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Current Zinc Intake and Risk of Diabetes and Coronary Artery Disease and Factors Associated with Insulin Resistance in Rural and Urban Populations of North India

Center of Nutrition and Heart Research Laboratory (R.B.S., M.A.N., S.S.R., S.B.), Medical Hospital and Research Center, Moradabad, INDIA
Zhejiang Medical University, (Z.G., Z.S.), Hangzhou, CHINA

Address reprint requests to: R.B. Singh, MD, FACN, Heart Research Lab., MHRC, Civil Lines, Moradabad-10 (UP) 244001, India

	ABSTRACT

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Objective: To determine the association between current zinc intake and prevalence of coronary artery disease (CAD) and diabetes as well as factors associated with insulin resistance.

Design, Subjects and Methods: In this cross sectional survey, 3575 subjects, aged 25 to 64 years, including 1769 rural (894 men, 875 women) and 1806 urban (904 men, 902 women) subjects were studied. The survey methods included questionnaires for 7-day food intake record, physical examination, and electrocardiography using World Health Organization criteria.

Results: The prevalence of CAD, diabetes and glucose intolerance was significantly higher among subjects consuming lower intakes of dietary zinc. There was a higher prevalence of hypertension, hypertriglyceridemia and low high-density lipoprotein cholesterol levels which showed significant upward trend with lower zinc intakes. Serum lipoprotein (a) and 2-hour plasma insulin levels also were associated with low zinc intake. Multivariate logistic regression analysis after adjustment for age showed that zinc intake and CAD were inversely associated. Serum zinc (odds ratio:men 0.77, women 0.57), serum triglycerides (men 0.86, women 0.81), blood pressure (0.83 men, women 0.76), diabetes mellitus (men 0.90, women 0.85), central obesity (men 0.88, women 0.87), glucose intolerance (men 0.66, women 0.57) and low high-density lipoprotein cholesterol (men 0.72, women 0.70) were significant risk factors for CAD (explained by tertiles of zinc status) in urban subjects. These associations were not observed in rural subjects.

Conclusion: Lower consumption of dietary zinc and low serum zinc levels were associated with an increased prevalence of CAD and diabetes and several of their associated risk factors including hypertension, hypertriglyceridemia and other factors suggestive of mild insulin resistance in urban subjects.

Key words: dietary zinc, serum zinc, diabetes, hypertension, hypertriglyceridemia, insulin resistance, lipoprotein (a)

	INTRODUCTION

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Coronary artery disease (CAD), diabetes and hypertension are three times more common among urban subjects compared to rural subjects [1–7]. Differences in diet, lifestyle characteristics, and nutrient intakes may contribute to the different prevalence of diseases among rural and urban populations [8–15]. Further studies showed that higher prevalence of diabetes (19 vs. 5%) and cardiovascular risk and mortality among Indian immigrants than Europids may be due to an insulin resistance syndrome [16,17]. Increased vulnerability of Indian urban subjects [1–7] and immigrants to developed countries [16–18] is difficult to explain by differences in conventional risk factors and diet and lifestyle characteristics [4–8].

Experimental and clinical studies indicate that zinc and chromium deficiencies may predispose glucose intolerance, diabetes mellitus, insulin resistance, atherosclerosis and CAD [19–26]. However no large epidemiologic studies have examined the relationship of zinc and chromium deficiency with CAD and diabetes. The status of trace minerals is relatively homogeneous among individuals in developing countries making it more difficult to determine whether trace minerals and magnesium are associated with diabetes and CAD within these populations. The relationship of trace elements with CAD and diabetes may be best examined by comparing populations that have larger variations in dietary consumption of minerals and more pronounced differences in the prevalence of diabetes and CAD [14]. In the present study, we examine the association of zinc status with risk of diabetes and CAD in rural and urban populations of north India.

	SUBJECTS AND METHODS

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After excluding 16 suburban streets, we randomly selected 20 streets out of remaining 180 streets for the urban sample as described previously [5]. The sample for rural subjects was selected from the Moradabad tehsil, population 0.1 million. After excluding six suburban villages, two villages were selected at random from the 62 remaining villages. The streets are divided into blocks and each block contains 50 to 150 adults.

Study Design
We contacted 4015 subjects (2024 rural and 1991 urban) who were randomly selected from two villages and 20 streets in the city. Of these subjects, 255 (12.6%) rural and 185 (9.3%) urban were unwilling to participate. The remaining 3575 subjects (1769 rural and 1806 urban), aged 25 to 64 years, inclusive, were included in this study. Interviews were performed with a pretested and validated questionnaire [4] by the nutritionists and a physician obtained detailed information on dietary intake and current, past, and family history of cardiovascular disease and diabetes.

Dietary intakes were obtained by weekly diet diaries maintained by all individuals in the household using food measures, food models and food portions [4]. A cross-check questionnaire based on weekly diet diaries was completed to assess actual intake of foods described in the diet diaries. Trace mineral and magnesium intakes were obtained by computation of Indian food composition tables [27].

The criteria for the diagnosis of CAD have been described previously [5]. Briefly, CAD was diagnosed if one or more criteria [28] were satisfied: a) documented history of chest pain suggestive of angina or infarction and previously diagnosed CAD; b) affirmative response to Rose questionnaire after excluding any obvious cause of pain due to local factors; c) CAD was also diagnosed in absence of criteria (a) and (b) but in the presence of electrocardiographic changes, namely Minnesota codes 1-1-1 through 1-1-7 or 1-2-1 through 1-2-7. Presence of major ST segment and major T wave and Q wave changes or Q wave changes only, in absence of high voltage R wave (Minnesota code 4-1-1 and 4-1-2 and 5-1 and 5-2), was also diagnosed as CAD. A 12- lead electrocardiogram was performed in all the subjects included in the study.

In all subjects, blood pressures were recorded by the same physician in the right arm after a 5-minute rest in a sitting position by a single mercury sphymomanometer [28]. Waist and hip girths were measured in the standing position. Waist was measured as the smallest horizontal girth between the costal margin and the illiac crests and hip as the greatest circumference at the level of greater trochanters.

Criteria
The criteria for the diagnosis of risk factors and CAD were based on World Health Organization [28]. Hypertension was diagnosed in presence of blood pressures >140/90 mmHg; diabetes mellitus by a positive glucose tolerance test showing fasting blood glucose >140 mg/dl (>7.7 mmol/L) and postprandial blood glucose >200 mg/dl (>11.1 mmol/L) 2 hours after 75 g of oral glucose. Hypertriglyceridemia was considered in the presence of serum triglycerides >185 mg/dl (>2.08 mmol/L). Subjects were divided according to dietary zinc intake into low (<7.0 mg/day), moderate (7 to 15 mg/day) and high (>15 mg/day) intake groups. Zinc status was defined by dietary zinc intake and serum zinc level.

Laboratory Data
A venous blood was obtained after an overnight fast for analysis of hemoglobin, blood counts, urea, glucose, albumin, triglycerides, and serum zinc [29], copper [38] and magnesium in all subjects. Each participant was asked to drink 75 g anhydrous glucose in 200 ml of water and a second blood sample was collected after 2 hours for analysis of glucose and insulin. Serum triglycerides and high-density lipoprotein cholesterol were estimated by enzymatic methods. Plasma insulin and lipoprotein (a) (Strategic Diagnostics, USA) were estimated in only some of the rural and urban subjects.

Statistical Analysis
Prevalence is given in percent and numerical variables as mean±standard deviation. Significance of various trends according to zinc intake was calculated by using a Chi square test for trend (Mantel-Haenzel) and Kendalls, for different groups. Significance of various risk factors was calculated by multivariate logistic regression analysis wherein the odds ratio and 95% confidence intervals were calculated. Only p values <0.05 were considered significant.

	RESULTS

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Table 1 shows the food and mineral intakes of the different population groups. The consumption of cereals (wheat, rice, and millet) was significantly higher in both rural men and women. However, intakes of visible fat, flesh foods and eggs, milk and milk products as well as sugar and jaggery were significantly higher in the urban men and women compared to rural men and women, respectively. Dietary zinc, chromium and magnesium intakes were significantly higher in rural men and women compared to urban subjects. Serum zinc and magnesium and zinc/copper ratio were significantly higher in rural men and women than urban subjects (Table 1).

	DISCUSSION

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No significant epidemiological studies have been published to describe the relationship between zinc status and insulin resistance, CAD or diabetes. The few studies [21,24,26] that have examined this question were based on hospitalized patients. One study showed [21] that five (25%) out of 20 patients with diabetes had zinc deficiency, however, the difference in fasting serum zinc concentrations between diabetic and control subjects, (84.2±17.7 vs. 96.4±8.0 µg/dl), respectively was not significant. Serum zinc did not correlate with age, body weight, insulin dose, creatinine clearance or indices of glycemic control. Zinc levels were significantly lower in patients with diabetes compared to nondiabetic patients who suffered a heart attack (58.6±6.9 vs. 68.2±6.2 µg/dl). Zinc concentrations were also reduced in the aorta, atherosclerotic plaque, liver, pancreas and myocardium of victims dying due to heart attack [31,32]. A few small population studies [12,14] showed that the consumption of zinc and magnesium was significantly higher among rural than urban subjects. National surveys among Indians indicate that zinc and chromium consumption are lower than recommended dietary allowances [8–11] which may be due to the substitution of highly refined cereals for millets and undermilled cereals in the urban than rural diets.

Experimental studies indicate that genetically insulin resistant diabetic mice show tissue zinc deficiency [20]. The involvement of zinc both in DNA and RNA polymerases and for DNA dependent RNA polymerase reactions emphasizes the fundamental role it plays in the processes of cell growth, replication, and zinc deficiency during pregnancy may cause genetic dysfunction [33–36]. It is possible that enhanced genetic expression of insulin resistance [17] and lipoprotein (a) [18] observed in Indians may be due to alterations in lipoprotein metabolism [24], impaired glucose metabolism in liver, and poor beta cell function as a result of poor zinc status during pregnancy and infancy. In utero undernutrition [35], possibly in conjunction with zinc deficiency, is a risk factor for adult cardiovascular disease and diabetes in Indians.

We observed, possibly for the first time, that serum concentrations of lipoprotein (a) significantly decreased with increased dietary zinc intake in both rural and urban men. It is possible that zinc deficiency during early life may be important in determining the serum levels of lipoprotein (a) which are fully expressed during the first year of life as a risk factor of diabetes and cardiovascular disease [18].

It is clear that zinc and magnesium status was better among rural subjects along with higher chromium intakes which protect beta cells of pancreas (Tables 1, 5) [19–24]. Since plasma insulin levels were available only in a small subset of subjects, it is not possible to confirm the presence of insulin resistance syndrome in our study. It is difficult to determine whether moderate zinc deficiency was widespread in the population studied, since all the values appear to be above 70 µg/dl which is usually the upper limit for zinc deficiency based on serum zinc. Some experts report that there are variations in the zinc and chromium content of foods calculated from food tables compared to actual values obtained by chemical analysis of foods [9,27]. However, subclinical zinc deficiency does exist in Indians [27], particularly in urban subjects which either independently or in conjunction with magnesium and chromium deficiency, may be an independent risk factor for cardiovascular disease and diabetes. It may be important to measure 5’nucleotides or thymulin to confirm the role of zinc in Indians [36].

The exact mechanism whereby zinc deficiency acts directly or by interaction with chromium, magnesium and antioxidants [13,26,27] in the pathogenesis of diabetes or CAD is not known. The effect of zinc deficiency in conjunction with antioxidant deficiency causing insulin resistance and higher lipoprotein (a) levels is also not known. Zinc is a cofactor for superoxide dismutase which is an intracellular antioxidant enzyme. It has been suggested that as pancreatic beta cells have low antioxidative enzyme activities, they might be more sensitive to free radical damage which worsens if there is a coexisting zinc deficiency [20]. Magnesium and chromium deficiency can further increase the damage as well as impair the insulin action [22,23]. Insulin is stored in the pancreatic beta cells as insulin zinc complex and variation in zinc insulin ratio has been shown to alter its antigenic properties [21]. Zinc is also capable of modulating insulin action and it also improves hepatic binding of insulin. Abnormal zinc metabolism, therefore, could play a role in the pathogenesis of diabetes and its vascular complications [21]. There is some evidence that both zinc deficiency and an excess can cause dyslipidemia and impair hepatic cholesterol synthesis and enhance oxidative stress [24]. Zinc supplementation may inhibit platelet adhesiveness, increase fibrinolytic activity, and enhance healing process which may be protective against coronary thrombosis and atherosclerosis [24,33].

In conclusion, the findings of our study indicate that zinc, magnesium and chromium intakes were significantly higher in rural compared to urban subjects which may reduce the risk of diabetes and CAD in rural Indians. The overall trend indicated higher risk of diabetes, CAD and other disturbances suggestive of insulin resistance specifically among urban subjects with low dietary zinc intakes. Zinc status appears to be a risk factor of diabetes and CAD.

	ACKNOWLEDGMENTS

Received July 1, 1997. Accepted April 1, 1998.

	REFERENCES

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