Transcript Insulin Resistance: Morbidity, Mortality, Diagnosis and

Insulin Resistance
Mortality/Morbidity, Diagnosis & Treatment
Martin 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 populationlevel 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 States in the
21st century. NEJM. 2005;352(11):1138-1145.
Morbidity: Prevalence of Diabetes
in the United States






An estimated 17 million have diabetes mellitus
90-95% have Type 2 diabetes mellitus (T2D)
20 million have impaired glucose tolerance (FG 110-120), and
have a 10% yearly risk of progressing to DM
5-fold increase in T2D in the latter half of the 20th century
10-fold increase among children and adolescents in the last decade.
Lifetime risk of DM for individuals born in 2000



32.8% for males and 38.5% for females. Females have higher residual
lifetime risks at all ages.
Highest estimated lifetime risk: Hispanics (males, 45.4% and females,
52.5%).
Loss of life-years if diagnosed with DM at 40 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.

Narayan KM - JAMA - 8-OCT-2003; 290(14): 1884-90

Morbidity/Mortality: Adding
Insulin (Resistance) to Injury







Metabolic Syndrome
Endothelial dysfunction
Congestive heart failure
Treatment Resistant Hypertension
Nonalcoholic fatty liver disease
Alzheimer’s disease
Cancer (colorectal, breast, prostate)
Morbidity: Metabolic Syndrome As
An American Crisis

High prevalence of metabolic syndrome among obese
children and adolescents. Biomarkers of increased CV
risks already exist in this population. Weiss, R at al. Obesity and
the metabolic syndrome in 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: Insulin
Resistance & Cancer Risk & Survival

Colorectal



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


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.
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 Resistance &
Cognitive Decline

Alzheimer’s Disease




Friedrich MJ. Insulin effects weigh heavy on the brain. JAMA
2006:296(14):1717-1718.
Fishel MA et al. Hyperinsulinemia provokes synchronous increases in
central inflammation and beta-amyloid in normal adults. Arch Neurol.
2005;62(10):1539-1544.
Steen E et al. Impaired insulin and insulin-like growth factor expression
and signaling mechanisms in Alzheimer’s disease—is the type 3 diabetes?
J Alzheimers Dis. 2005;7(1):63-80.
Cognitive decline in elderly with metabolic
syndrome

Yaffe K et al. The metabolic syndrome, inflammation, and risk of
cognitive decline. JAMA. 2004;292(18):2237-2242.)
Morbidity: NASH, HBP, & CHF

Close association between insulin resistance and
nonalcoholic fatty liver disease. (McCullough, AJ.
Thiazolidinediones for nonalcoholic steatohepatitis—promising but not ready for
prime time. NEJM. 2006;355(22):2361-2363.)

Hyperinsulinemia may directly contribute to elevated blood
pressure by enhancing sympathetic nervous system activity and
promoting renal sodium retention. INS may also indirectly
increase blood pressure by decreasing the signaling processes
that are important for vascular relaxation. (Sowers, J. R. and E. D.
Frohlich (2004). "Insulin and insulin resistance: impact on blood pressure and
cardiovascular disease." Med Clin North Am 88(1): 63-82.

Insulin resistance predicted congestive heart failure
incidence independently of established risk factors.
Ingelsson E. Insulin resistance and risk of congestive heart failure. JAMA - 20-JUL2005; 294(3): 334-41.
Mechanism of Insulin Resistance





Positive net energy balance
Hypertrophic adipocytes
Metabolic byproducts result in phosphorylation and
glycosylation of insulin receptor, which terminates the
insulin signal.
GLUT4 no longer moves to the cell membrane to let in
insulin.
Instead of glycogen storage, get circulation of free fatty
acids, lipid storage, inflammation (TNF-alpha, IL-6),
and reactive oxidative products from fatty acid
metabolism..
Mechanism of Insulin Resistance

Where does plasma glucose go under ideal
circumstances?




80-85% to muscle
5-10% to liver
<=5% to adipose tissue
Where does the fatty acid “spill over” in IR?






Blood (hypertriglyceridemia)
Adipocyte (central obesity)
Muscle (intramyocellular lipid deposition)
Liver (NASH)
Pancreas (Beta cell apoptosis and loss of insulin secretory
ability)
Endothelial cells (hypothesis)
Mechanisms: Adipose Tissue &
Insulin Sensitivity



What is the largest endocrine organ of the
human body?
Adipose tissue—even the very lean will have 1015 pounds of adipose that contributes at least
25 different adipokines.
The adipokines or adipocytokines are a group
of cell-to-cell signaling proteins secreted by
adipose tissue.
Adipocyte Products
ADIPOKINES ASSOCIATED WITH INSULIN
SENSITIVITY
1. ADIPONECTIN (ACRP)
2. LEPTIN
ADIPOKINES ASSOCIATED WITH INSULIN
RESISTANCE
3. RESISTIN (FOR RESISTANCE TO INSULIN)
4. TUMOR NECROSIS FACTOR (TNF)
5. INTERLEUKIN –6 (IL-6)
ADIPOCTYE PROTEINS AND LIPID METABOLISM
6. ADIPSIN
7. ACYLATION STIMULATING PROTEIN (ASP)
8. AQUAPORIN ADIPOSE (AQPap)
Adipocyte Products
ADIPOKINES AND HEMOSTASIS
9. PLASMINOGEN ACTIVATOR INHIBITOR –1 (PA1-1)
10. ADIPOCYTE RENIN–ANGIOTENSIN SYSTEM (RAS)
ADIPOSE AROMATASE AND INTRAADIPOSE
GLUCOCORTICOIDS
11. AROMATASE
12. 11 HYDROXYSTEROID DEHYDROGENASE (11 HSD-1)
OTHER ADIPOCYTE PROTEINS
13. 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 Resistance:
Dietary Factors 1



The primary cause is our food supply and meal
habits. Secondary is change in exercise habits.
Glucose “overload”
Fiber “shortage”
Refined grains in breads, pasta, crackers, etc.
 Fewer legumes & legumes bred for less fiber (soluble
fiber)
 Fewer high fiber fruits and vegetables

Causes of Insulin Resistance:
Dietary Factors 2

Fat “overload”







Marbled meat from inactive/immoblized feedlot animals
Vegetable oils (corn, soy, safflower, etc.)
Eating out: gourmet, family, and fast-food restaurants
Large portion sizes
Insufficient vitamins, minerals, and micronutrients from
eating too few whole grains, fruits and vegetables, and
insufficient sunlight.
Insufficient phytonutrients (fruits and vegetables)
Additives that interfere with cell signaling mechanisms
and structures.
Causes of IR: Responsiveness to
Dietary Composition

Deterioration in carbohydrate metabolism and lipoprotein
changes induced by modern, high fat diet in Pima Indians
and Caucasians.

Compared with the traditional diet, the modern diet was
associated with a decrease in oral glucose tolerance and higher
plasma cholesterol concentrations in both ethnic groups.
This occurred in the 14-day study time.


“Since glucose-mediated glucose disposal, beta-cell
function, and glucose tolerance deteriorated on the modern
diet, it is likely that diet composition affects the
prevalence of noninsulin-dependent diabetes mellitus
in both Pimas and Caucasians.” Swinburn B et al. Deterioration in
carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in
Pima Indians and Caucasians. J Clin Endocrinol Metab. 1991 Jul;73(1):156-65.
Useful Diagnostic findings
associated with Insulin Resistance



Visceral obesity and BMI :
 over 40 in a man
 over 35 in a woman
The total TGL to HDL ratio. If it is greater than 3, there's a 70%
chance or better that the patient is insulin resistant.
Lipoprotein subgroup analysis:
 dense LDL,
 associated with increased triglyceride levels,
 low HDL, and a
 shift toward high VLDL levels.
Diagnosis: Fasting Insulin and BS

Advantages:




Usual testing: part of the CMET, inexpensive, and relatively
easy.
Will screen for persons with relatively advanced insulin
resistance.
Useful for following the change in insulin resistance of a
given patient:
Used in research studies, such as the Diabetes Prevention
Program.

Disadvantages

Will miss a large number of people with early impaired
insulin resistance and glucose intolerance.
Problem: Early “ain’t” early enough

Diagnosis: Glucose Tolerance Test
with Insulin Levels




“…post-challenge glucose levels provide additional
information which may be helpful in the prediction
of CVD.”
“Debate continues whether such testing should be
undertaken, because administering glucose tolerance
tests is troublesome, results vary, and the clinical benefit
is not definite.”
Disadvantage: Time, cost, discomfort.
Estimating cardiovascular disease risk and the metabolic syndrome: a Framingham view.
Endocrinology and Metabolism Clinics - Volume 33, Issue 3 (September 2004)
Diagnosis: HgbA1C (Glycosylated
hemoglobin)

Advantages






Disadvantages


Independent Predictor of risk of all cause mortality
Easy and inexpensive
Functional (physiological) Reflection of all factors affecting
blood sugar and insulin resistance.
Easy concept for patients to understand
Serial comparisons helpful for patient education
Problems with insurance payment for screening
Ideal level: Below 5%
Diagnosis: IR & All-cause Mortality




The European Prospective Investigation of Cancer and
Nutrition-Norfolk study, found a continuous relationship
between all-cause mortality and glycosylated hemoglobin even
for values in the nondiabetic range in men ages 45-79 years.
An increase of 1% in HbA1c was associated with a 28% (P
< 0.002) increase in risk of death independent of age,
blood pressure, serum cholesterol, body mass index, and
cigarette smoking.
This effect remained (RR, 1.46; P = 0.05 adjusted for age and
risk factors) after men with known diabetes, a HbA1c
concentration greater than 7%, or a history of myocardial
infarction or stroke were excluded.
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)
Diagnosis: 2 hr postprandial testing


2 hr post-prandial insulin, BS, and lipid panel
Advantages



Relatively easy and inexpensive
Physiologic, functional test. Reflects what is actually
happening to that patient in real life.
Useful for patient coaching and feedback.




Different outcomes for different meals
Serial values show results of lifestyle change
Identifies insulin resistance years earlier than fasting studies
Disadvantages


Not using standard meal, results will vary
If LDL is calculated, fasting triglycerides are needed
Treatment Strategies: Overview

Downstream



Pharmacological Treatment of Consequences: Statins,
antihypertensives, platelet-aggregation inhibitors,
hypoglycemics, appetite suppressing drugs
Botanical treatment: Lipid lowering agents, plateletaggregation inhibitors, hypoglycemics
Upstream
 Treatment strategies based on primary causes, not
downstream effects.
 Recognize the social-environmental aspects of
primary causes.
 Support a change in lifestyle for the community.
 Model a change in lifestyle for the patient.
Treatment of IR: Upstream Choices


Problem: Refined grains and sweeteners
Foods are not only “fast” foods but “fast release” foods





American diet is high in calorie-dense, insulin-provoking
refined carbohydrates (e.g., flour, sugar, corn syrup)
Loss of blood-glucose moderating fiber
98% of grain products consumed in the US are refined
Refined grains: blood sugar and insulin responses 2-3
times greater than whole grains or coarse-milled
products
Loss of micronutrients involved in glucose regulation

vanadium, zinc, chromium, copper, iron, and nickel
White versus Whole Wheat
(Source: Nutrition Action Newsletter, May 2006)


Whole Wheat 100 %
White: % of nutrients, compared to whole wheat














Vitamin E 7%
Vitamin B6 13%
Riboflavin 19% (230%)*
Niacin 20% (93%)*
Magnesium 16%
Fiber 22%
Zinc 24%
Potassium 26%
Thiamine 27% (176%)*
Iron 30 % (120%)*
Copper 36%
Selenium 48%
Folate 59% (416%) *
*Added in “enriched products”
Treatment of IR: Upstream Choices


Treatment: Eat minimally processed foods.
Use only whole grains



100% whole wheat bread, oatmeal, barley, brown
rice, quinoa, millet, stone-ground corn meal, etc.
Cut out sugar. Use whole fruit for sweetness.
Replace animal protein with legumes (soluble
fiber, protein, vitamins, minerals)

3-bean salad, hummus, lentil and minestrone soups,
veggie chili, etc.
Upstream Treatment of IR:
Whole Grains

A diet high in rapidly absorbed carbohydrates and low in cereal
fiber has been found to be associated with an increased risk of
type 2 diabetes. Schulze MB et al. Glycemic index, glycemic load, and dietary fiber intake
and incidence of type 2 diabetes in younger and middle-aged women. AJCN. 2004;80:348-356.

Increasing whole grain foods to 3-servings daily may reduce the
risk of developing type 2 DM by as much as 30%. McKeown NM.
Whole grain intake and insulin sensitivity: evidence from observational studies. Nutr Rev.
2004;62(7):286-291.

A high CHO intake from low glycemic index sources may be
superior in terms of increasing fat oxidation and improving
overall glucose regulation than reducing CHO and increasing
protein and fat. Postprandial glycemia should be avoided even
when fasting glucose is normal. Brand-Miller JC. Postprandial glycemia,
glycemic index, and the prevention of type 2 diabetes. AJCN. 2004;80:243-244.
Treatment of IR: Upstream Choices


Problem: Imbalanced fat intake
High intake of transfats (crackers, bakery goods, etc.) 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 differing FABP2 genotypes." Metabolism 54(12): 1652-8.

High intake of saturated fats (meats) Haag, M. and N. G. Dippenaar (2005). "Dietary
fats, fatty acids and insulin resistance: short review of a multifaceted connection." Med Sci Monit 11(12):
RA359-67.

Low omega-3 fats. 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 alteration from carbohydrate to fat
oxidation." Am J Clin Nutr 84(3): 540-50.
Feedlot beef, poultry, and fish have few omega-3 fatty acids,
which help normalize insulin signaling.
 Increased use of corn oil, safflower oil, soy oil, which are
omega-3 poor.
Affects inflammation and signal transduction


Treatment of IR: Upstream Choices






Solution: Healthy fats
Eliminate all trans fats-- bakery goods, partially hydrogenated
oils in margarines, many commercial crackers and cookies.
 Less than 0.5 g need not be labeled, so look at contents: i.e.
partially hydrogenated oil
Severely limit high-saturated fat meats (beef, pork, bacon, etc.)
Avoid deep-fried foods.
Include high omega-3 fish or fish oil. (2 grams of EPA/DHA
daily average)
Use monounsaturated olive oil (preferably extra virgin) as
primary oil.
Insulin Resistance: Upstream
Treatment choices

Problem:



Meal patterns that “starve” people during the day and “gorge” at night.
The Sumo wrestler effect.
Meal habits with oversize portions, small hi-carb breakfasts, few fruits and
vegetables, & large dinners.
Solution:





3 meals per day
Larger high-protein, moderate fat breakfast (see handout)
Smaller dinners
No evening snacking
Increase fruits and vegetables


DASH and Mediterranean diets
Minimum of 5, preferably 10 servings per day
Insulin Resistance: Upstream
Treatment choices


Problem: Addition of additives that interfere with cell signaling
mechanisms and structures.
 trans fats
 artificial sweeteners
 increases appetite and causes weight gain
 gelatinous starches & sugary syrups in “fat-free” food
 flavor enhancers (example: MSG)
Solution:
 Eat food, not “food like substances.”
 Avoid items with more than a few ingredients, or whose
contents sound like a chemical catalogue
 Avoid trans fats completely
 Avoid foods with added sugars, corn syrup and artificial
sweeteners
Insulin Resistance: Upstream
Treatment choices



Problem: Lack of Exercise
Mechanism: Exercise reduces IR by increasing
GLUT-4 mediated transport of glucose into
target tissues.
Solution:
Regular exercise: starting with whatever is do-able:
example walk 15 minutes every day
 Make lifestyle more active: Avoid elevators, park at
corner of lot, etc.

Treatment: Diabetes Prevention
Program 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 in the incidence
of type 2 diabetes with lifestyle intervention or metformin. NEJM. 2002;346:393-403.
Treatment:
Finnish Diabetes Prevention Study


People at risk for Type 2 DM
Lifestyle intervention







Weight loss
Reduced total and saturated fat
Increased dietary fiber
Increased physical activity
7-year follow-up
Reduction in DM incidence sustained after lifestyle
counseling was stopped
Lindstorm J et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle
intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;
368:1673-1678.
Treatment: Adequate 25-OH
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 25hydroxyvitamin D3 in the blood”. (greater than 50
nmol/L) Am J Clin Nutrition 2004; 39; 362-71.
Vitamin D Levels in 58 patients in
Buckingham County 2006

Vitamin D Level
Number of patients
<10 ng/ml
8 (14%)
 10-20
29 (50%)
 21-30
10 (17%)
------------------------------------------------- 31-40
6 (10%)
 >41
5 (7%)

Botanical Hypoglycemics:
Metformin


Galega officinalis has
been known since the
Middle Ages for
relieving the
symptoms of diabetes
Also known as Goat's
Rue, French Lilac,
Italian Fitch or
Professor-weed.
Insulin Resistance: Downstream
Treatment choices: Botanicals

Botanical hypoglycemics: examples
Fiber: glucomannon
 Spices: Cinnamon: Cinnamon – Stimulates cellular
glucose uptake and glycogen synthesis to a similar
level as insulin (Jrnl of American College of Nutr
2001;20(4);327-36)
 Aryuvedics: gymnema, fenugreek
 Hops/acacia– Insinase
 Silymarin (milk thistle)
 TCM: bitter melon

IR Downstream Treatment Choices:
Nutritional Antioxidants

Anti-oxidants:



Alpha lipoic acid (Alpha-lipoic acid – Stimulates glucose
transport very effectively. Diabetes 2001; 50:1464-1471)
Green tea – increased glucose metabolism in adipocytes
(fat cells) (Experimental and Molecular Medicine 2003; 35(2):
136-139) Epigallocatechin gallate. ECGC Standardized
catachins. Reduces oxidation of LDL Reduces APO b.
Reduces mycellar absorption of cholesterol from GI tract.
Shunts to TI3K pathway. Increases insulin sensitivity through
2 or 3 pathways
Olive leaf, olive oil (monounsaturated) prevent oxidation of
LDL, raise nitrous oxide levels, and improve insulin resistance
(Mark Houston, MD. What Your Doctor May Not Tell You About Hypertension.
2003. New York: 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 Diet: 10 word
summary

From Michael Pollan:
 Eat Food
 Don’t eat a lot
 Eat mostly vegetables
 New York Times Magazine Jan 28, 2007.
(Also See Michael Pollan’s book: The
Omnivore’s Dilemma)