Dietary Interventions for Insulin Resistance and the Metabolic Syndrome Lisa M. Neff, MD Northwestern University Comprehensive Center on Obesity.

Dietary Interventions for Insulin Resistance and the

Metabolic Syndrome

Lisa M. Neff, MDNorthwestern University

Comprehensive Center on Obesity

“Dietary Interventions for Insulin Resistance

and the Metabolic Syndrome”

• Background– Metabolic Syndrome– Dietary Patterns and Insulin Sensitivity

• Pilot Study Design and Data

• Future Directions

The Metabolic Syndrome: NCEP/ATPIII/AHA Diagnostic Criteria

Individuals must have 3 or more of the following:– Abdominal obesity

• Waist circumference > 40” in men or > 35” in women

– High triglycerides • ≥ 150 mg/dL

– Low HDL cholesterol • < 40 mg/dL in men or < 50 mg/dL in women

– High blood pressure • ≥ 130/85 mmHg

– High fasting glucose• ≥ 100 mg/dL

DyslipidemiaHypertension

Polycystic ovary diseaseSleep apneaNon-alcoholic fatty liver diseaseCancerHyperuricemia & gout

Insulin resistance InflammationProthrombotic stateEndothelial dysfunctionCardiovascular disease

DiabetesAbdominal Obesity

Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006)




Is there an optimal dietary pattern for individuals with theMetabolic Syndrome?

Dietary Components Which May Affect Insulin Resistance

↓ IR• Whole grains• Fruits and

vegetables• Low fat dairy

products• Magnesium• Calcium• Dietary fiber• Omega-3 fatty

acids• Low GI foods

↑ IR• Saturated fat• Salt (deficiency

or excess)

• Alcohol (>30g/day)

Dietary Components Which May Affect Insulin Resistance

↓ IR• Whole grains• Fruits and

vegetables• Low fat dairy

products• Magnesium• Calcium• Dietary fiber• Omega-3 fatty

acids• Low GI foods

DASH Diet

The DASH Diet:Dietary Approaches to Stop Hypertension

• Originally conceived as the optimal diet for hypertension

• High in fruits and vegetables (typically 10 servings/day or more), whole grains, and low fat dairy products(2-3 servings/day or more)

• Moderate amounts of nuts, beans, fish and poultry

• Limited red meat, fried foods, and sweets• High in calcium, magnesium, potassium,

vitamins, phytochemicals, and fiber• Low in cholesterol, saturated fat, sugars, and

sodium

The DASH Diet: Epidemiologic Studies

• Increased intake of fruits, vegetables, and low fat dairy products is associated with:– Increased insulin sensitivity– Reduced risk of metabolic syndrome– Reduced risk of Type 2 diabetes– Reduced risk of hypertension

• High intakes of calcium and magnesium are associated with:– Increased insulin sensitivity– Reduced risk of metabolic syndrome– Reduced risk of Type 2 diabetes

The DASH Diet: Epidemiologic Studies

• In the Nurses Health Study, adherence to a DASH-style diet is associated with:– A lower risk of CHD (fatal and non-fatal)

(RR=0.76)– A lower risk of stroke (RR=0.82)– Lower plasma levels of CRP and IL-6

Fung et al. Arch Intern Med. 2008;168(7):713-20.

Magnesium and Metabolic Syndrome

• Magnesium appears to play a role in:– carbohydrate metabolism

• Mg++ is a cofactor for several glycolytic enzymes, including hexokinase, phosphofructokinase, and pyruvate kinase

– insulin action • Low intracellular Mg++ impairs the tyrosine kinase activity of the

insulin receptor

– modulating vascular tone and blood pressure• Low intracellular Mg++ may affect calcium channel activity,

raising intracellular Ca++, which has a vasoconstrictive effect

– thrombosis• Magnesium may alter platelet reactivity or aggregation

Magnesium and Metabolic Syndrome• In healthy human subjects, experimental

magnesium deficiency increases: (Nadler JL, Hypertension 1993, Nadler JL, Diabetes Care 1992)

– Insulin resistance– Basal and angiotensin-II stimulated aldosterone levels– Thromboxane A2 levels– Platelet reactivity

• In diabetics with hypomagnesemia, magnesium supplementation improves insulin sensitivity and reduces platelet reactivity (Rodriguez-Moran, Diabetes Care 2003; Nadler JL, Diabetes Care 1992)

• In a canine model of stent thrombosis, IV magnesium administration reduced thrombus formation (Rukshin V, Circulation 2002)

Calcium and Metabolic Syndrome

• Calcium appears to play a role in:– insulin action

• High levels of intracellular Ca++ may impair insulin signaling

– modulating vascular tone and blood pressure• High levels of intracellular Ca++ may have a

vasoconstrictive effect

Calcium and Metabolic Syndrome

• In hypertensive patients, oral calcium supplementation:– reduces intracellular calcium levels and may

improve insulin sensitivity (Sanchez M, Hypertension 1997)

– may produce modest improvements in systolic blood pressure (Allender PS, Ann Intern Med 1996; Bucher HC, JAMA 1996)

• Amlodipine therapy reduces intracellular Ca++, improves glycemic control, and increases insulin sensitivity (Beer NA, J Clin Endo Metab 1993, Ueshiba, Horm Metab Res 2003)

The DASH Diet: Clinical Trials

The DASH Diet: • Lowers blood pressure in

normotensive and hypertensive adults (Appel, NEJM 1997, Sacks, NEJM 2001)

• Reduces LDL cholesterol (Obarzanek, AJCN 2001)

• Reduces Framingham risk score (Maruther, Circulation 2009)

The DASH Diet: Clinical Trials

The DASH Diet: • May produce greater weight loss than standard

low-fat diets (Azadbakht, Diabetes Care 2005, Ard, Diabetes Care 2004)

• May reduce fasting glucose and improve insulin sensitivity more than standard weight loss diets (Azadbakht, Diabetes Care 2005, Ard, Diabetes Care 2004)

To our knowledge, no studies have examined the effects of the DASH diet on insulin sensitivity and glucose metabolism under controlled feeding conditions or during weight stability.

The DASH Diet:Clinical Trials

The DASH Diet:• May increase antioxidant capacity and

reduce oxidative stress (Lopes, Hypertension, 2003)

• May increase levels of adiponectin, the anti-inflammatory and insulin-sensitizing adipokine (Lien, Obesity, 2006)

• May reduce inflammatory markers such as C-reactive protein (Lien, Obesity, 2006)

The DASH Diet: Caveats

• The DASH diet may also– reduce HDL cholesterol, like other low-fat

diets (Obarzanek, AJCN, 2001)

– Increase TG (mean of 18 mg/dL), like other high carbohydrate diets (Erlinger, Circulation, 2003)

Ludwig, D. S. JAMA 2002;287:2414-2423.

Foods with similar Foods with similar carbohydrate carbohydrate content can affect content can affect blood glucose blood glucose levels differentlylevels differently

Glycemic IndexGlycemic Index

• Potato• Instant oatmeal• White bread• Watermelon

• Basmati rice• Stoneground whole wheat bread• Raisins• Pineapple

• Kidney beans• Chocolate ice cream• Oatmeal made with steel-cut oats• Spaghetti, al dente

Glycemic Index and Obesity High Glycemic Index Meal

Postprandial Hyperglycemia

Hyperinsulinemia

Relative Lipogenesis Reactive Hypoglycemia OBESITY Counterregulatory Hunger ↑ Food Intake Hormones

Glycemic Index and Diabetes High Glycemic Index Meal

Postprandial Hyperglycemia ↑ FFA

Hyperinsulinemia Glucotoxicity Lipotoxicity

Relative INSULIN Reactive RESISTANCE Hypoglycemia BETA CELL

FAILURE Counterregulatory Hormones

The Low Glycemic Index Diet:Epidemiologic Studies

• In some but not all studies, low GI diets are associated with:– Increased insulin sensitivity– Reduced adiposity– Reduced risk of metabolic syndrome– Reduced risk of type 2 diabetes

The Low Glycemic Index Diet:Clinical Trials

• Low GI diets: – Reduce postprandial glucose levels in normal

individuals and people with diabetes (Ludwig, JAMA, 2002)

– Produce modest improvements in HbA1c in patients with diabetes (Brand-Miller, Diabetes Care, 2003)

– May or may not affect insulin sensitivity (improvements noted in 2 of 7 studies)

The Low Glycemic Index Diet:Clinical Trials

• Low GI diets: – May be beneficial for weight management,

particularly in individuals with features of the metabolic syndrome (Pittas, Diabetes Care, 2005)

– May reduce LDL cholesterol and TG and increase HDL (Luscombe, EJCN, 1999 and Pereira, JAMA, 2004)

– May reduce inflammatory markers such as C-reactive protein (Pereira, JAMA, 2004) and IL-6 (Kallio, AJCN, 2008)

– May increase antioxidant capacity (Botero, Obesity, 2009)

Questions

• Does the DASH diet or the low GI improve insulin sensitivity, in the absence of weight loss?

• Does the DASH diet or the low GI diet improve other features of the metabolic syndrome (such as dyslipidemia and inflammation), in the absence of weight loss?

• Do these dietary patterns and weight loss have synergistic effects?

Pilot Study Overview

• 15-week feasibility study with 18 volunteers

• Three different study diets– DASH Diet– Low Glycemic Index Diet– American-Style Diet

• All food provided by Bionutrition for 13 weeks

Pilot Study Overview

• Inclusion criteria: ages 18-45, BMI ≥27, with: – fasting insulin ≥ 9 uIU/mL– OR fasting glucose ≥ 100 mg/dl– OR 2-hour OGTT ≥ 140 mg/dl

AND– ≥2 other features of the metabolic syndrome

• Abdominal obesity• High triglycerides• Low HDL• Prehypertension or hypertension

Study Overview

Run-in Phase on Usual Diet

Testing #1 on American Diet

Wt Stable on American Diet

Wt Stable on DASH Diet

Wt Stable on Low GI Diet

2 weeks

Outpatient

3-4 daysInpatient

2 weeksInpatient

8 weeksOutpatient

Weight loss phase


Wt Stable on American Diet


Testing #2 Testing #2 Testing #2


2 weeksInpatient

50% kcal reduction

Measures of Insulin Sensitivity• HOMA –

– Used to assess hepatic insulin sensitivity– a lower score indicates better insulin sensitivity

• OGTT – – Used to assess whole body insulin sensitivity– Frequent blood sampling for 3 hours following the consumption

of 75 grams of glucose– The Area Under the Curve (AUC) was calculated for glucose

and insulin using the trapezoidal method

• Hyperinsulinemic Euglycemic Clamp – – A measure of peripheral insulin sensitivity– High insulin infusion rate: 80 mU/m2 body surface area– Variable infusion rate of dextrose to keep blood glucose levels in

the range of 90-100 mg/dl.– A higher glucose infusion rate (GIR) indicates better insulin

sensitivity

Other Testing

Parameter Testing/ProceduresLipids Total, LDL-, and HDL-cholesterol,

TG, Lipoprotein subclass analysis by NMR spectroscopy

Blood pressure 24-hour BP monitor

Inflammation CRP, IL-6, TNF-α, IL-10, PAI-1

Other labs Adiponectin, free fatty acids

Body composition

Air displacement plethysmography

Energy metabolism

Indirect calorimetry

Composition of the Study Diets

Data are for a 1600 kcal diet

DASH Low GI American

Carbohydrate

(% of kcal)57 40 52

Fat

(% of kcal)25 30 32

Saturated fat

(% of kcal)6 10 10

Protein

(% of kcal)18 30 16




Calcium (mg) 1150 850 545

Magnesium (mg) 374 250 232

Potassium (mg) 3771 2780 1986

Sodium (mg) 1185 1180 2356




Cholesterol (mg) 121 191 150

Fiber (g) 31 21 16

GI 55 38 58




Fruit Intake (Servings/Day)

5 3 3*

Vegetable Intake (Servings/Day)

4 2 2

Dairy Intake (Servings/Day)

2 1.5 1

* predominantly juice and juice drinks

Baseline Characteristics of 18 Enrolled Volunteers who Completed ≥ 2 Testing Periods

Gender 50% female, 50% male

Race/Ethnicity 1 (6%) Non-Hispanic White

8 (44%) Hispanic

8 (44%) Black

1 (6%) Asian

Age Mean 33.5 +/- 6.9 yrs (range 22-45)

BMI 38.4 +/- 7.4 kg/m2 (range 30-56)

Baseline Metabolic Characteristics of 18 Enrolled Volunteers who Completed ≥ 2 Testing Periods

• 100% had elevated fasting insulin levels and abdominal obesity.

• 28% had fasting hyperglycemia.• 67% had low HDL levels.• 44% had hypertriglyceridemia.• 39% had prehypertension or

hypertension.• 50% had elevated CRP levels.

Baseline Parameters by Study Diet Assignment: Median (range)

American (n=5)

Low GI (n=7)

DASH (n=6)

BMI (kg/m2) 34.2 (33-48) 34.0 (30-56) 35.7 (32-48)

Waist Circ (cm)116 (111-142) 117 (104-145) 119 (114-153)

Steps/Day during Run-In

11,216 (8609-12,146)

6,001 (5085-13,196)

9,052 (2655-23,436)

Baseline Metabolic Parameters by Study Diet Assignment: Median (range)

American (n=5)

Low GI (n=7)

DASH (n=6)

Fasting Glucose (mg/dL)

87 (86-98) 95 (87-149) 93 (84-132)

Fasting Insulin (uIU/mL)

12.8 (7-20) 17.2 (9-26) 14.2 (10-21)

HbA1c (%) 5.5 (5.1-5.8) 6.0 (5.2-8.3) 5.9 (5.0-7.2)


American (n=5)

Low GI (n=7)

DASH (n=6)

Total Cholesterol (mg/dL)

217 (179-249) 196 (135-236) 207 (143-301)

TG (mg/dL) 131 (72-237) 112 (68-220) 183 (77-285)

HDL (mg/dL)38 (33-47) 36 (26-55) 39 (33-58)

LDL (mg/dL) 133 (124-169) 116 (68-178) 121 (83-200)


American (n=5)

Low GI (n=7)

DASH (n=6)

24h Mean Systolic BP (mmHg)

114 (98-142) 124 (94-138) 116 (108-140)

24h Mean Diastolic BP

(mmHg)60 (59-80) 75 (55-87) 72 (68-79)

CRP (mg/dL) 0.6 (0.1-1.0) 1.2 (0.2-1.4) 1.0 (0.5-4.1)

IL-6 (pg/mL) 2.0 (0.7-6.1) 4.2 (1.8-6.5) 3.7 (1.3-5.5)

Mean IL-6 level in healthy volunteers is 1.77 pg/mL.

Subjects’ Baseline Diets vs American Diet

American (at 3200 kcal)

Study volunteers (mean at baseline)

Carbohydrate

(% of kcal)52 48

Fat

(% of kcal)32 37

Saturated fat

(% of kcal)~11 12

Protein

(% of kcal)16 16

Comparison of Baseline and American Diets

American (at 3200 kcal)

Study volunteers (mean reported intake during run-in)

Calcium (mg) 1055 964

Magnesium (mg) 462 179

Potassium (mg) 3848 2087

Sodium (mg) 4387 4043

Comparison of Baseline and American Diets

American(at 3200 kcal)

Study volunteers(mean intake during run-in)

Cholesterol (mg) 313 383

Fiber (g) 30 19

Comparison of 3200 kcal American Diet and Average US Intake

American(at 3200 kcal)

Average American Intake (NHANES)

Fruit Intake (Servings/Day)

5.7* 1.1

Vegetable Intake (Servings/Day)

4.1 2.0

Dairy Intake (Servings/Day)

1.9 1-1.5

* predominantly juice and juice drinks

Weight Stability Phase Data• Subjects consumed the study diet for two

weeks prior to testing.

• Our goal for weight stability was +/-1% of initial weight.

• Volunteers wore pedometers for 1 week in each phase and were asked to keep activity levels constant.

• For this phase, reliable data were available for 5 volunteers in each group.

Weight Change from Baseline

-2

-1

0

1

2

Per

cen

t C

han

ge

American DASH Low GI

Weight Stability

Median Change (kg): - 0.1 -0.7 0

Change in Steps/Day from Baseline

-40

-20

0

20

40

60

80

100

120

Perc

en

t C

han

ge


Weight Stability

Median Change (steps): -907 -40 1976

Change in Fasting Glucose

-25

-20

-15

-10

-5

0

5

10

15

Perc

ent

Ch

an

ge


Weight Stability

Median Δ (mg/dl): 2 -6 0

Change in Fasting Insulin

-60

-40

-20

0

20

40

60P

erce

nt

Ch

ang

e


Weight Stability

Median Δ (uIU/ml): -3 -4 0

Change in HOMA

-80

-60

-40

-20

0

20

40

60

80P

erc

en

t C

ha

ng

e


Weight Stability

Median Δ: -0.6 -1.0 0

Change in Glucose AUC

-40

-20

0

20

40P

erc

en

t C

han

ge


Weight Stability

Median Δ: 39 -23 20

Change in Insulin AUC

-80

-60

-40

-20

0

20

40

60

80P

erc

en

t C

ha

ng

e


Weight Stability

Median Δ: -13 -43 -2

Change in Fructosamine

-10

-5

0

5

10P

erc

en

t C

han

ge


Weight Stability

Median Δ (umol/L): 1 -8 3

Change in GIR

-20

0

20

40

60

80P

erc

en

t C

han

ge


Weight Stability

Median Δ (mg/kg/min): 0.4 0.4 0.9

Change in Triglycerides

-50

-25

0

25

50

Perc

en

t C

han

ge


Weight Stability

Median Δ (mg/dl): -7 -9 -3

Change in HDL Cholesterol

-40

-20

0

20P

erc

en

t C

han

ge


Weight Stability

Median Δ (mg/dl): -5 -7 1

Change in LDL Cholesterol

-30

-20

-10

0

10

20

30P

erc

en

t C

han

ge


Weight Stability

Median Δ (mg/dl): -9 -17 6

Change in CRP

-60

-40

-20

0

20

40

60P

erc

en

t C

han

ge


Weight Stability

Median Δ (mg/dl): 0 -0.3 0.1

Change in IL-6

-40

-20

0

20

40

60

80P

erc

en

t C

han

ge


Weight Stability

Median Δ (pg/ml): 0.5 -0.4 0.2

Change in Systolic BP

-15

-10

-5

0

5P

erc

en

t C

han

ge


Weight Stability

Median Δ (mmHg): 1 -7 -5

Change in Diastolic BP

-15

-10

-5

0

5P

erc

en

t C

han

ge


Weight Stability

Median Δ (mmHg): -1 -2 -4

Potential Issues• Our small n limits our ability to reach conclusions

about the diets. • At higher kcal levels, our American Diet was

better than many of our volunteers’ baseline diets.

• Our American Diet group tended to be healthier and more active at baseline than the volunteers in the other groups.

• Although weight change was generally very small in all groups, DASH volunteers tended to have more weight loss.

Potential Issues• Physical activity tended to increase in the Low

GI group from Run-In to Weight Stability.

• Premenopausal women were included in the study; testing likely occurred during different phases in the menstrual cycle.

• We relied on calculated GI to develop our low GI diet.

• We used a basic clamp technique, so we are unable to confirm suppression of gluconeogenesis.

Summary of Weight Stability Data• Improvements in insulin sensitivity and other

metabolic syndrome parameters are possible as a result of dietary changes

• Hepatic and whole-body IS may improve more with a DASH diet

• Peripheral IS improved similarly with all three diets

• The DASH diet may have a more favorable effect on inflammation

• The low GI diet may have a more favorable effect on HDL

• Both the DASH and a low-sodium low GI diet may reduce blood pressure after only two weeks

Post Weight Loss Data

• Subjects consumed the 50%-reduced calorie study diet for 8 weeks

• Weight was re-stabilized at the lower weight for two weeks before testing.

Weight Change

-15

-10

-5

0

Per

cen

t C

han

ge


Median Δ (kg): -10.6 -10.6 -5.0

Change in HOMA after Weight Loss

-80

-60

-40

-20

0

20P

erc

en

t C

han

ge


Change in GIR after Weight Loss

-50

0

50

100

150

200P

erc

en

t C

ha

ng

e


Change in HbA1c after Weight Loss

-20

-10

0

10P

erc

en

t C

han

ge


Median Δ (%): 0 -0.2 -0.2

Change in CRP after Weight Loss

-100

-50

0

50

100P

erc

en

t C

ha

ng

e


↑

Future Directions

NewStudy

(n = 39)

Wt Stable on Western Diet

Testing #1

Wt Stable on Western Diet




Age range 18-65, no premenopausal women

Physical activity and sleep will be controlled

New procedures to limit weight change to < 1%, Bod Pods will be done at both timepoints

2 weeksInpatient

2 weeksInpatient

Acknowledgements

• Jan Breslow, MD• Jeanne Walker, NP• Suzanne Magnotta,

MS, RD• RUH Bionutrition

Dept.• Inpatient and

Outpatient Nursing Staff

• Rogosin Institute Laboratory

• Our dedicated volunteers

• Study funding from the Rockefeller University CTSA Pilot Grant Program

• Salary support from the KL2 Clinical Scholars’ Program

THANK YOU FOR YOUR ATTENTION!

Dietary Interventions for Insulin Resistance and the Metabolic Syndrome Lisa M. Neff, MD Northwestern University Comprehensive Center on Obesity.

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