Yogurt and diabetes: overview of the recent epidemiological studies

Jordi Salas-Salvadó

Human Nutrition Unit Faculty of Medicine and Health Sciences of Reus Department of Biochemistry and Biotechnology

Universitat Rovira i Virgili

Yogurt and diabetes: Overview of the recent epidemiologic studies

Conflict of interest regarding this presentation:

• I am member of the Executive Committee of the Spanish Danone Institute.

• YINI programme has paid for travel and accommodation expenses for this presentation.

YOGURT AND DIABETES

DIABETES: THE GLOBAL BURDEN

More than 387 million people in the word have diabetes. By 2030 is expected this will have risen to 592 million people.

• The prevalence of T2DM is increasing in parallel to the obesity epidemics.

• 80% of the T2DM individuals have between 45-64 y and are living in developing countries.

• T2DM is a potent risk factor for cardiovascular disease, blindness, renal failure, and lower limb amputation, decreasing quality of life.

• T2DM is responsible of the 5 % of the total mortality.

• In the next 10 years is expected that mortality by diabetes will increase by 50%.

DIABETES: THE GLOBAL BURDEN

Ge

net

ic b

ackg

rou

nd

Physical activity

Smoking

Alcohol intake

Diet

Overweight DIABETES

RISK

Life

styl

e ri

sk f

acto

rs

RISK FACTORS FOR DIABETES

Increase risk Decrease risk

Foods Sugar-rich beverages, fruit juices** Meat and processed meat** Hydrogenated oils and margarines * Eggs*

Whole grains** Coffee and tea** Low-fat milk and dairy products** Moderate alcohol consumption* Fruits and vegetables* Pulses* Nuts (in women)*

Nutrients Saturated fatty acids* Trans fatty acids*

Fiber** Unsaturated fatty acids** Antioxidants* Magnesium* Vitamin D*

Dietary patterns High glycemic index diets** Western dietary pattern**

Low glycemic index diets* Mediterranean diet** Prudent diet***

***High level of evidence from several prospective observational studies and randomized trials. **Moderate evidence from several prospective observational studies or meta-analysis. *Reasonable evidence from some prospective observational studies or expert opinions.

Foods, nutrients and dietary patterns in the prevention of type 2 diabetes

Salas-Salvadó et al, NMCD 2011

Epidemiologic studies

OXIDATION

INFLAMMATION

Endothelial dysfunction

Insulin resistance/secretion

DIABETES

Genetic background

Low glycemic index

Fiber

MUFA / PUFA

Magnesium

Antioxidants

(-)

(-)

(-)

(-)

(-)

High glycemic index

SFA

TFA (+)

(+)

(+)

MECHANISMS

Salas-Salvadó et al, NMCD 2011

(-)

DAIRY PRODUCTS

OBESITY

CANCER

RISK

CARDIOVASCULAR DISEASE DIABETES

METABOLIC

SYNDROME

Minerals

Vitamins

Proteins

calcium

magnesium

potassium

phosphor

zinc

Vit. A

Vit. D

Vit. B2, B3, B6, B12

Vit. K2

Probiotic effects

“fermented foods”

OSTOPOROSIS

CH “lactose”

Fat

DAIRY PRODUCTS

Nutritional concerns: Rich in natural trans fatty acids

Rich in saturated fatty acids Rich in salt (ie. cheese)

Rich in added sugar (some yogurts and processed dairy foods) Irrational beliefs that lead to a decrease in consumption:

“Humans are the unique animals that consume dairy products through the life”

DAIRY PRODUCTS

In the last years some guidelines recommend to consume low-fat dairy

products or to limit them

DAIRY PRODUCTS

Astrup A. Yogurt and dairy product consumption to prevent cardiometabolic diseases: epidemiologic and experimental studies. Am J Clin Nutr. 2014. “The consumption of yogurt and other dairy products, in observational studies is associated with a reduced risk of weight gain and obesity as well as of CVD, and these findings are, in part, supported by randomized trials”.

Recent published evidences support the idea that dairy products can be beneficial (or not harmful) for several chronic metabolic conditions and CVD.

“four meta-analysis of prospective studies have shown a decrased risk of

diabetes in those individuals with a higher consumption of dairy

products”.

DAIRY PRODUCTS AND DIABETES

Ericson U. Am J Clin Nutr 2015

Total intake of high-fat dairy products was inversely associated with incident T2D (HR for highest compared with lowest quintiles: 0.77; CI 0.68-0.87; P-trend<0.001). Most robust inverse associations were seen for intakes of high-fat fermented milk (P-trend<0.01) and for cheese in women (P-trend=0.02). Intakes of saturated fatty acids with 4–10 carbons, lauric acid (12:0), and myristic acid (14:0) were associated with decreased risk (P-trend<0.01).

Conclusions: Decreased T2D risk at high intake of high- but not of low-fat dairy products suggests that dairy fat partly could have contributed to previously observed protective associations between dairy intake and T2D.


IS FAT FROM DAIRY UNHEALTHY AND INCREASES

THE RISK OF DIABETES?

Odd chain 15:00

Pentadecanoic

Odd chain 17:00

Heptadecanoic

Trans 16:1n-7 Transpalmitoleic

Even chain 14:00; 16:00

18:00

Swedish participants (Krachler 2008)

Erythrocyte membrane (-) (-) (+) palmitoleic

CHS (Mozzafarian 2010)

Circulating (-)

Insulin resistance

EPIC-Norfolk (Patel 2010)

Erythrocyte membrane, circulating NS (-) NS (+) palmitoleic

EPIC-Postdam (Kröger 2011)

Erythrocyte membrane (-)

(-)

NS myristic

NS palmitoleic

(+) stearic

MESA (Mozzafarian 2013)

Circulating (-)

Insulin resistance

EPIC-Interact (Farouhi 2014)

Circulating (-)

(-)

(+)

IRAS (Santoven 2014)

Circulating

(-) Insulin sensitivity

Β-cell function

NS

CHS: Cardiovascular Health Study; MESA: Multi-Ethnic Study of Atherosclerosis

IRAS: Triethnic Multicenter Insulin Resistance Atherosclerosis Study

Circulating or erythrocyte membrane fatty acid composition and diabetes incidence or glucose and insulin metabolism

Odd chain fatty acids

protect from diabetes


Widely distributed in many food

Endogenously

synthesized

Astrup A.

A changing view on saturated fatty acids and dairy: from enemy to friend Am J Clin Nutr. 2014;100(6):1407-8. “The totality of evidence does not support that dairy SFAs increase the risk of coronary artery disease or stroke or CVD mortality” “In contrast, lean dairy is clearly associated with decreased risk of T2D, and this effect is partly independent of any effect of body fat loss” “There is no evidence left to support the existing public health advice to limit consumption of dairy to prevent CVD and T2D”


DAIRY PRODUCTS

Turner KM, Keogh JB, Clifton PM. Dairy consumption and insulin sensitivity: a systematic review of short- and long-term intervention studies. Nutr Metab Cardiovasc Dis. 2015 Jan;25(1):3-8.

Conclusions (in adults): • 4 Showed a positive effect on insulin sensitivity as assessed by HOMA. • 1 Showed a negative effect • 5 Showed No effect. As the number of weight stable intervention studies is very limited and participant numbers small, these findings need to be confirmed by larger trials in order to conclusively determine any relationship between dairy intake and insulin sensitivity.

What makes the yogurt different? Possible probiotic effects: changing gut microbiota and body metabolism

Is a marker of a healthy lifestyle?

Replace other unhealthy or healthy

foods when consumed?

YOGURT AND HEALTH

In epidemiologic prospective studies usually yogurt consumption is

inversely related to body weight gain, obesity, metabolic syndrome,

diabetes and cardiovascular disease.

“ONLY YOGURT HAS BEEN ASSOCIATED TO A LOWER RISK OF DIABETES”

YOGURT AND DIABETES

17% lower risk of diabetes incidence in those consuming 3 or more servings of yogurt per week

41,436 men in the Health Professionals Follow-Up Study 67,138 women in the Nurses' Health Study 85,884 women in the Nurses' Health Study II 3,984,203 person-years of follow-up 15,156 incident T2D cases

HRs for a serving yogurt consumption per day and type 2 diabetes

YOGURT AND DIABETES

The Australian Diabetes Obesity and Lifestyle Study

The Whitehall II Prospective Study

EPIC-Interact Study

Women’s Health Initiative

Japan Public Health Center–based Prospective Study

Women’s Health Study

Health Professional Follow-up Study

Nurses Health Study I

Nurses Health Study II

Per 1 serving

18% lower risk

Tertile 1 Tertile 2 Tertile 3 P-Trend

Total dairy intake (g/day) 130 246 404

1 0.94 (0.75,1.19) 1.08 (0.86,1.37) 0.537

High-fat dairy intake (g/day) 0 35 25

1 0.76 (0.58,0.98) 1.09 (0.87,1.37) 0.080

Low-fat dairy intake (g/day) 16 160 325

1 0.95 (0.76,1.20) 0.92 (0.73,1.17) 0.540

Milk intake (g/day) 97 201 353

1 0.95 (0.76,1.20) 1.11 (0.88,1.41) 0.432

Yoghurt intake (g/day) 0 21 80

1 0.84(0.64,1.10) 0.72(0.55,0.95) 0.017

Cheese intake (g/day) 3 13 32

1 1.05 (0.84,1.32) 1.04 (0.83,1.31) 0.760

High-fat fermented dairy intake (g/day) 0 8 22

1 1.23 (0.96,1.57) 1.16 (0.91,1.49) 0.397

Low-fat fermented dairy intake (g/day) 0 21 80

1 0.89 (0.60,1.16) 0.76 (0.60,0.99) 0.049

Model 1: adjusted for age, sex

Model 2: Model 1 +BMI, family history of diabetes, smoking, alcohol, physical activity index, social class, education level

Model 3: Model 2 + energy, fibre, fruit, vegetables, red meat, processed meat, coffee intake

Tertile cut-offs are based on energy-adjusted intakes in the subcohort, calculated using the residual method

YOGURT AND DIABETES

O’Connor et al, Diabetologia 2014

A nested case-cohort within the EPIC-Norfolk Study (including a random subcohort (n=4,000) and cases of incident diabetes (n=892, including 143 cases in the subcohort) followed-up for 11 years.

Most of the studies were conducted in apparently healthy young or

middle-aged individuals from different populations.

No study has examined the association between dairy intake and risk

of diabetes in elderly individuals at high cardiovascular risk.

YOGURT AND DIABETES

PREDIMED – Participants’ characteristics

MeDiet + VOO

(n=2487)

MeDiet + Nuts

(n=2396)

Control

(n=2349)

Age, y (SD) 67 (6) 67 (6) 67 (6)

Women (%) 57 54 58

Diabetes (%) 50 47 48

Hypertension (%) 82 82 84

Current smokers (%) 14 15 14

Dyslipidemia (%) 72 73 72

BMI, kg/m2 (SD) 30 (4) 30 (4) 30 (4)

Waist circumf., cm (SD) 100 (10) 100 (10) 101 (11)

MeDiet 14-p score (SD) 8.7 (2) 8.7 (2) 8.3 (2)

Trial started October 2003, terminated July 2011

Mean follow-up for 5 years

POPULATION STUDIED

Objectives To assess the associations between total consumption of dairy and

specific dairy subgroups and development of diabetes.

To estimate the effects of the substitution of one serving of dairy

products for other serving of alternative foods on diabetes risk in an

elderly Mediterranean population at high cardiovascular risk.

YOGURT AND DIABETES

Prospective analysis - non-diabetic PREDIMED participants at baseline.

3,454 participants (1980 ♂, 2536 ♀).

270 incident cases of diabetes (median follow-up of 4.1 years).

RESEARCH DESIGN AND METHODS

Low-fat dairy (71%)

To

tal d

air

y (

36

2 g

/d)

Total milk (63%)

Non-reduced fat dairy (29 %)

Low-fat milk (85%)

Total fermented dairy

Dairy consumption was adjusted for total energy intake using the nutrient residual method and we calculated and used the cumulative

average of dairy consumption.

Semi-skim/skim milk and skim yogurt

Whole milk, condensed milk, milkshake, whole yogurt, whipped

cream, custard, ice cream and all types of cheeses

To

tal d

air

y (

36

2 g

/d)

Total yogurt (24%)

Total cheese (11%)

Non-reduced fat milk (15%)

Low-fat yogurt (70%)

Non-reduced fat yogurt (30%)

All types of yogurt and cheese

YOGURT AND DIABETES A validated semiquantitative 137- item food frequency questionnaire: Information about dairy products was assessed in fifteen items of the FFQ.

HRs for type 2 diabetes according to tertiles of total, low-fat and whole-fat dairy

food consumption in the PREDIMED cohort

“Total and low- fat dairy

consumption was inversely

associated to a lower risk of

diabetes”

3.454 non-diabetic participants

270 incident cases of diabetes

(median follow-up of 4.1 years).

Díaz-López et al, Eur J Nutr 2015

DAIRY AND DIABETES

aTertile cut-offs are based on energy-adjusted cumulative average dairy food intake and values are medians

(interquartile range).

Cox regression models were used to assess the RR (95% CI) of diabetes according to tertiles of dairy food intake.

Model 1: Adjusted for age, sex and BMI.

Model 2: Additionally adjusted for dietary intervention group,

physical activity, educational level, smoking, hypertension,

dyslipidemia, and fasting glucose, HDL-cholesterol and

triglyceride levels.

Model 3: Additionally adjusted for cumulative average dietary

intakes in energy-adjusted quintiles (vegetables, legumes,

fruits, cereals, meat, fish, olive oil, nuts) and alcohol and

alcohol squared in g/day.

All models were stratified by recruitment center.

Total dairy, median (g/day): T1: 200; T2: 342; T3: 539 Low-fat dairy, median (g/day): T1: 85; T2: 256; T3: 462 Whole-fat dairy, median (g/day): T1: 0; T2: 20; T3: 97

HRs for type 2 diabetes according to tertiles of total, low-fat and whole-fat milk

food consumption in the PREDIMED cohort

“Milk was not significantly

associated to the risk of

diabetes”





MILK AND DIABETES

aTertile cut-offs are based on energy-adjusted cumulative average dairy food intake and values are medians (interquartile R


Total milk, median (g/day): T1:109; T2: 216; T3: 400 Low-fat milk, median (g/day): T1: 32; T2: 200; T3: 370 Whole-fat milk, median (g/day): T1: 0; T2: 6; T3: 41











HRs for type 2 diabetes according to tertiles of specific yogurt consumption in

the PREDIMED cohort

“Independently of the fat

content, a higher consumption

of yogurt has associated to a

lower risk of diabetes”





YOGURT AND DIABETES

aTertile cut-offs are based on energy-adjusted cumulative average dairy food intake and values are medians (Interquartil R).


Total yogurt, median (g/day):T1: 13; T2: 71; T3: 128 Low-fat yogurt, median (g/day): T1: 3; T2: 44; T3: 120 Whole-fat yogurt, median (g/day): T1: 0; T2: 7; T3: 45











HRs for type 2 diabetes according to tertiles of specific yogurt consumption in

the PREDIMED cohort

“Independently of the fat

content, a higher consumption

of yogurt has associated to a

lower risk of diabetes”





YOGURT AND DIABETES

aTertile cut-offs are based on energy-adjusted cumulative average dairy food intake and values are medians (interquartile

range). Cox regression models were used to assess the RR (95% CI) of diabetes according to tertiles of dairy food intake.

Total yogurt, median (g/day): T1: 13; T2: 71; T3: 128 Low-fat yogurt, median (g/day): T1: 3; T2: 44; T3: 120 Whole-fat yogurt, median (g/day): T1: 0; T2: 7; T3: 45

An average increment of one

serving/day of the standard serving of

yogurt (125 g) was associated with a

33% lower risk of T2D.











HRs (95% CI) for type 2 diabetes associated with the substitution of one serving of yogurt and low-fat milk for one serving of other alternative foods in the PREDIMED cohort

Substituted foods Yogurt (125 g) Low-fat milk (200 mL)

Dairy desserts (100g)a 0.58 (0.29-1.18) 0.71 (0.35-1.41)

Biscuits and chocolate confectionary (50g) 0.60 (0.38-0.94) 0.69 (0.47-1.03)

Whole-grain biscuits and homemade pastries (50 g) 0.55 (0.32-0.96) 0.63 (0.38-1.05)

aPetit Suisse cheese or custard or ice cream. The servings are based on energy-adjusted cumulative average food intake. Values are given as HR (95% CI) from Cox regression models adjusted for age, sex, BMI, dietary intervention, physical activity, educational level, smoking, hypertension, or antihypertensive use (yes/no) and dyslipidemia (yes/no), and fasting glucose, HDL-cholesterol and triglycerides levels. All models were stratified by recruitment center.

YOGURT SUBSTITUTION AND DIABETES


In this prospective study conducted on elderly subjects at high cardiovascular risk, we report for the first time that:

a high intake of dairy products was associated with decreased risk of T2D.

the intake of low-fat dairy products, mainly milk and both low-fat yogurt and non reduced-fat yogurt, were the main contributors to this association.

substitutions of one serving of yogurt per day for one serving of a combination of biscuits and chocolate, or whole-grain biscuits and homemade pastries per day was associated with a reduced risk of T2D incidence.

YOGURT AND DIABETES

Cox regression models adjusted for intervention group, sex, age, physical activity and BMI and baseline current smoker, and hypoglycemic, hypolipidemic,

antihypertensive and insulin treatment, cumulative average consumption of vegetables, fruit, legumes, cereals, fish, red meat, alcohol, biscuits, olive oil and nuts.

Independent of the fat content,

Yogurt consumption was

inversely associated with the

incidence of MetS and its

components

Yogurt consumption and incidence of MetS or its components: PREDIMED study

1.868 participants without MetS at

baseline; 930 incident cases of

MetS (mean follow-up: 3.2 y)

P for trend=0.230

P for trend=0.004

P for trend=0.689

P for trend=0.348

P for trend=0.183

P for trend=0.048

P for trend=0.005

P for trend=0.001

P for trend<0.001

P for trend<0.001

P for trend=0.095

P for trend=0.126

P for trend=0.864

P for trend=0.011

P for trend=0.001

Central obesity

High fasting plasma glucose

High blood pressure

Low HDL-c

High triglicerides

Metabolic Syndrome P for trend=0.144

TOTAL YOGURT

Central obesity


High blood pressure

Low HDL-c

High triglicerides


WHOLE-FAT YOGURT

Central obesity


High blood pressure

Low HDL-c

High triglicerides


LOW-FAT YOGURT

0.5 1.0 2.0

HAZARD RATIO (95% CI)

Hazard ratios (95% CI) of metabolic syndrome and its components across energy-

adjusted tertiles of yogurt consumption (Tertile 3 vs Tertile 1).

↓23%

↓22%

↓27%

“Low-fat dairy products were inversely associated with MetS incidence”

“The consumption of cheese was associated with an increased risk of MetS incidence”

YOGURT AND METABOLIC SYNDROME

Babio et al, 2015

120,877 U.S. women and men

Free of chronic diseases and not obese

at baseline.

Relationships between changes in food and

beverage consumption and weight changes

every 4 years, according to study cohort.

Mozaffarian et al, N Engl J Med 2011

YOGUR AND OBESITY

Effects related to the Ca2+ metabolism • An increase in intracellular Ca2+:

• Favors insulin secretion and glucose uptake. • Increases lipogenesis and inhibits lipolysis.

• Calcium present in dairy inhibits fatty acid absorption.

Effects related to the protein a bioactive peptides in yogurt • Inducing satiety. • Intestinal hormone activation inducing insulin secretion. • Whey protein consumed with a carbohydrate meal substantially increased insulin, and

the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Probiotic effects of the yogurt

Insulin secretion induced by menaquinones (Vit K2) synthetized by the intestinal bacteria

Beneficial effects of other components in yogurt • Minerals (phosphor, magnesium, potassium, zinc) and vitamins (A, D, B2, B3, B6, B12) and

dairy fat.

POSSIBLE MECHANISMS

CONCLUSIONS

A high intake of dairy products was associated with decreased risk of T2D in several prospective studies.

Frequent yogurt consumption was consistently associated to a lower risk of diabetes and this association was independent of the fat content.

Substitutions of one serving of yogurt per day for one serving of other “unhealthy” snacks or food alternatives per day was associated with a reduced risk of T2D incidence.

Several mechanisms have been suggested in order to explain these associations, however more mechanistic studies are needed.

Large clinical trials with an appropriate design are warranted to definitively demonstrate that yogurt consumption protects from diabetes.

UNANSWERED RESEARCH QUESTIONS

If there is a cause-effect relationship between yogurt consumption and type 2 diabetes, does dairy intake exert directs effects on insulin sensitivity or are the effects on diabetes risk exerted through changes in weight?

Which components of dairy products exert the health effects? proteins, sugars, minerals, vitamins or constituents associated with fermentation?

Are all the types of fat content on dairy products similar in terms of conditioning the risk of disease?

What is the net effect on cardiovascular disease of consuming reduced fat dairy products with added sugar?

Baseline characteristics of the study population by tertile of total dairy intake.

Total dairy intake (g/day)a

Tertile 1 (n=1151) Tertile 2 (n=1152) Tertile 3 (n=1151) P

≤ 278 278-417 ≥ 417 valueb

Total dairy intake (g/day) 182 ± 73 343 ± 39 561 ± 119

Age (years) 66 ± 6 67 ± 6 67 ± 6 <0.001

Women, n (%) 506 (44) 744 (64) 891 (77) <0.001

BMI (kg/m2) 29.7 ± 3.5 29.89 ± 3.5 30.44 ± 3.7 <0.001

Overweight/obesity, n (%) 1080 (94) 1090 (95) 1110 (96) 0.014

Hypertension, n (%) 1039 (91) 1056 (92) 1044 (91) 0.64

Tobacco use <0.001

Never smoker, n (%) 560 (49) 754 (65) 842 (73)

Current smoker, n (%) 250 (22) 154 (13) 140 (12)

Former smoker, n (%) 341 (29) 244 (22) 169 (14)

Education level, n (%) <0.001

Primary education 789 (68) 895 (77) 932 (81)

Secondary education or academic/graduate 362 (32) 257 (22) 219 (19)

Leisure-time physical activity, (MET-min/day) 253.9 ± 232.6 222.4 ± 223.5 216.2 ± 206.1 <0.001

Medication use, n (%)

Antihypertensive agents 873 (75) 905 (78) 879 (76) 0.20

Statins or other hypolipidemic drugs 580 (50) 591 (51) 1148 (47) 0.07

Biochemistry, mg/dL

Fasting glucose 99.7 ± 15.5 97.3 ± 15.4 97.7 ± 16.8 0.002

Total cholesterol 218.7 ± 38.2 218.9 ± 37.5 222.7 ± 42.9 0.03

HDL-cholesterol 54.5 ± 14.2 56.2 ± 14.3 57.0 ± 13.8 <0.001

LDL-cholesterol 137.1 ± 33.7 137.1 ± 33.5 140.1 ± 40.4 0.10

Triglycerides 136.2 ± 78.9 129.1 ± 69.4 129.9 ± 68.6 0.049

Data are mean ± SD or number (%). aTertile cut-offs are based on energy-adjusted cumulative average dairy intake. bP value for differences between tertiles by ANOVA. cTotal energy-adjusted.

RESULTS RESEARCH DESIGN AND METHODS YOGURT AND DIABETES

HRs (95% CI) for type 2 diabetes according to specific dairy food intake in the PREDIMED cohort

Dairy intake (g/d)a

Variable Tertile 1 Tertile 2 Tertile 3 P for trend

Total cheese intake 11(6-15) 25 (22-28) 40 (35-48)

Cases/person-years, n 95/4760 81/5893 94/4491

Multivariate model 1 1.00 ref. 0.99 (0.72-1.35) 1.15 (0.85-1.55) 0.34



Total fermented dairy intake 39 (22-55) 100 (85-118) 167 (147-213)

Cases/person-years 127/4553 65/4834 78/4454




RESULTS RESEARCH DESIGN AND METHODS CHEESE, FERMENTED DAIRY AND DIABETES


Health & Medicine

Yogurt and diabetes: overview of the recent epidemiological studies