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Nutrition in Clinical Care

Effect and mechanisms of action of vinegar on glucose metabolism, lipid profile, and body weight Eleni I Petsiou, Panayota I Mitrou, Sotirios A Raptis, and George D Dimitriadis The aim of this review is to summarize the effects of vinegar on glucose and lipid metabolism. Several studies have demonstrated that vinegar can help reduce hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity. Other studies, however, have shown no beneficial effect on metabolism. Several mechanisms have been proposed to explain these metabolic effects, including delayed gastric emptying and enteral absorption, suppression of hepatic glucose production, increased glucose utilization, upregulation of flow-mediated vasodilation, facilitation of insulin secretion, reduction in lipogenesis, increase in lipolysis, stimulation of fecal bile acid excretion, increased satiety, and enhanced energy expenditure. Although some evidence supports the use of vinegar as a complementary treatment in patients with glucose and lipid abnormalities, further large-scale long-term trials with impeccable methodology are warranted before definitive health claims can be made. © 2014 International Life Sciences Institute

INTRODUCTION The use of food additives of natural origin to treat diseases has increased significantly in recent years, despite a lack of evidence showing medical benefit. The reasons for this increase include certain traditional beliefs held by various ethnic groups, the ease of access to information on the Internet, and preferences for natural treatments that are perceived to be more reliable, to have minimal side effects, and to be lower in cost. Diabetic patients are 1.6 times more likely to use complementary and alternative medical products than nondiabetics.1 Moreover, obese individuals, who are usually unwilling to reduce their daily caloric intake, are often prone to use dietary gimmicks or alternative products that promise weight loss and beneficial metabolic effects. Vinegar has been used extensively since the era of Hippocrates as an antifungal and antibacterial agent for

the treatment of numerous infections and ailments, including persistent coughs, head lice, insect bites, warts, ear infections, and wounds.2 In recent decades, however, there has been increasing interest in the metabolic effects of vinegar. The main component of vinegar is acetic acid, which gives vinegar its sour taste and pungent smell. Additional components in vinegar include other organic acids (formic, lactic, malic, citric, succinic, and tartaric), amino acids, peptides, vitamins, mineral salts, and polyphenolic compounds (e.g., catechin, caffeic, ferulic acid).3–5 The aim of this review is to summarize the effects and the suggested mechanisms of action of vinegar on glucose and lipid metabolism in hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity. For this purpose, a PubMed search of the English-language literature was performed using a combination of terms: vinegar, acetic acid, diabetes mellitus, glucose metabolism,

Affiliations: EI Petsiou and GD Dimitriadis are with the 2ndDepartment of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, Attikon University Hospital, Haidari, Greece. SA Raptis is with the 2ndDepartment of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, Attikon University Hospital, Haidari, Greece, and the Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications (H.N.D.C), Athens, Greece. PI Mitrou is with the Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications (H.N.D.C), Athens, Greece. Correspondence: GD Dimitriadis, 2ndDepartment of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, Attikon University Hospital, 1 Rimini Street, GR-12462 Haidari. Greece. E-mail: [email protected] and [email protected], Phone: +30-210-5831255, Fax: +30-210-5326454. Key words: acetic acid, glucose metabolism, lipid metabolism, obesity, vinegar doi:10.1111/nure.12125 Nutrition Reviews® Vol. 72(10):651–661

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hyperglycemia, hyperinsulinemia, insulin resistance, insulin secretion, gastric emptying, enteral absorption, skeletal muscle, adipose tissue, liver, hyperlipidemia, cholesterol, triglycerides, free fatty acids, body weight, obesity, and safety. The initial MEDLINE search resulted in 4,519 citations. After duplicate citations were excluded, 3,676 citations remained. Ten additional citations were identified from manual bibliographic checks using Google. A focus on studies that were eligible for the purposes of this review resulted in the final selection of 77 papers. Of these, 21 animal and 24 human studies evaluated the effects of vinegar on glucose and lipid metabolism or body weight. Tables 1 and 26–28 summarize the clinical studies included, as classified by type, field of investigation, and characteristics of participants.

EFFECT OF VINEGAR ON GLUCOSE METABOLISM The consumption of vinegar with meals has been used as a home remedy for diabetes long before the advent of pharmacologic glucose-lowering therapies.29 Over the past 25 years, several in vivo and in vitro studies have examined the effect and the mechanisms of action of vinegar on glucose metabolism in healthy subjects and in subjects with diabetes mellitus. Effect of vinegar in healthy subjects Previous studies in healthy individuals provide evidence that a single dose of vinegar prior to a starchy meal reduces postprandial glucose7–10,12,14 and/or insulin responses.6,8,9,11–14 Interestingly, vinegar consumption prior to the ingestion of a dextrose drink did not reduce postprandial glycemia, which suggests that vinegar does not have an antiglycemic effect when added to a meal composed of monosaccharide dextrose.19 Furthermore, the antiglycemic effect was not observed when the vinegar was neutralized with sodium bicarbonate, a finding that implies a mechanism related to acidity.7 The significance of the timing of vinegar ingestion was indicated by a study that demonstrated a more pronounced antiglycemic effect when vinegar was ingested immediately before a meal versus 5 h before a meal.19 Further studies provide evidence that other factors, such as the glycemic load of the test meal and/or the dose of vinegar, can also influence the effects of vinegar on glucose metabolism. The addition of vinegar to a meal with a high glycemic index has been reported to lower the glycemic9,10,12 and insulinemic responses.9,12 In accordance with these findings, Johnston and Buller13 reported that vinegar ingestion significantly reduced the postprandial glucose and insulin responses following a highglycemic-load meal. Furthermore, they recorded a 652

reduction in energy consumption for the remainder of the day in those individuals who had consumed vinegar in addition to the high-carbohydrate meal, suggesting a beneficial effect of vinegar on satiety. On the other hand, individuals who consumed vinegar along with a lowglycemic-load meal showed a reduction in postprandial insulin response without a significant reduction in postprandial glucose response and with no effect on energy consumption for the remainder of the day.13 Another experiment showed a dose-response relationship of vinegar – apart from the glycemic load of the meal – in both the metabolic responses and the satiety rate: the higher the acetic acid level, the higher the satiety level and the lower the postprandial glucose and insulin levels.14 However, the inverse dose-response relationship between the level of acetic acid and glucose response in healthy adults was contradicted by a different study showing that 10 g of vinegar was more effective in reducing postprandial glycemia (23–28% reduction) than 20 g of vinegar (6–10% reduction).19 These results correlate well with findings in patients with type 2 diabetes, in whom high amounts of vinegar (50 g) added to a high-carbohydrate meal did not affect 2-h postprandial blood glucose or insulin levels.23 The long-term effects of acetic acid ingestion were examined in a prospective, randomized, double-blind, placebo-controlled clinical trial conducted in 114 nondiabetic subjects who consumed 30 mL of apple cider vinegar daily for 8 weeks.25 Although this study supported a downward trend in HbA1c, it was not statistically significant. Given the 15% dropout rate of the trial, further studies with a greater number of participants and a longer (at least 3 months) period of vinegar intake are warranted. Effect of vinegar in individuals with insulin resistance and/or diabetes mellitus Previous studies in subjects with insulin resistance and/or diabetes mellitus provide controversial results, suggesting that various factors can influence the antiglycemic effect of vinegar. Vinegar administration before a highcarbohydrate meal was found to improve not only postprandial glucose and insulin fluxes but also whole-body insulin sensitivity (by 34%) in insulin-resistant subjects, yet these effects were less pronounced in a group of subjects with type 2 diabetes.11 In the latter group, insulin sensitivity was improved by 19%, and the reduction in glucose and insulin levels did not reach statistical significance.11 These findings may suggest that vinegar exerts maximal effects in subjects with marked insulin resistance and preserved pancreatic insulin secretion. A recent trial examined the effect of vinegar on postprandial glucose and insulin responses relative to the Nutrition Reviews® Vol. 72(10):651–661

Nutrition Reviews® Vol. 72(10):651–661

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Participants

Crossover, placebo-controlled Crossover, placebo-controlled Randomized, crossover

10 T1D subjects

16 T2D subjects

12 T2D subjects

Mitrou et al. (2010)22 Kahraman et al. (2011)23 van Dijk et al. (2012)24 Panetta et al. (2013)25 Wu et al. (2013)26 Acute

Acute

Acute

4d

Acute

Acute

Chronic (12 wk)

Acute

2d

Chronic (2 wk)

Acute

60 mL strawberry vinegar

Intervention

Vinegar (20 mL ACV, 40 mL water, 0.3 tsp saccharin)

2 Tbsp ACV at bedtime for 2 d

200 mL water ± 30 mL ACV

18 g or 23 g or 28 g WV

Cold storage + vinaigrette (8 g olive oil & 28 g WV) 20 g ACV

Reduction in FG in day 2, particularly in subjects with typical FG > 7.2 mmol/L Glucose levels in the first 100 min were greater after vinegar ingestion. Vinegar was unable to suppress enteral glucose absorption

Reduced the GI index (43%) and insulinemic index (31%) of freshly boiled potatoes Reduction in insulin response in both meals. Reduction in glucose response in high-GL meal Dose-dependent reduction in PPG and insulin response as well as increase in satiety Reduction in gastric emptying rates

Decreased insulin response without effect on PPG in healthy subjects. Reduced PPG and insulin levels as well as increased insulin sensitivity in insulin-resistant subjects. No effect in diabetic subjects

Reduction in glycemic and insulinemic responses with pickled cucumber Reduced the GI of rice (by 23–33%)

Glucose response decreased by 31.4% only after vinegar + bread. No difference in gastric emptying Reduction in PPG, insulin, and paracetamol levels. Decreased gastric emptying rate

No effect on PPG, insulin response decreased by 20%

Outcome(s)

Restoration of ovulatory function as well as a modest (statistically nonsignificant) decrease in HOMA-IR

100-mL beverage containing 15 g ACV

Abbreviations: AcNa, sodium acetate; AcOH, acetic acid; ACV, apple cider vinegar; FG, fasting glucose; GI, glycemic index; GL, glycemic load; HbA1-c, hemoglobin A1c; HOMA-IR, homeostasis model assessment–estimated insulin resistance, PPG, postprandial plasma glucose; T1D, type 1 diabetes; T2D, type 2 diabetes, Tbsp, tablespoon; tsp, teaspoon; PCOS, polycystic ovary syndrome; WV, white vinegar.

No difference in HbA1-c

30 mL ACV

1 reference pill (15 mg AcOH), 1 HbA1c fell in the vinegar group (by 0.16%) but rose in the reference pickle (700 mg AcOH), or 2 Tbsp pill group (by 0.06%) and in the pickle group (by 0.22%) vinegar (1400 mg AcOH) twice daily White bagel, 20 g butter, 200 g 2 g, 10 g, or 20 g vinegar, ingested 10 g vinegar, consumed 2 min prior to meal, reduced PPG. Vinegar did juice (3 trials) or dextrose 2 min or 5 h before the meal, or not alter PPG when ingested with monosaccharides. AcNa did not solution (1 trial) 1.2 g sodium acetate per 40 g reduce PPG water, ingested 2 min before the meal 50 g pureed potatoes and 250 mL 20 g wine vinegar Reduction in PPG in high-GI meal. No effect on postprandial insulin lowfat milk (high-GI), or 100 g whole-grain bread, 55 g lettuce, & 20 g lowfat cheese (low-GI) 15% rice vinegar, 15% black Maximum forearm blood flow in response to shear stress increased in vinegar made from unpolished all vinegar groups compared with placebo group rice, or 15% black vinegar made from forbidden rice Bread, cheese, turkey, ham, orange 30 mL vinegar + 20 mL water Reduction in PPG by 20% juice, butter, & cereal bar 275 g baked beans, 195 g rice, Salad with 50 g grape vinegar Higher PPG in the 1st h after vinegar supplementation. No differences 106 g salad in postprandial insulin Beverage with 75 g glucose 25 g WV No effect on PPG or postprandial insulin levels

Mashed potatoes, 1 Tbsp margarine + 120 mL sugar-free beverage Foods consumed as part of daily routine

1 oz cheese at bedtime

300 g rice pudding

Bagel + juice (high GL) or chicken + rice (low GL) White wheat bread

Freshly boiled potatoes

100 g lettuce, olive oil ± white AcOH (vinegar) or AcNa bread (neutralized vinegar) 122 g white bread, 8 g olive oil, Vinaigrette sauce (20 g WV, 20 g 23 g cheese, 1 g paracetamol as water, 8 g olive oil) a gastric emptying marker White bread, cheese, butter Milk + fresh cucumber or yogurt + pickled cucumber White rice Vinegar + roasted algae (sushi) or pickled food White bagel, butter, orange juice 20 g ACV

50 g sucrose/300 mL water

Meal

97 nondiabetic Parallel, randomized, double-blind, Chronic (8 wk) Foods consumed as part of daily subjects placebo-controlled routine 7 nondiabetic women Clinical Chronic (90–110 d) Foods consumed as part of daily with PCOS routine

Double-blind, crossover, placebo-controlled

10 healthy postmenopausal women

Sakakibara et al. (2010)21

Liatis et al. (2010)20

Four trials with 8–10 Double-blind, randomized, subjects/trial: crossover, placebo- controlled healthy (3 trials) or T2D subjects (1 trial) 16 T2D subjects Crossover, placebo-controlled

Johnston et al. (2010)19

Parallel, placebo-controlled

Randomized, crossover, placebo-controlled Randomized, crossover, placebo-controlled

24 T2D subjects

5 healthy subjects

10 T1D subjects with gastroparesis 11 T2D subjects

12 healthy subjects

Acute

Acute

Crossover, placebo- controlled Randomized, crossover, placebo-controlled Randomized, crossover, placebo-controlled Crossover, investigator-blinded

Acute

Crossover, placebo- controlled

11 healthy subjects

Acute

Crossover, placebo- controlled

28 nondiabetic subjects 8 healthy, 11 insulinresistant, & 10 T2D subjects 13 healthy subjects

Crossover, placebo- controlled Acute

Acute

Crossover, placebo-controlled

Crossover, placebo- controlled

Acute

Crossover, placebo-controlled

10 healthy subjects

Vinegar ingestion Acute

Trial design

Johnston et al. (2009)18

Leeman et al. (2005)12 Johnston & Buller (2005)13 Ostman et al. (2005)14 Hlebowicz et al. (2007)15 White & Johnston (2007)16 Salbe et al. (2009)17

Ostman et al. (2001)9 Sugiyama et al. (2003)10 Johnston et al. (2004)11

Ebihara & 7 healthy subjects Nakajima (1988)6 5 healthy subjects Brighenti et al. (1995)7 Liljeberg & Bjorck 10 healthy subjects (1998)8

Reference

Table 1 Summary of clinical trials evaluating the effects of vinegar on glucose metabolism in humans.

Abbreviations: ACV, apple cider vinegar; BMI, body mass index; BW, body weight; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; TAGs, triglycerides; T2D, type 2 diabetes; WHR, waist-to-hip ratio.

Table 2 Summary of clinical trials evaluating the effect of vinegar consumption on lipid metabolism and/or body weight in humans. Reference Participants Trial design Duration of trial Meal Intervention Outcome(s) 155 obese, healthy Parallel, randomized, Chronic (12 wk) Foods consumed as part 500-mL beverage with BW, BMI, visceral fat, WHR Kondo et al. Japanese subjects double-blind, of daily routine 15 mL or 30 mL ACV ratio, and TAGs decreased (2009)27 placebo-controlled with both vinegar doses. BMI, BW, and WHR ratio returned to their initial values 4 wk post-treatment Crossover, placeboAcute 275 g baked beans, Salad with 50 g grape No differences in TAG levels Kahraman et al. 16 T2D subjects controlled 195 g rice, 106 g salad vinegar (2011)23 19 hyperlipidemic Quasi-experimental Chronic (8 wk) Foods consumed as part 30 mL ACV twice daily Reduced cholesterol, LDL, and Beheshti et al. subjects of daily routine TAGs after 8 wk compared (2012)28 with baseline 97 nondiabetic Parallel, randomized, Chronic (8 wk) Foods consumed as part 1. Treatment group: 30 mL No significant differences Panetta et al. subjects double-blind, of daily routine ACV found in HDL, LDL, total (2013)25 placebo-controlled 2. Control group: 30 mL of cholesterol, TAGs, or hs-CRP 1.7% balsamic vinegar solution in water 654

carbohydrates consumed by individuals with type 2 diabetes.20 A thought-provoking finding of this study was that vinegar had a significant antiglycemic effect when added to a high-glycemic isocaloric meal but not when added to a low-glycemic, high-fiber mixed meal.20 A possible explanation is that the slow carbohydrate absorption caused by fiber cannot be further delayed by vinegar.20 Moreover, in good correlation with the above trials conducted in healthy individuals,7,19 studies in type 2 diabetic patients show that the antiglycemic effect prevalent when acetic acid is ingested with a starch load is lost when the same quantity of acetate is administered as a sodium acetate solution or when the test meal is replaced by monosaccharide dextrose, showing that acidity and the form of the carbohydrates of the test meal could also affect the action of vinegar.19,24 Besides the demonstrated effects of vinegar on postprandial glucose and insulin levels, there is evidence that vinegar ingestion at bedtime can have a beneficial impact on fasting glucose concentrations, an effect that is more pronounced in subjects with inadequate glucose control.16 The long-term effects of acetic acid ingestion have been examined in a small pilot trial.18 In this trial, 27 subjects with well-controlled type 2 diabetes were randomized to consume 1400 mg or 700 mg of acetic acid or a placebo pill containing 15 mg of acetic acid with meals twice daily.After 12 weeks of treatment, HbA1c values fell by 0.16% in the group that consumed 1400 mg of acetic acid but increased by 0.06% and 0.22% in the other two groups, respectively. These data suggest that regular ingestion of vinegar modestly improves glycemic control. They also indicate a dose-response relationship, confirming previous findings that demonstrated an effective dosage of acetic acid of ≥1400 mg in healthy subjects.14 The long-term effect of vinegar in insulin resistance has been also studied in 6 patients with polycystic ovary syndrome.26 In this study, 750 mg of acetic acid for 90–110 days restored ovulatory function (similar to the insulin sensitizer drug metformin30). The improvement in insulin sensitivity was modest, which could be attributed to the small sample size or the inadequate dose of vinegar (750 mg).26 The effect of vinegar on postprandial glucose levels in subjects with type 1 diabetes has been examined in a small trial that employed the artificial pancreas. 22 In this study, 30 mL of vinegar consumed 5 min before a carbohydrate-rich mixed meal decreased postprandial hyperglycemia by almost 20% compared with placebo, implying that 2 tablespoons of vinegar could be used as a complementary food to reduce hyperglycemia in patients with type 1 diabetes.22 These findings suggest that the underlying mechanisms of vinegar’s action on glucose metabolism go beyond the improvement of insulin sensitivity in subjects with preserved pancreatic function. Nutrition Reviews® Vol. 72(10):651–661

Figure 1 Proposed underlying mechanisms of the effects of vinegar on glucose metabolism. Proposed mechanisms of action on glucose metabolism Although still unclear, several mechanisms have been proposed to explain the effects of vinegar on glucose metabolism (Figure 1). Gastric emptying. Postprandial blood glucose concentration is determined by the rate of glucose appearance in the circulation and the rate of glucose clearance by peripheral tissues. Gastric emptying plays an important role in postprandial blood glucose levels, since a reduction in the gastric emptying rate can lead to a lower postprandial blood glucose concentration.31 The influence of vinegar on gastric emptying was studied in healthy volunteers, using paracetamol as a marker. The presence of acetic acid reduced postprandial glucose and insulin responses to a starchy meal. Based on the lowered paracetamol levels observed after the test meal with vinegar, the effect of vinegar on glucose metabolism may be attributable, at least in part, to a delayed gastric emptying rate.8 These results are in accordance with previous findings demonstrating that vinegar ingestion delays gastric emptying, as estimated by realtime ultrasonography in insulin-dependent diabetes mellitus patients with gastroparesis.15 Experiments investigating the influence of sodium acetate and acetic acid on blood glucose response in healthy subjects7 and in patients with type 2 diabetes19 indicate that the mechanism by which vinegar reduces the glycemic response to a mixed meal may be related to Nutrition Reviews® Vol. 72(10):651–661

acidity. Several studies have evaluated the ability of organic acids to slow gastric emptying.32–34 The findings show that the slowing of gastric emptying depends on the stimulation of sensors to acids found in the proximal half of the intestine.35,36 A dose-dependent inhibition of gastric emptying by acids is related to both pH (free hydrogen anion) and titratable acidity (free and bound hydrogen anion). A more potent, low-pH-sensitive inhibitory mechanism has been demonstrated in the most proximal duodenum, while a second, less potent mechanism sensitive to titrable acidity at more modest pHs has been also demonstrated along the proximal 150 cm of the small intestine.36 Stimulation of these intestinal receptors by acids stops an effective gastric propulsive activity. However, acidity should cause the release of secretin and bicarbonates, which would neutralize the acid and promote gastric emptying. A further portion of acid gastric contents would be transferred to the duodenum, and the process would be repeated. The rate of gastric emptying is therefore determined by the amount of acid transferred from the stomach to the duodenum and by the rate of secretion of pancreatic and duodenal bicarbonates, which neutralize the acid.35 Enteral carbohydrate absorption. Another mechanism that could explain the antiglycemic effect of vinegar is the suppression of enteral carbohydrate absorption. In an in vitro study, this effect was attributed to the suppression of disaccharidase activity and not to the inactivation of glucose transport in the intestinal cells.37 Acetic acid treatment for 15 days suppressed sucrase, lactase, maltase, and 655

trehalase activities in a concentration- and timedependent manner. Since acetic acid treatment did not affect the de novo synthesis of the sucrase-isomaltase complex at either the transcriptional or the translational level, this suppression probably occurred during posttranslational processing; thus, acetic acid may inhibit a post-translational step such as the intracellular trafficking of de novo synthesized disaccharidases, their glycosylation, or their sorting into the polarized membrane.37 These effects of vinegar on the suppression of disaccharidase activity37 could explain, to a certain extent, the lack of any beneficial effect of vinegar consumption on glucose metabolism in trials using monosaccharide glucose as a test meal in healthy subjects19 and in individuals with type 2 diabetes.24 These results contrast with those of a recent in vivo study in which an oral octreotide/insulin suppression test was used to suppress endogenous insulin secretion, allowing estimation of the glucose absorption rate after an oral carbohydrate load (a meal of mashed potatoes) with or without the addition of vinegar. Glucose levels were increased (rather than decreased) after vinegar ingestion, compared with placebo, suggesting that vinegar has no effect on enteral carbohydrate absorption. These results, however, should be considered with caution, since the study had several limitations (such as a small number of participants and/or an insufficient amount of octreotide).17 Endogenous production of glucose by the liver. Vinegar ingestion at bedtime has resulted in reduced fasting glucose concentrations in individuals with type 2 diabetes (especially in those with fasting glucose >7.2 mmol/L), indicating an effect of vinegar on endogenous glucose production by the liver.16 The underlying mechanisms are still unclear. Animal experiments have demonstrated that acetic acid consumption enhances hepatic glycogen stores, possibly by decreasing the glycolysis/ gluconeogenic ratio in liver38,39 through activation of both pathways of glycogen synthesis: the indirect pathway by inhibition of fructose-2,6-bisphosphate synthesis, and the direct pathway by activation of the preferential utilization of glucose-6-phosphate for glycogenesis due to the suppression of glycolysis and the pentose phosphate pathway.38 Further animal experiments suggest that the effect of acetate on glucose metabolism in the liver could be mediated, at least in part, by activation of the 5′-AMPactivated protein kinase (AMPK) pathway.40 Acetate is a short-chain fatty acid metabolized in the liver (via portal circulation) and converted to acetyl-coenzyme A by acetyl-coenzyme A synthase, which results in simultaneous production of AMP. The increase in AMP concentration leads to an increase in the AMP/ATP ratio following phosphorylation/activation of the AMPK pathway. 656

AMPK activation affects glucose metabolism by inhibiting the expression of gene-encoding glucogenetic enzymes (such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase), which results in a reduction in fasting plasma glucose.40 In addition, acetic acid has been shown to protect against fat accumulation in the rat liver and to improve glucose tolerance via a decrease in the expression of genes involved in lipogenesis (mediated by activation of AMPK) and an enhancement of fatty acid oxidation in the liver.39 As a result, acetic acid may benefit patients with diabetes mellitus, especially those with marked metabolic disturbances that contribute to an increase in morning fasting glucose, a process known as the dawn phenomenon. Glucose metabolism in skeletal muscle. Skeletal muscle is considered as an important tissue for the disposal of glucose in response to insulin, especially in the postprandial state.41 Previous animal studies have demonstrated an effect of acetic acid on glucose metabolism in skeletal muscle.38,39,42 Similar to the effect of acetic acid in the liver, acetic acid enhanced glycogen repletion in skeletal muscle as well. However, the mechanisms of action within these tissues are different. As mentioned before, acetic acid in the liver decreases the glycolysis/ gluconeogenic ratio and enhances fatty acid utilization.38,39 In skeletal muscle, acetic acid results in an increased glycogen content, mainly from the accumulation of glucose-6-phosphate due to suppression of glycolysis without enhancement of fatty acid oxidation.38,39 Moreover, earlier animal studies provide evidence that acetate treatment might increase the expression of myoglobin and glucose transporter type 4 (GLUT4) genes in the skeletal muscle.43 Increases in the transcripts of myoglobin and GLUT4 by acetate treatment might be mediated by activation of myocyte enhancer factor 2 via AMPK activation.43 Blood flow. Insulin, through its ability to increase blood flow, stimulates glucose uptake.41 Previous studies have suggested that insulin-mediated increases in blood flow and the effects of insulin on tissue glucose uptake and metabolism are tightly coupled processes and, therefore, are important determinants of tissue sensitivity to insulin.44–47 The effects of insulin on blood flow are mediated by an increase in endothelium-derived nitric oxide, which is produced by endothelial nitric oxide synthase.21 Nonetheless, a recent study in humans suggests that vinegar intake can enhance flow-mediated vasodilation via upregulation of endothelial nitric oxide synthase activity.21 This effect could, at least in part, account for the dose-dependent, biphasic induction of endothelial nitric oxide synthase phosphorylation, most likely via cAMPdependent protein kinase and AMPK pathways.21 These Nutrition Reviews® Vol. 72(10):651–661

observations indicate that the increased blood flow following vinegar consumption may be a key step that could lead to improved vascular reactivity and endothelial function and, finally, to improved insulin action. Insulin secretion. Most studies in subjects with insulin resistance (type 2 diabetes, impaired glucose tolerance)11,20,26 provide evidence that vinegar ingestion decreases postprandial hyperinsulinemia, possibly via an improvement in insulin action. Interestingly, recent experiments have revealed that, compared with tap water, balsamic vinegar given for 4 weeks to Otsuka Long-Evans Tokushima Fatty rats increased insulin staining in pancreatic islets.48 This improvement in β-cell function was attributed to decreased cholesterol levels and increased β-cell ATP-binding cassette transporter subfamily A member 1 expression in islets, which is a plasma membrane protein that mediates the efflux of cellular cholesterol in β cells. These findings suggest that balsamic vinegar could improve β-cell dysfunction by decreasing lipotoxicity.48 Although this study had several limitations (it did not demonstrate a change in pancreatic β-cell mass after vinegar treatment; circulating insulin levels were not measured; and cholesterol levels in β cells were not quantified49,50), it still correlates well with another study in 6 streptozotocin-induced diabetic rats, which showed that treatment with white rice vinegar for 1 month resulted in improved fasting and random hyperglycemia as well as increased fasting insulin levels and β-cell proportions.51 EFFECT OF VINEGAR ON LIPID METABOLISM The antilipidemic effect of vinegar has been investigated in animals, but only limited information from human trials is available. Several studies revealed that chronic administration of acetic acid reduces total serum cholesterol and triglyceride levels in rats fed a cholesterol-rich diet containing 1% cholesterol.52 However, subsequent experiments in rats provide evidence that apple cider vinegar ingestion can lower total plasma cholesterol and triglycerides and reduce amounts stored in the liver only when normal levels of lipids are consumed. In contrast, this effect was not observed when the lipid intake was increased.53 Moreover, animal studies have demonstrated that, besides a lipid-lowering effect on serum and hepatic triglyceride and total cholesterol levels,54,55 chronic administration of persimmon vinegar also helps prevent the metabolic disorders induced by chronic administration of alcohol.55 Besides these findings in metabolically healthy animals, reductions in plasma triglyceride and total cholesterol levels were also found in obese56 and/or type 2 diabetic57,58 rats given chronic acetate treatments. Chronic administration of vinegar has been shown to result not only in a reduction of low-density lipoproNutrition Reviews® Vol. 72(10):651–661

tein cholesterol (LDL-c) but also in an increase of highdensity lipoprotein cholesterol (HDL-c) in control rats.59 Similarly, in rats with type 2 diabetes, an increase in HDLc58,59 and a decrease in serum triglycerides58,59 and LDL-c58 were found. However, these results are in contrast with findings from a recent study demonstrating that vinegar treatment had no effect on plasma HDL-c and LDL-c concentrations in healthy or obese rats.56 This might be attributable to the foods used, which did not induce a high glycemic index, since previous studies have suggested that vinegar may reduce LDL-c and increase HDL-c as a result of its ability to lower the glycemic index of highglycemic-index foods.14,59 Further experiments in rats that developed hepatic steatosis after a high-cholesterol diet have shown that apple cider vinegar decreased triglyceride and very-low-density lipoprotein levels as well as hepatic steatosis, although total cholesterol and LDL-c levels were increased.60 In addition to studies on the effect of chronic administration of vinegar, a study in rabbits examined the effects of acute vinegar intake on lipid profile.61 In this study, 10 mL of vinegar added to a hypercholesterolemic diet resulted in a decrease in total cholesterol, LDL-c, oxidized-LDL, and apolipoprotein B levels. Levels of triglycerides, HDL-c, and apolipoprotein A, however, were not affected by vinegar intake. In humans, a double-blind, placebo-controlled trial conducted by a vinegar manufacturer studied the effect of either 15 mL or 30 mL of vinegar in 155 obese Japanese subjects during a 12-week period. Both vinegar doses resulted in a decrease in serum triglyceride levels, as early as week 4.62 However, this decrease could have been due to the reduction in body weight and fat mass caused by vinegar intake. These findings correlate well with those of another study in 19 treatment-naive patients with hyperlipidemia.28 In this trial, which was not placebo controlled, the consumption of 30 mL of apple cider vinegar twice a day for 8 weeks was effective in reducing the serum levels of total cholesterol, triglycerides, and LDL-c. In addition, a nonsignificant increase in HDL-c was reported.28 These findings are in contrast with the results of a prospective, randomized, double-blind, placebocontrolled clinical study in 114 nondiabetic subjects who consumed 30 mL of apple cider vinegar for 8 weeks. In this trial, there was no evidence that vinegar affected triglycerides, total cholesterol, LDL-c, or HDL-c. This study, however, has several limitations, the most important one being the group of mixed subjects (one-third of the participants were on statin and/or fish oil treatment).25 Most data on the lipid-lowering effect of vinegar are derived either from animal models or from a few human studies that had important limitations. Additional carefully designed, long-term clinical trials are warranted to 657

investigate the long-term effects of vinegar on lipid metabolism. Proposed mechanisms of action on lipid metabolism Several animal studies suggest that the hypolipidemic effects of acetic acid on levels of total serum cholesterol and triglycerides could be attributed to the inhibition of the metabolic pathways of cholesterogenesis and lipogenesis in the liver, through the activation of AMPK, an inhibitor of fatty acid and sterol synthesis.52,57 It has been shown that AMPK activation decreases sterol regulatory element-binding protein-1.52 The suppression of sterol regulatory element-binding protein-1 activity results in the reduction of both the mRNA level and the activity of ATP-citrate lyase, which plays an important role in supplying acetyl-coenzyme A to the pathways of cholesterogenesis and fatty acid synthesis.52,57 Moreover, the addition of vinegar to a high-cholesterol diet increases the expression of the acyl-coenzyme A oxidase (acox) gene, suggesting that acetate might increase fatty acid oxidation, thereby attenuating the cholesterolmediated increase in the hepatic triglyceride concentration and, finally, suppressing the elevation of plasma triglycerides.52,57 Finally, acetate treatment has shown to promote the fecal excretion of bile acid, possibly through the stimulation of secretin release.52 The beneficial effects of vinegar on HDL-c and LDL-c levels59 could be attributable, at least in part, to the decrease in the glycemic index of foods containing acetic acid,10,14 since it has been demonstrated that foods with a lower glycemic index are able to increase HDL-c and reduce LDL-c in humans.63,64 Another possible mechanism could be the effect of the polyphenols and flavonoids in vinegar,58,59,65 given that polyphenols have been shown to decrease serum LDL-c in humans66 and increase serum HDL-c in hamsters,67 possibly via the suppression of intestinal lipoprotein secretion68 and/or through suppression of lipid peroxidation and inhibition of lipase activity.69 In fact, during animal experiments in which the effect of different kinds of vinegar on lipid profiles has been examined, apple cider vinegar (which is rich in polyphenolics) resulted in the highest HDL-c58,60 and the lowest LDL-c levels.58

EFFECT OF VINEGAR ON BODY WEIGHT Several animal studies have reported that orally administrated acetate/vinegar for 1–6 months in healthy,27,56 obese,27 and obesity-linked type 2 diabetic Otsuka LongEvans Tokushima Fatty rats43,57 has a beneficial effect on body weight27,43,56,57 and/or accumulation of abdominal and liver fat.27,43,54,57 These findings contradict those of a 658

study in rats, which showed that acetic acid added to a cholesterol-rich diet for 19 days had no effect on body weight or food intake.52 This discrepancy might be explained by the short period of vinegar administration. In humans, a double-blind, placebo-controlled trial conducted by a vinegar manufacturer62 investigated the effects of vinegar intake on the reduction of body fat mass in 155 obese Japanese for a 12-week period.62 The results showed a decrease in body weight, body fat mass, waist circumference, and body mass index as early as week 4 in both vinegar groups in a dose-dependent manner. The degree of reduction, though not very high (1–2 kg of body weight and 0.4–0.7 points of body mass index), could still be beneficial for the mildly obese Japanese, who tend to have obesity-related diseases. Interestingly, body weight, body mass index, and waist circumference returned to their initial values after a post-treatment period of 4 weeks, suggesting that continuous administration may be necessary to maintain the antiobesity effects of vinegar. Based on the data available from several animal studies27,43,54,57 and 1 double-blind, placebo-controlled human trial,62 there is scarce evidence for a beneficial action of vinegar on body weight. Further long-term, randomized control studies are essential to determine the value of vinegar in conventional nutrition care and dietary management. Proposed mechanisms of action on body weight Several mechanisms of the favorable effects of vinegar/ acetic acid on body weight and/or visceral fat accumulation have been proposed. The first is a reduction in lipogenesis, achieved through a decrease in the transcripts of several lipogenic genes in the liver.57 Previous animal studies suggest that acetate has an inhibitory effect on the activity of carbohydrate-responsive element-binding protein, which is a transcription factor regulating several genes required for the conversion of glucose to fatty acids in the liver.57 The second proposed mechanism is an increment of lipolysis, via an increase in the transcripts of several lipolytic genes.27,43,53 It has been revealed that acetate upregulates the expression of genes encoding fatty oxidation enzymes, such as acyl-coenzyme A oxidase and carnitine palmitoyl transferase-1, and thermogenic proteins, such as uncoupling protein-2, through an AMPK/ peroxisome proliferator-activated receptor α-mediated pathway.27,43,53 A third possible mechanism is an increase in oxygen consumption,27,43,70 which could be attributed to the increase in myoglobin (a hemoprotein, expressed in myocytes, that facilitates the diffusion of oxygen) via AMPK activation.43 Another proposed mechanism is an increase in energy expenditure via upregulation in the expression of the peroxisome proliferator-activated Nutrition Reviews® Vol. 72(10):651–661

receptor α gene and fatty acid oxidation-related enzymes.27,43,70 Finally, a fifth mechanism put forth is an increase in satiety and a decrease in energy intake, which could be attributed to the effect of vinegar on the reduction of the glycemic index of foods.13,14,57

trolled trials to examine potential adverse reactions of regular ingestion of vinegar are lacking, existing evidence shows that moderate consumption of commercial vinegar (≈2 tablespoons with each meal as a dressing) is rather safe.

SAFETY AND TOLERABILITY OF VINEGAR

CONCLUSION

There are scarce reports in the literature regarding adverse reactions following vinegar ingestion. Inflammation of the oropharynx and second-degree caustic injury of the esophagus and cardia have been reported in a woman who drank 1 tablespoon of rice vinegar to dislodge a piece of crab shell from her throat, though her symptoms resolved spontaneously after several days.71 In addition, unintentional aspiration of vinegar has provoked an episode of laryngospasm and subsequent vasovagal syncope, which also resolved spontaneously.72 The safety of vinegar ingestion for 12 weeks has been examined in 27 patients with type 2 diabetes who consumed 1 of 3 forms of vinegar supplementation (commercially made pills containing 15 mg of acetic acid, pickles containing ≈1400 mg of acetic acid, or vinegar containing 2800 mg of acetic acid) while continuing their normal eating habits.73 In this study, 50–56% of participants who consumed pickles or vinegar manifested at least one adverse event (acid reflux, burping, flatulence, or changes in bowel activity) at week 6 of the trial, as compared with 11% in the reference treatment group (P = 0.11) who consumed the pills. Regarding the laboratory parameters, vinegar treatment decreased urinary pH and tended to increase (although not statistically significant) aspartate aminotransferase concentrations.73 In addition to these gastrointestinal and metabolic side effects, a case of hypokalemia was observed in a young woman who had reportedly consumed approximately 250 mL of apple cider vinegar daily for 6 years.74 On the other hand, during a study in 155 obese Japanese subjects who received a placebo drink, 15 mL of vinegar (containing 750 mg acetic acid), or 30 mL vinegar (containing 1500 mg acetic acid) for 12 weeks, no abnormalities of liver or kidney function or adverse events were reported.62 Accordingly, daily intake of 90 mL of vinegar (4500 mg acetic acid) for 4 weeks in healthy subjects did not cause any side effects.62 It must noted that the concentration of acetic acid in commercial vinegar is 4–7%. However, preparations containing free or chemically non-neutralized acetic acid at concentrations of ≥20% are considered dangerous and, if ingested, can cause severe injury to the esophagus.75 Moreover, in insulin-treated diabetes mellitus patients with gastroparesis, vinegar ingestion could further delay gastric emptying, possibly resulting in postprandial hypoglycemia.76 As a result, although large and carefully con-

The majority of clinical studies mentioned in this review have demonstrated that vinegar/acetic acid can beneficially affect glucose metabolism in healthy subjects6,7,9,10,12–14,19 and in patients with insulin resistance or diabetes mellitus.11,16,18,22 However, there are also studies showing no beneficial effect on glucose metabolism.7,11,19,20,24 These discrepancies could be attributed to several factors, such as the dosage of vinegar,14,19 the acidity,7,19 the timing of vinegar ingestion,19 the form of the carbohydrates of the test meal (monosaccharides or complex carbohydrates),19,24 the glycemic index of the meal,20 or the level of insulin secretion and remaining pancreatic secretion of the study population.11 Several mechanisms have been proposed to explain the effect of vinegar on glucose metabolism, including delayed gastric emptying,8,15,31 suppression of disaccharidase activity,37 suppression of hepatic glucose production, increase in glucose utilization in the peripheral tissues,38–40,42,43 upregulation of flow-mediated vasodilatation,21 and facilitation of insulin secretion.48,51 Vinegar has also been shown to protect from lipid accumulation in liver and skeletal muscle.43 Since accumulation of excess lipid in the peripheral tissues disturbs insulin signaling, the ability of acetate to reduce the lipid content in skeletal muscle and liver may contribute to the improvement of glucose tolerance and insulin resistance. Moreover, the dietary intake of vinegar has been reported to decrease triglyceride levels and reduce total cholesterol and LDL-c in several animal52–58,61 and a few human28,62 studies, some of which had important limitations. Findings on the effect of acetate on HDL-c are still unclear; animal studies show a beneficial effect,58,59 whereas human studies do not.25,28 The discrepancy between these studies could be due to both the type of the subjects (animals or humans) and several limitations, such as small sample size, study group selection, and lack of a control group. Besides the protective effects of vinegar on the accumulation of lipids in peripheral tissues, there is also scant evidence for a beneficial action on body weight in several animal experiments27,43,54,57 as well as in a single, double-blind, placebo-controlled human study.62 Possible mechanisms explaining the effect of vinegar on lipid metabolism, fat accumulation, and body weight could include a reduction in lipogenesis,57 an increase in lipolysis,27,43,53 the stimulation of fecal bile acid excretion,52 an increase in oxygen consumption and energy

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expenditure,27,43,70 and an increase in satiety and a decrease in energy intake.13,14,57 These effects of vinegar on lipid metabolism, as well as the previously mentioned actions on glucose metabolism, seem to be mediated, at least in part, by the activation of the key metabolic “master switch” AMPK, expressed in liver,27,42,52 skeletal muscle,42 adipose tissues,42 and blood vessels.21 In conclusion, there is some evidence supporting the favorable effects of vinegar on cardiovascular risk factors, such as hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity. The majority of the data, however, are derived from animal models and/or acute experiments in a few human individuals, and the scant randomized placebo-controlled trials in humans had serious limitations and very low numbers of participants. Moreover, the issue of publication bias, a well-known phenomenon in clinical literature, must be considered. Thus, studies with positive results not only have a better chance of being published but also are published earlier and in journals with higher impact factors than studies with negative results.77 This is likely to lead to an overrepresentation of positive studies in the literature. In conclusion, although vinegar is a safe, widely available, and affordable product, further large-scale, long-term clinical trials that address the limitations in the current evidence are warranted before definitive health claims can be made. Acknowledgments The authors express their gratitude to Ms Alexandra Moraiti for reviewing the English language of the manuscript. Declaration of interest. The authors have no relevant interests to declare. REFERENCES 1. Garrow D, Egede LE. Association between complementary and alternative medicine use, preventive care practices, and use of conventional medical services among adults with diabetes. Diabetes Care. 2006;29:15–19. 2. Johnston CS, Gaas CA. Vinegar: medicinal uses and antiglycemic effect. MedGenMed. 2006;8:61. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1785201/. Accessed October 24, 2012. 3. Cocchi M, Durante C, Grandi M, et al. Simultaneous determination of sugars and organic acids in aged vinegars and chemometric data analysis. Talanta. 2006;69:1166–1175. 4. Morales ML, Tesfaye W, Garcia-Parrilla MC, et al. Evolution of the aroma profile of sherry wine vinegars during an experimental aging in wood. J Agric Food Chem. 2002;50:3173–3178. 5. Natera R, Castro R, de Valme Garcia-Moreno M, et al. Chemometric studies of vinegars from different raw materials and processes of production. J Agric Food Chem. 2003;51:3345–3351. 6. Ebihara K, Nakajima A. Effect of acetic acid and vinegar on blood glucose and insulin responses to orally administered sucrose and starch. Agric Biol Chem. 1988;52:1311–1312. 7. Brighenti F, Castellani G, Benini L, et al. Effect of neutralized and native vinegar on blood glucose and acetate responses to a mixed meal in healthy subjects. Eur J Clin Nutr. 1995;49:242–247.

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