there is evidence that specific components within dairy such as milkfat, vitamin ... mechanisms by which specific dairy
REVIEW
Dairy Components and Risk Factors for Cardiometabolic Syndrome: Recent Evidence and Opportunities for Future Research1,2 Beth H. Rice, Christopher J. Cifelli, Matthew A. Pikosky, and Gregory D. Miller* Dairy Research Institute, Rosemont, IL
ABSTRACT
Cardiometabolic syndrome (CMS), a cluster of metabolic abnormalities that increases the risk of cardiovascular disease (CVD) and type 2 diabetes, affects over one-third of American adults and accounts for billions of dollars in health care costs annually. Current evidence indicates an inverse association between consumption of dairy foods and risk of CMS and its related disease outcomes. Although the specific mechanism(s) underlying the beneficial effects of dairy consumption on the development of CMS, CVD, and type 2 diabetes have not been fully elucidated, there is evidence that specific components within dairy such as milkfat, vitamin D, calcium, magnesium, potassium, and whey proteins may be individually or collectively involved. Specifically, each of these dairy components has been implicated as having a neutral or beneficial effect on one or more elements of CMS, including the serum lipid profile, blood pressure, fasting glucose, and body composition. Although several mechanisms have been identified by which components in dairy may beneficially affect symptoms associated with CMS, further research is required to better understand how dairy and its components may contribute to metabolic health. The purpose of this review is to present the mechanisms by which specific dairy components modulate risk factors for CMS and identify opportunities for future research. Adv. Nutr. 2: 396– 407, 2011.
Introduction
costs (7,8), which has been estimated to increase nearly 25% for each additional risk factor associated with CMS (9). Therefore, the management and prevention of CMS is of utmost public health and economic importance (10). Although there are genetic components to CMS, it is also directly influenced by modifiable lifestyle factors, including dietary behaviors (1). A review of observational investigations found that the consumption of dairy foods contributed to the prevention of CMS and its related disease outcomes (11). It was observed that the consumption of 3–4 servings/d of dairy was associated with a 29% reduced risk of developing CMS compared with the consumption of 10% of MUFA to the diets of Americans aged $ 2 y (27). The consumption of MUFA has been shown to be protective against risk factors associated with CMS (28). MUFA beneficially affect the ratio of HDL-C:TC when isocalorically compared to SFA and carbohydrates (28). Compared with PUFA-rich diets, MUFA-rich diets have comparable effects on the serum lipid and lipoprotein profiles, although MUFA tend to reduce TG less but elevate HDL-C more than PUFA (28). The beneficial effect of MUFA on HDL-C levels may be due in part to reduced stimulation of cholesteryl ester transfer protein, a key enzyme in reverse cholesterol transport, which was demonstrated in mice fed high-fat and MUFA-rich diets with and without the presence of cholesterol (29). Recent reviews of epidemiological and clinical evidence concluded that MUFA intake, particularly from oleic acid,
Clinical markers $1.7 mmol/L (150 mg/dL) or receiving pharmacological treatment for elevated TG #1.03 mmol/L (40 mg/dL) for men, #1.3 mmol/L (50 mg/dL) for women $130 mm Hg systolic blood pressure or $85 mm Hg diastolic blood pressure or receiving antihypertensive pharmacological treatment with a history of hypertension $6.05 mmol/L (110 mg/dL) or receiving drug treatment for elevated glucose $102 cm for men, $ 88 cm for women
Adapted with permission from (1).
beneficial effect of low-fat dairy intake on systolic blood pressure and neutral effects on plasma TG and fasting glucose (14). The authors also reported decreased plasma HDL-C levels, although the decrease may have been attributable to the exchange of carbohydrate for protein intake when participants switched from the control diet to the low-fat dairy diet (14). In the Report of the Dietary DGAC on the DGA 2010, the DGAC recognized that more research was necessary to determine whether components in dairy such as calcium, protein, and fatty acids provide protection from metabolic syndrome (2). The objectives of this review are to describe the potential mechanisms by which the aforementioned components in dairy foods may modulate risk factors associated with CMS and discuss gaps in knowledge that warrant future research.
Current status of knowledge Dairy components and symptoms of CMS Milkfat. Fortified whole cow milk contains w34 g of fat/L, more than one-half of which is saturated (16) (Table 2). The most abundant SFA in milkfat are palmitic (16:0), stearic (18:0), and myristic (14:0) acids, which make up w44, 18, and 15% of the total SFA in milkfat, respectively (16). The 2010 DGA indicates that reducing saturated fat intake to recommend levels can help reduce the risk of CVD; however, the relationship between saturated fat and CVD risk has been brought into question (17,18). It has been well established that milkfat raises serum HDL-C, helping to maintain an HDL-C:TC ratio that is inversely related to CVD (19). This ratio has been considered a better predictor of CVD than individual lipoprotein and TC measures alone (20,21). HDL-C has been implicated in beneficial effects on CVD risk through reverse cholesterol transport, inhibition of LDL oxidation and subsequent inflammatory pathways, and prevention of cellular damage (22). This may explain why elevated HDL-C has been associated with protection from CVD, even when alongside elevated LDL-C (22). Furthermore, palmitic and stearic acids in milkfat occupy the sn-2 position of TG, which is typically the position of unsaturated fatty acids in plant oils (22,23). The selectivity of pancreatic lipase to hydrolyze TG at the sn-1 and sn-3 positions leads to the production of FFA and 2-monoglyceride
Table 2. Fatty acid composition of retail milk samples from the United States1,2 g/100 g of milkfat
Fatty acid 4:0 6:0 8:0 10:0 12:0 14:0 15:0 16:0 17:0 18:0 20:0 14:1 16:1 18:1, trans-6 18:1, trans-9 18:1, trans-10 18:1, trans-11 18:1, trans-12 18:1, cis-9 18:2, cis-9, cis-12 18:3 18:2, cis-9, trans-11 Other S SFA S MUFA S PUFA 1 2
4.15 2.13 1.19 2.59 2.87 9.53 0.89 28.08 0.52 11.68 0.09 0.82 1.48 0.32 0.29 0.55 1.48 0.54 23.58 3.19 0.38 0.55 3.1 63.72 29.06 4.12
Adapted with permission from (39). Sigma symbol ¼ SUM.
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was also associated with neutral or beneficial effects on blood pressure (30). In rats, dietary oleic acid was shown to increase the cell membrane content of oleic acid, producing a membrane structure that favored the docking of signaling proteins involved in blood pressure control (31). The result of increased signaling capabilities induced by oleic acid was the enhancement of a vasodilation pathway that provoked decreased blood pressure (31). In humans, oleic acid has been demonstrated to beneficially alter the membrane lipid environment and the activity of signaling proteins in hypertensive patients (32,33). Oleic acid consumption may also beneficially affect central adiposity (28). This may be because oleic acid appears to preferentially accumulate in subcutaneous as opposed to visceral fat stores (34). In healthy men and women, oleic acidrich foods were demonstrated to increase fat oxidation and energy expenditure (35). It is hypothesized that the doublebond position of oleic acid may contribute to its preferential oxidation compared to other fatty acids (36,37). A further beneficial attribute of MUFA on the development of CMS is that MUFA also have the ability to regulate glycemic response and insulin sensitivity (28). A recent review reported that MUFA, particularly oleic acid, had neutral or beneficial effects on glycemic response or insulin sensitivity when fed at levels of w20% of total fat intake (28). In healthy participants, it was demonstrated that b-cell function and insulin sensitivity in the postprandial condition improved linearly as the proportion of oleic acid to palmitic acid in high-fat diets increased (38). Further research to elucidate the direct mechanism by which oleic acid or other MUFA influence b-cell function in postprandial metabolism is necessary to better understand its effects on insulin sensitivity and glycemic response (38). Although oleic acid is the second most abundant fatty acid in milkfat and may contribute to the neutral and beneficial effects on the development of CMS, the studies reviewed here did not use milkfat as a source of MUFA. Research to evaluate the effects of MUFA, specifically oleic acid derived directly from milkfat, is necessary to elucidate its effects on CMS. It is important to note that milkfat is comprised of w115 nmol/L) reduced the prevalence of CMS by nearly 50% compared to lower serum levels of 25-(OH)-cholecalciferol (< w85 nmol/L) (53). The proposed mechanisms by which vitamin D may modulate metabolic health include reduction of dyslipidemia through maintenance of calcium homeostasis, stimulation of insulin production and release, and regulation of the renin-angiotensin-aldosterone system, which leads to improved blood pressure control (51). An analysis of NHANES-III data showed that plasma TG levels were lower in individuals with serum 25-(OH)cholecalciferol >92.5 nmol/L compared to those with 1700 participants enrolled in the Framingham Offspring Study, the TC:HDL-C ratio was higher in participants with serum 25-(OH)cholecalciferol 3000 IU/d (83 mg/d) combined with energy restriction resulted in greater reductions in serum TG compared to energy restriction alone (56). In contrast, supplementation with 400 or 800 IU/d (10 or 20 mg/d) of cholecalciferol in free living participants for 1 y had no effect on serum TG in healthy Pakistani adults (57). Similarly, in 4 other randomized trials, cholecalciferol supplements had no effect on serum lipids or
lipoproteins in adults (58–61). Other randomized trials designed to test the effects of cholecalciferol on serum lipid and lipoprotein concentrations have simultaneously administered calcium (62–66) and most have yielded similar neutral effects (51). Major et al. (65), however, showed that supplementation with 1200 mg of calcium in addition to 15 mg of cholecalciferol/d for 15 wk lowered the ratios of TC:LDL-C and LDL-C:HDL-C, as well as of LDL-C concentrations compared with placebo in women consuming energy-restricted diets that had low calcium intake at baseline. Conflicting data from randomized trials may be partially explained by gender and/or differences in dietary calcium adequacy at baseline. Despite possible confounding effects by calcium intake in some trials, foods fortified with vitamin D, such as milk and some yogurts, have been consistently shown to improve serum 25-(OH)-cholecalciferol status in 25-(OH)-cholecalciferol–deficient, –insufficient, and –sufficient populations (49). The studies that have utilized dietary supplements of vitamin D lend insight into the contribution of vitamin D to the beneficial effects of dairy consumption on metabolic health, but evidence indicates that food sources of vitamin D (natural and fortified) are an efficient and effective route of delivery for this nutrient (49). In addition to the potential effects of cholecalciferol intake on the lipid component of CMS, other benefits may occur with respect to regulation of glucose and insulin metabolism. The regulation of parathyroid hormone (PTH) and intracellular calcium by serum 25-(OH)-cholecalciferol may beneficially modulate insulin sensitivity through effects in adipocytes and skeletal muscle cells (67). Several intervention studies in humans have shown improved responses to glucose with cholecalciferol treatment (59,61,68), but beneficial effects from cholecalciferol appeared to be specific to individuals who were deficient at baseline (61) or who had preexisting metabolic abnormalities (59,61,68). Randomized trials investigating the effects of serum 25-(OH)-cholecalciferol status as well as treatment with cholecalciferol from various sources (i.e. foods vs. supplements) to determine optimal amounts of vitamin D consumption and status, and the effects on glucose control in both healthy and metabolically at-risk individuals are necessary at this time. The evidence suggesting a beneficial role of vitamin D on blood pressure control is inconsistent (51,69). The regulation of the rennin-angiotensin-aldosterone system by 1,25dihydroxycholecalciferol as well as an ability to suppress PTH are hypothesized mechanisms by which vitamin D favorably effects blood pressure control (51). Renin, a protease produced in the kidney, catalyzes the conversion of angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to produce angiotensin II, a potent vasoconstrictor (51). Angiotensin II is a stimulator of aldosterone secretion and therefore a catalyst for hypertension when elevated (51). Increases in PTH have been demonstrated to stimulate calcium influx in vascular smooth muscle cells, leading to contraction and increased vascular Dairy and cardiometabolic syndrome 399
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resistance (70). The suppressive effect of 1,25-dihydroxycholecalciferol on PTH (51) may limit calcium influx into vascular smooth muscle cells, therefore contributing to its effects on blood pressure by promoting vascular relaxation. However, the mechanisms by which 1,25-dihydroxycholecalciferol may regulate blood pressure have not been thoroughly investigated in humans (51,69). Observational evidence demonstrated that exposure to UV light in combination with increasing serum 25-(OH)cholecalciferol lowered blood pressure in adults with hypertension (71). Additionally, it was reported that persons living at higher latitudes, with less exposure to UV light, had elevated blood pressure (72). Large prospective cohort studies, however, have had mixed results (73,74). The effect of cholecalciferol on blood pressure may be attributed to effects on systolic blood pressure, which was lowered in normotensive women with intakes of cholecalciferol > 400 IU/d (10 mg/d) (75), an effect not seen in women with intakes less than this amount (74). No association was detected between serum 25-(OH)-cholecalciferol and blood pressure in elderly participants (76) or between serum 25-(OH)cholecalciferol and risk of future hypertension in Norwegian participants (77). Inverse associations, however, were observed between serum 25-(OH)-cholecalciferol and blood pressure in American adults reported in 3 different analyses of NHANES-III data (54,78,79). Overall, observational studies have demonstrated an inverse association between serum 25-(OH)-cholecalciferol and blood pressure. Randomized clinical trials investigating the effect of serum 25-(OH)-cholecalciferol status on the development of hypertension are necessary to verify findings from epidemiological investigations (51). Furthermore, evidence that will lead to consensus regarding the level of serum 25-(OH)-cholecalciferol below which metabolic health may be compromised is necessary at this time.
Minerals: calcium, potassium, and magnesium. Dairy foods contribute 50% of calcium and >10% of magnesium and potassium to the American diet, with milk being the leading food source of calcium, potassium, and magnesium in the diet of Americans aged 2 y and older (27). All 3 of these minerals have been implicated in regulating various symptoms of CMS (25). Randomized controlled trials have consistently demonstrated beneficial (65,80–82) or neutral (83–85) effects from calcium supplementation on plasma lipids. In a randomized crossover study, Lorenzen and Astrup (86) showed that whereas high-fat diets raised TC, LDL-C, and HDL-C independent of calcium content, the inclusion of high dietary calcium decreased TC and LDL-C. Additionally, the high-calcium diets decreased the TC:HDL-C ratio and increased the HDL-C:LDL-C ratio compared to the lowcalcium diet (86). The finding that dairy calcium partly counteracted the ability of dairy fat to raise TC and LDL-C without decreasing HDL-C may have been in part because of an increase in fecal fat excretion, which was observed in both the high-calcium and high-fat diets (86). 400 Rice et al. Downloaded from https://academic.oup.com/advances/article-abstract/2/5/396/4557932 by guest on 05 June 2018
Similarly, in another controlled trial, participants that consumed 2200 mg/d of calcium from fortified foods for 10 d experienced decreased TC and LDL-C and no effect on HDL-C compared to when they consumed their habitual diets (80). Shahkhalili et al. (82) showed that the consumption of chocolate fortified with 900 mg of calcium for 2 wk resulted in increased excretion of palmitic and stearic acids, and LDL-C decreased by 15% with no change in HDL-C. In contrast to the above studies, Karanja et al. (84) reported that when healthy men and women were either counseled to increase calcium consumption to 1500 mg/d or given a calcium supplement of 1500 mg/d, there were no effects on serum lipids compared to control. This may be because calcium consumption among participants was already adequate at baseline ($800 mg/d). Collectively, the results from these interventions demonstrate a neutral and likely beneficial role of calcium on the serum lipid profile, potentially mediated by fecal fat excretion. Results from intervention trials indicate that the beneficial effects of dairy foods on blood pressure may be in part ascribed to the calcium, potassium, and magnesium they contribute to the diet (87). Several meta-analyses of randomized clinical trials conducted over the last 2 decades indicate that calcium supplementation between 500 and 2000 mg/d decreases systolic and diastolic blood pressure, with results being more profound for systolic blood pressure (88–91). It has been suggested that the ability of calcium, potassium, and magnesium to decrease sodium retention through multiple mechanisms may be the underlying mechanism by which adequate dairy consumption affects blood pressure control (87). Excessive intake of dietary sodium may increase intracellular calcium, which can in turn increase vascular tone, peripheral vascular resistance, and blood pressure (92). Conversely, increased dietary calcium has the opposite effect as dietary sodium and leads to decreased intracellular calcium, thereby decreasing vascular resistance and blood pressure (87,92). An alternative mechanism by which dietary calcium may beneficially affect blood pressure has been attributed to hormonal regulation of intracellular calcium levels by 1,25-dihydroxycholecalciferol (92). 1,25-Dihydroxycholecalciferol stimulates calcium influx via the vitamin D receptor, which promotes contraction and peripheral resistance (92). Adequate intake of dietary calcium reduces 1,25-dihydroxycholecalciferol, subsequently decreasing blood pressure (92). It should be noted that certain populations, such as the elderly and African Americans, are more responsive to the antihypertensive effects of dietary calcium than others (92). This is because of their heightened sensitivity to dietary sodium, which makes them more dependent on calcium release from the extracellular space as opposed to intracellular stores (93). A recent meta-analysis of clinical trials indicated that mean supplementation of w1200 mg/d of calcium decreased diastolic blood pressure by 0.99 mm HG and systolic blood pressure by 1.86 mm HG, with effects being even greater in individuals with low calcium intake at baseline (
