Insulin ResistanceInsulin ResistanceMortality/Morbidity, Diagnosis & Mortality/Morbidity, Diagnosis &

TreatmentTreatmentMartin P Albert, MD and Peggy A. Wright, PhD, RDMartin P Albert, MD and Peggy A. Wright, PhD, RD

“The trend in the life expectancy of humans during the past thousand years has been characterized by a

slow, steady increase….Unless effective population-level

interventions to reduce obesity and chronic disease associated with it

are developed, the steady rise in life expectancy observed in the modern

era may soon come to an end and the youth of today may, on average,

live less healthy and possibly even shorter lives than their parents”.

Olshansky SJ et al. A potential decline in life expectancy in the United Olshansky SJ et al. A potential decline in life expectancy in the United States in the 21States in the 21stst century. NEJM. 2005;352(11):1138-1145. century. NEJM. 2005;352(11):1138-1145.

Morbidity: Prevalence of Morbidity: Prevalence of Diabetes in the United Diabetes in the United

StatesStates An estimated 17 million have diabetes mellitusAn estimated 17 million have diabetes mellitus 90-95% have Type 2 diabetes mellitus (T2D)90-95% have Type 2 diabetes mellitus (T2D) 20 million have impaired glucose tolerance (FG 20 million have impaired glucose tolerance (FG

110-120), and have a 10% yearly risk of progressing 110-120), and have a 10% yearly risk of progressing to DMto DM

5-fold increase in T2D in the latter half of the 20th 5-fold increase in T2D in the latter half of the 20th centurycentury

10-fold increase among children and adolescents in the 10-fold increase among children and adolescents in the last decade. last decade.

Lifetime risk of DM for individuals born in 2000Lifetime risk of DM for individuals born in 2000 32.8% for males and 38.5% for females. Females have 32.8% for males and 38.5% for females. Females have

higher residual lifetime risks at all ages. higher residual lifetime risks at all ages. Highest estimated lifetime risk: Hispanics (males, 45.4% Highest estimated lifetime risk: Hispanics (males, 45.4%

and females, 52.5%).and females, 52.5%). Loss of life-years if diagnosed with DM at 40 years Loss of life-years if diagnosed with DM at 40 years

Men: 11.6 life-years and 18.6 quality-adjusted life-years Men: 11.6 life-years and 18.6 quality-adjusted life-years Women: 14.3 life-years and 22.0 quality-adjusted life-years. Women: 14.3 life-years and 22.0 quality-adjusted life-years. Narayan KM - Narayan KM - JAMAJAMA - 8-OCT-2003; 290(14): 1884-90 - 8-OCT-2003; 290(14): 1884-90

Morbidity/Mortality: Morbidity/Mortality: Adding Insulin (Resistance) Adding Insulin (Resistance)

to Injuryto Injury Metabolic Syndrome Metabolic Syndrome Endothelial dysfunctionEndothelial dysfunction Congestive heart failureCongestive heart failure Treatment Resistant HypertensionTreatment Resistant Hypertension Nonalcoholic fatty liver diseaseNonalcoholic fatty liver disease Alzheimer’s diseaseAlzheimer’s disease Cancer (colorectal, breast, prostate)Cancer (colorectal, breast, prostate)

Morbidity: Metabolic Morbidity: Metabolic Syndrome As An American Syndrome As An American

CrisisCrisis High prevalence of metabolic syndrome among High prevalence of metabolic syndrome among

obese children and adolescents. Biomarkers of obese children and adolescents. Biomarkers of increased CV risks already exist in this increased CV risks already exist in this population. population. Weiss, R at al. Obesity and the metabolic syndrome in Weiss, R at al. Obesity and the metabolic syndrome in children and adolescents. NEJM. 2004;350(23):2362-2374.children and adolescents. NEJM. 2004;350(23):2362-2374.

“These results from a representative sample of US adults show that the metabolic syndrome is highly prevalent (24%) …..the large numbers of US residents with the metabolic syndrome may have important implications for the health care sector”. Ford ES, Giles WH, Dietz WH. J Am Med Assoc 2002;287: 356

The underlying problem of metabolic syndrome is insulin resistance.

Mortality/Morbidity: Mortality/Morbidity: Insulin Resistance & Insulin Resistance &

Cancer Risk & SurvivalCancer Risk & Survival ColorectalColorectal

Keku TO et al. Insulin resistance, apoptosis, and colorectal adenoma risk. 2005. Cancer Epidemiol Biomarkers Prev;14(9):2076-81.

Higginbotham S et al. Dietary glycemic load and risk of colorectal cancer in the Women's Health Study. 2004. J Natl Cancer Inst;96(3):229-33.

Breast Borugian MJ et al. Insulin, macronutrient intake, and physical activity:

are potential indicators of insulin resistance associated with mortality from breast cancer? 2004. Cancer Epidemiol Biomarkers Prev;13(7):1163-72

Bozcuk H et al. Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. 2004. Cytokine;27(2-3):58-65.

Ovarian Augustin LS et al. Dietary glycemic index, glycemic load and ovarian

cancer risk: a case-control study in Italy. 2003. Ann Oncol;14(1):78-84. Prostate

Hsing AW et al. Insulin resistance and prostate cancer risk. 2003. J Natl Cancer Inst;95(1):67-71.

Morbidity: Insulin Morbidity: Insulin Resistance & Cognitive Resistance & Cognitive

DeclineDecline Alzheimer’s Disease Alzheimer’s Disease

Friedrich MJ. Insulin effects weigh heavy on the brain. Friedrich MJ. Insulin effects weigh heavy on the brain. JAMA 2006:296(14):1717-1718.JAMA 2006:296(14):1717-1718.

Fishel MA et al. Hyperinsulinemia provokes Fishel MA et al. Hyperinsulinemia provokes synchronous increases in central inflammation and synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol. beta-amyloid in normal adults. Arch Neurol. 2005;62(10):1539-1544.2005;62(10):1539-1544.

Steen E et al. Impaired insulin and insulin-like growth Steen E et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in factor expression and signaling mechanisms in Alzheimer’s disease—is the type 3 diabetes? J Alzheimer’s disease—is the type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80.Alzheimers Dis. 2005;7(1):63-80.

Cognitive decline in elderly with Cognitive decline in elderly with metabolic syndromemetabolic syndrome Yaffe K et al. The metabolic syndrome, inflammation, Yaffe K et al. The metabolic syndrome, inflammation,

and risk of cognitive decline. JAMA. and risk of cognitive decline. JAMA. 2004;292(18):2237-2242.)2004;292(18):2237-2242.)

Morbidity: NASH, HBP, & Morbidity: NASH, HBP, & CHFCHF

Close association between insulin resistance Close association between insulin resistance and nonalcoholic fatty liver disease.and nonalcoholic fatty liver disease. (McCullough, (McCullough, AJ. Thiazolidinediones for nonalcoholic steatohepatitis—promising but AJ. Thiazolidinediones for nonalcoholic steatohepatitis—promising but not ready for prime time. NEJM. 2006;355(22):2361-2363.)not ready for prime time. NEJM. 2006;355(22):2361-2363.)

Hyperinsulinemia may directly contribute to elevated Hyperinsulinemia may directly contribute to elevated blood pressure by enhancing sympathetic nervous blood pressure by enhancing sympathetic nervous system activity and promoting renal sodium retention. system activity and promoting renal sodium retention. INS may also indirectly increase blood pressure by INS may also indirectly increase blood pressure by decreasing the signaling processes that are important decreasing the signaling processes that are important for vascular relaxation. for vascular relaxation. (Sowers, J. R. and E. D. Frohlich (Sowers, J. R. and E. D. Frohlich (2004). "Insulin and insulin resistance: impact on blood pressure (2004). "Insulin and insulin resistance: impact on blood pressure and cardiovascular disease." and cardiovascular disease." Med Clin North AmMed Clin North Am 8888(1): 63-82.(1): 63-82.

Insulin resistance predicted congestive heart Insulin resistance predicted congestive heart failure incidence independently of established failure incidence independently of established risk factors. risk factors. Ingelsson E. Insulin resistance and risk of Ingelsson E. Insulin resistance and risk of

congestive heart failure. congestive heart failure. JAMAJAMA - 20-JUL-2005; 294(3): 334-41. - 20-JUL-2005; 294(3): 334-41.

Mechanism of Insulin Mechanism of Insulin ResistanceResistance

Positive net energy balancePositive net energy balance Hypertrophic adipocytesHypertrophic adipocytes Metabolic byproducts result in Metabolic byproducts result in

phosphorylation and glycosylation of insulin phosphorylation and glycosylation of insulin receptor, which terminates the insulin receptor, which terminates the insulin signal. signal.

GLUT4 no longer moves to the cell GLUT4 no longer moves to the cell membrane to let in insulin.membrane to let in insulin.

Instead of glycogen storage, get circulation Instead of glycogen storage, get circulation of free fatty acids, lipid storage, of free fatty acids, lipid storage, inflammation (TNF-alpha, IL-6), and inflammation (TNF-alpha, IL-6), and reactive oxidative products from fatty acid reactive oxidative products from fatty acid metabolism.. metabolism..

Mechanism of Insulin Mechanism of Insulin ResistanceResistance

Where does plasma glucose go under ideal Where does plasma glucose go under ideal circumstances?circumstances? 80-85% to muscle80-85% to muscle 5-10% to liver5-10% to liver <=5% to adipose tissue<=5% to adipose tissue

Where does the fatty acid “spill over” in Where does the fatty acid “spill over” in IR?IR? Blood (hypertriglyceridemia)Blood (hypertriglyceridemia) Adipocyte (central obesity)Adipocyte (central obesity) Muscle (intramyocellular lipid deposition)Muscle (intramyocellular lipid deposition) Liver (NASH)Liver (NASH) Pancreas (Beta cell apoptosis and loss of insulin Pancreas (Beta cell apoptosis and loss of insulin

secretory ability)secretory ability) Endothelial cells (hypothesis)Endothelial cells (hypothesis)

Mechanisms: Adipose Mechanisms: Adipose Tissue & Insulin SensitivityTissue & Insulin Sensitivity

What is the largest endocrine organ What is the largest endocrine organ of the human body?of the human body?

Adipose tissue—even the very lean Adipose tissue—even the very lean will have 10-15 pounds of adipose will have 10-15 pounds of adipose that contributes at least 25 different that contributes at least 25 different adipokines. adipokines.

The The adipokinesadipokines or or adipocytokinesadipocytokines are a group of cell-to-cell signaling are a group of cell-to-cell signaling proteins secreted by adipose tissue.proteins secreted by adipose tissue.

ADIPOKINES ASSOCIATED WITH INSULIN SENSITIVITY1. ADIPONECTIN (ACRP)2. LEPTIN

ADIPOKINES ASSOCIATED WITH INSULIN RESISTANCE3. RESISTIN (FOR RESISTANCE TO INSULIN)4. TUMOR NECROSIS FACTOR (TNF)5. INTERLEUKIN –6 (IL-6)

ADIPOCTYE PROTEINS AND LIPID METABOLISM6. ADIPSIN7. ACYLATION STIMULATING PROTEIN (ASP)8. AQUAPORIN ADIPOSE (AQPap)

Adipocyte Products

Adipocyte Products

ADIPOKINES AND HEMOSTASIS9. PLASMINOGEN ACTIVATOR INHIBITOR –1 (PA1-1)10. ADIPOCYTE RENIN–ANGIOTENSIN SYSTEM (RAS)

ADIPOSE AROMATASE AND INTRAADIPOSE GLUCOCORTICOIDS11. AROMATASE12. 11 HYDROXYSTEROID DEHYDROGENASE (11 HSD-1)

OTHER ADIPOCYTE PROTEINS13. METALLOTHIONEIN AND ITS GENES (MT-1; MT-2)14. FASTING–INDUCED ADIPOSE FACTOR (FIAF)15. LIPOPROTEIN LIPASE; CHOLESTERYL ESTER

TRANSFERANCE:16. APOLIPOPROTEIN E; RETINOL BINDING PROTEIN

Causes of Insulin Causes of Insulin Resistance: Dietary Factors Resistance: Dietary Factors

11 The primary cause is our food supply The primary cause is our food supply

and meal habits. Secondary is change in and meal habits. Secondary is change in exercise habits.exercise habits.

Glucose “overload”Glucose “overload” Fiber “shortage”Fiber “shortage”

Refined grains in breads, pasta, crackers, Refined grains in breads, pasta, crackers, etc.etc.

Fewer legumes & legumes bred for less fiber Fewer legumes & legumes bred for less fiber (soluble fiber)(soluble fiber)

Fewer high fiber fruits and vegetablesFewer high fiber fruits and vegetables

Causes of Insulin Causes of Insulin Resistance: Dietary Factors Resistance: Dietary Factors

22 Fat “overload”Fat “overload” Marbled meat from inactive/immoblized feedlot Marbled meat from inactive/immoblized feedlot

animalsanimals Vegetable oils (corn, soy, safflower, etc.)Vegetable oils (corn, soy, safflower, etc.) Eating out: gourmet, family, and fast-food Eating out: gourmet, family, and fast-food

restaurantsrestaurants Large portion sizesLarge portion sizes

Insufficient vitamins, minerals, and Insufficient vitamins, minerals, and micronutrients from eating too few whole grains, micronutrients from eating too few whole grains, fruits and vegetables, and insufficient sunlight.fruits and vegetables, and insufficient sunlight.

Insufficient phytonutrients (fruits and Insufficient phytonutrients (fruits and vegetables)vegetables)

Additives that interfere with cell signaling Additives that interfere with cell signaling mechanisms and structures.mechanisms and structures.

Causes of IR: Causes of IR: Responsiveness to Dietary Responsiveness to Dietary

CompositionComposition Deterioration in carbohydrate metabolism and Deterioration in carbohydrate metabolism and

lipoprotein changes induced by modern, high lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians.fat diet in Pima Indians and Caucasians.

Compared with the traditional diet, the modern diet Compared with the traditional diet, the modern diet was associated with a decrease in oral glucose was associated with a decrease in oral glucose tolerance and higher plasma cholesterol tolerance and higher plasma cholesterol concentrations in both ethnic groups. concentrations in both ethnic groups.

This occurred in the 14-day study time. This occurred in the 14-day study time. ““Since glucose-mediated glucose disposal, beta-Since glucose-mediated glucose disposal, beta-

cell function, and glucose tolerance deteriorated cell function, and glucose tolerance deteriorated on the modern diet, on the modern diet, it is likely that diet it is likely that diet composition affects the prevalence of composition affects the prevalence of noninsulin-dependent diabetes mellitus in noninsulin-dependent diabetes mellitus in both Pimas and Caucasians.” both Pimas and Caucasians.” Swinburn B et al.Swinburn B et al. Deterioration in carbohydrate metabolism and lipoprotein changes Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasiansinduced by modern, high fat diet in Pima Indians and Caucasians. . J Clin J Clin Endocrinol Metab. 1991 Jul;73(1):156-65.Endocrinol Metab. 1991 Jul;73(1):156-65.

Useful Diagnostic findings Useful Diagnostic findings associated with Insulin associated with Insulin

Resistance Resistance

Visceral obesity and BMI : Visceral obesity and BMI : over 40 in a man over 40 in a man over 35 in a womanover 35 in a woman

The total TGL to HDL ratio. If it is greater than 3, The total TGL to HDL ratio. If it is greater than 3, there's a 70% chance or better that the patient is there's a 70% chance or better that the patient is insulin resistant. insulin resistant.

Lipoprotein subgroup analysis: Lipoprotein subgroup analysis: dense LDL,dense LDL, associated with increased triglyceride levels,associated with increased triglyceride levels, low HDL, and a low HDL, and a shift toward high VLDL levels.shift toward high VLDL levels.

Diagnosis: Fasting Insulin Diagnosis: Fasting Insulin and BSand BS

Advantages: Advantages: Usual testing: part of the CMET, inexpensive, Usual testing: part of the CMET, inexpensive,

and relatively easy.and relatively easy. Will screen for persons with relatively advanced Will screen for persons with relatively advanced

insulin resistance. insulin resistance. Useful for following the change in insulin Useful for following the change in insulin

resistance of a given patient: resistance of a given patient: Used in research studies, such as the Diabetes Used in research studies, such as the Diabetes

Prevention Program.Prevention Program. DisadvantagesDisadvantages

Will miss a large number of people with early Will miss a large number of people with early impaired insulin resistance and glucose impaired insulin resistance and glucose intolerance.intolerance.

Problem: Problem: Early “ain’t” early enoughEarly “ain’t” early enough

Diagnosis: Glucose Diagnosis: Glucose Tolerance Test with Insulin Tolerance Test with Insulin

LevelsLevels “…“…post-challenge glucose levels provide post-challenge glucose levels provide

additional information which may be additional information which may be helpful in the prediction of CVDhelpful in the prediction of CVD.”.”

““Debate continues whether such testing Debate continues whether such testing should be undertaken, because should be undertaken, because administering glucose tolerance tests is administering glucose tolerance tests is troublesome, results vary, and the clinical troublesome, results vary, and the clinical benefit is not definite.”benefit is not definite.”

Disadvantage: Time, cost, discomfort.Disadvantage: Time, cost, discomfort.  

Estimating cardiovascular disease risk and the metabolic syndrome: a Estimating cardiovascular disease risk and the metabolic syndrome: a Framingham viewFramingham view. Endocrinology and Metabolism Clinics. Endocrinology and Metabolism Clinics - Volume 33, - Volume 33, Issue 3 (September 2004)Issue 3 (September 2004)

Diagnosis: HgbA1C Diagnosis: HgbA1C (Glycosylated hemoglobin)(Glycosylated hemoglobin)

AdvantagesAdvantages Independent Predictor of risk of all cause mortalityIndependent Predictor of risk of all cause mortality Easy and inexpensiveEasy and inexpensive Functional (physiological) Reflection of all factors Functional (physiological) Reflection of all factors

affecting blood sugar and insulin resistance.affecting blood sugar and insulin resistance. Easy concept for patients to understandEasy concept for patients to understand Serial comparisons helpful for patient education Serial comparisons helpful for patient education

DisadvantagesDisadvantages Problems with insurance payment for screening Problems with insurance payment for screening

Ideal level: Below 5%Ideal level: Below 5%

Diagnosis: IR & All-cause Diagnosis: IR & All-cause MortalityMortality

The European Prospective Investigation of Cancer The European Prospective Investigation of Cancer and Nutrition-Norfolk study, found a continuous and Nutrition-Norfolk study, found a continuous relationship between all-cause mortality and relationship between all-cause mortality and glycosylated hemoglobin even for values in the glycosylated hemoglobin even for values in the nondiabetic range in men ages 45-79 years. nondiabetic range in men ages 45-79 years.

An increase of 1% in HbA1c was associated with An increase of 1% in HbA1c was associated with a 28% (a 28% (PP < 0.002) increase in risk of death < 0.002) increase in risk of death independent of age, blood pressure, serum independent of age, blood pressure, serum cholesterol, body mass index, and cigarette cholesterol, body mass index, and cigarette smoking.smoking.

This effect remained (RR, 1.46; This effect remained (RR, 1.46; PP = 0.05 adjusted for = 0.05 adjusted for age and risk factors) after men with known diabetes, age and risk factors) after men with known diabetes, a HbA1c concentration greater than 7%, or a history a HbA1c concentration greater than 7%, or a history of myocardial infarction or stroke were excluded.of myocardial infarction or stroke were excluded.

Srikanth S, Deedwania P. Comprehensive risk reduction of cardiovascular risk factors in the diabetic Srikanth S, Deedwania P. Comprehensive risk reduction of cardiovascular risk factors in the diabetic

patient: an integrated approach. Cardiology Clinics - Volume 23, Issue 2 (May 2005)patient: an integrated approach. Cardiology Clinics - Volume 23, Issue 2 (May 2005)

Diagnosis: 2 hr Diagnosis: 2 hr postprandial testingpostprandial testing

2 hr post-prandial insulin, BS, and lipid panel2 hr post-prandial insulin, BS, and lipid panel AdvantagesAdvantages

Relatively easy and inexpensiveRelatively easy and inexpensive Physiologic, functional test. Reflects what is Physiologic, functional test. Reflects what is

actually happening to that patient in real life.actually happening to that patient in real life. Useful for patient coaching and feedback. Useful for patient coaching and feedback.

Different outcomes for different mealsDifferent outcomes for different meals Serial values show results of lifestyle changeSerial values show results of lifestyle change

Identifies insulin resistance years earlier than Identifies insulin resistance years earlier than fasting studiesfasting studies

DisadvantagesDisadvantages Not using standard meal, results will varyNot using standard meal, results will vary If LDL is calculated, fasting triglycerides are If LDL is calculated, fasting triglycerides are

needed needed

Treatment Strategies: Treatment Strategies: OverviewOverview

DownstreamDownstream Pharmacological Treatment of Consequences: Pharmacological Treatment of Consequences:

Statins, antihypertensives, platelet-aggregation Statins, antihypertensives, platelet-aggregation inhibitors, hypoglycemics, appetite suppressing inhibitors, hypoglycemics, appetite suppressing drugsdrugs

Botanical treatment: Lipid lowering agents, Botanical treatment: Lipid lowering agents, platelet-aggregation inhibitors, hypoglycemics platelet-aggregation inhibitors, hypoglycemics

UpstreamUpstream Treatment strategies based on primary Treatment strategies based on primary

causes, not downstream effects.causes, not downstream effects. Recognize the social-environmental aspects Recognize the social-environmental aspects

of primary causes.of primary causes. Support a change in lifestyle for the Support a change in lifestyle for the

community.community. Model a change in lifestyle for the patient.Model a change in lifestyle for the patient.

Treatment of IR: Treatment of IR: Upstream ChoicesUpstream Choices

Problem: Refined grains and sweetenersProblem: Refined grains and sweeteners Foods are not only “fast” foods but “fast release” Foods are not only “fast” foods but “fast release”

foods foods American diet is high in calorie-dense, insulin-provoking American diet is high in calorie-dense, insulin-provoking

refined carbohydrates (e.g., flour, sugar, corn syrup) refined carbohydrates (e.g., flour, sugar, corn syrup) Loss of blood-glucose moderating fiberLoss of blood-glucose moderating fiber 98% of grain products consumed in the US are 98% of grain products consumed in the US are

refinedrefined Refined grains: blood sugar and insulin responses Refined grains: blood sugar and insulin responses

2-3 times greater than whole grains or coarse-2-3 times greater than whole grains or coarse-milled productsmilled products

Loss of micronutrients involved in glucose Loss of micronutrients involved in glucose regulationregulation vanadium, zinc, chromium, copper, iron, and nickel

White versus Whole White versus Whole WheatWheat

(Source: Nutrition Action Newsletter, May 2006)(Source: Nutrition Action Newsletter, May 2006) Whole Wheat 100 %Whole Wheat 100 % White: % of nutrients, compared to whole wheatWhite: % of nutrients, compared to whole wheat

Vitamin E 7%Vitamin E 7% Vitamin B6 13%Vitamin B6 13% Riboflavin 19% (230%)*Riboflavin 19% (230%)* Niacin 20% (93%)*Niacin 20% (93%)* Magnesium 16%Magnesium 16% Fiber 22%Fiber 22% Zinc 24%Zinc 24% Potassium 26%Potassium 26% Thiamine 27% (176%)*Thiamine 27% (176%)* Iron 30 % (120%)*Iron 30 % (120%)* Copper 36%Copper 36% Selenium 48%Selenium 48% Folate 59% (416%) *Folate 59% (416%) *

*Added in “enriched products” *Added in “enriched products”

Treatment of IR: Treatment of IR: Upstream ChoicesUpstream Choices

Treatment: Eat minimally processed foods.Treatment: Eat minimally processed foods. Use only whole grains Use only whole grains

100% whole wheat bread, oatmeal, barley, 100% whole wheat bread, oatmeal, barley, brown rice, quinoa, millet, stone-ground corn brown rice, quinoa, millet, stone-ground corn meal, etc. meal, etc.

Cut out sugar. Use whole fruit for Cut out sugar. Use whole fruit for sweetness.sweetness.

Replace animal protein with legumes Replace animal protein with legumes (soluble fiber, protein, vitamins, minerals)(soluble fiber, protein, vitamins, minerals) 3-bean salad, hummus, lentil and minestrone 3-bean salad, hummus, lentil and minestrone

soups, veggie chili, etc.soups, veggie chili, etc.

Upstream Treatment of IR: Upstream Treatment of IR:

Whole GrainsWhole Grains A diet high in rapidly absorbed carbohydrates and low A diet high in rapidly absorbed carbohydrates and low

in cereal fiber has been found to be associated with an in cereal fiber has been found to be associated with an increased risk of type 2 diabetes. increased risk of type 2 diabetes. Schulze MB et al. Glycemic Schulze MB et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. AJCN. 2004;80:348-356.younger and middle-aged women. AJCN. 2004;80:348-356.

Increasing whole grain foods to 3-servings daily may Increasing whole grain foods to 3-servings daily may reduce the risk of developing type 2 DM by as much as reduce the risk of developing type 2 DM by as much as 30%. 30%. McKeown NM. Whole grain intake and insulin sensitivity: evidence from McKeown NM. Whole grain intake and insulin sensitivity: evidence from observational studies. Nutr Rev. 2004;62(7):286-291.observational studies. Nutr Rev. 2004;62(7):286-291.

A high CHO intake from low glycemic index sources A high CHO intake from low glycemic index sources may be superior in terms of increasing fat oxidation may be superior in terms of increasing fat oxidation and improving overall glucose regulation than reducing and improving overall glucose regulation than reducing CHO and increasing protein and fat. Postprandial CHO and increasing protein and fat. Postprandial glycemia should be avoided even when fasting glucose glycemia should be avoided even when fasting glucose is normalis normal. Brand-Miller JC. Postprandial glycemia, glycemic index, . Brand-Miller JC. Postprandial glycemia, glycemic index, and the prevention of type 2 diabetes. AJCN. 2004;80:243-244.and the prevention of type 2 diabetes. AJCN. 2004;80:243-244.

Treatment of IR: Upstream Treatment of IR: Upstream ChoicesChoices

Problem: Imbalanced fat intakeProblem: Imbalanced fat intake High intake of transfats (crackers, bakery goods, High intake of transfats (crackers, bakery goods,

etc.)etc.) Lefevre, M., J. C. Lovejoy, et al. (2005). "Comparison of the acute response to meals Lefevre, M., J. C. Lovejoy, et al. (2005). "Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes." differing FABP2 genotypes." MetabolismMetabolism 5454(12): 1652-8.(12): 1652-8.

High intake of saturated fats (meats)High intake of saturated fats (meats) Haag, M. and N. G. Haag, M. and N. G. Dippenaar (2005). "Dietary fats, fatty acids and insulin resistance: short review of a Dippenaar (2005). "Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection." multifaceted connection." Med Sci MonitMed Sci Monit 1111(12): RA359-67.(12): RA359-67.

Low omega-3 fats.Low omega-3 fats. Mostad, I. L., K. S. Bjerve, et al. (2006). "Effects of n-3 fatty Mostad, I. L., K. S. Bjerve, et al. (2006). "Effects of n-3 fatty acids in subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent acids in subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent alteration from carbohydrate to fat oxidation." alteration from carbohydrate to fat oxidation." Am J Clin NutrAm J Clin Nutr 8484(3): 540-50.(3): 540-50.

Feedlot beef, poultry, and fish have few omega-3 Feedlot beef, poultry, and fish have few omega-3 fatty acids, which help normalize insulin signaling. fatty acids, which help normalize insulin signaling.

Increased use of corn oil, safflower oil, soy oil, Increased use of corn oil, safflower oil, soy oil, which are omega-3 poor.which are omega-3 poor.

Affects inflammation and signal transductionAffects inflammation and signal transduction

Treatment of IR: Upstream Treatment of IR: Upstream ChoicesChoices

Solution: Healthy fatsSolution: Healthy fats Eliminate all trans fats-- bakery goods, partially Eliminate all trans fats-- bakery goods, partially

hydrogenated oils in margarines, many commercial hydrogenated oils in margarines, many commercial crackers and cookies. crackers and cookies. Less than 0.5 g need not be labeled, so look at Less than 0.5 g need not be labeled, so look at

contents: i.e. partially hydrogenated oilcontents: i.e. partially hydrogenated oil SeverelySeverely limit high-saturated fat meats (beef, pork, limit high-saturated fat meats (beef, pork,

bacon, etc.) bacon, etc.) Avoid deep-fried foods.Avoid deep-fried foods. Include high omega-3 fish or fish oil. (2 grams of Include high omega-3 fish or fish oil. (2 grams of

EPA/DHA daily average)EPA/DHA daily average) Use monounsaturated olive oil (preferably extra Use monounsaturated olive oil (preferably extra

virgin) as primary oil.virgin) as primary oil.

Insulin Resistance: Insulin Resistance: Upstream Treatment Upstream Treatment

choiceschoices ProblemProblem: :

Meal patterns that “starve” people during the day and Meal patterns that “starve” people during the day and “gorge” at night. The Sumo wrestler effect. “gorge” at night. The Sumo wrestler effect.

Meal habits with oversize portions, small hi-carb Meal habits with oversize portions, small hi-carb breakfasts, few fruits and vegetables, & large dinners. breakfasts, few fruits and vegetables, & large dinners.

SolutionSolution: : 3 meals per day3 meals per day Larger high-protein, moderate fat breakfast (see Larger high-protein, moderate fat breakfast (see

handout)handout) Smaller dinnersSmaller dinners No evening snackingNo evening snacking Increase fruits and vegetablesIncrease fruits and vegetables

DASH and Mediterranean dietsDASH and Mediterranean diets Minimum of 5, preferably 10 servings per dayMinimum of 5, preferably 10 servings per day

Insulin Resistance: Insulin Resistance: Upstream Treatment Upstream Treatment

choiceschoices Problem: Problem: Addition of additives that interfere with cell Addition of additives that interfere with cell

signaling mechanisms and structures.signaling mechanisms and structures. trans fatstrans fats artificial sweeteners artificial sweeteners

increases appetite and causes weight gainincreases appetite and causes weight gain gelatinous starches & sugary syrups in “fat-free” gelatinous starches & sugary syrups in “fat-free”

foodfood flavor enhancers (example: MSG)flavor enhancers (example: MSG)

Solution: Solution: Eat food, not “food like substances.”Eat food, not “food like substances.” Avoid items with more than a few ingredients, or Avoid items with more than a few ingredients, or

whose contents sound like a chemical cataloguewhose contents sound like a chemical catalogue Avoid trans fats completelyAvoid trans fats completely Avoid foods with added sugars, corn syrup and Avoid foods with added sugars, corn syrup and

artificial sweetenersartificial sweeteners

Insulin Resistance: Insulin Resistance: Upstream Treatment Upstream Treatment

choiceschoices ProblemProblem: Lack of Exercise: Lack of Exercise Mechanism:Mechanism: Exercise reduces IR by Exercise reduces IR by

increasing GLUT-4 mediated transport increasing GLUT-4 mediated transport of glucose into target tissues.of glucose into target tissues.

SolutionSolution: : Regular exercise: starting with whatever Regular exercise: starting with whatever

is do-able: example walk 15 minutes is do-able: example walk 15 minutes every dayevery day

Make lifestyle more active: Avoid Make lifestyle more active: Avoid elevators, park at corner of lot, etc. elevators, park at corner of lot, etc.

Treatment: Diabetes Treatment: Diabetes Prevention Program Prevention Program

Research Group Research Group “Lifestyle changes and treatment with

metformin both reduced the incidence of diabetes in persons at risk. The lifestyle intervention was more effective than metformin”. Exercise and weight loss also improve endothelial function.

A moderate diet and 150 minutes of walking each week decreased the incidence of new diabetes by 58% in subjects with impaired glucose tolerance, and was effective in all age groups, whereas metformin treatment was associated with a 31% decreased risk of diabetes, but was not effective in subjects older than 60 years Diabetes Prevention Program Research Group. Reduction Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM. 2002;346:393-403.NEJM. 2002;346:393-403.

Treatment:Treatment:Finnish Diabetes Finnish Diabetes Prevention StudyPrevention Study

People at risk for Type 2 DMPeople at risk for Type 2 DM Lifestyle interventionLifestyle intervention

Weight lossWeight loss Reduced total and saturated fatReduced total and saturated fat Increased dietary fiberIncreased dietary fiber Increased physical activityIncreased physical activity

7-year follow-up7-year follow-up Reduction in DM incidence sustained Reduction in DM incidence sustained

after lifestyle counseling was stoppedafter lifestyle counseling was stopped Lindstorm J et al. Sustained reduction in the incidence of type 2 Lindstorm J et al. Sustained reduction in the incidence of type 2

diabetes by lifestyle intervention: follow-up of the Finnish diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006; 368:1673-1678.Diabetes Prevention Study. Lancet. 2006; 368:1673-1678.

Treatment: Adequate 25-Treatment: Adequate 25-OH vitamin DOH vitamin D

“The data show a positive correlation of 25-hydroxyD3 with insulin sensitivity and a negative effect of hypovitaminosis D on beta cell function. Individuals with hypovitaminosis D are at higher risk to insulin resistance and metabolic syndrome”. Am J Clin Nutrition 2004; 79: 820-25.

“The recommended adequate intakes for vitamin D areinadequate, and, in the absence of exposure to sunlight,a minimum of 1000 IU vitamin D3 is required to maintain a health concentration of 25-hydroxyvitamin D3 in the blood”. (greater than 50 nmol/L) Am J Clin Nutrition 2004; 39; 362-71.

Vitamin D Levels in 58 Vitamin D Levels in 58 patients in Buckingham patients in Buckingham

County 2006County 2006 Vitamin D LevelVitamin D LevelNumber of patientsNumber of patients

<10 ng/ml<10 ng/ml 8 (14%)8 (14%) 10-2010-20 29 (50%)29 (50%) 21-3021-30 10 (17%)10 (17%)---------------------------------------------------------------------------------------------------- 31-4031-40 6 (10%)6 (10%) >41>415 (7%)5 (7%)

Botanical Hypoglycemics: Botanical Hypoglycemics: Metformin Metformin

Galega officinalisGalega officinalis has been known has been known since the Middle since the Middle Ages for relieving Ages for relieving the symptoms of the symptoms of diabetesdiabetes

Also known as Also known as Goat's Rue, Goat's Rue, French Lilac, French Lilac, Italian Fitch or Italian Fitch or Professor-weed.Professor-weed.

Insulin Resistance: Insulin Resistance: Downstream Treatment Downstream Treatment

choices: Botanicalschoices: Botanicals Botanical hypoglycemics: examplesBotanical hypoglycemics: examples

Fiber: glucomannonFiber: glucomannon Spices: Cinnamon: Spices: Cinnamon: Cinnamon – Cinnamon –

Stimulates cellular glucose uptake and Stimulates cellular glucose uptake and glycogen synthesis to a similar level as glycogen synthesis to a similar level as insulin (insulin (Jrnl of American College of NutrJrnl of American College of Nutr 2001;20(4);327-36)2001;20(4);327-36)

Aryuvedics: gymnema, fenugreekAryuvedics: gymnema, fenugreek Hops/acacia– InsinaseHops/acacia– Insinase Silymarin (milk thistle)Silymarin (milk thistle) TCM: bitter melonTCM: bitter melon

IR Downstream Treatment IR Downstream Treatment Choices: Nutritional Choices: Nutritional

AntioxidantsAntioxidants Anti-oxidants:Anti-oxidants: Alpha lipoic acid (Alpha lipoic acid (Alpha-lipoic acid – Stimulates Alpha-lipoic acid – Stimulates

glucose transport very effectively. glucose transport very effectively. DiabetesDiabetes 2001; 2001; 50:1464-147150:1464-1471))

Green tea – increased glucose metabolism in Green tea – increased glucose metabolism in adipocytes (fat cells) adipocytes (fat cells) ((Experimental and Experimental and Molecular MedicineMolecular Medicine 2003; 35(2): 136-139) 2003; 35(2): 136-139) Epigallocatechin gallate. ECGC Standardized Epigallocatechin gallate. ECGC Standardized catachins. Reduces oxidation of LDL Reduces APO catachins. Reduces oxidation of LDL Reduces APO b. Reduces mycellar absorption of cholesterol from b. Reduces mycellar absorption of cholesterol from GI tract. Shunts to TI3K pathway. Increases insulin GI tract. Shunts to TI3K pathway. Increases insulin sensitivity through 2 or 3 pathwayssensitivity through 2 or 3 pathways

Olive leaf, olive oil Olive leaf, olive oil (monounsaturated) prevent (monounsaturated) prevent oxidation of LDL, raise nitrous oxide levels, and oxidation of LDL, raise nitrous oxide levels, and improve insulin resistance improve insulin resistance (Mark Houston, MD. What Your (Mark Houston, MD. What Your Doctor May Not Tell You About Hypertension. 2003. New York: Doctor May Not Tell You About Hypertension. 2003. New York: Warner Books.)Warner Books.)

Problem: Wrong dietary recommendations for CHD

“Based on current evidence, replacement of total, unsaturated, and even possibly saturated fats with refined, high-glycemic index carbohydrates is unlikely to reduce CHD risk and may increase risk in persons predisposed to insulin resistance.”

Solution: Correct dietary recommendations. 1) rich in whole grains and other minimally

processed carbohydrates; 2) includes moderate amounts of fats particularly

unsaturated fats and omega-3 polyunsaturated fats from seafood and plant sources;

3) is lower in refined grains and carbohydrates; and 4) eliminates packaged foods, baked goods, and fast

foods containing trans fatty acids Mozaffarian, D. (2005). "Effects of dietary fats versus

carbohydrates on coronary heart disease: a review of the evidence." Curr Atheroscler Rep 7(6): 435-45.

Insulin Resistance and Insulin Resistance and Diet: 10 word summary Diet: 10 word summary

From Michael Pollan: From Michael Pollan: Eat FoodEat Food Don’t eat a lotDon’t eat a lot Eat mostly vegetablesEat mostly vegetables New York Times Magazine Jan 28, New York Times Magazine Jan 28,

2007. (Also See Michael Pollan’s 2007. (Also See Michael Pollan’s book: The Omnivore’s Dilemma)book: The Omnivore’s Dilemma)