko reported Mn blood levels to beapproximately one-half of the normal values(128). In contrast, Lisun-Lobanova found el-evated Mn levels in diabetic patients aged 61-70 yr (131). In a study of serum Mn levels inpatients with various diseases, 62% of diabeticpatients (type not specified) had elevated Mnlevels> 1.6 �tg/100 mL. Levels < 1 zg/100 mL

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were observed in 7% of diabetic patients stud-ied (132). Although serum Mn levels reportedin the older literature are high according tomodern standards, inclusion of control sub-jects in each study allows a valid comparisonbetween serum Mn concentrations of diabeticpatients and that of control subjects. It is note-worthy that elevated serum Mn levels werereported in patients with myocardial infarction(132, 149) and with atherosclerosis (150).Whether the elevated serum Mn levels in asubgroup of diabetic patients are an indepen-dent risk factor for cardiovascular disease re-mains to be seen.

Iron

Iron (Fe) overload, as in hemochromatosis,can cause glucose intolerance secondary topancreatic tissue injury (151, 152). Conversely,Fe deficiency does not seem to have a signif-icant effect on glucose homeostasis but is as-sociated with increased serum triglyceride level(153). Fe status of diabetic patients has notbeen well studied, but Fe mobilization or up-take and utilization appear to be delayed (154).In experimental streptozotocin-induced dia-betic rats, tissue Fe content in liver, kidney,and femur was increased (138). In a similarstudy, streptozotocin-induced diabetic ratsand control rats were fed equivalent quanti-ties of Fe, and the diabetic rats had Fe con-tent increased in liver and muscle andreduced in duodenum (136). In another studystreptozotocin-induced diabetes was associatedwith 4.9-fold increase in urinary Fe excretionwithout reduction in plasma, liver, and kidneyFe content (140). Overall, diabetic state is notassociated with Fe deficiency and there appearsto be no evidence of major alterations in Festatus of diabetic patients who do not haverenal failure or gastrointestinal neuropathywith malabsorption (154). Further studies inhuman and experimental diabetes are clearlywarranted.

Selenium

In recent years, there has been a growingunderstanding of the role of selenium (Se) inhuman and animal nutrition. Se, being an in-tegral part of glutathione peroxidase, has aprotective role against tissue damage caused

by peroxides produced from lipid metabolism(155). Se deficiency in humans causes de-creased glutathione peroxidase activity andcardiomyopathy (156-158). In Se-deficientrats, insulin secretory reserve was significantlyreduced, and glucose intolerance developed inrats maintained on Se and vitamin E-deficientdiets (159).

The literature on Se status in diabetic pop-ulations is meager. In a study of 27 childrenwith insulin-dependent diabetes, the meanserum Se level was higher than that in healthycontrol subjects (160). There was no correla-tion between Se concentrations and children’sage, sex, weight, height, fasting plasma glucoselevels, or glycosylated hemoglobin levels. Al-though serum Se levels may not necessarilyreflect tissue levels, it appears that diabeticchildren do not have Se deficiency contrib-uting to the known complications of diabetesmellitus.

Aluminum, titanium, and silicon

In one study from Russia (129), diabeticpatients had reduced blood levels of titaniumand silicon. In patients with gangrene, plasmaaluminum was increased but aluminum con-tent of cellular elements of blood was reduced.

Vitamins

Vitamin A

Vitamin A is a surface-membrane-activeagent, which has a diphasic concentration-dependent effect on insulin release (161, 162).At low concentrations, vitamin A stimulatesinsulin release while at high concentrations ithas an inhibitory effect which may be me-diated in part by impairment of intracellularglucose oxidation (162).

The status of vitamin A in diabetic patientsis not well studied. In rats with streptozotocin-induced diabetes, 12-fold increase in vitaminA intake did not affect the degree of hypergly-cemia and glycosuria, but wound healing wassignificantly enhanced (163). At present, thereis no evidence to suggest that diabetic patientsmay have vitamin A deficiency that may becontributing to impaired wound healing.

Although hypercarotenemia has been foundin some diabetics (164), overwhelming evi-

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dence suggests that serum levels of caroteneand vitamin A in Type II diabetic patients arenormal (165, 166). The rise in serum vitaminA level following oral administration of f3 car-otene was similar to that seen in healthy con-trols and indicates that Type II diabetic pa-tients do not have any defects in absorptionor conversion of� carotene to vitamin A (166).However, high postabsorptive serum levels ofvitamin A have been observed in diabetic pa-tients with increased serum �3-lipoprotein 1ev-els (167, 168).

Group B Vitamins

Of the group B vitamins, thiamin, vitaminB-6, and vitamin B-l2 have been associatedwith carbohydrate intolerance or diabetesmellitus.

The daily requirement of thiamin is depen-dent on the amount of carbohydrate con-sumed. However, the high-carbohydrate, high-fiber diet currently recommended to diabeticpatients appears to provide sufficient thiaminto meet the metabolic needs of the individual(169). Thiamin status of diabetic patients iscontroversial. Haugen reported a significantlylow blood thiamin level in insulin-dependentdiabetic patients (170). Conversely, elderlypatients with noninsulin-dependent diabeteshad normal blood levels of thiamin (170).Erythrocyte transketolase (ETK) activity, anindirect measure of thiamin status, was foundto be reduced in Type I and Type II diabeticpatients (171), but the reduced ETK activitycould not be corrected by the addition of thia-mm pyrophosphate, which suggests that thelow ETK activity in diabetic patients was dueto a reduced apoenzyme level rather than todeficiency of the cofactor for ETK activity,namely, thiamin (171). In a group of Japanesediabetics (type unspecified), plasma thiaminlevels were elevated (172), and thefe was a sta-tistically significant though weak correlationbetween plasma glucose and thiamin levels.Similar correlations were found in rabbits withalloxan-induced diabetes (172). The elevatedthiamin levels were attributed by the authorsto impaired tissue transport (173). However,this speculation is not supported by conclusiveexperimental evidence. At present there areno data to suggest that thiamin supplemen-tation should be recommended for diabetic

patients. The occasional patient with diabeticneuropathy may respond to thiamin admin-istration (174).

Plasma vitamin B-6 and pyridoxal 5’-phosphate concentrations were significantlyreduced in patients with diabetes mellitus (169,175-177). Sebastian et al found vitamin B-6deficiency in one-third of the diabetic patientsstudied (175); those with poor control of bloodglucose had more pronounced deficiency.Insulin-treated patients had lower plasma vi-tamin B-6 levels than those treated with oralhypoglycemic agents (175). The reason for vi-tamin B-6 deficiency in diabetic patients is notknown. Of interest is the observation thatplasma levels of vitamin B-6 gradually declinefollowing an oral glucose load (178). Insulinresponse to an oral glucose load is significantlyimpaired in pyridoxine-deficient rats, and invitro pancreas perfusion experiments showedthat secretion of both insulin and glucagon wasimpaired in pyridoxine deficiency (179). Pyr-idoxine deficiency in experimental animalsand humans has been associated with glucoseintolerance (180-184). The role for vitaminB-6 in glucose homeostasis has been suggestedby its effect on tryptophan metabolism (185).In vitro experiments have shown that the me-tabolites of tryptophan degradation, quinolinicacid and hydroxyanthranilic acid, have inhib-itory effects on enzymes regulating carbohy-drate metabolism (186, 187). Interestingly, di-abetic patients were found to have abnormal-ities in tryptophan metabolism such asincreased formation of hydroxykynurenineand xanthurenic acid (188); xanthurenic acidbinds insulin and reduces its biological activity(189). Similar changes in tryptophan metab-olism were reported in two other clinical statescharacterized by carbohydrate intolerance:glucocorticoid therapy and oral contraceptiveagent use (190). Pharmacological doses of vi-tamin B-6 can reverse the abnormalities oftryptophan metabolism and may improvecarbohydrate tolerance in pregnancy (191,192) and in women taking oral contraceptiveagents (193). However, two studies in pregnantwomen failed to show beneficial effects of vi-tamin B-6 on gestational diabetes (194, 195).At present it is not known if improvement ofglucose tolerance secondary to vitamin 8-6administration is related to the role of this vi-

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tamin in tryptophan metabolism. In a studyof women on oral contraceptive steroids, vi-tamin 8-6 normalized tryptophan metabolismin all, yet carbohydrate tolerance improvedonly in those with evidence of vitamin B-6deficiency (196). Hence, the effect of vitaminB-6 on carbohydrate metabolism is not solelymediated by its effect on tryptophan metab-olism. Vitamin 8-6 administration had no ef-fect on glucose homeostasis in diabetic patientswith vitamin B-6 deficiency (197). As is thecase with thiamin, supplementation of the di-abetic diet with vitamin 8-6 cannot be justifiedexcept for those with severe neuropathy wherea trial of pharmacological doses of vitamin 8-6may be useful in the occasional patient (174).

Vitamin B-l2 deficiency is associated par-ticularly with insulin-dependent diabetes mel-litus. Pernicious anemia and diabetes mellituscan occur in the same individual as part ofpolyglandular autoimmune syndromes (198).In Type I polyglandular failure, the incidenceof diabetes mellitus is 2-4% and the incidenceof pernicious anemia is 13-15%. Diabetesmellitus occurs more often in Type II poly-glandular failure, but the incidence of perni-cious anemia in this syndrome is <1%. InType III polyglandular failure, both diabetesmellitus and pernicious anemia have been de-scribed in association with thyroid disease.

Vitamin C

Numerous reports have suggested an inti-mate interrelationship between vitamin C andglucose homeostasis (199-2 14). Guinea pigsmaintained on a low-protein diet and largedoses of vitamin C develop hyperglycemia(204). Dehydroascorbic acid (DHAA), an ox-idative metabolite of ascorbic acid (vitaminC), is a diabetogenic agent (200-203). Admin-istration of DHAA to rats causes degranulationof� cells of pancreas and hyperglycemia (201,202). Pre-injection of rats with reduced glu-tathione or cysteine prevents development ofhyperglycemia, which suggests that the dia-betogenic effect of DHAA is mediated throughits interaction with the sulffiydryl groups es-sential for islet cell integrity (215). The clinicalimplication of these observations is unclear:it is not known if large doses of vitamin C willinduce overt diabetes in a predisposed indi-vidual.

Clinical studies from India have indicatedthat plasma ascorbate concentrations werelower and dehydroascorbate concentrationswere higher in diabetic patients irrespective ofage, sex, duration of the disease, type of treat-ment, and glycemic control (207-209). Sub-sequent studies from Leeds in the UnitedKingdom (214) and Portland in the UnitedStates (213) did not confirm elevated plasmaDHAA levels in Type I or Type II diabeticpatients. Racial differences or marginal dietaryascorbate deficiency in Asian patients may ac-count for this discrepant finding.

Type II diabetic patients have higher turn-over of ascorbic acid. Within 7 d after discon-tinuing vitamin C supplements in diabetic pa-tients, the plasma ascorbate level fell to pre-supplementation levels in contrast to thecontrol nondiabetic subjects who retained thehigh levels of plasma ascorbate (208).

Diabetes mellitus appears to influence tis-sue content of ascorbic acid. In rats withstreptozotocin-induced diabetes, liver andkidney content of ascorbate was significantlyreduced (210). In Type II diabetic subjects,the mean leukocyte ascorbate concentrationwas not reduced in spite of lower plasma levels(208). However, in vivo studies have clearlydemonstrated that hyperglycemia can induceintracellular depletion of ascorbic acid inmononuclear leukocytes, probably by com-petitive inhibition of cellular ascorbate trans-port since ascorbate and glucose appear tohave a common transport mechanism (212).Similarly, insulin-dependent diabetics havereduced platelet vitamin C content, which maycontribute to the enhanced aggregation ofplatelets in diabetic subjects (216). Otherwise,the biological significance of low plasma andpossibly low tissue vitamin C levels in diabeticpatients is not known.

In Type II diabetic patients vitamin C sup-plementation at a dose of 500 mg/d for 15 dresulted in an increase in the plasma ascorbatelevel but did not alter blood glucose control(213). In a subgroup of Type II diabetic pa-tients with poor dietary vitamin C intake, lowleukocyte ascorbate concentrations, and hy-percholesterolemia, vitamin C therapy nor-malized the vitamin C levels and correctedthe hypercholesterolemia, probably by activat-ing the ascorbate-dependent cholesterol 7a-

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hydroxylase enzyme (206). Moreover, thecutaneous capillary fragility in diabetes wascorrected by 1 g daily supplements of vitaminC (217).

At present, minimum daily vitamin C re-quirement for the diabetic population is notknown. In the absence of poor dietary vitaminC intake or decreased leukocyte content of vi-tamin C, there seems to be no justification forhigh-dose vitamin C therapy in diabetic pa-tients. Animal experiments have suggested thatpharmacological doses of ascorbic acid anddehydroascorbic acid are neurotoxic and dia-betogenic (200-203, 218). Although the rele-vance of these findings to diabetic patient isnot known, caution should be exercised inrecommending high doses of vitamin C sup-plements. Vitamin C in large doses can inter-fere with glucose measurements (219) and thushamper the monitoring of diabetes control.

Vitamin E

In rats maintained on vitamin E-deficientdiets, insulin secretory capacity is reduced andglucose intolerance develops in those withcombined deficiency of vitamin E and sele-nium (159). However, clinical studies have in-dicated that vitamin E deficiency is not a fea-ture of diabetes mellitus.

Darby et al (220) reported that human di-abetics had higher plasma tocopherol levelsthan did normal subjects. In confirming theseresults we found that both plasma a- and total,but not “y-, tocopherols were elevated (221).a- and total tocopherols were also increasedin platelets from diabetics. The normal de-crease in platelet tocopherol levels that occurswith aging is not present in patients with di-abetes. There is a tendency for plasma andplatelet tocopherol levels to be higher in pa-tients with Type II diabetes mellitus than thosewith Type I diabetes. Tocopherol levels arehigher in adipose tissue of Type II diabetesthan of normal controls (222). Elevated a-tocopherol levels have been found in serumand tissues from spontaneously diabetic BBrats but not in nondiabetic control rats (223).Tissue �y-tocophero1 levels were reduced inthese animals. These defects were returned tonormal by insulin treatment, which suggeststhat excess accumulation of tocopherols in di-

abetics is a metabolic consequence of the in-sulin deficiency.

In view of the known ability of vitamin Eto inhibit platelet aggregation (224) and theenhanced platelet aggregation in patients withdiabetes (225), it seems likely that the reportedincrease in vitamin E in diabetics may be anattempt to compensate for the increased ad-hesiveness of diabetic platelets. Unfortunately,in the single study done to examine the rela-tionship of vitamin E to platelet aggregationin Type II diabetes mellitus, numbers of pa-tients were small and vitamin E levels in theplatelets were found not to be increased butrather to be reduced (226). In this study Vi-tamin E content in the platelets was inverselycorrelated with adenosine diphosphate-inducedplatelet aggregability and platelet thrombox-ane production. This finding is compatiblewith the hypothesis that vitamin E excess insome diabetics plays a protective role againstthe tendency for increased platelet aggrega-bility in diabetics. Further studies on the re-lationship between vitamin E and platelet ag-gregability in diabetes mellitus are indicated.

Diabetic osteopenia

It is generally accepted that young Type Idiabetic patients have reduced bone mass(227-232). The reduction in bone mass inchildren with diabetes mellitus has been at-tributed to reduced rate of accretion of boneduring the growth period. In older insulin-dependent Type I diabetic patients, bonemineral loss appears to be an important factorin the development of osteopenia (233, 234).It is not clear whether the osteopenia is moresevere among females than among males(227-230). In the growing-adolescent patientpopulation, it appears that females havegreater deficit of bone mass than do males(228). Effects of diabetes mellitus on bonemass in adult onset Type II diabetes is notwell studied (227, 235). Levin et al foundminimal changes of bone mass in a group ofType II diabetic patients (227). In a rat modelof Type II diabetes, bone turnover and met-abolic balance studies of calcium and phos-phate were normal (236).

The underlying etiology of osteopenia in di-abetic patients is not known; altered metabolic

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�lPTH2#{176}to�Mg�

f Ca’�in the urine


FIG 1. Schematic representation of the alterations in calcium metabolism which may contribute to diabetic osteopenia.

milieu or diabetic microangiopathy have bothbeen proposed as possible causes. Diabeticmicroangiopathy appears to have a minor role,if any, because rate of bone loss is highest inthe first 2 years of diabetes onset, a lime beforesignificant microangiopathy develops (230,234, 237). The various metabolic abnormali-ties in juvenile diabetic patients that may con-tribute to the low bone mass include low serummagnesium and ionized calcium, low serumimmunoreactive parathyroid hormone (PTH),and low serum 1,25-dihydroxycholecalciferol.Serum levels of 24,25-dihydroxycholecalcif-erol are normal. In addition, these patientshave hypercalciuria, hypermagnesuria, andincreased intestinal calcium absorption (98,231, 238, 239). These findings were not doc-umented in a study of adult Type I or TypeII diabetic subjects (240). Increased intestinalcalcium absorption in juvenile diabetic pa-tients can be attributed to the increase in ab-sorptive capacity of intestinal mucosa of dia-betic subjects (241) and may not necessarilybe in conflict with the finding of reduced

serum 1,25-dihydroxycholecalciferol in thesepatients. In alloxan-induced diabetic rats thenet calcium absorption per gram dry weightof intestine was significantly reduced (242).The blood glucose level has been shown tomodulate the activity of Ca2�-ATPase (cal-cium pump) (243), and we have found thatwhite blood cell calmodulin (a regulator ofcakium pump) is significantly lower in diabeticpatients than in age-matched control subjects(244). It is possible that these alterations maycontribute to the abnormalities of calcium andbone metabolism observed in some diabeticpatients.

Based on the available data, a likely scenariofor the pathogenesis of the osteopenia of dia-betes mellitus is that urinary loss of magne-sium leads to hypomagnesemia. Hypomag-nesemia leads to decreased PTH secretion andaction (245), which results in decreased for-mation of 1 ,25-dihydroxycholecalciferol (246).The insulin deficiency state will further impairformation of 1,25-dihydroxycholecalciferol(247). This results in inability to enhance in-

Altered bonemetabolism 20 too)�PTHbJ�Mg ++

ci lionized Co

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testinal calcium absorption in the face ofmarked hypercalciuria, leading to calcium de-pletion. Bouts of hypophosphatemia asso-ciated with poor diabetic control (4) will fur-ther aggravate calcium loss from bone (Fig 1).

Conclusion

Experimental evidence has suggested thatdeficiencies in many of the trace elements in-cluding zinc, chromium, magnesium, copper,and manganese as well as vitamin B-6 defi-ciency may lead to glucose intolerance. How-ever, adequately controlled studies that estab-lish the role of trace elements in the pathogen-esis of carbohydrate intolerance are notavailable. Although the majority of diabeticpatients do not have micronutrient deficiencies,zinc, chromium, and magnesium deficiencieshave been identified in a subgroup of patients.The trace-metal urinary losses are accentuatedduring uncontrolled hyperglycemia and gly-cosuria. Serum or tissue content of certain ele-ments such as copper, manganese, iron, andselenium can be higher in diabetic patients thanin nondiabetic controls. Serum ascorbic acid,group B vitamins (thiamin, 8-6, and 8-12) andpossibly 1,25-dihydroxycholecalciferol con-centrations may be low in diabetic patients. Vi-tamin A and vitamin E levels are normal orincreased. These alterations may contribute tosome of the complications of diabetes, and thereis a place for judicious replacement of micro-nutrients in diabetic patients with demonstrateddeficiencies. The inconsistency of responses ofdiabetic patients to mineral or vitamin supple-mentation may be secondary to the heteroge-neity of this patient population with regard tothe micronutrient status. It is likely that theresponse of patients to supplements is deter-mined by nutritional state so that only thosewith micronutrient deficiencies will respond tothe supplements favorably. Patients who aremaintained on high-fiber diet or those who areacidotic or glycosuric are at particular risk ofdeveloping profound deficiency of certain mi-cronutrients such as zinc and magnesium. Ad-equacy of mineral and vitamin intake shouldbe established when severely restricted diets areprescribed to diabetic patients. Most studies re-viewed in this manuscript do not distinguishwhat may be secondary effects of chronic mal-

nutrition from the disease process of diabetesmellitus per se. Further studies are needed inwhich diabetic patients are compared withcontrol subjects with matched nutritionalstatus. C]

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