Plasma lipoproteins and incidence of non-insulin-dependent diabetes mellitus in Pima Indians: protective effect of HDL cholesterol in women

Atherosclerosis 128 (1997) 113 – 119

Plasma lipoproteins and incidence of non-insulin-dependent diabetes mellitus in Pima Indians: protective effect of HDL cholesterol in women Anne Fagot-Campagnaa,*, K.M. Venkat Narayana, Robert L. Hansona, Giuseppina Imperatorea, Barbara V. Howardb, Robert G. Nelsona, David J. Pettitta, William C. Knowlera a

National Institute of Diabetes and Digesti6e and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ 85014, USA b Medlantic Research Institute, Washington, District of Columbia, USA Received 31 July 1996; revised 9 September 1996; accepted 9 September 1996

Abstract The role of plasma lipoproteins in the development of non-insulin-dependent diabetes mellitus (NIDDM) was studied in 787 non-diabetic (2-h glucoseB11.1 mmol/l) Pima Indians (265 men and 522 women). Subjects were followed for a mean of 9.8 (range: 1.8–16.4) years, during which 261 (76 men and 185 women) developed NIDDM. In men and women, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglyceride, low-density lipoprotein triglyceride and total triglyceride, controlled for age, predicted NIDDM (PB 0.01 for each). These effects diminished when controlled for age, sex, body mass index, systolic blood pressure and 2-h glucose. However, high-density lipoprotein (HDL) cholesterol, controlled for age, body mass index, systolic blood pressure and 2-h glucose, was a significant protective factor for NIDDM in women (hazard rate ratio (HRR)= 0.35, 95% CI (0.23–0.54), P B0.001, 90th compared with 10th percentile) but not in men (HRR = 1.04, 95% CI (0.53 – 2.05), P = 0.915). This association remained significant in women when controlled for fasting or 2-h plasma insulin concentrations, other estimates of insulin resistance or alcohol consumption. The protective effect of HDL cholesterol was similar among women with normal (2-h glucose B 7.8 mmol/l) or impaired (7.8 mmol/l5 2-h glucoseB 11.1 mmol/l) glucose tolerance at baseline. These results indicate that lipoprotein disorders are an early accompaniment of the abnormalities that lead to NIDDM. Keywords: Lipoproteins; Insulin resistance; Glucose; Sex; Incidence

1. Introduction A number of correlated factors, including insulin resistance, hyperinsulinemia, hypertension, high concentrations of very-low-density-lipoprotein (VLDL) triglycerides, and low concentrations of high-densitylipoprotein (HDL) cholesterol, are associated with impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM) [1]. Whereas, it is well established that insulin resistance and NIDDM worsen * Corresponding author. Tel.: +1 602 2005202; fax: + 1 602 2005225; e-mail: [email protected] Published by Elsevier Science Ireland Ltd. PII S 0 0 2 1 - 9 1 5 0 ( 9 6 ) 0 5 9 7 8 - 3

lipid abnormalities, it is unclear whether lipid abnormalities lead to insulin resistance or NIDDM [2–6]. In some studies, lipid abnormalities predicted the development of NIDDM, but they may not be causal because their effects diminished in analyses controlled for confounding by glucose concentrations [4] or insulin resistance [2,6]. Pima Indians have a high incidence of NIDDM and are generally insulin resistant and obese [7,8], but they have, on average, low plasma total cholesterol levels [9–11]. The present study examined the relationship between plasma lipoprotein concentrations and risk of

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developing NIDDM in 787 Pima men and women aged] 15 years followed for a mean of 9.8 years.

2. Material and methods

2.1. Research design Since 1965, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has conducted a longitudinal study of NIDDM in the Gila River Indian Community in central Arizona [7]. The inhabitants of this Community are primarily Pima or Tohono O’odham Indians. All residents aged] 5 years are invited to participate in biennial research examinations. At each examination, height and weight are measured with the subject wearing light clothing and no shoes; body mass index (BMI) is calculated as weight (kg) divided by the square of height (m2). Blood pressures are measured with a mercury sphygmomanometer with the subject in the supine position. The first and fourth Korotkoff sounds are recorded to the nearest 2 mmHg. Venous blood samples are collected after an overnight fast. A 75 g oral glucose tolerance test is administrated and diabetes is diagnosed if the 2-h plasma glucose concentration is ] 11.1 mmol/l (200 mg/ dl) [12] or if a glucose concentration ]11.1 mmol/l is found in the course of routine medical care [8]. Impaired glucose tolerance is diagnosed if the 2-h glucose is ] 7.8 mmol/l (140 mg/dl) and B 11.1 mmol/l (200 mg/dl) [12]. Plasma insulin concentrations are determined by the Herbert modification of the radioimmunoassay of Berson and Yalow [13]. Subjects were classified into three groups based on alcohol consumption (beer, wine or other alcohol): (a) non-drinkers; (b) those drinking less than three drinks daily; and (c) those consuming three drinks or more daily, including occasional heavy drinking. From 1979 to 1982, plasma lipoproteins (low-density lipoprotein (LDL), VLDL and total triglycerides, and HDL, LDL, VLDL and total cholesterol) were measured at a biennial examination in 1625 subjects, aged ]15 years. Venous blood samples were collected in ethylene–diaminetetraacetic acid (EDTA) after an overnight fast. Plasma was separated after centrifugation at approximately 700 ×g for 15 min at 10°C. A sample was removed for measurements of total cholesterol and triglyceride. Lipoproteins were isolated by using ultracentrifugation procedures described previously [9]. Recovery of cholesterol in the lipoprotein fractions isolated by ultracentrifugation averaged 94%. Triglycerides and cholesterol in plasma and isolated lipoproteins were quantified on an autoanalyzer II (Technicon Instruments, Tarrytown, NY) using the cholesterol extraction method of Rush et al. [14] and the triglyceride enzymatic method of Bucolo and David

[15]. These assays were standardized with control plasma calibration pools supplied by the Center for Disease Control (CDC, Atlanta, GA), to be comparable to those of the Lipid Research Clinics. The coefficient of variation for the measurement of control pools was 2.8% for high cholesterol, 3.6% for low cholesterol, and 4.8% for triglyceride. The present analysis includes all subjects who had lipoprotein measurements at a biennial research examination, did not have diabetes at baseline, and had at least one follow-up examination. The study was approved by the institutional review board of the NIDDK and by the Gila River Indian Community.

2.2. Statistical analysis Analyses including lipoproteins were performed separately for men and women. The relationship between baseline lipid measurements and NIDDM incidence was assessed by Cox’s proportional hazards regression analysis [16]. Follow-up time was calculated from the baseline examination (between 1979 and 1982) to either the date of NIDDM diagnosis or the last examination (between 1979 and 1994), whichever occurred first. The hazard rate ratio (HRR) of developing NIDDM was calculated comparing the 90th with the 10th percentile of each continuous variable. Baseline values for age, BMI, systolic blood pressure, 2-h glucose and insulin concentrations were used, and alcohol consumption was included in the regression models as two dichotomous indicator variables, moderate drinking (yes/no) and heavy drinking (yes/no). The interaction between baseline plasma cholesterol and other variables was evaluated by the likelihood ratio test [17]. The validity of the proportionality assumption for fixed covariates was determined as suggested by Kalbfleisch and Prentice [18]. For most of the analyses, 2-h plasma glucose violated the proportionality assumption. Proportional hazards models, therefore, were stratified by 2-h glucose quartiles at baseline. Seven measures of insulin resistance and/or pancreatic b-cell function were derived from fasting insulin (IF), 2-h insulin (I2) in mU/ml, fasting glucose (GF) and 2-h glucose (G2) in mmol/l (m) or mg/100 ml (g). Partial Spearman correlations, adjusted for age, were used to evaluate the association between these measures and lipoproteins. The following measures of insulin resistance were used: fasting insulin and 2-h glucose; 2-h insulin and 2-h glucose; insulin sensitivity index 1: (104/(IF × GFg)) [19,20]; insulin sensitivity index 2: (1/ (ln(IF)× ln(GFm))) [21]; insulin ratio: (I2/IF); corrected insulin response if G2g \ 80 mg/dl and G2g \GFg ((100×I2)/(G2g × (G2g − 70))) [22]; b-cell function if GFm \ 3.5 mmol/l ((20× IF)/(GFm − 3.5)) [20]. Incidence rates of NIDDM by strata of age, sex and HDL cholesterol category were calculated as cases per

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1000 person-years and standardized by the direct method for age and sex to the 1980 US population. When a person moved from one age stratum to another, the person-years were apportioned accordingly. The significance of the difference in incidence rates of NIDDM between groups was determined by a x 2 test for stratified incidence data [23]. The Mantel-Haenszel procedure was used to control for age and sex [24]. The hypothesis of a linear trend over strata was evaluated with the Mantel extension test [25]. Logarithms of VLDL cholesterol, LDL-cholesterol, HDL cholesterol, VLDL triglycerides, LDL triglycerides, total triglycerides, and insulin resistance estimates (except for insulin sensitivity index 2) were used to normalize their distributions.

Table 1 shows characteristics of the subjects at baseline. 46 (17.4%) men and 126 (24.1%) women had impaired glucose tolerance at baseline. The subjects were followed for a mean of 9.8 (range: 1.8–16.4) years, during which 76 men and 185 women developed NIDDM. Table 2 presents HRRs and 95% confidence intervals for variables potentially related to NIDDM. Multivariate proportional hazards models for lipoproteins and NIDDM incidence were fit separately for men and women because of the different lipoprotein distributions between the sexes. High VLDL cholesterol, VLDL triglyceride, LDL triglyceride and total triglyceride predicted NIDDM, controlled for age (Table 3). These effects, however, diminished and were not significant when controlled for age, BMI, systolic blood Table 1 Characteristics of subjects at baseline. Number of subjects (N) and means 9S.D.

a

Table 2 Proportional hazards models for risk of NIDDM, number of subjects (N), number of incident cases (n), HRR and 95% confidence intervals (CI), 90th compared with 10th percentile from the whole population

Agea Female sexa BMIb Systolic blood pressureb 2-h glucoseb,c Fasting insulinb 2-h insulinb Insulin sensitivity index 1b Insulin sensitivity index 2b Insulin ratiob Corrected insulin responseb b-Cell functionb

N

n

HRR

95% CI

787 787 787 787 787 763 763 761 761 763 594 760

261 261 261 261 34 253 253 253 253 253 222 253

1.91 1.07 3.06 1.79 56.88 4.67 4.31 0.20 0.14 0.90 0.59 2.77

1.42–2.57 0.82–1.40 2.27–4.13 1.30–2.48 19.99–161.84 3.42–6.36 3.03–6.12 0.14–0.27 0.09–0.21 0.67–1.21 0.41–0.85 2.03–3.79

a Uncontrolled; b controlled for age and sex; c n and HRR given for 3 years of follow-up to respect the proportionality assumption.

3. Results

Age (years) BMI (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mmol/l) 2-h glucose (mmol/l) Fasting insulin (pmol/l)a 2-h insulin (pmol/l)a VLDL cholesterol (mmol/l)a LDL cholesterol (mmol/l)a HDL cholesterol (mmol/l)a Total cholesterol (mmol/l) VLDL triglycerides (mmol/l)a LDL triglycerides (mmol/l)a Total triglycerides (mmol/l)a

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N

Men

Women

787 787 787

31.79 14.2 31.49 7.3 125.3916.0

30.89 13.3 32.19 6.8 112.09 14.6

787

76.09 11.6

68.49 11.4

787 787 763 763 760 760 760 786 773 780 783

5.3890.59 6.3691.72 148.5 624.1 0.34 2.93 1.14 4.569 0.78 0.69 0.39 1.26

5.30 9 0.63 6.669 1.68 156.7 779.3 0.30 2.72 1.18 4.37 90.82 0.57 0.37 1.16

Values are number of subjects and geometric means.

pressure and 2-h glucose. On the other hand, a high HDL cholesterol was a protective factor when controlled for age in men (P=0.080) and in women (PB 0.001) and remained highly significant when controlled for age, BMI, systolic blood pressure and 2-h glucose in women (PB 0.001). Among the 522 women at baseline, 15 were being treated with antihypertensive medication, 28 were taking contraceptive pills and 24 were pregnant. Although these factors may have modified lipid levels, the protective role of HDL cholesterol on NIDDM was similar when the analysis was performed with those 67 women excluded, when controlled for age, BMI, systolic blood pressure and 2-h glucose (HRR = 0.41, 95% CI (0.25– 0.68), PB 0.001). Although HDL cholesterol and some of the insulin resistance estimates were correlated (Spearman coefficient between HDL cholesterol and fasting insulin in women: RS = − 0.32), high HDL cholesterol was still a highly significant protective factor for NIDDM in women in each model controlled for age, BMI, systolic blood pressure and each insulin resistance estimate (model with 2-h glucose and fasting insulin: HRR = 0.39, 95% CI (0.25–0.61), PB 0.001). Possible interactions between BMI, systolic blood pressure and insulin, and HDL cholesterol were explored in 490 women with no missing values for these variables, and none was statistically significant (data not shown). In particular, interactions between age or glucose and HDL cholesterol were not significant among women. Because menopause and impaired glucose tolerance could have worsened the lipid abnormalities, analyses were performed separately among 413 women agedB 45.5 years (HRR= 0.55, 95% CI (0.33– 0.94), P= 0.028) and 74 women aged ]45.5 years (HRR= 0.10, 95% CI (0.03–0.41), P= 0.001), and

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Table 3 Proportional hazards models, HRR and 95% confidence intervals (CI) for plasma lipoproteins and NIDDM incidence, according to sex. 90th compared with 10th percentile by sex 10th percentile (mmol/l)

90th percentile (mmol/l)

HRRa

95% CIa

HRRb

95% CIb

Menc VLDL cholesterol LDL cholesterol HDL cholesterol Total cholesterol VLDL triglycerides LDL triglycerides Total triglycerides

0.16 2.15 0.85 3.57 0.28 0.24 0.65

0.72 3.88 1.62 5.66 1.55 0.64 2.30

1.82 1.25 0.58 1.20 2.40 2.76 1.18

1.14 – 2.90 0.67 – 2.32 0.31 – 1.07 0.63 – 2.29 1.36 – 4.24 1.46 – 5.22 1.05 – 1.31

1.30 0.81 1.04 0.92 1.63 1.74 1.08

0.76–2.22 0.41–1.59 0.53–2.05 0.45–1.87 0.83–3.20 0.84–3.60 0.94–1.23

Womenc VLDL cholesterol LDL cholesterol HDL cholesterol Total cholesterol VLDL triglycerides LDL triglycerides Total triglycerides

0.14 2.05 0.85 3.41 0.25 0.23 0.67

0.60 3.61 1.69 5.43 1.22 0.62 2.05

1.72 1.08 0.30 0.83 1.70 1.90 1.83

1.17 – 2.52 0.74 – 1.56 0.20 – 0.46 0.58 – 1.19 1.16 – 2.47 1.29 – 2.82 1.26 – 2.64

1.36 0.96 0.35 0.82 1.34 1.40 1.38

0.93–1.99 0.65–1.41 0.23–0.54 0.56–1.18 0.92–1.95 0.93–2.10 0.95–2.02

a

Controlled for age; b controlled for age, BMI, systolic blood pressure and 2-h glucose; c because of missing values, number of subjects varies between 254 and 265 in men, and 506 and 521 in women. Number of incident cases varies between 74 and 76 in men, and 178 and 185 in women.

among 370 women with normal glucose tolerance (HRR = 0.43, 95% CI ( 0.24 – 0.77), P = 0.005) and 120 women with impaired glucose tolerance at baseline (HRR = 0.40, 95% CI (0.17 – 0.95), P = 0.038), when controlled for age, BMI, systolic blood pressure, fasting insulin and 2-h glucose. Age-adjusted mean HDL cholesterol in both men and women was significantly higher in heavy drinkers than in moderate or non-drinkers (data not shown). In proportional hazards models, alcohol consumption was not a risk factor for NIDDM in men or in women. In a model including age, BMI, systolic blood pressure, alcohol consumption, 2-h glucose, and HDL cholesterol, interactions between HDL and alcohol were not significant in either men or women. HRRs and 95% confidence intervals for HDL cholesterol were unchanged when controlled for age, BMI, systolic blood pressure, alcohol consumption and 2-h glucose (HRR = 0.99, 95% CI (0.50 – 1.99), P = 0.983 in men and HRR=0.35, 95% CI (0.22 – 0.53), P B 0.001 in women). Fig. 1 shows the cumulative incidence of NIDDM according to the baseline 10th, 50th and 90th percentiles of HDL cholesterol by sex, controlled for age, BMI, systolic blood pressure and 2-h glucose used as continuous variables. The effect of HDL cholesterol on NIDDM incidence was highly significant in women (PB 0.001) but not in men (P =0.632). Age-standardized incidence rates of NIDDM are shown in Fig. 2, separately for men and women, and by quartile groups of HDL cholesterol. The trend across the quartile groups of HDL cholesterol for NIDDM prediction was highly significant in women (x 2 =19; degree of free-

dom= 1; PB 0.001) but not in men (x 2 = 0.732; degree of freedom= 1; P= 0.392).

4. Discussion In a population with a high incidence of NIDDM and insulin resistance [7,8], and, on average, low plasma HDL and total cholesterol [9–11], a high HDL cholesterol was a strong protector from diabetes in women. The HDL cholesterol’s protective effect was independent of glucose tolerance, insulin resistance and alcohol consumption, but was found only in women. On the other hand, high levels of VLDL cholesterol and VLDL, LDL and total triglycerides were predictive

Fig. 1. Cumulative incidence of NIDDM in men and women, according to the baseline 10th (0.85 mmol/l in men and women), 50th (1.10 and 1.17 mmol/l in men and women, respectively) and 90th percentiles (1.62 and 1.69 mmol/l in men and women, respectively) of HDL cholesterol using proportional hazards models controlled for age, BMI, systolic blood pressure and 2-h glucose as a continuous variable.

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Fig. 2. Age-standardized NIDDM incidence rates in men and women, stratified by baseline quartile groups of HDL cholesterol by sex. The P-value is for a test of linear trend of incidence rates with quartile groups of HDL cholesterol.

of NIDDM in men and women, but these effects were weaker when controlled for glucose. Triglyceride levels increase in NIDDM in response to increased hepatic VLDL triglyceride synthesis and secretion, and this may be due to increased glucose and free fatty acids and to insulin resistance [26]. Triglyceride or VLDL levels are reported to predict impaired glucose tolerance or NIDDM but previous analyses were not controlled for glucose [3,5,27,28] or insulin [29–31] or were not independent of glucose [4] or insulin [2,6]. The age-sex-adjusted relative risk of NIDDM comparing subjects with triglycerides\and5 2.5 mmol/l was somewhat lower among Pima Indians (HRR = 1.65, 95% CI (1.09 – 2.48)) than was reported among elderly subjects in Finland (69 incident cases, odds ratio = 3.52, 95% CI (2.03 – 6.11)) [32]. The b coefficients for one S.D. for VLDL triglycerides, controlled for age, BMI, systolic blood pressure and 2-h glucose, were more similar to those from the Framingham study for men ( +0.20 and +0.22, respectively) than for women ( + 0.12 and +0.27, respectively), with approximately the same precision (274 incident cases) [28]. These results, as well as the weaker predictive value of VLDL cholesterol and VLDL and LDL triglycerides for incidence of NIDDM when controlled for 2-h glucose and BMI in our study, suggest a confounding effect by insulin resistance. However, a modest effect of the levels of these lipid values, independent of insulin resistance, can not be excluded. The higher the triglyceride level, the greater the loss of cholesteryl ester from HDL to VLDL and the lower the plasma HDL cholesterol concentration [26]. Insulin resistance or hyperinsulinemia may also directly modulate HDL concentration but we know little about how HDL cholesterol changes [33]. HDL cholesterol is mainly synthesized by the liver and is dependent on lipoprotein lipase for anabolism, which is under insulin control, and on hepatic lipase for catabolism, for which insulin control is unclear [34]. Nevertheless, in our study, and in contrast to the triglyceride and NIDDM relationship, the protective relationship between a high HDL cholesterol and NIDDM incidence was highly

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significant in women after adjustment for glucose and fasting insulin. Because data on glucose disposal were not available for most subjects in the present study, we used other estimates of insulin resistance [19–22,35] and the strength of the relationship between HDL cholesterol and NIDDM incidence changed only slightly when insulin resistance was accounted for. The HRR for a low HDL cholesterol level ( B 1.0 mmol/l) and NIDDM was lower in the Pima Indians when controlled for age and sex only (HRR= 1.57, 95% CI (1.21–2.05), PB 0.001) than in the elderly subjects of the Finnish study (69 incident cases, odds ratio=2.55, 95% CI (1.48–4.39), PB 0.001) [32]. However, no adjustment for glucose was performed in the Finnish study, as in three other studies [28,29,36] in which HDL cholesterol was a risk factor for NIDDM [28,36]. In the San Antonio study (76 incident cases), the odds ratio for a 0.13 mmol/l difference in HDL cholesterol was 0.82 (95% CI (0.72–0.93)) when adjusted for fasting and 2-h glucose, BMI and the difference between systolic and diastolic blood pressure [37]. Our results for the same HDL difference were HRR= 1.10, 95% CI (0.20–5.92) in men and HRR=0.09, 95% CI (0.03– 0.24) in women. Nevertheless, the effect of HDL cholesterol on NIDDM was less in the San Antonio study when adjusted for insulin [2]. In a small sample of Pima Indians in whom insulin resistance was measured with the euglycemic clamp, the association between HDL cholesterol and NIDDM incidence was not statistically significant and no sex difference were found when adjusted for insulin resistance ([38] and G. Paolisso, P.A. Tataranni, C. Bogardus, E. Ravussin, B.V. Howard, unpublished observations). Because of the high number of incident cases, our study more precisely estimates any predictive relationship between lipid abnormalities and NIDDM incidence than the other studies. Although we can not exclude the possibility that a high HDL cholesterol may have a direct effect to lower NIDDM incidence, or may be a marker of a different genetic predisposition, some other factor may be responsible for both NIDDM and low HDL cholesterol. A high abdominal fat distribution is related to low HDL cholesterol [1] but the results of the present study were adjusted for BMI. Among Pima Indians, BMI correlated very well with waist circumference (Pearson correlations r= 0.900 in men and r= 0.914 in women) and with percentage of body fat estimated by bioelectric resistance (r= 0.866 in men and r=0.813 in women) in another study [39], in which measures of fat distribution added little to the predictive ability of BMI alone for NIDDM incidence. Alcohol consumption increases HDL cholesterol [40]. Heavy drinking may increase risk for NIDDM in men [41] but the effects of moderate drinking on glucose are equivocal in women [41,42]. If HDL cholesterol is a

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protective factor and alcohol a risk factor for NIDDM, alcohol consumption may be a confounder for the non-significant relationship between HDL cholesterol and NIDDM incidence in men. A high HDL cholesterol may also reflect a higher level of physical exercise [43], and physical activity may have a different effect in men and women. However, one might expect, if high HDL cholesterol from physical activity, but not from alcohol consumption, is protective, that HDL cholesterol would be a weaker protective factor in drinkers. Nevertheless, this was not the case in our analyses in men nor in women, although HDL cholesterol increased with alcohol consumption. It may be due to misclassifications between occasional heavy drinkers and occasional (moderate) drinkers. HDL cholesterol was associated with NIDDM incidence only in women. Women have higher levels of HDL cholesterol than men [43], and sex hormones may affect several enzymes involved in the metabolism of HDL cholesterol and triglycerides, and may also affect lipolysis [44] and hepatic lipase activity [45]. A low sex hormone binding globulin (SHBG) concentration is also associated with androgenicity and with low HDL cholesterol levels, and two studies have shown that low levels of SHBG predicted NIDDM, independently of BMI, abdominal fat distribution and insulin, in women [46,47] but not in men [46]. However, since no estimates of sex hormones concentrations, physical activity, and body fat distribution other than BMI, were available in the present study, one can only speculate as to whether these factors may have confounded the relationship between high HDL cholesterol and incidence of NIDDM. We found a protective effect of a high HDL cholesterol on NIDDM incidence in women, but not in men, in a population that has, on average, low plasma HDL cholesterol, but a high incidence rate of NIDDM. This effect was independent of glucose tolerance, insulin resistance estimates and alcohol consumption. The measurement of HDL cholesterol might be useful for screening women at risk of developing NIDDM if confirmed in other populations. Further studies should address the potential confounding effects of alcohol, physical activity, body fat distribution and dietary factors, and the role of sex hormones in the relationship between HDL cholesterol and diabetes incidence, with special regard to insulin resistance.

Acknowledgements The authors would like to thank the members of the Gila River Indian Community who participated in the study, the DAES staff for their assistance, and Dr. Steven Haffner for reviewing this manuscript.

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