美国科学家发现杏仁饮食有助于降低罹患糖尿病心血管病风险

Original Research Almond Consumption and Cardiovascular Risk Factors in Adults with Prediabetes Michelle Wien, DrPH, David Bleich, MD, Maya Raghuwanshi, MD, Susan Gould-Forgerite, PhD, Jacqueline Gomes, MBA, Lynn Monahan-Couch, MPH, Keiji Oda, MPH University of Medicine and Dentistry of New Jersey, Newark, New Jersey (M.W., D.B., M.R., S.G.-F., J.G.), West Chester University, West Chester, Pennsylvania (L.M.-C.), Loma Linda University, Loma Linda, California (K.O.) Objective: The authors tested the hypothesis that in adults with prediabetes, an almond-enriched American Diabetes Association (ADA) diet improves measures of insulin sensitivity and other cardiovascular risk factors compared with an ADA nut-free diet. Methods: Design: Randomized parallel-group trial. Setting: Outpatient dietary counseling and blood analysis. Subjects: Sixty-five adult participants with prediabetes. Intervention: Sixteen weeks of dietary modification featuring an ADA diet containing 20% of energy from almonds (approximately 2 oz per day). Measures of Outcome: Outcomes included fasting glucose, insulin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, TC:HDL-C, and HbA1c, which were measured at weeks 0, 8, and 16. Body weight, body mass index (BMI), waist circumference, blood pressure, and nutrient intake were measured at weeks 0, 4, 8, 12, and 16. Results: The almond-enriched intervention group exhibited greater reductions in insulin (21.78 mU/ml vs. +1.47 mU/ml, p 5 0.002), homeostasis model analysis for insulin resistance (20.48 vs. +0.30, p 5 0.007), and homeostasis model analysis for beta-cell function (213.2 vs. +22.3, p 5 0.001) compared with the nut-free control group. Clinically significant declines in LDL-C were found in the almond-enriched intervention group (212.4 mg/dl vs. 20.4 mg/dl) as compared with the nut-free control group. No changes were observed in BMI (20.4 vs. 20.7 kg/m2, p 5 0.191), systolic blood pressure (24.4 mm Hg vs. 23.5 mm Hg, p 5 0.773), or for the other measured cardiovascular risk factors. Conclusions: An ADA diet consisting of 20% of calories as almonds over a 16-week period is effective in improving markers of insulin sensitivity and yields clinically significant improvements in LDL-C in adults with prediabetes. INTRODUCTION Prediabetes currently affects up to 13% of the U.S. adult population and 16% of U.S. teens [1], which translates to 54 million individuals [2]. Prediabetes is a precursor to type 2 diabetes mellitus (T2DM), which is present in approximately 8% of the U.S. population. Fifty percent of patients with prediabetes will progress to T2DM unless there is aggressive intervention (i.e., diet modification and exercise to facilitate moderate weight loss or use of medications that improve glucotoxicity without elevating endogenous insulin) [3]. The American Diabetes Association (ADA) guidelines address the need for medical nutrition therapy and public health interventions for patients with prediabetes to decrease the risk of developing T2DM and cardiovascular disease (CVD) [4]. Population-based prospective cohort studies [5,6] have demonstrated that lifestyle modification including diet can reduce the progression of prediabetes to T2DM, which has stimulated enthusiasm for evaluating novel nutrition approaches among patients with prediabetes. Such approach- es have the potential to also improve the cluster of diabetogenic and atherogenic abnormalities including insulin resistance, dyslipidemia, and hypertension. Thus, health care professionals are seeking feasible and innovative patient- oriented strategies in the context of beneficial nutritional therapies. Address reprint requests to: Michelle Wien, DrPH, Loma Linda University, Department of Nutrition, School of Public Health, 24951 N. Circle Drive, Nichol Hall 1107, Loma Linda, CA 92350. E-mail: mwien@llu.edu A subset of the lipid data was presented at a poster session at the 2008 Experimental Biology Meeting in San Diego, California, on April 6, 2008. This research was supported in part by a grant from the Almond Board of California. Journal of the American College of Nutrition, Vol. 29, No. 3, 189–197 (2010) Published by the American College of Nutrition 189 Almonds contain high levels of fiber, arginine, magnesium, polyphenolic compounds, vitamin E, and monounsaturated fatty acids (MUFA), specifically oleic acid. Population-based prospective cohort studies have shown an association between frequent nut consumption and reduced risk of T2DM and CVD [7–9]. These findings have generated proposed mechanisms for these associations including improved insulin sensitivity, increased antioxidant activity, and reduced concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Prior in vivo studies have shown that MUFA enhances the intestinal secretion of glucagon-like peptide-1 (GLP-1) [10–12], an incretin hormone that improves the regulation of postprandial glucose disposal and insulin secretion [13]. In addition, Wang et al. [14] have shown that lipid infusions containing primarily polyunsaturated fats (PUFA) trigger a gut-brain-liver axis that increases insulin sensitivity in the liver. Intermediary roles for gut hormones, including incretins, remain possible in this circuit and offer a conceptual basis for antidiabetes diets. We sought to explore a possible role for daily almond consumption in persons with prediabetes as a simple, cost- effective nutrition intervention to preserve beta-cell function and improve insulin sensitivity and other CVD risk factors. We therefore conducted a randomized trial of an almond-enriched diet in the context of ADA diet guidelines to test the hypothesis that in individuals with prediabetes, an almond- enriched ADA diet improves measures of insulin sensitivity and other CVD risk factors compared with an ADA nut-free diet. MATERIALS AND METHODS We conducted a parallel-group randomized trial at the University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, testing the hypothesis that an almond-enriched ADA diet would be more effective than a nut-free ADA diet on improving measures of insulin sensitivity in individuals with prediabetes. The total study time period for each participant was 16 weeks. Eligibility Criteria Research participants were recruited from a pool of adult employees at UMDNJ, from patients attending the UMDNJ- Newark–based Endocrine and Diabetes Clinics, and from community-based health fairs. Inclusion criteria included the presence of prediabetes according to the 2005 ADA diagnostic guidelines (fasting blood glucose between 100 and 125 mg/dl or casual blood glucose $ 140–199 mg/dl), body mass index (BMI) 20–35 kg/m2, and willingness to discontinue vitamin E supplement usage. Persons with a self-reported allergy to almonds, history of irritable bowel disease or diverticulitis, use of corticosteroids or immunosuppressant medications, or presence of liver disease, renal disease, and/or severe dyslipidemia (triglyceride [TG] . 400 mg/dl or TC . 300 mg/dl) were excluded. The study protocol was approved by the UMDNJ-Newark campus Institutional Review Board, and all participants gave written informed consent. Participants were randomized without stratification using computer-generated random integer generator software (www. random.org) to consume almonds (almond enriched, interven- tion) or to avoid nuts (nut-free, control). The principal investigator enrolled the participants and generated the allocation sequence, which was concealed until the interven- tions were assigned. Intervention Design During the week 0 visit, daily energy needs for ADA diet meal plans were computed based on resting energy expenditure (REE) measurements obtained from a handheld self-calibrating indirect calorimeter device (MedGem, model 100, Microlife USA, Inc., Dunedin, FL). The 510K class II medical device measures oxygen consumption (VO2) and assesses REE in 5 to 10 minutes using the Weir equation [15] and a constant RQ value of 0.85. All but 5 participants were evaluated for REE after an overnight fast (12–14 hours) but were tested at least 4 hours after a meal. Participants sat in a quiet room for a 15- minute rest period and during testing. The study dietitian prescribed an individualized ADA diet according to the REE results and the participant’s self-reported activity level. Participants with a BMI . 25 kg/m2 (all but 14 participants) were prescribed energy intake deficits of 250–500 kcal in accordance with the ADA’s guidelines to achieve modest weight loss in persons with prediabetes [4]. No meals were provided, and alcoholic beverages were limited to 2 per day for men and 1 per day for women. Participants consumed either an ADA diet with 20% of energy from almonds and avoided other tree nuts and peanuts (intervention) or consumed an ADA diet without tree nuts and peanuts (control). The amount of almonds was determined based on published data reporting favorable changes in insulin, glucose, and lipid levels in subjects with impaired glucose tolerance consuming a diet containing 20% of energy from MUFA [16]. The prescribed ADA diets contained 15%–20% protein, ,10% saturated fat, 60%–70% carbohydrate and MUFA, and cholesterol , 300 mg/d. A 3-day food and activity record (2 weekdays and 1 weekend day) was requested from participants 1 week prior to the start of the study. At week 0, each participant met with the study dietitian for a 1-hour counseling session to receive their individualized ADA diet. The intervention group received instruction on how to select 80% of their energy needs using the ADA Food Exchange System. Monthly supplies of prepackaged raw or dry roasted almonds were provided at Almond Consumption and Cardiovascular Risk Factors 190 VOL. 29, NO. 3 clinic visits for the intervention participants. The clinic supplied the entire almond portion of the diet to the intervention participants, who were instructed to use only the prepackaged study almonds. Both groups received instruction to consume the same number of servings of carbohydrate exchanges for a given calorie level. In light of the 20% energy contribution from the almonds, control group participants were prescribed compensatory servings from the meat and fat exchange lists. In addition, each participant received 20- minute counseling sessions for reinforcement of their ADA diet at weeks 4, 8, and 12 (total of 120 minutes per participant). Dietary Adherence To evaluate adherence, a 3-day food/activity record was completed by each participant at weeks 4, 8, 12, and 16. The study dietitian reviewed the records according to the prescribed number of ADA food exchanges and provided reinforcement. The records were analyzed using the U.S. Department of Agricul- ture’s database Web site (http://www.mypyramidtracker.gov/). Dietary adherence was operationally defined as consuming within 75% of the prescribed diet, which is the approximate midpoint of the within- and between-subject variation in energy expenditure as measured by doubly-labeled water versus self- reported dietary intake [17]. Poor dietary adherence prompted additional individualized follow-up phone calls for reinforce- ment. Outcomes Outcomes included fasting glucose, insulin, TC, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, TC:HDL-C, and HbA1c. We also examined change in body weight, BMI, waist circumference (WC), and blood pressure (BP). Plasma a- tocopherol concentrations were evaluated as a biological marker to assess almond consumption compliance. In addition, self- reported dietary intake was examined in the context of changes from baseline to the second 8 weeks of the study. Anthropometrics and Laboratory Assessment Height was measured to the nearest centimeter using a stadiometer at week 0. Weight and BP were obtained at each clinic visit. Weight was measured using an internally calibrated segmental body composition scale/analyzer (model BC-418 MA, Tanita, Arlington Heights, IL) and recorded to the nearest 0.01 lb. BMI was calculated as weight (kg)/height (m2). BP was measured using a calibrated automated digital monitor (Omron HEM-711). WC was measured to the nearest 0.1 cm, midway between the last rib and the ileac crest. Venous blood samples were collected at the New Jersey Medical School General Clinical Research Center after a 12- to 14-hour fast at weeks 0, 8, and 16. Blood was disregarded in 5 participants at a single time point and for 1 participant at 2 time points due to blood draw protocol violations and/or acute medical conditions known to affect biological measures. Serum glucose, insulin, TC, LDL-C, HDL-C, TG, and HbA1c were measured by the UMDNJ University Hospital Clinical Laboratory according to Clinical Laboratory Improvement Amendment methods and standardized enzymatic procedures. Serum insulin levels were measured using direct enzyme- linked immunoassay methods by LabCorp, Inc. and ICAM Research Laboratory, UMDNJ. Plasma a-tocopherol concen- trations were measured by LabCorp, Inc. using high-perfor- mance liquid chromatography with fluorometric detection. Insulin resistance was assessed using homeostasis model analysis (HOMA) based on fasting glucose and insulin levels [18]. HOMA for insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) were calculated using the formula [insulin(pM) 3 glucose(mM)]/22.5 and [20 3 insulin(pM)]/ [glucose(mM) 2 3.5], respectively. Sample Size To achieve 80% power using a 5% significance level to detect a 20% difference in HOMA-IR, a total of 44 participants was required. Eighty-two individuals met inclusion criteria and 17 declined to participate; thus, 65 participants were enrolled into the trial. Analysis Sample size and power calculations were performed using SAS version 9.1 (SAS Institute, Cary, NC). Data were entered into an SPSS version 12.0 (SPSS Inc., Chicago, IL) database, and statistical analysis was performed using SPSS and SAS. Bivariate statistical analysis using the chi-square test for differences in proportions and 2-sided independent t tests were performed on baseline characteristics using a probability value of 0.05. To assess the significance of changes in anthropo- metric and metabolic variables, a mixed-model repeated- measures analysis of covariance was used with diet, week, and diet 3 week interaction as fixed effects, adjusting for baseline measurements of the outcome variable. A natural log transformation was performed on outcome variables for the modeling analysis when indicated to improve normality, and the results were exponentiated for reporting purposes. An appropriate within-subject covariance structure was deter- mined for each of the outcome variables, and an unstructured, compound symmetric or first-order autoregressive covariance structure was applied. Additional analyses for glucose, insulin, HOMA-IR, and HOMA-B models were performed and adjusted for weight by adding the baseline weight as a covariate. An intent-to-treat analysis was performed, and all percentage change values presented are calculated from least- squares means (LSM) estimated from mixed models. Week 0, 8, and 16 measurements were included in the analysis, with the Almond Consumption and Cardiovascular Risk Factors JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 191 exception of weight, BMI, WC, and BP that included additional measurements from weeks 4 and 12. The assump- tion used in the intent-to-treat model with regard to the aforementioned disregarded samples and missing data and unmeasured endpoints for the dropouts was that they were missing at random. RESULTS Study recruitment occurred from January 2006 to January 2007, and the last participant completed the study in April 2007. Sixty-five individuals met all inclusion criteria and enrolled (intervention arm, n 5 32; control arm, n 5 33). During the study, 11 participants withdrew (intervention arm, n 5 7; control arm, n 5 4), primarily due to work and personal schedule conflicts. Participants randomized into the intervention and control arms were similar in terms of baseline characteristics (Table 1). The intent-to-treat analyses are presented based on percentage change in LSM (Table 2). Both groups experienced declines in weight, BMI, and WC during the study, but there were no significant differences between groups in these measurements at any time point (p 5 0.191 to p 5 0.557). Fasting blood glucose levels decreased ,2 mg/dl (,2%) in both groups (p 5 0.978). However, almond consumption was associated with a greater reduction in fasting insulin (21.78 mU/ml [223.3%] vs. +1.47 mU/ml [+19.2%], p 5 0.002), HOMA-IR (20.48 [224.9%] vs. +0.30 [+15.5%], p 5 0.007) and HOMA-B (213.2 [217.8%] vs. +22.3 [+30.0%], p 5 0.001). The magnitudes of change in insulin, HOMA-IR, and HOMA-B were virtually unaffected after adjusting for weight. The intervention group experienced a 2.11-mU/ml (27.6%) reduction in fasting insulin by week 8 and overall reduction of 1.78 mU/ml (23.3%) at week 16, in contrast to the control group, who showed a 0.06-mU/ml (0.8%) increase by week 8 and overall increase of 1.47 mU/ml (19.2%) at week 16 (Fig. 1). Two participants in each group were taking lipid-lowering medications. There was no significant change in TC, HDL-C, or TG between the almond-enriched intervention and the nut- free control group. While failing to meet the prespecified cutoff for statistical significance, a clinically significant decline in LDL-C was found in the almond-enriched intervention group (212.4 mg/dl vs. 20.4 mg/dl, p 5 0.052) as compared with the nut-free control group. No significant changes were observed in HbA1c, systolic BP, or diastolic BP between the almond-enriched intervention and the nut-free control group. The mean intake of almonds for participants in the intervention group was 60 g per day. There was a 0.27-mg/L (2%) decrease in the mean plasma a-tocopherol level in the nut-free control group (p 5 0.65) at week 8 in contrast to a 1.74-mg/L (17%) increase observed in the almond-enriched intervention (p , 0.01). Approximately 80% of participants met the operational definition of dietary adherence in both groups. There was no difference in self-reported mean dietary intakes from week 4 to 8 (first 8 weeks) and week 12 to 16 (second 8 weeks); therefore, the 2 sets of 3-day food records were collapsed (Table 3). Using paired data to evaluate within-group changes from baseline to the second 8 weeks of the study, a 5% decrease in energy from carbohydrate was observed in the intervention group in the context of a 5% increase in total fat, 5% increase in MUFA, 1% increase in PUFA, 5-g/d increase in fiber, and 10-mg a-tocopherol equivalent (TE) increase in Table 1. Baseline Characteristics by Intervention and Control Armsa Characteristic Intervention (n 5 32) Control (n 5 33) Age (y) 53 6 9 54 6 11 Gender Female 22 (69) 26 (79) Male 10 (31) 7 (21) Race Caucasian 12 (38) 13 (40) Hispanic 4 (12) 5 (15) African American 14 (44) 9 (27) Asian 2 (6) 6 (18) Weight (kg) 82.9 6 14.4 80.5 6 14.4 Body mass index (kg/m2) 30 6 5 29 6 5 Waist circumference (cm) 95 6 13 96 6 12 Resting energy expenditure (kcal) 1708 6 364 1635 6 375 Plasma lipids, mg/dlb Total cholesterol 202 6 36 199 6 42 LDL cholesterol 117 6 32 118 6 38 HDL cholesterol 63 6 16 59 6 12 Triglycerides 113 6 58 124 6 75 Total cholesterol:HDL cholesterol 3.40 6 0.93 3.49 6 1.10 HbA1c (%) 5.8 6 0.6 6.1 6 0.5 Fasting blood glucose, mg/dlb 101 6 13 104 6 14 Fasting insulin, mU/ml 11.4 6 9.4 9.0 6 5.6 HOMA-IR 2.9 6 2.5 2.4 6 1.7 HOMA-B 112 6 82 83 6 60 Systolic blo