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(Hypertension. 2002;40:679.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Hypertension, Insulin, and Proinsulin in Participants With Impaired Glucose Tolerance

The Diabetes Prevention Program Research Group

Correspondence to Steven M. Haffner, MD, DPP Coordinating Center, The George Washington University, Biostatistics Center, 6110 Executive Blvd, Suite 750, Rockville MD 20852. E-mail dppmail{at}biostat.bsc.gwu.edu

	Abstract

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The association of insulin resistance and hyperinsulinemia to blood pressure has remained controversial. We examined the association of insulinemia to hypertension and blood pressure using baseline measurements for participants of the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized controlled trial of 3819 participants with impaired glucose tolerance, and is designed to evaluate interventions for the delay or prevention of type 2 diabetes. The relationship between hypertension and insulinemia is described overall and by ethnicity. The effects of demographics (age and gender), adiposity, and glucose on the relationship are also presented. Asian Americans and African Americans had a similarly high prevalence of hypertension as did whites; American Indians had a lower prevalence of hypertension. Among participants not on antihypertensive medications, systolic blood pressure was significantly (but weakly) correlated with fasting insulin (r=0.12), homeostasis model assessment of insulin resistance (HOMA IR; r=0.13), and fasting proinsulin (r=0.10) when adjusted for age and gender (all, P<0.001). Systolic blood pressure showed similar correlations to fasting insulin in each ethnic group. After further adjustment for body mass index, the association of fasting insulin to systolic and diastolic blood pressures weakened considerably but remained significant (systolic: r=0.06, P=0.002; DBP: r=0.06, P<0.001). We conclude that a weak but significant association between insulin, (and proinsulin and HOMA IR) and blood pressure exists but is largely explained by overall adiposity. This association is similar among ethnicities, with the possible exception of Hispanics. The relation between insulin concentrations and blood pressure explains relatively little of the ethnic differences in hypertensive prevalence.

Key Words: insulin • insulin resistance • blood pressure • ethnicity • diabetes mellitus • obesity

	Introduction

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Predictors of hypertension include age, obesity, alcohol consumption, and glucose intolerance.^1–10 Modan et al¹¹ suggested a relationship between insulin levels and blood pressure in 1985, and Ferrannini et al¹² reported that in a lean cohort, hypertensive participants were more insulin resistant than were nonhypertensive participants. Reaven¹³ included hypertension in his description of syndrome X. A number of other reports have found that hyperinsulinemia and/or insulin resistance are correlated with hypertension.^14–19 Several groups have hypothesized that hyperinsulinemia and/or insulin resistance may play a role in the etiology of hypertension.^20–23 Insulin has been shown to stimulate the sympathetic nervous system,²⁴ increase renal sodium retention, ²⁵ modulate cation transport, ²⁶ and induce hypertrophy of vascular smooth muscle.²⁷ However, the association between insulin and hypertension has been controversial,²⁸ with a number of studies finding no association between insulin and blood pressure.^29–31 Acute insulin infusions in humans and animals were found, in most studies, to have a vasodilator hypotensive rather than a hypertensive effect.^32–36 Ferrannini et al¹⁹ have proposed that insulin resistance might lead to hypertension because of diminished insulin-induced vasodilation and the imbalance between its pressor and depressor effects.

The reasons for the divergent results in studies of insulin and hypertension are not clear but may reflect the small size of many studies, and the heterogeneity of study participants with respect to obesity, race, and diabetic status. For example, Saad et al³⁷ found a relation between blood pressure and insulin resistance in whites but not in African Americans or Pima Indians. In contrast, Falkner et al³⁸ did find a relation between insulin resistance and blood pressure in lean African American men. Laakso et al³⁹ found a relation between hypertension and insulin resistance in lean, but not in obese, diabetic hypertensive participants; in contrast, in other studies,^18,19 insulin resistance was correlated with blood pressure across a range of body weight. Lastly, it has been shown that many earlier insulin assays may recognize proinsulin.⁴⁰ In some studies, ^41,42 proinsulin levels were more correlated with blood pressure than were specific insulin assays.

To elucidate some of the issues (particularly ethnic differences) concerning blood pressure and insulin concentrations, we examined the relationship of fasting insulin, fasting proinsulin, and homeostasis model assessment of insulin resistance (HOMA IR) to hypertension and blood pressure measured at baseline in participants with impaired glucose tolerance (IGT) from the Diabetes Prevention Program (DPP).⁴³ The DPP has a number of advantages for examining the association, notably for a narrow range of glucose tolerance (2-hour plasma glucose range of 7.8 to 11.0 mmol/L); furthermore, the cohort was large and included diverse ethnic groups: white (n=2112), African American (n=748), Hispanic (n=609), Asian American (n=163), and American Indian (n=174).

	Methods

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Participants
The DPP is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in participants aged 25 years with IGT (defined as 2-hour plasma glucose from 7.8 to 11.0 mmol/L based on 75-g oral glucose tolerance test), elevated fasting glucose (5.3 to 7.0 mmol/L, except in American Indians), and body mass index (BMI) of at least 24 kg/m² (22 kg/m² among Asian Americans). The current report includes 3819 participants seen at baseline. This number includes not only participants in 3 arms currently in the DPP—(1) standard lifestyle, (2) intensive lifestyle, and (3) metformin—but also participants randomized to the troglitazone arm, which was discontinued.⁴³ Participants who were on medicines believed to increase insulin resistance and worsen glucose tolerance (ß-blockers, thiazide diuretics, steroids, and nicotinic acid) were excluded from the study. Full details of the protocol have been published.⁴³

Procedures and Measurements
Participants underwent an extensive interview for information on ethnicity, current medications, medical history (including hypertension), smoking, diet, physical activity, etc. Overall adiposity was assessed by BMI. Waist circumference was assessed in the standing position, midway between the highest point of the iliac crest and the lowest point of the costal margin in the mid-axillary line. Hip circumference was measured at the level of the femoral greater trochanter. All anthropomorphic measures reflect the average of 2 measurements.

Blood pressure was assessed twice in a sitting position after a 5-minute rest period, and the mean was used for analysis. The prevalence of hypertension (ie, hypertension status in Table 1) was defined as the use of antihypertensive medications for physician-diagnosed hypertension and/or a systolic blood pressure (SBP) of 140 and/or a diastolic blood pressure (DBP) of 90 mm Hg.

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics by Ethnic Group

Participants were asked to fast for 12 hours and blood samples were drawn on arrival at the clinic (for fasting glucose, insulin, and proinsulin), at 30 minutes (for plasma glucose and insulin), and at 120 minutes (for plasma glucose) after a 75-g oral glucose tolerance test. Specimens were processed and sent to the central biochemistry laboratory (University of Washington in Seattle).

Analyses of plasma glucose were performed enzymatically on the Abbot Spectrum Multichromatic Analyzer. Glucose in the specimen was quantitatively measured by the combined catalytic activities of hexokinase and glucose-6-phosphate dehydrogenase.⁴⁴ Quality control samples of normal and high glucose levels used for monitoring glucose assay performance showed an interassay coefficient of variation (CV) of <3%. Total immunoreactive insulin was performed by a double-antibody radioimmunoassay developed in the Diabetes Endocrinology Research Center Immunoassay Core Laboratory. The assay is a 48-hour, polyethylene glycol (PEG)-accelerated assay involving a primary antibody, guinea pig anti-human insulin, and a secondary antibody, goat anti-guinea pig immunoglobulin.

Proinsulin is measured by a commercially available radioimmunoassay (Linco Research Inc). The control samples for proinsulin showed interassay CV of <16% for the low concentration (P=0.001) and of <7% for the high concentrating pool. The cross-reactivity of the proinsulin insulin assay with insulin is very low (<1%).

The immunochemical measurement of albumin in urine was performed using Dade Behring reagent on a Behring Nephelometer (BNII), which detects albumin in urine at the level of 0.12 mg/dL. The urinary albumin/creatinine ratio was used as an estimate of albumin excretion.

HOMA IR was used as a surrogate for the direct measurement of insulin resistance and was calculated as follows:⁴⁵ HOMA IR=[fasting insulin (µU/mL)xfasting glucose (mmol/L)]/22.5.

The correlation between HOMA IR and fasting insulin was r=0.988. This high correlation is expected, because HOMA IR is computed from the fasting insulin concentration. The correlation between fasting insulin and proinsulin was r=0.609.

Statistical Analyses
Baseline characteristics were described using mean±SD for quantitative variables and the numbers and corresponding percentages for categorical variables. Comparisons among groups were made by use of ANOVA⁴⁶ for quantitative variables and the ² test of independence for categorical variables. The nominal probability values are listed with no adjustment for multiple comparisons.

Logistic regression models⁴⁷ were used to describe the effect of covariates on the odds of a dichotomous-dependent variable (ie, prevalence of hypertension), expressed as an odds ratio (OR) per unit increase in the covariate. The strength of the association of the model (all covariates simultaneously) and of the covariates individually is assessed by the entropy R², a measure of the proportion of the variance in risk explained.

Partial Pearson correlation⁴⁸ and its probability value were used to summarize the association between baseline characteristics when adjusting for other covariates. The regression coefficient (ß) estimate describes the mean change in the dependent variable (blood pressure) per unit change in a covariate (independent variable) obtained from a linear regression model.⁴⁹ A group by covariate interaction tests whether the relationship between the covariate and blood pressure is different among the ethnic groups.

	Results

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Table 1 shows the distribution of clinical and metabolic factors at baseline by ethnic group. The mean age was 50.7 years, and 67.5% of participants were women. The 5 major ethnic groups were white (55.4%), African American (19.7%), Hispanic (15.9%), American Indian (4.6%), and Asian American (4.4%). The mean BMI was 33.9 kg/m² (range, 22.1 to 70.9 kg/m²), with Asian Americans having lower BMI (29.5 kg/m²) than that of the other groups. Women had lower waist circumferences than did men.

The mean fasting glucose level was 5.9 mmol/L. American Indians had lower fasting glucose levels (mean, 5.6 mmol/L) than the other ethnic groups by the DPP eligibility criteria of not requiring a fasting glucose 5.3 mmol/L because of their very high incidence of type 2 diabetes. The mean fasting insulin level was 159.4 pmol/L, the mean fasting proinsulin level was 18.1 pmol/L, and the mean HOMA IR was 7.0.

Hypertension
The overall prevalence of hypertension was 28.0%. African Americans and Asian Americans had a similarly high prevalence of hypertension (36.4% and 37.7%, respectively), whereas Hispanics and American Indians had the lowest prevalence of hypertension (21.5% and 13.8%, respectively).

Table 2 shows the clinical characteristics associated with the prevalence of hypertension. Age, male gender, ethnic group, higher levels of fasting glucose, higher levels of insulinemia (fasting insulin, proinsulin, and HOMA IR), greater adiposity (BMI and waist circumference), and urinary albumin/creatinine ratio were all strongly associated with the prevalence of hypertension (P<0.001).

View this table: [in this window] [in a new window]   TABLE 2. Clinical Characteristics by Hypertension Status

Table 3 shows the effect of the independent variables fasting insulin, HOMA, fasting proinsulin, and urine albumin/creatinine ratio on the dependent-variable prevalence of hypertension in logistic regression models. All of these independent variables were significantly associated with the prevalence of hypertension. Demographic variables and fasting insulin explained 1.13% of the variation in the prevalence of hypertension (Model 1b). After adjustment for BMI (Model 1c) or waist circumference (Model 1d), the odds ratio, an estimate of the strength of the association, and R², a measure of the strength of the association, were markedly attenuated. Although the association remained statistically significant, further adjustment for fasting glucose (Model 1e) had only a modest effect. In this table, HOMA IR had similar effects to those of fasting insulin. The effects of fasting proinsulin and albumin/creatinine ratio were similar, neither explaining >1% of the variation in prevalence, although each were statistically significant. Thus, this paper will focus on fasting insulin.

View this table: [in this window] [in a new window]   TABLE 3. Effect of Fasting Insulin, HOMA IR, and Proinsulin on Hypertension Prevalence

Table 4 shows the full regression model from Model 1e. Fasting insulin (P<0.001), age (P<0.001), and BMI (P<0.001) were all statistically significantly related to the prevalence of hypertension. African Americans (OR=1.65) and Asian Americans (OR=2.21) had significantly higher prevalence of hypertension than did whites (P<0.001), whereas American Indians (OR=0.66) had a lower prevalence of hypertension (P=0.077). Fasting glucose was positively but not significantly related to the prevalence of hypertension.

View this table: [in this window] [in a new window]   TABLE 4. Estimated Effects of Covariates on the Prevalence of Hypertension From Full Model 1e

Table 5 shows partial correlations between the blood pressure and baseline characteristics adjusted for age and gender in participants not on hypertensive medicines (n=3140). Six hundred seventy-nine subjects were on hypertensive drugs and thus were excluded. Additional adjustment for BMI is also presented. In the overall population, SBP was significantly correlated with age (r=0.26), BMI (r=0.18), waist circumference (r=0.16), fasting glucose (r=0.09), fasting proinsulin (r=0.10), HOMA IR (r=0.13), urinary albumin/creatinine (r=0.09) (all P<0.001), and hip ratio (r=0.13) (data not shown) when adjusted for age and gender. In analyses performed separately by ethnic group, fasting insulin was weakly but significantly related to SBP in whites (r=0.16) and African Americans (r=0.12) but not in Hispanics (r=0.03), American Indians (r=0.08), or Asian Americans (r=0.17) (although analysis in Asian Americans was limited by small numbers of participants). The association between DBP and fasting insulin (adjusted for age and gender) also showed a weak but significant relation to insulin. When we examined the partial correlations adjusted for age, gender, and BMI, we found that fasting glucose, fasting insulin, HOMA IR, and urinary albumin/creatinine remained significantly related to SBP. However, after the additional adjustment for BMI, the relation between fasting insulin and SBP was markedly attenuated. Fasting insulin remained significantly correlated with DBP only in the overall group and in whites.

View this table: [in this window] [in a new window]   TABLE 5. Partial Correlations of Blood Pressure vs Baseline Characteristics Adjusted for Age, Gender, and BMI by Ethnic Group*

	Discussion

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The relation between blood pressure and hyperinsulinemia (insulin resistance) has been controversial.²⁸ We have shown in a large cohort that blood pressure is modestly associated with fasting insulin, HOMA IR, and fasting proinsulin and only accounts for little of the ethnic differences in hypertension prevalence. In demographically adjusted models, the correlation between fasting insulin and blood pressure is 0.1, meaning that 1% of the variance in blood pressure is attributable to insulinemia. An alternative way to express this is that a 10 µU/mL increase in the insulin concentration is associated with a 19% increase in hypertension prevalence (Table 3).

The study of the relation between insulin and blood pressure in IGT subjects has both advantages and disadvantages. These associations are modest in part because the distribution of fasting insulin, proinsulin, and HOMA IR may be truncated both because a narrow range of glucose tolerance was studied (IGT participants) and because the participants in the DPP were on the average obese (mean BMI, 33.9 kg/m²). On the other hand, the truncated distribution of glucose tolerance and obesity may reduce the importance of these confounding variables. Nevertheless, adjustment for overall obesity (ie, BMI) or upper-body adiposity (ie, waist circumference) markedly attenuated the relation between blood pressure and insulin, even though these relationships remained statistically significant. Indeed, the effect of BMI on hypertensive prevalence (Table 4) and blood pressure (Table 5) was much stronger than the effect of fasting insulin. Interestingly, the effect of upper-body adiposity (waist circumference) and weight:height ratio (WHR, data not shown) on blood pressure was not greater than that of BMI.

Because the DPP population was large, we were able to examine the association between insulin and blood pressure in a number of subgroups. Perhaps the most interesting of these questions is whether blood pressure and insulin association differs by race. Saad et al³⁷ showed that insulin resistance measured by a hyperinsulinemic euglycemic clamp was associated with blood pressure in whites but not in African Americans or Pima Indians. In contrast, Falkner et al³⁸ did show a relation between insulin and blood pressure in lean African American men. The reasons for the discrepancies between the 2 studies^37,38 with respect to the current report are not clear, but the participants in the report by Falkner et al³⁸ were much leaner than those in the study of Saad et al³⁷ (BMI, 31 versus 24 kg/m², respectively). In the current report of very obese IGT participants, the relationships between insulin and blood pressure were similar in whites to those observed in African Americans and American Indians. Interestingly, no significant relation between insulin and blood pressure was observed in Hispanics. In previous work in Hispanics (Mexican Americans), insulin levels have been related to blood pressure in both cross-sectional⁵⁰ and prospective^8,9,51 studies. We examined the relation of fasting insulinemia to SBP and DBP within the Hispanic subgroups using partial correlations adjusted for age and gender: Mexican (n=327; SBP, r=0.07; DBP, r=0.06); Puerto Rican (n=63; SBP, r=0.03; DBP, r=0.11); Cuban (n=35; SBP, r=0.37; DBP, r=0.34); and other Spanish and Hispanic (n=18; SBP, r=-0.06; DBP, r=0.01)]. These analyses are limited by small numbers and show weaker relations than in whites except in the Cuban group, which is very small (n=35). A possible explanation for the weak correlation between insulin and blood pressure in Hispanics is that the association between BMI and SBP was weaker in Hispanics than in other ethnic groups (Table 5: Hispanics, r=0.10; whites, r=0.19).

In the current report, the overall population was very obese. However, among these obese participants, there was a weak relationship between insulin and blood pressure, especially DBP. Some previous studies have shown a strong relation in lean participants,¹² whereas other studies have found an association in lean participants but not in obese diabetic participants.³⁹ Another study showed significant associations in both lean and obese participants.¹⁸ Bonora et al⁵² found no relation between insulin resistance and hypertension in either obese nondiabetic or diabetic participants.

In the present report, we also compared HOMA IR and fasting proinsulin concentrations to blood pressure and hypertension. Neither HOMA IR nor fasting proinsulin was superior to fasting insulin in the strength of the association with hypertension. It is not surprising that fasting insulin and HOMA IR behave similarly because the correlation between these 2 variables is extremely strong (r=0.988). In previous small studies, fasting proinsulin has been shown to be more highly associated with blood pressure than with fasting insulin concentrations in diabetic⁴¹ and nondiabetic Mexican Americans and non-Hispanics.⁴² We could not confirm these results in the present report in participants with IGT.

Among participants with impaired glucose tolerance, African Americans had a significantly higher prevalence of hypertension, whereas American Indians and Hispanics had significantly lower prevalence of hypertension relative to that of whites. These results on prevalence of hypertension are consistent with previous reports in African Americans, ^53,54 American Indians,⁵⁵ and Hispanics.^54,56,57 We found a higher prevalence of hypertension in Asian Americans (37.7%) and African Americans (36.4%) than in whites (27.3%) (Table 1). After adjustment for BMI, the prevalence of hypertension remained significantly higher in African Americans and Asian Americans and lower in American Indians than in the referent white group (Table 4). Hispanics had a slightly lower prevalence of hypertension than did whites, but these differences were not statistically significant. These observations are again similar to previous reports.^53–57 Interestingly, in a full logistic regression model (Table 4) for the prevalence of hypertension, Asian Americans had a significantly greater risk of hypertension (OR=2.21), which is even higher than the estimated risk of hypertension for African Americans (OR=1.65). The higher predicted risk of hypertension after the adjustment for obesity in Asian Americans (Table 5) is probably owing to the lower BMI in Asian Americans than in the other ethnic groups (eg, BMI: Asian American, 29.5 kg/m², versus whites, 34.1 kg/m²). Risk factors for hypertension in Asian Americans need further studies.

Because of small number of Asian Americans in the study, it is difficult to make inferences in specific subgroups (East Asian, n=62; Southeast Asian, n=15; Pacific Islander, n=20; Southern Asian, n=53; and other, n=13). In these subgroups, the range of adjusted prevalence varied from 30.8% to 55.0%. In Asian Americans, the correlation of fasting insulin with SBP was 0.17 (P=0.054), and DBP was 0.05 (P=0.549) (Table 5). The relation between fasting insulin and SBP or DBP does not differ by Asian American subgroup (probability value for interactions=0.089 and 0.493, respectively, although the power to detect an interaction was small). As in other studies, albumin excretion was significantly related to blood pressure and insulin.⁵⁸

A number of mechanisms have been proposed to explain possible relations between hypertension and insulin resistance, including stimulation of the sympathetic nervous system,²⁴ increases in renal sodium retention, ²⁵ modulation of cation transplant,²⁶ and hypertrophy of vascular smooth muscle.²⁷ Racial differences in ion regulation have been found and could possibly account for differences in the relation between insulin and blood pressure in different ethnic groups.⁵⁹ However, acute infusion in both animals and humans in most studies have led to a vasodilation hypotensive effect rather than a hypertensive effect.^32–36 Administration of insulin therapy to diabetic and nondiabetic participants does not lead to a hypertensive effect in the absence of hypoglycemia.^60–62

The present study has a number of limitations. First, we did not assess insulin resistance directly but rather assessed it by fasting insulin (or the closely related HOMA IR). The measurement of insulin resistance may be more precise than that of fasting insulin but is much more expensive and may have poor patient acceptance, thereby limiting its use in epidemiologic studies or clinical trials. Fasting insulin is highly correlated with insulin resistance in nondiabetic participants.⁶³ Several studies that measured both fasting insulin and insulin resistance have found that insulin resistance did correlate better with SBP and diastolic blood pressure than fasting insulin, although the differences were small.¹⁹ Second, the participants were participants in a clinical trial and thus self-selected. In addition, persons treated for hypertension with thiazide diuretics or ß-blockers were excluded.⁴³ This is likely to be potentially more of a problem for estimates of the prevalence of hypertension than for the analysis of relation between insulin and proinsulin. The prevalence of hypertension in this trial by ethnic group in fact is similar to that in previous reports in the literature.^53–57 The limitation of participants to those with impaired glucose tolerance and a largely very obese population might limit the generalizability of the correlations. However, this could be an advantage, in that the population is more homogenous, and confounding may be less of a problem. Another strength is that the population is large and includes a wide range of ethnic groups. We also assessed HOMA IR and fasting proinsulin; neither of which, however, was superior to fasting insulin. Lastly, many of the subjects were on hypertensive drugs that might modify metabolic characteristics and thus modify correlations between insulin and blood pressure.

Perspectives
We found a significant (but modest) relation between fasting insulin and the prevalence of hypertension, SBP, and DBP. Contrary to some previous reports, this relation was similar in American Indians, African Americans, and whites. However, insulin and blood pressure were not significantly correlated in Hispanics. The associations between insulin and blood pressure accounted for little of the ethnic differences in hypertension prevalence and were attenuated by adjustment for obesity, although the relation of insulin with blood pressure remained statistically significant. Thus, insulin concentrations do not appear to be a major determinant of blood pressure in participants with impaired glucose tolerance; indeed, the effect of obesity on blood pressure is much greater than the effect of insulin on blood pressure. Whether these results would have been different if insulin resistance had been measured directly is uncertain, but given the experience from previous reports,¹⁹ we believe the direct measurement of insulin resistance would not have changed the basic conclusions.

	Acknowledgments

 
This study was supported by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development, the National Institute on Aging, the National Center on Minority Health and Health Disparities (NCMHD), National Center for Research Resources General Clinical Research Center Program, the Office of Research on Women’s Health, the Indian Health Service, the Centers for Disease Control and Prevention, the American Diabetes Association, Bristol-Myers Squibb, and Parke-Davis.

We thank the thousands of volunteers in this program for their devotion to the goal of diabetes prevention. LifeScan Inc, Health O Meter, Hoechst Marion Roussel Inc, Lipha Pharmaceuticals Inc, Merck-Medco Managed Care Inc, Merck and Co, Nike Sports Marketing, Slim Fast Foods Co, and Quaker Oats Co donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp, Matthews Media Group Inc, and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center.

	Footnotes

 
¹Prepared by Steven M. Haffner, MD (chair), Ronald Goldberg, MD, Robert Ratner, MD, John Lachin, PhD, Marinella Temprosa, MS, Trevor Orchard, MD, Mark Molitch, MD, and Mohammad Saad, MD. A complete list of members of the DPP Research Group appears in the article "The Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin." (New Engl J Med. 2002;346:393–403).

Received May 20, 2002; first decision June 10, 2002; accepted August 21, 2002.

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