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Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and clinical interventions Simin Liu Department of Epidemiology Brown University Division of Endocrinology, Department of Medicine Rhode Island Hospital
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Page 1: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency

and quality of epidemiologic observations and clinical

interventions

Simin Liu Department of Epidemiology

Brown University Division of Endocrinology, Department of Medicine

Rhode Island Hospital

Page 2: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Overview

♦  A diet that affects glucose homeostasis may be fundamental to vascular health outcomes •  Glycemic response, glycemic index, and glycemic load

•  Supports from evolutionary theory, epidemiologic observations, and experimental evidence

–  Functional measures to study diet and disease in human populations

–  Biological intermediaries for diabetes and cardiovascular disease

–  Sex, body weight, and age as important modifiers

♦  Conclusions •  Integrative framework for research

•  Preventive recommendation

Page 3: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Diets (high GL/insulin demand) Genes

Obesity

Insulin resistance

Hyperinsulinemia Hyperglycemia

Dyslipidemia+TG

- HDL

Hypertension:Na+ retention;

SNS+Contractility+

Hemodynamic changes:inflammation,

Impaired fibinolysisand tthrombosis

Relative insulin deficiency

↑ Glycation of LDL ↑ Sorbitol ↓ NO/vasodilatory response

Coronary Heart Disease

Pathogenesis of DM/CHD Related to Insulin Resistance

Liu, 1998; Liu and Manson, 2001

↓Gluco-recognition ↓ Beta-cell mass; ↑Amyloid deposit

Page 4: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Traditional Epidemiology: Common Risk Factors for Three Major Metabolic Diseases

Risk factors Type 2 DM CHD Colon Ca.

Age ↑↑↑ ↑↑↑ ↑↑↑ Tobacco ↑ ↑↑ ↑↑ Physical inactivity ↑↑ ↑↑ ↑↑ Obesity ↑↑↑↑↑↑↑ ↑↑ ↑↑ Sex?? Excess energy intake ↑? ↑? ↑? Saturated fat ↑ ? ↑? ↑? Red meat ↑? ↑? ↑ Refined carbohydrates ↑↑? ↑↑? ↑↑? Dietary fibers ↓↓? ↓↓ ↓? Fruits & vegetables ↓↓? ↓↓ ↓? Whole grains ↓↓ ↓↓ ↓? Nuts/legumes ↓↓? ↓↓ ↓? Moderate Alcohol ↓↓ ↓↓ ↑? ……

Modified from Giovannucci 1995 and Liu 1998

Page 5: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Sex differences related to vascular outcomes in prospective studies

Diabetes and risk of CVD mortality stronger in women

BMI and risk of type 2 diabetes stronger in women

Willett NEJM 1999; Huxley BMJ 2005

Page 6: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Dose-response relation between blood glucose and CHD risk (Levitan et al. Arch Int Med, 2004)

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

50 75 100 125 150 175 200

Plasma glucose (mg/dL)

Log

rela

tive

risk

Fasting

Postchallenge

Fasting

Postchallenge

Page 7: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

The effect of decreasing PPG with acarbose, an -glucosidase inhibitor, on DM development in a multicenter double-blind, placebo-controlled, randomized trial Chiasson et al. Lancet 2002

Page 8: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

The effect of decreasing PPG with acarbose, an -glucosidase inhibitor, on CVD development in a multicenter double-blind, placebo-controlled, randomized trial Chiasson et al. JAMA 2004

Page 9: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

0!500!1000!1500!

Kilo

calo

ries

Con

sum

ed!

1! 2! 3! 4! 5!Time (hr)

Cumulative Voluntary Food Intake

High GI!Med GI!Low GI!

GI & Voluntary Food Intake Ludwig et al. Pediatrics 1999, 103:e261

Page 10: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Low GI diets improve triglycerides Low GI diet compared with high GI diet

-25 -20 -15 -10 -5 0 5

Frost et al 1994

Fontvieille et al 1992

Wolever et al 1992

Fontvieille et al 1988

Jenkins et al 1985

Jenkins et al 1987

Jarvi et al 1999

Brand et al 1991

25 type 2 , 12 wks

18 type 1 & 2, 5 wks

6 type 2, 6 wks

8 type 1, 3 wks

12 CHD, 4 wks

30 CHD, 4 wks

20 type 2, 24 days

Average change in 8 studies = -12% !*Include extensive data from Prof.Y.X. Yang Chinese CDC

Page 11: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Changes in HbA1c or fructosamine Low GI diets compared with high GI diets

-35 -30 -25 -20 -15 -10 -5 0

Frost et al 1994

Fontvieille et al 1992

Brand et al 1991

Wolever et al 1992

Wolever et al 1992

Jenkins et al 1988

Fontvielle 1988

Collier et al 1988

Gilbertson et al 2000

25 type 2 , 12 wks!18 type 1 & 2, 5 wks!

16 type 2, 12 wks!6 type 2, 6 wks!

15 type 2, 2 wks!

8 type 2, 4 weeks!

8 type 1, 3 weeks!

7 type 1 children, 6 wks!104 type 1 children, 12 mo!

!

Average difference in HbA1c in 9 studies = -11% !Adapted from Brand-Miller et al. 2001 !

Page 12: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Change in Glycemic Control Low vs high GI diets

•  Glycemic control - 10% improvement for a 10 unit decrease in GI

•  Comparison with other interventions

DCCT - 20% UKPDS - 11.5%

Insulin analogues - 2.5%

Acarbose - 6.5%

Adapted from Stephen Colagiuri Aust Nutr Soc 2001

Page 13: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

80

90

100

110

120

130

140

150

160

1 2 3 4 5Quintile of Intake

Glycemic Index (p=0.03)

Carbohydrate (p=0.005)

Glycemic Load (p<0.001)

Fasting plasma TG concentrations by GL, GI and carbohydrate intake

Liu et al. AJCN 2001

Nurses’ Health Study

Fast

ing

Trig

lyce

rides

(mg/

dl)

12.039b

Page 14: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Fasting Plasma TG Levels by Dietary Glycemic Load

Postmenopausal Women with Different BMI’s

0

50

1 00

1 50

2 00

Q u in t il e o f E n ergy-ad ju s te d G lyce mic L oad

Q1 Q2 Q3 Q4 Q5

Fasting TG (mg/dl)

Liu et al. AJCN, 2001

BMI > 25BMI < 25

Page 15: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Adjusted geometric mean plasma concentrations of high-sensitivity C-reactive protein (hs-CRP) by quintiles (Q1–Q5) of energy-adjusted dietary glycemic load

in 244 women in 2 BMI categories

Liu S et al. Am J Clin Nutr 2002;75:492-498

Subsequently confirmed by Rhodes et al in a randomized trial of overweight pregnant women AJCN 2010

Page 16: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

30

35

40

45

50

55

60

65

1 2 3 4 5

Quintile of dietary glycemic index

High

den

sity

lipo

prot

ein

chol

este

rol

leve

l (m

g/dL

)

Normal weightOver weight

30

35

40

45

50

55

60

65

1 2 3 4 5

Quintile of dietary glycemic load

High

den

sity

lipo

prot

ein

chol

este

rol

leve

l (m

g/dL

)

40

60

80

100

120

140

160

180

1 2 3 4 5

Quintile of dietary glycemic index

Trig

lyce

ride

leve

l (m

g/dL

)

40

60

80

100

120

140

160

180

1 2 3 4 5

Quintile of dietary glycemic loadTr

igly

cerid

ele

vel (

mg/

dL)

P for interaction = 0.87 P for interaction = 0.0001

P for interaction = 0.81 P for interaction = 0.32

30

35

40

45

50

55

60

65

1 2 3 4 5

Quintile of dietary glycemic index

High

den

sity

lipo

prot

ein

chol

este

rol

leve

l (m

g/dL

)

Normal weightOver weight

30

35

40

45

50

55

60

65

1 2 3 4 5

Quintile of dietary glycemic load

High

den

sity

lipo

prot

ein

chol

este

rol

leve

l (m

g/dL

)

40

60

80

100

120

140

160

180

1 2 3 4 5

Quintile of dietary glycemic index

Trig

lyce

ride

leve

l (m

g/dL

)

40

60

80

100

120

140

160

180

1 2 3 4 5

Quintile of dietary glycemic loadTr

igly

cerid

ele

vel (

mg/

dL)

P for interaction = 0.87 P for interaction = 0.0001

P for interaction = 0.81 P for interaction = 0.32

Geometric mean high density lipoprotein cholesterol and triglyceride levels*

*Adjusted for age, smoking (current, past, never), exercise (4 category), hormone replacement therapy use (current, past, never), family history of MI, history of diabetes, body mass index (4 category), and intakes of total energy, alcohol intake (4 category), and quintile of total fat, protein, cholesterol, folate, and magnesium intake. Dietary glycemic load additionally adjusted for quintile of fiber intake

Page 17: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Relation between HDL-cholesterol concentration and glycemic index in men and women (Frost et al, 1999)

Page 18: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Mean concentrations of HDL by glycemic index among men and women aged 20+ years, NHANES III,

1988-1994 (Ford and Liu, Arch Int Med 2000)

11.11.21.31.41.51.6

<76%76-79%80-83%84-87%

>87%

<76%76-79%80-83%84-87%

>87%

Glycemic index quintiles

HDL cholesterol

(mmol/l)

Adjusted for age, race or ethnicity, education, smoking status, body mass index, alcohol intake, physical activity, percent kilocalories from protein (quintiles), percent kilocalories from fat (quintiles), total energy intake (quintiles).

Men

Women

P<0.0001

Page 19: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

-200"

0"

200"

400"

600"

800"

1000"

1200"BX

D-20/TyJ"

AXB-19/PgnJ"

BXHA1"

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%  Total  Adipo

se  Growth  

(0  to

 8  W

eeks)  

Male  Female  

       Results:  Diet-­‐by-­‐sex  interac3on  

Slide courtesy of Drs Tom Drake & Jake Lusis

Page 20: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Q1(Low)Q2Q3Q4Q5(High)0

0.25

0.5µmol/l

Mean concentrations of Carotenoids by glycemic index among 15270 US adults, NHANES III

Quintile of dietary glycemic index

lycopene

Lutein/zeax

beta-carotene

Crptoxanthin

α-carotene

Liu and Ford, 2002

Page 21: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Q1(Low)Q2Q3Q4Q5(High)20

25

30

35

40

45

50

Quintile Of Dietary Glycemic Index

Mean concentrations of serum Vitamin E and Vitamin C by glycemic index among 15270 US adults, NHANES III

Vitamin C (nmol/L)

Vitamin E (µmol/L)

Liu and Ford, 2002

Page 22: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Potential biochemical mechanisms High GI/GL feeding causes: ♦ Postprandial hyperglycemia & hyperinsulinemia -

(immediate responses) ♦ Counterregulatory hormonal responses which

stimulate appetite, FFA production, and possibly protein breakdown – (late responses)

♦ Shifts in substrate utilization away from fat towards carbohydrates

♦ Increased enzymatic capacities for carbohydrate oxidation and lipogenesis, and decreased enzymatic capacity of fat oxidation

Page 23: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Adjusted estimates of relative risk of type 2 diabetes according to GL by sex from a meta-analysis of all prospective cohorts with 7.5 million years of

followup (up to August 2012)

Livesay et al. Am J Clin Nutr 2013

Page 24: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Multivariate relative risk of CHD by body mass index and glycemic load

1.11

2.03 1.97

0.941.2

1.74

1.00 1.05 1.42

0.000.501.001.502.002.50

RR

< 23 23-29 >29Tertile 1

Tertile 2Tertile 3

BMI

GL

Test for interaction, P < 0.01

Liu et al 2000

Page 25: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Different constituents of a low GI/GL diet

♦  Fruits and vegetables

♦  Whole grains

♦  Nuts

♦  Legumes (peas, beans, soybeans)

♦ Fish

♦ Dairy foods

Page 26: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Conclusion ♦  Due to our genetic mal-adaptation to westernized lifestyle/

environment, we are increasingly becoming a metabolically efficient population

♦  Substantial evidence indicates significant biological importance and clinical utilities of the GI/GL concepts, in that •  1) carbohydrate-containing foods differ in their abilities to raise plasma

glucose and insulin (Level A), •  2) diets characterized by high GL adversely affect metabolic intermediates

(Level B), •  3) may increase risk of vascular outcomes (diabetes and cardiovascular

diseases) especially among those who are prone to insulin resistance (Level B and C)

♦  Can we conclusively demonstrate the efficacy of glucose

homeostasis diet on vascular health in randomized trials: •  Not feasible •  Not ethical •  Not necessary

Page 27: Dietary carbohydrates and metabolic outcomes: …...Dietary carbohydrates and metabolic outcomes: assessing the totality, consistency and quality of epidemiologic observations and

Conclusion ♦  When thinking about diet, which is only one aspect of our

westernized environment, we need to keep in mind what kind of people we have become metabolically.

•  Consider sex, body weight, and age as important modifiers when

assessing diet-disease relation and making dietary recommendation – Reduce heterogeneity and improve biological understanding of the “glucose homeostasis” diet

•  Regarding the clinical utility of the GI concept, –  It is better than the “simple/complex” in classifying carbohydrates – Does go beyond individual food-based guidelines, even in the context

of caloric density and nutrient composition – GI is most useful for ranking high/dense-carbohydrate foods


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