Dietary Interventions for Insulin Resistance and the Metabolic Syndrome

1
Dietary Interventions for Insulin Resistance and
the Metabolic Syndrome

• Lisa M. Neff, MD
• Northwestern University
• Comprehensive Center on Obesity

2
Dietary Interventions for Insulin Resistance
and the Metabolic Syndrome

• Background
• Metabolic Syndrome
• Dietary Patterns and Insulin Sensitivity
• Pilot Study Design and Data
• Future Directions

3
The Metabolic Syndrome NCEP/ATPIII/AHA
Diagnostic Criteria

• Individuals must have 3 or more of the following
• Abdominal obesity
• Waist circumference gt 40 in men or gt 35 in
  women
• High triglycerides
• 150 mg/dL
• Low HDL cholesterol
• lt 40 mg/dL in men or lt 50 mg/dL in women
• High blood pressure
• 130/85 mmHg
• High fasting glucose
• 100 mg/dL

4
DyslipidemiaHypertension
DiabetesAbdominal Obesity

• Polycystic ovary disease
• Sleep apnea
• Non-alcoholic fatty liver disease
• Cancer
• Hyperuricemia gout

Insulin resistance Inflammation Prothrombotic
state Endothelial dysfunction Cardiovascular
disease
5
Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006)
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Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006)
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Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006)
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Grundy Nature Reviews Drug Discovery 5, 295306
(April 2006)
9
Is there an optimal dietary pattern for
individuals with theMetabolic Syndrome?

10
Dietary Components Which May Affect Insulin
Resistance

• ? IR
• Saturated fat
• Salt (deficiency or excess)
• Alcohol (gt30g/day)

• ? IR
• Whole grains
• Fruits and vegetables
• Low fat dairy products
• Magnesium
• Calcium
• Dietary fiber
• Omega-3 fatty acids
• Low GI foods

11
Dietary Components Which May Affect Insulin
Resistance
DASH Diet

• ? IR
• Whole grains
• Fruits and vegetables
• Low fat dairy products
• Magnesium
• Calcium
• Dietary fiber
• Omega-3 fatty acids
• Low GI foods

12
The DASH DietDietary 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

13
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

14
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)
  (RR0.76)
• A lower risk of stroke (RR0.82)
• Lower plasma levels of CRP and IL-6

Fung et al. Arch Intern Med. 2008168(7)713-20.
15
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

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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)

17
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

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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)

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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)

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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.

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The DASH DietClinical 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)

22
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)

23
Glycemic Index
Foods with similar carbohydrate content can
affect blood glucose levels differently
Ludwig, D. S. JAMA 20022872414-2423.
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• 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

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Glycemic Index and Obesity

• High Glycemic Index Meal
• Postprandial Hyperglycemia
• 
  Hyperinsulinemia
• Relative
  Lipogenesis
• Reactive
• Hypoglycemia
  OBESITY
• 
  
• Counterregulatory Hunger
  ? Food Intake
• Hormones

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Glycemic Index and Diabetes

• High Glycemic Index Meal
• Postprandial Hyperglycemia ? FFA
• Hyperinsulinemia Glucotoxicity
  Lipotoxicity
• Relative INSULIN
• Reactive RESISTANCE
• Hypoglycemia
  BETA CELL FAILURE
• Counterregulatory
• Hormones

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The Low Glycemic Index DietEpidemiologic 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

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The Low Glycemic Index DietClinical 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)

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The Low Glycemic Index DietClinical 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)

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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?

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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

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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

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Study Overview
2 weeks Outpatient
Run-in Phase on Usual Diet
Testing 1 on American Diet
3-4 days Inpatient

Wt Stable on American Diet
Wt Stable on DASH Diet
Wt Stable on Low GI Diet
2 weeks Inpatient
Testing 2
Testing 2
Testing 2
8 weeks Outpatient
Weight loss phase
50 kcal reduction
Wt Stable on DASH Diet
Wt Stable on American Diet
Wt Stable on Low GI Diet
2 weeks Inpatient
Testing 3
Testing 3
Testing 3
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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

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Other Testing
Parameter Testing/Procedures
Lipids Total, LDL-, and HDL-cholesterol, TG, Lipoprotein subclass analysis by NMR spectroscopy
Blood pressure 24-hour BP monitor
Inflammation CRP, IL-6, TNF-a, IL-10, PAI-1
Other labs Adiponectin, free fatty acids
Body composition Air displacement plethysmography
Energy metabolism Indirect calorimetry

36
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

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Composition of the Study Diets
Data are for a 1600 kcal diet DASH Low GI American
Calcium (mg) 1150 850 545
Magnesium (mg) 374 250 232
Potassium (mg) 3771 2780 1986
Sodium (mg) 1185 1180 2356

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Composition of the Study Diets
Data are for a 1600 kcal diet DASH Low GI American
Cholesterol (mg) 121 191 150
Fiber (g) 31 21 16
GI 55 38 58

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Composition of the Study Diets
Data are for a 1600 kcal diet DASH Low GI American
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
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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)
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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.

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Baseline Parameters by Study Diet Assignment
Median (range)
American (n5) Low GI (n7) DASH (n6)
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)

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Baseline Metabolic Parameters by Study Diet
Assignment Median (range)
American (n5) Low GI (n7) DASH (n6)
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)

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Baseline Metabolic Parameters by Study Diet
Assignment Median (range)
American (n5) Low GI (n7) DASH (n6)
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)

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Baseline Metabolic Parameters by Study Diet
Assignment Median (range)
American (n5) Low GI (n7) DASH (n6)
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.
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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

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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

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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

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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
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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.

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Weight Stability
American DASH Low
GI
Median Change (kg) - 0.1 -0.7
0
52

Weight Stability

American DASH Low
GI
Median Change (steps) -907 -40
1976
53

Weight Stability

American DASH Low
GI
Median ? (mg/dl) 2 -6
0
54

Weight Stability

American DASH Low
GI
Median ? (uIU/ml) -3 -4
0
55

Weight Stability

American DASH Low GI
Median ? -0.6 -1.0
0
56

Weight Stability

American DASH Low GI
Median ? 39
-23 20
57

Weight Stability

American DASH Low GI
Median ? -13 -43
-2
58

Weight Stability

American DASH Low GI
Median ? (umol/L) 1 -8
3
59

Weight Stability

American DASH Low GI
Median ? (mg/kg/min) 0.4 0.4
0.9
60

Weight Stability

American DASH Low GI
Median ? (mg/dl) -7
-9 -3
61

Weight Stability

American DASH Low GI
Median ? (mg/dl) -5 -7
1
62

Weight Stability

American DASH Low GI
Median ? (mg/dl) -9 -17
6
63

Weight Stability

American DASH Low GI
Median ? (mg/dl) 0 -0.3
0.1
64

Weight Stability

American DASH Low GI
Median ? (pg/ml) 0.5
-0.4 0.2
65

Weight Stability

American DASH Low GI
Median ? (mmHg) 1 -7
-5
66

Weight Stability

American DASH Low GI
Median ? (mmHg) -1 -2
-4
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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.

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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.

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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

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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.

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American DASH Low GI
Median ? (kg) -10.6
-10.6 -5.0
72

American DASH Low GI
73

American DASH Low GI
74

American DASH Low GI
75

American DASH Low GI
76

American DASH Low GI
Median ? () 0
-0.2 -0.2
77

?
?

American DASH Low GI
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Future Directions
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NewStudy(n 39)
Wt Stable on Western Diet
2 weeks Inpatient
Testing 1
Wt Stable on Western Diet
Wt Stable on DASH Diet
Wt Stable on Low GI Diet
2 weeks Inpatient
Testing 2
Testing 2
Testing 2
Age range 18-65, no premenopausal women Physical
activity and sleep will be controlled New
procedures to limit weight change to lt 1, Bod
Pods will be done at both timepoints
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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

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THANK YOU FOR YOUR ATTENTION!