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Invited review: Potential effects of short- and long-term intake of fermented dairy products on prevention and control of type 2 diabetes mellitus

Open AccessPublished:April 01, 2022DOI:https://doi.org/10.3168/jds.2021-21484

      ABSTRACT

      The consumption of fermented dairy products has been linked with lowering the risk of type 2 diabetes mellitus (T2DM), but studies have yet to demonstrate a definite association. We evaluated evidence from a cross-sectional analysis of longitudinal studies and human and animal experimental trials to further understand the current knowledge linking short- and long-term consumption of fermented dairy products to T2DM. Most cohort studies revealed a protective effect of fermented dairy products on T2DM development, with yogurt noted as the most consistent food item protecting against the disease. Human experimental trials and animal studies revealed improvements in biomarkers of glycemic control with short-term monitored intake of fermented dairy products from various sources. Therefore, fermented dairy products may offer protection against the development and may have therapeutic benefits for individuals with T2DM. This could influence on dietary recommendations and the development of functional foods aiming to minimize the risk of T2DM.

      Key words

      INTRODUCTION

      According to the International Diabetes Federation, about 10% of the world population are currently living with diabetes, corresponding to a total of 463 million individuals worldwide (
      • International Diabetes Federation
      About diabetes: Type 1 diabetes.
      ). The American Diabetes Association (
      • American Diabetes Association
      Diabetes complications.
      ) reported many health problems associated with this condition, including cardiovascular disease (CVD), nephropathy, retinopathy, neuropathy, and gestational complications. Additionally, diabetes poses a significant financial burden, with 10% of the global health expenditure being spent on research, prevention, and treatment (
      • International Diabetes Federation
      About diabetes: Type 1 diabetes.
      ). Therefore, effective, efficient, affordable, and practical evidence-informed approaches should be developed for the prevention and treatment of diabetes whenever possible.
      Type 1 diabetes mellitus (T1DM), an autoimmune genetic condition, is the least preventable type of diabetes. In fact, T1DM is predominantly diagnosed in childhood and requires insulin therapy because the body is unable to produce the hormone (
      • International Diabetes Federation
      About diabetes: Type 2 diabetes.
      ). Conversely, type 2 diabetes mellitus (T2DM), which accounts for 90% of all diabetes cases worldwide, is not insulin-dependent and can be prevented and managed through diet and exercise (
      • International Diabetes Federation
      About diabetes: Type 2 diabetes.
      ). Notably, although T2DM most commonly presents in adults over 40 yr, its onset in children and adolescents has been increasing due to changes in lifestyle, physical inactivity, and eating habits (
      • Global Diabetes Community
      Type 2 diabetes.
      ).
      The consumption of fermented dairy products is thought to potentially prevent or help to control T2DM through mechanisms of increased satiety, improved insulin sensitivity, increased glucose tolerance and maintenance of the gut microbiota (
      • Fernandez M.A.
      • Panahi S.
      • Daniel N.
      • Tremblay A.
      • Marette A.
      Yogurt and cardiometabolic diseases: A critical review of potential mechanisms.
      ;
      • Fernandez M.A.
      • Marette A.
      Novel perspectives on fermented milks and cardiometabolic health with a focus on type 2 diabetes.
      ;
      • Givens D.I.
      Review: Dairy foods, red meat and processed meat in the diet: Implications for health at key life stages.
      ;
      • Sivamaruthi B.S.
      • Kesika P.
      • Prasanth M.I.
      • Chaiyasut C.
      A mini review on antidiabetic properties of fermented foods.
      ). Previous work suggests the potential of fermented dairy products in preventing T2DM and decreasing postprandial glycaemia (
      • Gijsbers L.
      • Ding E.L.
      • Malik V.S.
      • de Goede J.
      • Geleijnse J.M.
      • Soedamah-Muthu S.S.
      Consumption of dairy foods and diabetes incidence: A dose-response meta-analysis of observational studies.
      ;
      • Grom L.C.
      • Coutinho N.M.
      • Guimarães J.T.
      • Balthazar C.F.
      • Silva R.
      • Rocha R.S.
      • Freitas M.Q.
      • Duarte M.C.K.H.
      • Pimentel T.C.
      • Esmerino E.A.
      • Silva M.C.
      • Cruz A.G.
      Probiotic dairy foods and postprandial glycemia: A mini-review.
      ). However, research results are inconsistent, and a recent meta-analysis of observational studies reported a neutral association between intake of fermented dairy and T2DM (
      • Fernandez M.A.
      • Marette A.
      Novel perspectives on fermented milks and cardiometabolic health with a focus on type 2 diabetes.
      ). A large amount of research has targeted mainly yogurt intake and its effect on T2DM. A meta-analysis of 9 randomized controlled trials (RCT) that compared probiotic-enriched yogurt and conventional yogurt concluded that neither product improved the levels of glycated hemoglobin (HbA1c), fasting blood sugar (FBS) and fasting insulin or insulin resistance in individuals with diabetes or in those with higher BW (
      • Barengolts E.
      • Smith E.D.
      • Reutrakul S.
      • Tonucci L.
      • Anothaisintawee T.
      The effect of probiotic yogurt on glycemic control in type 2 diabetes or obesity: A meta-analysis of nine randomized controlled trials.
      ). The meta-analysis was limited by the lack of examination of the effect of fermented dairy consumption on diabetes prevention. Moreover, this meta-analysis only explored the effect of yogurt on diabetes risk without evaluating the effect of other fermented dairy products such as kefir and cheese. Conversely, prospective cohort studies exploring the association between yogurt and T2DM have consistently found a protective effect of yogurt consumption against the development of prediabetes and T2DM (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ;
      • Gijsbers L.
      • Ding E.L.
      • Malik V.S.
      • de Goede J.
      • Geleijnse J.M.
      • Soedamah-Muthu S.S.
      Consumption of dairy foods and diabetes incidence: A dose-response meta-analysis of observational studies.
      ;
      • Panahi S.
      • Tremblay A.
      The potential role of yogurt in weight management and prevention of type 2 diabetes.
      ;
      • Salas-Salvadó J.
      • Guasch-Ferré M.
      • Díaz-López A.
      • Babio N.
      Yogurt and diabetes: Overview of recent observational studies.
      ;
      • Fernandez M.A.
      • Marette A.
      Novel perspectives on fermented milks and cardiometabolic health with a focus on type 2 diabetes.
      ). The present review aims to address current research gaps by evaluating the findings of prospective cohort studies, human experimental trials, and animal studies that focused on the association between intake of fermented dairy and development or management of T2DM. The objective of this review was to gain insightful and comprehensive knowledge of the potential long- and short-term effects of fermented dairy, dairy subgroups and specific fermented dairy products on the prevention and treatment of T2DM.

      PROSPECTIVE COHORT STUDIES

      This review covers cross-sectional data from prospective cohort studies aimed at identifying associations between dairy products and T2DM (Table 1). Dietary data were assessed through different variations of validated food frequency questionnaires (FFQ), except in one study in which a 7-d food diary was used to identify the types and amounts of foods consumed (
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ). Furthermore, in 2 studies, FFQ were combined with other dietary assessment methods to increase reporting accuracy.
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      employed a Mediterranean diet adherence questionnaire combined with the traditional FFQ to assess certain nutritional habits that correspond with Mediterranean diet recommendations, and
      • Sonestedt E.
      • Wirfält E.
      • Wallström P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      incorporated a standard menu book of dietary interviews in conjunction with FFQ to collect dietary data. In all studies, the authors grouped dairy foods by product type, degree of fermentation or fat content to draw associations between dairy products or subgroups and the risk of T2DM. All the studies included in this review were controlled for important confounding factors such as age, sex, body mass index, physical activity level, smoking status, socioeconomic factors, and dietary variables in the statistical analyses. Although the cohorts were followed for 3 to 30 years, dietary data were obtained only once, at baseline, except in 3 studies, in which up to 4 dietary assessments were conducted over time and included in the analysis (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ;
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ;
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ).
      Table 1Summary of cross-sectional data from prospective cohort studies
      ReferenceN
      N = number of participants.
      CharacteristicProductChange in biomarkers and disease prevalence or incidence
      RPD = risk of prediabetes; OR = odd ratios; S/NS = significant (S) or not (NS); RCVD = risk of cardiovascular disease; RD = risk of diabetes. Upward-pointing arrows = increased; downward-pointing arrows = decreased.
      SexAge (yr)CountryDIP
      DIP = diabetes, impaired glucose tolerance, or prediabetes at baseline.
      (%)
      Duration (yr)PrediabeticDiabeticCardiovascular diseases
      Male (%)Female (%)MeanRangeRPDORS/NSRDORS/NSRCVDORS/NS
      Brouwer-Brolsma et al. (2018)112,08641594525+Netherlands08Skim milk0.95SNullN/A
      N/A = not applicable.
      N/A
      Fermented dairy0.94SNullN/AN/A
      Full-fat dairy1.03S1.18S
      Nonfermented dairy1.01S1.09S
      Buttermilk0.97SNullN/AN/A
      Custard1.13SNullN/AN/A
      Full-fat yogurt1.07SNullN/AN/A
      Low-fat cheese0.97SNullN/AN/A
      Full-fat milk1.11SNullN/AN/A
      MilkNullNullN/A1.08S
      Brouwer-Brolsma et al. (2016)2,97440606555+Netherlands016Fermented, nonfermented, low-fat dairy; high-fat dairy; sugar containingNullNullN/A
      Yogurt0.86NS
      Buziau et al. (2019)8,74801005340–50Australia015Total dairyNullN/AN/ANullN/AN/A
      Fermented dairyNullN/AN/A0.8NS
      Nonfermented dairyNullN/AN/ANullN/AN/A
      Yogurt0.81NS0.84NS
      CheeseNullN/AN/ANullN/AN/A
      Díaz-López et al. (2016)3,8334555N/A35–80Spain04Total dairy0.68S
      Low-fat dairy0.65S
      Yogurt0.6S
      Fermented dairy0.59S
      Cheese1.38NS
      Eussen et al. (2016)2,39154466140–75Netherlands253Total dairy0.76S
      Skim dairyNullN/AN/A
      Fermented dairy0.69S
      Nonfermented dairyNullNullS
      CheeseNullNullN/A
      YogurtNullN/AN/A
      Full-fat dairy2.01S
      Johansson et al. (2019)86,93147535325–70Sweden030Nonfermented milk.1.17S
      No cheese1.33S
      Low-fat fermented milk1.17S
      Low-fat nonfermented milk1.26S
      High-fat fermented milk0.87S
      Butter0.8S
      Mena-Sánchez et al. (2018)6,57251496555–75Spain653Fermented dairy
      Yogurt
      Cheese
      O'Connor et al. (2014)4,127N/AN/AN/A40–79UK011Total dairyNullN/AN/A
      High-fat dairyNullN/AN/A
      MilkNullN/AN/A
      CheeseNullN/AN/A
      High-fat fermented dairyNullN/AN/A
      Low-fat dairy0.81NS
      Low-fat fermented dairy0.76S
      Yogurt0.72S
      Sluijs et al. (2012)24,475N/AN/A52N/AEurope016Total dairyNullN/AN/A
      Milk1.1NS
      Yogurt; fermented milk0.9NS
      Cheese0.88S
      Fermented dairy0.84S
      Soedamah-Muthu et al. (2013)4,52675255635–55UK024Total dairy1.3NS0.9NS
      High-fat dairyNullN/AN/ANullN/AN/A
      Low-fat dairyNullN/AN/A0.9NS
      Total milkNullN/AN/A0.9NS
      Low-fat milkNullN/AN/ANullN/AN/A
      Fermented dairyNullN/AN/ANullN/AN/A
      YogurtNullN/AN/ANullN/AN/A
      CheeseNullN/AN/A0.8NS
      Sonestedt et al. (2011)26,445386258N/ASweden012Fermented milk0.88S
      Nonfermented milkNullN/AN/A
      Cheese0.82S
      ButterNullN/AN/A
      CreamNullN/AN/A
      Low-fat milk0.88NS
      Sonestedt et al. (2011)5,95348524630–60Denmark05Total dairyNullN/AN/A
      Low-fat dairyNullN/AN/A
      Full-fat dairyNullN/AN/A
      Milk and milk productsNullN/AN/A
      CheeseNullN/AN/A
      Fermented dairyNullN/AN/A
      Stuber et al. (2021)35,982N/AN/A4920–70Netherlands015Whole-fat milk; Buttermilk; Skim milk; Skim fermented milk; Whole-fat yogurtNullN/AN/A
      1 N = number of participants.
      2 DIP = diabetes, impaired glucose tolerance, or prediabetes at baseline.
      3 RPD = risk of prediabetes; OR = odd ratios; S/NS = significant (S) or not (NS); RCVD = risk of cardiovascular disease; RD = risk of diabetes. Upward-pointing arrows = increased; downward-pointing arrows = decreased.
      4 N/A = not applicable.
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      analyzed data from a sample of 112,086 healthy, nondiabetic individuals from the Lifeline Cohort study (Table 1). The participants varied in age, with a minimum age of 25 yr and a mean age of 45 yr. The data analysis revealed a small but significantly lower risk of prediabetes with higher intake of skim milk, fermented dairy, buttermilk and low-fat cheese. Intake of full-fat and nonfermented dairy products modestly, yet significantly, increased the risk of developing prediabetes and T2DM. Noteworthy, although the sample size in this study was very large, data cannot be extrapolated to individuals aged over 45 yr who tend to be at high risk of developing T2DM. In contrast, in their smaller study of 2,974 older, nondiabetic individuals,
      • Brouwer-Brolsma E.M.
      • van Woudenbergh G.J.
      • Oude Elferink S.J.
      • Singh-Povel C.M.
      • Hofman A.
      • Dehghan A.
      • Franco O.H.
      • Feskens E.J.M.
      Intake of different types of dairy and its prospective association with risk of type 2 diabetes: The Rotterdam Study.
      did not identify any association between dairy products or subgroups and the risk of T2DM, except for yogurt, which offered protection against diabetes, although this association was not significant (Table 1). Similar results were reported in the Australian Longitudinal Study on Women's Health, with yogurt being the only product that showed an inverse correlation with T2DM; however, this association was not statistically significant when the results were adjusted for energy intake and other dietary variables (
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ). In both studies, individuals did not have diabetes at baseline, and therefore recommending yogurt consumption for blood sugar control in individuals with pre-existing diabetes is questionable. On the other hand, in populations at high risk of CVD, dairy products, including fermented dairy, may offer much greater and more significant protection against T2DM, as shown by
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ; Table 1). In 3,833 participants from the PERIMED study, the authors found that higher intake of total dairy, fermented dairy, low-fat dairy, and yogurt were each significantly associated with a decreased risk of T2DM by a large margin of 32 to 41%. In the same study, higher cheese intake was shown to increase the risk of T2DM; however, this association was not significant. Other researchers also took interest in this particular cohort to evaluate the effects of fermented dairy products on biomarkers of CVD and glycemic control (
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      ).
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      assessed the intakes of 6,572 participants in the PERIMED study and found that higher intake of fermented products was associated with slight improvements in fasting blood glucose levels. This study was limited by the lack of evaluation of long-term effects of fermented dairy products consumption on the development and long-term control of T2DM. In another cross-sectional analysis including data from 86,931 Swedish nondiabetic participants, a specific fermented product, cheese, was found to confer protection against T2DM; conversely, not consuming cheese was associated with a 33% increase in the disease risk (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ; Table 1). In the same study, higher intake of low-fat fermented and nonfermented milk was significantly associated with an increased risk of T2DM, whereas intake of high-fat fermented milk and butter were each inversely associated with a risk of T2DM. Conversely, intake of low-fat dairy was linked to a decreased risk of diabetes in 4,127 participants living in the UK; this association was significant only for fermented products (
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ). It is worth noting that although both studies show opposing results (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ;
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ), they are also evaluating risk in different populations where overall dietary and exercise habits are different therefore such results should be interpreted with caution when extrapolated to different populations. Other researchers found that higher intake of fermented dairy could decrease the risk of prediabetes regardless of fat content in healthy and diabetic individuals, as revealed by a cross-sectional analysis of data from participants in a Dutch observational study (n = 2,391) in which 25% of participants had impaired glucose tolerance or newly diagnosed T2DM at baseline (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ).
      Similarly, fermented products can protect against T2DM, as shown in a large European observational cohort study including 24,475 nondiabetic individuals (
      • Sluijs I.
      • Forouhi N.G.
      • Beulens J.W.
      • van der Schouw Y.T.
      • Agnoli C.
      • Arriola L.
      • Balkau B.
      • Barricarte A.
      • Boeing H.
      • Bueno-de-Mesquita H.B.
      • Clavel-Chapelon F.
      • Crowe F.L.
      • de Lauzon-Guillain B.
      • Drogan D.
      • Franks P.W.
      • Gavrila D.
      • Gonzalez C.
      • Halkjaer J.
      • Kaaks R.
      • Moskal A.
      • Nilsson P.
      • Overvad K.
      • Palli D.
      • Panico S.
      • Quirós J.R.
      • Ricceri F.
      • Rinaldi S.
      • Rolandsson O.
      • Sacerdote C.
      • Sánchez M.J.
      • Slimani N.
      • Spijkerman A.M.
      • Teucher B.
      • Tjonneland A.
      • Tormo M.J.
      • Tumino R.
      • van der A D.L.
      • Sharp S.J.
      • Langenberg C.
      • Feskens E.J.M.
      • Riboli E.
      • Wareham N.J.
      The amount and type of dairy product intake and incident type 2 diabetes: Results from the EPIC-InterAct Study.
      ). However, higher intake of fermented products may have a neutral effect on the risk of T2DM (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ;
      • Stuber J.M.
      • Vissers L.E.T.
      • Verschuren W.M.M.
      • Boer J.M.A.
      • van der Schouw Y.T.
      • Sluijs I.
      Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.
      ) or offer some protection against disease complications via decreased insulin resistance and improved glycemic control indicators, including glucose tolerance, FBS, HbA1c and 2-h postprandial glucose (
      • Sonestedt E.
      • Wirfält E.
      • Wallström P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      ;
      • Struijk E.A.
      • Heraclides A.
      • Witte D.R.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Toft U.
      • Lau C.J.
      Dairy product intake in relation to glucose regulation indices and risk of type 2 diabetes.
      ;
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ; Table 1).
      In addition to evaluating diabetes risk, some of the studies in this review found associations between intake of dairy products and cardiovascular risk. A significant association with CVD was reported in only 2 studies.
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      identified a 23% increased risk in myocardial infarction with higher intake of nonfermented milk, whereas
      • Sonestedt E.
      • Wirfält E.
      • Wallström P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      found that higher intake of fermented dairy was inversely linked to CVD and higher intake of cheese was associated with a lower risk of CVD in women only (Table 1). In the latter study, nonfermented dairy had no effect on the CVD risk but was associated with lower serum low-density lipoprotein cholesterol levels. Fermented dairy and yogurt were correlated with a lower risk of CVD in the Australian Longitudinal Study on Women's Health, but this association was not significant when the results were adjusted for energy intake and other dietary variables (
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ). Finally, fermented dairy and yogurt may improve overall health outcomes because they were found to be significantly related to a decreased risk of all cause-mortality (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ; Table 1).

      Prospective Cohort Studies by Dairy Subgroups and Products

      Similar to the categorical descriptions used in the cross-sectional analysis, we grouped dairy foods based on the degree of fermentation (fermented or nonfermented), fat content (skim to low fat or high to full fat) and product type (cheese, yogurt, buttermilk, butter, cream, or custard). This section provides an overview of the potential effect of these subgroups and products on disease risk.

      Total Dairy Intake

      The associations between total dairy intake and T2DM were evaluated in 5 studies, only 2 identified significant correlations (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ;
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ). Participants from the PERIMED cohort with higher dairy intake showed a significant reduction (32%) in the risk of developing T2DM (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ). A similar correlation was observed in a group of older Dutch participants (mean age = 61 yr), who had a 24% reduced risk of developing prediabetes associated with a higher intake of dairy products (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ). Disease biomarkers such as glucose tolerance were also improved in these participants; however, this relationship was not significant. Although most of these studies reported a null association between T2DM and total dairy intake,
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      identified an increased risk in a group of 4,526 London office staff. However, the authors found that a higher intake of dairy products was correlated with a reduction in the CVD risk. Notably, neither of these associations was significant, and they should therefore be interpreted with caution.

      Total Nonfermented Dairy

      Three studies evaluated the potential effect of total nonfermented dairy, regardless of fat content, on the risk of prediabetes and diabetes. One study found no association between total nonfermented dairy and disease risk (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ), and another found a very small increase (1%) in the risk of prediabetes (
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ). The latter study also reported a 9% increase in the risk of T2DM, and another longer-term study following a group of Swedish participants over 33 years found that higher intake of nonfermented dairy increased the risk of T2DM by a significant margin of 17% (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ).

      Nonfermented Dairy Products with Varied Fat Content

      Based on the studies included in this review, fat content appeared to significantly affect the risk of T2DM. Specifically, high-fat, nonfermented dairy products were either not associated with T2DM or significantly increased its risk. Older adults may be at the highest risk, with a 2-fold increase in the incidence of prediabetes associated with a higher intake of full-fat dairy (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ). Younger individuals may also be vulnerable; one study showed that they could have up to an 18% increased risk of prediabetes or T2DM with higher intake of full-fat nonfermented products (
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ). The latter study identified a decreased risk of prediabetes with higher intake of skim milk. This is consistent with the results of other studies included in this review, most of which revealed either a null or an inverse association between low-fat nonfermented dairy products and risk of diabetes. For instance, these products offered significant protection against T2DM in a group of participants from the PERIMED study (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ). Moreover, although
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      found no association between low-fat dairy products and prediabetes, they identified a 27% improvement in glucose tolerance with higher intake of such products, which was significant. Only one study found a positive association between T2DM and higher intake of low-fat products (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ). Although the study participants had similar characteristics as those in the other cohorts with regard to mean age, ethnic background, and prevalence of diabetes at baseline, they were followed for a particularly long period of time (30 yr). They also completed 3 dietary assessments throughout the study instead of only one assessment at baseline as in most studies in this review.
      In another study, 16 prospective cohort studies from 12 countries (63,682 participants) found significant inverse associations between higher concentrations of fatty acid intake biomarkers of milk (15:0, 17:0, and t16:1n7) and incidence of T2D (
      • Imamura F.
      • Fretts A.
      • Marklund M.
      • Ardisson Korat A.V.
      • Yang W.S.
      • Lankinen M.
      • Qureshi W.
      • Helmer C.
      • Chen T.A.
      • Wong K.
      • Bassett J.K.
      • Murphy R.
      • Tintle N.
      • Yu C.I.
      • Brouwer I.A.
      • Chien K.L.
      • Frazier-Wood A.C.
      • Del Gobbo L.C.
      • Djoussé L.
      • Geleijnse J.M.
      • Giles G.G.
      • de Goede J.
      • Gudnason V.
      • Harris W.S.
      • Hodge A.
      • Hu F.
      • Koulman A.
      • Laakso M.
      • Lind L.
      • Lin H.J.
      • McKnight B.
      • Rajaobelina K.
      • Risérus U.
      • Robinson J.G.
      • Samieri C.
      • Siscovick D.S.
      • Soedamah-Muthu S.S.
      • Sotoodehnia N.
      • Sun Q.
      • Tsai M.Y.
      • Uusitupa M.
      • Wagenknecht L.E.
      • Wareham N.J.
      • Wu J.H.
      • Micha R.
      • Forouhi N.G.
      • Lemaitre R.N.
      • Mozaffarian D.
      Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.
      ). In this study, the intake of 15:0 fatty acids was associated with 26% lower risk of T2D with stronger association in women than in men. Although the use of these biomarkers is advantageous in avoiding the limitations of self-reported dietary questionnaires due to misclassification or bias in reporting, it has the disadvantage of not being able to distinguish between the different food sources of fat, such as cheese, yogurt, milk, or other foods.

      Fermented Dairy Products

      This review found that fermented dairy products were most often correlated with either a null or an inverse relationship with T2DM and its associated risks. This observation was consistent even when fat content was considered. Total fermented dairy intake was not associated with prediabetes or T2DM in 3 studies (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ;
      • Brouwer-Brolsma E.M.
      • van Woudenbergh G.J.
      • Oude Elferink S.J.
      • Singh-Povel C.M.
      • Hofman A.
      • Dehghan A.
      • Franco O.H.
      • Feskens E.J.M.
      Intake of different types of dairy and its prospective association with risk of type 2 diabetes: The Rotterdam Study.
      ;
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ). Conversely, some studies found that higher intake of fermented dairy can significantly decrease the risk of prediabetes (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ;
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ), T2DM (
      • Sluijs I.
      • Forouhi N.G.
      • Beulens J.W.
      • van der Schouw Y.T.
      • Agnoli C.
      • Arriola L.
      • Balkau B.
      • Barricarte A.
      • Boeing H.
      • Bueno-de-Mesquita H.B.
      • Clavel-Chapelon F.
      • Crowe F.L.
      • de Lauzon-Guillain B.
      • Drogan D.
      • Franks P.W.
      • Gavrila D.
      • Gonzalez C.
      • Halkjaer J.
      • Kaaks R.
      • Moskal A.
      • Nilsson P.
      • Overvad K.
      • Palli D.
      • Panico S.
      • Quirós J.R.
      • Ricceri F.
      • Rinaldi S.
      • Rolandsson O.
      • Sacerdote C.
      • Sánchez M.J.
      • Slimani N.
      • Spijkerman A.M.
      • Teucher B.
      • Tjonneland A.
      • Tormo M.J.
      • Tumino R.
      • van der A D.L.
      • Sharp S.J.
      • Langenberg C.
      • Feskens E.J.M.
      • Riboli E.
      • Wareham N.J.
      The amount and type of dairy product intake and incident type 2 diabetes: Results from the EPIC-InterAct Study.
      ;
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ), and glucose tolerance (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ). More specific analyses of low-fat fermented dairy identified null (
      • Stuber J.M.
      • Vissers L.E.T.
      • Verschuren W.M.M.
      • Boer J.M.A.
      • van der Schouw Y.T.
      • Sluijs I.
      Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.
      ), positive (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ), and negative (
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ) correlations with T2DM. In contrast to nonfermented dairy, intake of high-fat fermented dairy products did not increase the disease risk. For example,
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      identified a 23% reduction in the risk of T2DM with higher intake of high-fat fermented dairy, whereas
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      found no correlation between higher fat dairy intake and the risk of diabetes. In addition to potentially offering some protection against diabetes, fermented dairy products were found to decrease the risk of CVD and its associated complications (
      • Sonestedt E.
      • Wirfält E.
      • Wallström P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      ;
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      ;
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ).

      Cheese

      Cheese is a generic term for fermented milk products that are produced using enzyme coagulation or acid coagulation methods and subjected to a ripening period. Cheeses are the most varied type of fermented dairy products. Numerous proteolytic, lipolytic and glycolytic activities occur during cheese ripening, eventually producing novel bioactive compounds (
      • Ayyash M.M.
      • Abdalla A.K.
      • AlKalbani N.S.
      • Baig M.A.
      • Turner M.S.
      • Liu S.Q.
      • Shah N.P.
      Invited review: Characterization of new probiotics from dairy and nondairy products—Insights into acid tolerance, bile metabolism and tolerance, and adhesion capability.
      ). Cheese typically has a neutral effect on the risk of developing prediabetes or T2DM (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ;
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ;
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ;
      • Buziau A.M.
      • Soedamah-Muthu S.S.
      • Geleijnse J.M.
      • Mishra G.D.
      Total fermented dairy food intake is inversely associated with cardiovascular disease risk in women.
      ). However, although
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      found no association between cheese intake and T2DM, they reported that the older adults in their cohort displayed improved glucose tolerance with higher cheese intake. Protection against T2DM was also shown in a large European study including 244,475 individuals from the EPIC-InterAct cohort (
      • Sluijs I.
      • Forouhi N.G.
      • Beulens J.W.
      • van der Schouw Y.T.
      • Agnoli C.
      • Arriola L.
      • Balkau B.
      • Barricarte A.
      • Boeing H.
      • Bueno-de-Mesquita H.B.
      • Clavel-Chapelon F.
      • Crowe F.L.
      • de Lauzon-Guillain B.
      • Drogan D.
      • Franks P.W.
      • Gavrila D.
      • Gonzalez C.
      • Halkjaer J.
      • Kaaks R.
      • Moskal A.
      • Nilsson P.
      • Overvad K.
      • Palli D.
      • Panico S.
      • Quirós J.R.
      • Ricceri F.
      • Rinaldi S.
      • Rolandsson O.
      • Sacerdote C.
      • Sánchez M.J.
      • Slimani N.
      • Spijkerman A.M.
      • Teucher B.
      • Tjonneland A.
      • Tormo M.J.
      • Tumino R.
      • van der A D.L.
      • Sharp S.J.
      • Langenberg C.
      • Feskens E.J.M.
      • Riboli E.
      • Wareham N.J.
      The amount and type of dairy product intake and incident type 2 diabetes: Results from the EPIC-InterAct Study.
      ). Similarly, in a 30-yr prospective cohort study, not consuming cheese was associated with a 33% increased risk of developing T2DM, and this association was significant (
      • Johansson I.
      • Esberg A.
      • Nilsson L.M.
      • Jansson J.H.
      • Wennberg P.
      • Winkvist A.
      Dairy product intake and cardiometabolic diseases in northern Sweden: A 33-year prospective cohort study.
      ). Finally, some studies reported that cheese intake may protect against CVD in older individuals (
      • Mena-Sánchez G.
      • Babio N.
      • Martínez-González M.
      • Corella D.
      • Schröder H.
      • Vioque J.
      • Romaguera D.
      • Martínez J.A.
      • Lopez-Miranda J.
      • Estruch R.
      • Wärnberg J.
      • Bueno-Cavanillas A.
      • Serra-Majem L.
      • Tur J.A.
      • Arós F.
      • Tinahones F.J.
      • Sánchez V.M.
      • Lapetra J.
      • Pintó X.
      • Vidal J.
      • Vázquez C.
      • Ordovás J.M.
      • Delgado-Rodriguez M.
      • Matía-Martín P.
      • Basora J.
      • Buil-Cosiales P.
      • Fernandez-Carrion R.
      • Fitó M.
      • Salas-Salvadó J.
      Fermented dairy products, diet quality, and cardio-metabolic profile of a Mediterranean cohort at high cardiovascular risk.
      ) and older women (
      • Sonestedt E.
      • Wirfält E.
      • Wallström P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      ).

      Yogurt

      Yogurt is an acid-coagulated dairy product produced by adding lactic acid bacteria to ferment lactose and produce mainly lactic acid. Historically, yogurt has been a well-known fermented product. In this review, yogurt was found to protect against the risk of disease, with only one of 8 studies showing an increased risk of diabetes and higher intake of full-fat yogurt (
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ). Yogurt was associated with a significant decrease in the risk of developing T2DM in a population of Spanish individuals at high risk of CVD (
      • Díaz-López A.
      • Bulló M.
      • Martínez-González M.A.
      • Corella D.
      • Estruch R.
      • Fitó M.
      • Gómez-Gracia E.
      • Fiol M.
      • García de la Corte F.J.
      • Ros E.
      • Babio N.
      • Serra-Majem L.
      • Pintó X.
      • Muñoz M.
      • Francés F.
      • Buil-Cosiales P.
      • Salas-Salvadó J.
      Dairy product consumption and risk of type 2 diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk.
      ), in older adults (
      • Eussen S.J.P.M.
      • van Dongen M.C.J.M.
      • Wijckmans N.
      • den Biggelaar L.
      • Oude Elferink S.J.W.H.
      • Singh-Povel C.M.
      • Schram M.T.
      • Sep S.J.S.
      • van der Kallen C.J.
      • Koster A.
      • Schaper N.
      • Henry R.M.A.
      • Stehouwer C.D.A.
      • Dagnelie P.C.
      Consumption of dairy foods in relation to impaired glucose metabolism and type 2 diabetes mellitus: The Maastricht Study.
      ) and in a group of British individuals (
      • O'Connor L.M.
      • Lentjes M.A.H.
      • Luben R.N.
      • Khaw K.T.
      • Wareham N.J.
      • Forouhi N.G.
      Dietary dairy product intake and incident type 2 diabetes: A prospective study using dietary data from a 7-day food diary.
      ). Conversely, some studies identified no association between yogurt intake and T2DM (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ;
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ;
      • Stuber J.M.
      • Vissers L.E.T.
      • Verschuren W.M.M.
      • Boer J.M.A.
      • van der Schouw Y.T.
      • Sluijs I.
      Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.
      ) or CVD (
      • Soedamah-Muthu S.S.
      • Masset G.
      • Verberne L.
      • Geleijnse J.M.
      • Brunner E.J.
      Consumption of dairy products and associations with incident diabetes, CHD and mortality in the Whitehall II Study.
      ).

      Buttermilk

      Buttermilk is a fermented dairy product. Traditionally, it is the liquid left over after churning butter from cultured cream. Because modern butter is made from sweet cream rather than cultured cream, currently most buttermilk is cultured with properties similar to the traditional buttermilk. Because buttermilk is not a very popular product in Western diets, it is not surprising that buttermilk intake was only assessed in 2 of the studies included in this review (
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      ;
      • Stuber J.M.
      • Vissers L.E.T.
      • Verschuren W.M.M.
      • Boer J.M.A.
      • van der Schouw Y.T.
      • Sluijs I.
      Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.
      ). A slight decrease in the risk of prediabetes and no correlation with the risk of T2DM was identified in a very large Dutch study by
      • Brouwer-Brolsma E.M.
      • Sluik D.
      • Singh-Povel C.M.
      • Feskens E.J.M.
      Dairy product consumption is associated with pre-diabetes and newly diagnosed type 2 diabetes in the Lifelines Cohort Study.
      . Similarly, a null association with disease risk was identified by
      • Stuber J.M.
      • Vissers L.E.T.
      • Verschuren W.M.M.
      • Boer J.M.A.
      • van der Schouw Y.T.
      • Sluijs I.
      Substitution among milk and yogurt products and the risk of incident type 2 diabetes in the EPIC-NL cohort.
      .

      Human Experimental Studies

      The RCT involving human subjects offer the best-quality evidence. Unfortunately, few human studies have evaluated the effects of fermented dairy products on T2DM and cardiometabolic complications. Table 2 provides an overview of 4 human experimental trials that explored different fermented dairy products and their effect on some biomarkers of glycemic control, including insulin resistance and FBS, HbA1c, and homocysteine levels. The RCT shown in Table 2 followed individuals who had been diagnosed with diabetes for less than 20 yr over periods of 8 to 12 wk. In one study, all participants were male (El-Bashiti and Zabut, 2019), whereas the 3 other studies included both males and females. All 4 studies reported that fermented dairy may offer protection against T2DM and related complications (Table 2). By evaluating the effect of metformin only and metformin and kefir in combination,
      • El-Bashiti T.A.
      • Zabut B.M.
      • Abu Safia F.F.
      Effect of probiotic fermented milk (kefir) on some blood biochemical parameters among newly diagnosed type 2 diabetic adult males in Gaza Governorate.
      found that a daily intake of 250 mL of kefir resulted in significantly lower FBS and HbA1c levels compared with those in the control group, who only received metformin (Table 2). This difference was both statistically and clinically significant, and by the end of the study, the group that received the fermented product displayed a 54 mg/dL reduction in FBS levels and a 2% reduction in HbA1c levels.
      • Hove K.D.
      • Brøns C.
      • Færch K.
      • Lund S.S.
      • Rossing P.
      • Vaag A.
      Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: A randomised double-blind placebo-controlled study.
      also found that a daily intake of 300 mL of fermented milk (Lactobacillus helveticus, Cardi04 yogurt) significantly decreased FBS levels by 18 mg/dL compared with that in the control group, who received the same amount of nonfermented milk (Table 2). Additionally, the intervention group had a lower mean heart rate at the end of the study. Conversely,
      • Ostadrahimi A.
      • Taghizadeh A.
      • Mobasseri M.
      • Farrin N.
      • Payahoo L.
      • Beyramalipoor Gheshlaghi Z.
      • Vahedjabbari M.
      Effect of probiotic fermented milk (kefir) on glycemic control and lipid profile in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial.
      reported that a daily intake of 600 mL of conventional fermented milk did not result in improvements in glycemic control indicators. Meanwhile, the same product enriched with probiotics resulted in a 43 mg/dL reduction in the FBS level, which was significant, and a 1.2% reduction in HbA1c level at the end of the 8-wk trial (
      • Ostadrahimi A.
      • Taghizadeh A.
      • Mobasseri M.
      • Farrin N.
      • Payahoo L.
      • Beyramalipoor Gheshlaghi Z.
      • Vahedjabbari M.
      Effect of probiotic fermented milk (kefir) on glycemic control and lipid profile in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial.
      ). Probiotic-enriched fermented milk was also superior to standard fermented milk in its potential to protect against diabetes owing to the significant reduction in insulin resistance (HOMA-IR) observed with the former product (
      • Alihosseini N.
      • Moahboob S.A.
      • Farrin N.
      • Mobasseri M.
      • Taghizadeh A.
      • Ostadrahimi A.R.
      Effect of probiotic fermented milk (kefir) on serum level of insulin and homocysteine in type 2 diabetes patients.
      ). Nevertheless, both products may protect against diabetes-related complications and CVD, as evidenced by the significant decrease in homocysteine levels with daily intake of 600 mL of either product over a period of 8 wk (
      • Alihosseini N.
      • Moahboob S.A.
      • Farrin N.
      • Mobasseri M.
      • Taghizadeh A.
      • Ostadrahimi A.R.
      Effect of probiotic fermented milk (kefir) on serum level of insulin and homocysteine in type 2 diabetes patients.
      ).
      Table 2Potential effects of fermented dairy products on type 2 diabetes via human intervention studies
      DIP = diabetes, impaired glucose tolerance, or prediabetes at baseline; A-IR = average insulin resistance; HL = homocysteine level; S/NS = significant (S) or not (NS); FBS = fasting blood sugar; A-FBS = average fasting blood sugar; HbA1c = glycated hemoglobin. Upward-pointing arrows = increased; downward-pointing arrows = decreased. N/A = not applicable.
      ReferenceNMale (%)Female (%)Age (yr)CountryDIP (%)Duration of illness (yr)Study duration (wk)ProductMicroorganismA-IRS/NSHLS/NSFBS (mg/dL)A-FBS (mg/dL)S/NSHbA1c (%)Average HbA1c (%)S/NS
      El-Bashiti and Zabut (2019)42100037–65Palestine100New10Kefir + metforminN/A↓5492S↓2%0.072S
      Hove et al. (2015)41N/AN/A40–70Denmark1001+12Fermented yogurtLactobacillus helveticus↓18142S
      Ostadrahimi et al. (2015)68495135–65Iran100<208Fermented milk (kefir) + probioticsStreptococcus thermophilus, Lacticaseibacillus casei, Lactobacillus acidophilus, Bifidobacterium lactis↓43139S↓1.26.4S
      Alihosseini et al. (2017)60574335–65Iran100<208Fermented milk (kefir) + probioticsS. thermophilus, Lcb. casei, Lb. acidophilus, B. lactisSS
      Fermented milkS. thermophilus and Lactobacillus bulgaricusNSS
      1 DIP = diabetes, impaired glucose tolerance, or prediabetes at baseline; A-IR = average insulin resistance; HL = homocysteine level; S/NS = significant (S) or not (NS); FBS = fasting blood sugar; A-FBS = average fasting blood sugar; HbA1c = glycated hemoglobin. Upward-pointing arrows = increased; downward-pointing arrows = decreased. N/A = not applicable.

      ANIMAL TRIALS

      This review presents an overview of animal studies that explored the potential effect of fermented dairy products on diabetes control, as shown in Table 3. Healthy and diabetic rats or mice were assigned to either a control group that received only a standard diet or an intervention group that, in addition to the standard diet, received a specific amount of the fermented dairy product under study. The RCT examined the effect of one to 3 fermented dairy products to evaluate the influence of particular characteristics of the products on diabetes control. Specifically, properties such as dose, degree of fermentation (low, moderate, or high), type of microorganisms, dairy source and product fortification (e.g., fermented milk enriched with n-3 or CLA) were of particular interest. As shown in Table 3, fermented dairy resulted in improvements in markers of diabetes control, even when they were provided at lower doses (
      • Nurliyani
      • Harmayani E.
      • Sunarti
      Antidiabetic potential of kefir combination from goat milk and soy milk in rats induced with streptozotocin-nicotinamide.
      ;
      • Kusmiati M.
      • Nurpalah R.
      • Mardiana U.
      • Nugraha R.W.
      The effectiveness of “x” kefir brand towards glucose level on post prandial pre-diabetes male mice (Mus musculus) Swiss Webster strains orally. Article 012135 in Proc. J. Phys. Conf. Ser.
      ).
      • Nurliyani
      • Harmayani E.
      • Sunarti
      Antidiabetic potential of kefir combination from goat milk and soy milk in rats induced with streptozotocin-nicotinamide.
      evaluated the effect of 3 doses of kefir prepared from goat milk and black rice extract and determined that all doses improved pancreatic B-cell regeneration in rats. This restoration of cellular structure was clinically meaningful and comparable to improvements observed with the use of the antidiabetic agent glibenclamide.
      • Kusmiati M.
      • Nurpalah R.
      • Mardiana U.
      • Nugraha R.W.
      The effectiveness of “x” kefir brand towards glucose level on post prandial pre-diabetes male mice (Mus musculus) Swiss Webster strains orally. Article 012135 in Proc. J. Phys. Conf. Ser.
      also showed that consumption of kefir by diabetic rats improved their HbA1c levels; this was true for all 3 doses evaluated in this study (Table 3). Interestingly, the lowest kefir dose in the same study resulted in the greatest improvement in 2-h postprandial glucose levels. On comparing the effects of different bacterial strains on diabetes control,
      • Widodo W.
      • Harsita P.A.
      • Sukarno A.S.
      • Nurrochmad A.
      Antidiabetic effect of milk fermented using intestinal probiotics.
      found that milk fermented with the Lactobacillus strain AP resulted in a 25 mg/dL reduction in plasma glucose levels, whereas fermentation with the Lactobacillus strain AG did not improve glucose levels in diabetic rats (Table 3). However, both products improved lipid profile markers. Interestingly, although this product reduced blood glucose levels in both diabetic and nondiabetic rats, the reduction was more pronounced in diabetic rats. The probiotic content of a fermented product may significantly affect its potential to improve biomarkers of glycemic control. For instance,
      • Manaer T.
      • Yu L.
      • Zhang Y.
      • Xiao X.J.
      • Nabi X.H.
      Anti-diabetic effects of shubat in type 2 diabetic rats induced by combination of high-glucose-fat diet and low-dose streptozotocin.
      found that the intake of shubat (fermented camel milk) with moderate or high probiotic content, but not low probiotic content resulted in a modest yet significant improvement in FBS levels and a considerable reduction in HbA1c levels (Table 3). Additionally, shubat with moderate or high probiotic content helped restore pancreatic islet cell structures in ways similar to those by antidiabetic medication; conversely, shubat with low probiotic content did not have the same effect.
      Table 3Potential effects of fermented dairy products on diabetes control using animal models
      ReferenceAnimalNDurationProductMicroorganismChange in biomarkers
      FBS = fasting blood sugar level; FBSA = average fasting blood sugar level; S/NS = significant (S) or not (NS); BG = 2-h postprandial blood glucose; BGA = 2-h postprandial glucose average; PG = plasma glucose; PGA = average plasma glucose; HbA1c = glycated hemoglobin; RPH = restoration in pancreatic cell histology islets or B cells; TG = triglycerides. Upward-pointing arrows = increased; downward-pointing arrows = decreased.
      FBS (mg/dL)FBSA (mg/dL)S/NSBG (mg/dL)BGA (mg/dL)S/NSPG (mg/dL)PGAHbA1c (%)S/NSRPHTGS/NS
      Kusmiati et al. (2019)Mice2514 dLow-dose kefirN/A
      N/A = not applicable.
      ↓1255S↓2478S
      Moderate-dose kefirN/A↓1154S↓660S
      High-dose kefirN/A↓956S↓1874S
      Manaer et al. (2015)Rats634 wkLow-probiotic shubat10 lactic acid bacteria and 4 yeasts↑3.825.9NS↓8NSNo
      Moderate-probiotic shubat↓1.620.6S↓10NSYes
      High-probiotic shubat↓3.918.3S↓16SYes
      Nurliyani et al. (2015)Rats304 wkLow-dose kefirLactic acid bacteriaYes
      Moderate-dose kefirYes
      High-dose kefirYes
      Nurliyani et al. (2015)Rats3035 dGoat milk kefirN/A↓92127No↓9S
      Song et al. (2016)Mice406 wkFermented milk 0.2% (low CLA)Streptococcus thermophilus, Lactobacillus delbrueckii bulgaricusNullSNullN/AN/ANullN/A
      Fermented milk 0.6% (high CLA)NullSN/AN/AS
      Widodo et al. (2019)Rats2515 dFermented milkLacticaseibacillus casei AP↓25147
      Fermented milkLcb. casei AGNullN/A
      1 FBS = fasting blood sugar level; FBSA = average fasting blood sugar level; S/NS = significant (S) or not (NS); BG = 2-h postprandial blood glucose; BGA = 2-h postprandial glucose average; PG = plasma glucose; PGA = average plasma glucose; HbA1c = glycated hemoglobin; RPH = restoration in pancreatic cell histology islets or B cells; TG = triglycerides. Upward-pointing arrows = increased; downward-pointing arrows = decreased.
      2 N/A = not applicable.
      Finally, fortification of fermented dairy may increase the products' potential for protection against diabetes-related complications. For example, as shown in Table 32,
      • Song K.
      • Song I.-B.
      • Gu H.-J.
      • Na J.-Y.
      • Kim S.
      • Yang H.-S.
      • Lee S.-C.
      • Huh C.-K.
      • Kwon J.
      Anti-diabetic effect of fermented milk containing conjugated linoleic acid on type II diabetes mellitus.
      found that enrichment with low levels of CLA significantly increased FBS levels over time in mice, whereas mice that were fed fermented milk with higher CLA content experienced a gradual decrease in FBS levels starting the second week of the 6-wk study (Table 3).

      MECHANISMS OF EFFECT

      The potential mechanisms of action of fermented dairy products include decrease in food intake and increase in satiety, improvement of glycemic and insulin resistance, altered gut hormone response, substitution of less healthy foods, change in gut microbiota, and an increase in body fat reduction (
      • Panahi S.
      • Tremblay A.
      The potential role of yogurt in weight management and prevention of type 2 diabetes.
      ). In general, milk and dairy products have been recognized as strong insulin secretagogues, as their intake causes acute hyperinsulinemia (
      • Tucker L.A.
      • Erickson A.
      • LeCheminant J.D.
      • Bailey B.W.
      Dairy consumption and insulin resistance: The role of body fat, physical activity, and energy intake.
      ). The resultant hyperinsulinemia may be advantageous and even protective for controlling blood glucose levels, especially in those with high levels or T2DM (
      • Tucker L.A.
      • Erickson A.
      • LeCheminant J.D.
      • Bailey B.W.
      Dairy consumption and insulin resistance: The role of body fat, physical activity, and energy intake.
      ). Dairy consumption may also decrease insulin resistance by stimulating satiation and reducing calorie intake (
      • Onvani S.
      • Haghighatdoost F.
      • Surkan P.J.
      • Azadbakht L.
      Dairy products, satiety and food intake: A meta-analysis of clinical trials.
      ). According to a meta-analysis of clinical studies, consuming more than 500 mL of dairy products was significantly linked to improved satiety and reduced calorie intake in the subsequent meal (
      • Onvani S.
      • Haghighatdoost F.
      • Surkan P.J.
      • Azadbakht L.
      Dairy products, satiety and food intake: A meta-analysis of clinical trials.
      ). Additionally, in dairy products, lactose has a lower glycemic index (GI; GI = 46) than glucose polymers (GI = 110) formed by hydrolysis of various types of starches (potato starch, rice, or corn), and hence, cause a lower glycemic response (
      • Romero-Velarde E.
      • Delgado-Franco D.
      • García-Gutiérrez M.
      • Gurrola-Díaz C.
      • Larrosa-Haro A.
      • Montijo-Barrios E.
      • Muskiet F.A.J.
      • Vargas-Guerrero B.
      • Geurts J.
      The importance of lactose in the human diet: Outcomes of a Mexican consensus meeting.
      ). Lactose low GI is mostly due to the noninsulinogenic response to galactose. This might provide a metabolic benefit over glucose polymers, which produce a greater rise in plasma glucose and insulin (
      • Romero-Velarde E.
      • Delgado-Franco D.
      • García-Gutiérrez M.
      • Gurrola-Díaz C.
      • Larrosa-Haro A.
      • Montijo-Barrios E.
      • Muskiet F.A.J.
      • Vargas-Guerrero B.
      • Geurts J.
      The importance of lactose in the human diet: Outcomes of a Mexican consensus meeting.
      ). This scenario might be even better in fermented dairy products, where lactose is found in extremely low concentrations due to lactose fermentation into lactic acid.
      Lactate is produced by lactic acid bacteria during the fermentation process, and d-lactate is formed in different proportions of the resultant lactate (
      • Levitt M.D.
      • Levitt D.G.
      Quantitative evaluation of D-lactate pathophysiology: New insights into the mechanisms involved and the many areas in need of further investigation.
      ). In contrast to l-lactate, which is easily and effectively metabolized, d-lactate metabolism is slow and limited to a small amount (
      • Fabian E.
      • Kramer L.
      • Siebert F.
      • Högenauer C.
      • Raggam R.B.
      • Wenzl H.
      • Krejs G.J.
      d-Lactic acidosis—Case report and review of the literature.
      ). Also, a relationship between diabetic acidosis and elevated plasma d-lactate levels was first observed in cats and in human individuals with short bowel syndrome (
      • Lu J.
      • Zello G.A.
      • Randell E.
      • Adeli K.
      • Krahn J.
      • Meng Q.H.
      Closing the anion gap: Contribution of d-lactate to diabetic ketoacidosis.
      ). The ingestion of d-lactate containing foods such as yogurt has been reported as a potential source of d-lactate (
      • Levitt M.D.
      • Levitt D.G.
      Quantitative evaluation of D-lactate pathophysiology: New insights into the mechanisms involved and the many areas in need of further investigation.
      ). However, human cells produce small quantities of d-lactate (
      • Fabian E.
      • Kramer L.
      • Siebert F.
      • Högenauer C.
      • Raggam R.B.
      • Wenzl H.
      • Krejs G.J.
      d-Lactic acidosis—Case report and review of the literature.
      ). Additionally, consumption and malabsorption of high readily fermentable carbohydrate have been recognized as the major cause of d-lactic acid production by intestinal flora, which, under favorable conditions, results in an absorption rate of d-lactate sufficient to increase plasma d-lactate in individuals with short bowel syndrome (
      • Levitt M.D.
      • Levitt D.G.
      Quantitative evaluation of D-lactate pathophysiology: New insights into the mechanisms involved and the many areas in need of further investigation.
      ). Thus, more research into the involvement of d-lactate from fermented dairy products in the complications of diabetic acidosis is needed.
      Some researchers have hypothesized that phenolic compounds, antioxidants, and γ-aminobutyric acid may be essential to the antidiabetic properties of fermented foods (
      • Sivamaruthi B.S.
      • Kesika P.
      • Prasanth M.I.
      • Chaiyasut C.
      A mini review on antidiabetic properties of fermented foods.
      ). As such phenolic compounds, produced through the catabolism of protein by bacteria (
      • O'Connell J.E.
      • Fox P.F.
      Significance and applications of phenolic compounds in the production and quality of milk and dairy products: A review.
      ), seem to have a protective effect against hyperglycemia by preventing carbohydrate metabolism and inhibiting the enzymatic activity of α-glucosidase and α-amylase (
      • Taslimi P.
      • Gulçin İ.
      Antidiabetic potential: In vitro inhibition effects of some natural phenolic compounds on α-glycosidase and α-amylase enzymes.
      ). Additionally, dairy products fermented by lactic acid bacteria can protect against the development of diabetes and its complications through their higher antioxidant contents and reactive oxygen species scavenging activities (
      • Virtanen T.
      • Pihlanto A.
      • Akkanen S.
      • Korhonen H.
      Development of antioxidant activity in milk whey during fermentation with lactic acid bacteria.
      ). Finally, γ-aminobutyric acid, which is produced by lactic acid bacteria in fermented dairy, may improve glycemic control through its effect on pancreatic islet cell hormone homeostasis and B-cell mass, which are manifested through the suppression of glucagon activity, increase in insulin secretion and stimulation of B-cell replication (
      • Wang Q.
      • Ren L.
      • Wan Y.
      • Prud'homme G.J.
      Gabaergic regulation of pancreatic islet cells: Physiology and antidiabetic effects.
      ).

      CONCLUSIONS AND FUTURE RESEARCH

      This review suggests that higher intake of fermented dairy products may have some potential in decreasing the risk of developing T2DM in the long term, as revealed by longitudinal cohort studies. Similar protection was reiterated in the few short-term animal and human experimental controlled trials, which identified improvements in the glycemic control markers in association with intake of specific amounts of fermented dairy products from various sources, including goat and cow milks. The inconsistency in the listed results may be caused by the variability in the studied products in terms of processing and composition as well as the contribution of different confounding factors. Additionally, in general, the dietary data were only obtained at one time point and through recall, thereby limiting the generalizability and accuracy of the reported intakes. Furthermore, the exact amounts consumed are sometimes not reported and are often inconsistent across studies, thereby limiting the ability to formulate recommendations regarding amounts required to offer protection. The results of this review cannot be generalized to populations from different ethnicities and cultural backgrounds because the included longitudinal studies solely comprised European cohorts, except for one study that was conducted in Australia. Therefore, further research must address regional, cultural and ethnic differences and include diverse populations. In general, the longitudinal studies in this review included healthy, nondiabetic adults and, therefore, the protection observed with the long-term intake of fermented dairy may not be the same in other groups such as diabetic individuals, children, and pregnant women. Further research specific to such populations must be performed to identify how fermented dairy products affect these high-risk populations. Although a modest number of controlled trials consistently revealed improvements in glycemic control biomarkers with short-term intake of fermented dairy in diabetic individuals, additional studies are required to confirm such therapeutic benefits. Finally, a combined use of self-reported dietary data and intake biomarkers may improve the accuracy of the investigations of the link between intake and incidence of disease.

      ACKNOWLEDGMENTS

      Authors appreciate the funds provided by United Arab Emirates University (Al Ain, United Arab Emirates). Author contributions included S. F. Awwad, writing original draft, conceptualization; A. Abdalla, writing original draft; A. Kamal-Eldin, F. C. Howarth, and L. Stojanovska, writing review and editing; M. M. Ayyash, conceptualization, writing review and editing. The authors have not stated any conflicts of interest.

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