Enormous Economic Enormous Economic Consequences of Consequences of Diabetes in the United Diabetes in the United StatesStates

Indirect Costs:Indirect Costs: $40 Billion$40 Billion

Annual Total: $132 Billion*Annual Total: $132 Billion*

Indirect costs due to disability

and early mortality:$40 billion$40 billion

*Approximate 2002 US Dollars

Diabetes/diabetes supplies:$23 billion$23 billion

Direct Costs:Direct Costs: $92 Billion$92 Billion

Excess prevalence of

general medical conditions:$44 billion$44 billion

Excessprevalence of chronic

complications:$25 billion$25 billion

Hogan P, et al. Diabetes Care. 2003;26:917–932.

Shortens average Shortens average life expectancy life expectancy

by up to 15 yearsby up to 15 years

Especially prevalent in Especially prevalent in African and Hispanic African and Hispanic

AmericansAmericans

Impact of Type 1 and Impact of Type 1 and Type 2 DiabetesType 2 Diabetes

DiabetesDiabetes

6th leading 6th leading cause of death cause of death

Adapted from http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04.Diabetes Research Working Group. NIH Pub #99-4398;1999:1–129.

Individuals Individuals diagnoseddiagnosed by 1.3 by 1.3

million each million each yearyear

Increasingly Increasingly affects all age affects all age

groupsgroups

Type 2 Accounts for the Vast Type 2 Accounts for the Vast Majority of Diabetes Mellitus Majority of Diabetes Mellitus CasesCases

Type 2 diabetesType 2 diabetes– About >75% of the diabetes populationAbout >75% of the diabetes population– Dual impairment: Insulin deficiency & Insulin resistanceDual impairment: Insulin deficiency & Insulin resistance– No longer a disease of adults onlyNo longer a disease of adults only– ObesityObesity– Genetic linkGenetic link

Type 1 diabetesType 1 diabetes– Approximately 10% of diabetes populationApproximately 10% of diabetes population– Absolute insulin requirementAbsolute insulin requirement– Autoimmune mediatedAutoimmune mediated

CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.

PrediabetesPrediabetes

Historically has been called impaired Historically has been called impaired glucose tolerance, or borderline glucose tolerance, or borderline diabetesdiabetes

Very high probability of leading to Very high probability of leading to diabetesdiabetes

Broadly defined as a fasting glucose of Broadly defined as a fasting glucose of 110-125mg/dl or impaired glucose 110-125mg/dl or impaired glucose tolerance of 140-199 mg/dl 2 hours tolerance of 140-199 mg/dl 2 hours after a 75 gram glucose loadafter a 75 gram glucose load

Metabolic syndromeMetabolic syndrome(syndrome X)(syndrome X) This syndrome is a relatively recently This syndrome is a relatively recently

recognized group of characteristics recognized group of characteristics that puts a patient at risk for type 2 that puts a patient at risk for type 2 diabetes. They includediabetes. They include– Central obesityCentral obesity– HypertensionHypertension– HyperlipidemiaHyperlipidemia– Insulin resistance or glucose intoleranceInsulin resistance or glucose intolerance– Proinflammatory stateProinflammatory state

Prevalence of Diabetes Is Prevalence of Diabetes Is EscalatingEscalating

2001

1990 1995

(Includes Gestational Diabetes)

Source: Mokdad A, et al. Diabetes Care. 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc. 2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79.

No Data < 4% 4%-6% 6%-8% 8%-10% > 10%

The Role of the Pancreas in The Role of the Pancreas in Blood Sugar RegulationBlood Sugar Regulation

Alpha Cells• Glucagon

• Acts on liver to release glycogen

• Increases blood sugar

Beta Cells• Insulin

• Decreases blood sugar

Delta Cells• Somatostatin

• Stops glucagon and growth hormone

• Decreases blood sugar

Colorado State University. http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/pancreas/anatomy.html. Accessed December 3, 2003.

Normal PhysiologicNormal Physiologic Insulin Insulin Sensitivity and Sensitivity and Cell Function Cell Function Produce EuglycemiaProduce Euglycemia

Pancreas

Normal Insulin Sensitivity

Liver

EuglycemiaEuglycemia

Islet Cell Degranulation;Insulin Released in Response to Elevated Plasma Glucose Muscle Adipose Tissue

Increased Glucose Transport

Decreased Lipolysis

↓ GlucoseProduction

↑ GlucoseUptake

Normal PhysiologicPlasma Insulin

Decreased Glucose Output

Normal Cell Function

Decreased Plasma FFADecreased Plasma FFA

Type 1 DiabetesType 1 Diabetes

BetaBeta cell destructioncell destruction– Usually leading to absolute Usually leading to absolute

insulin deficiencyinsulin deficiency Immune mediatedImmune mediated IdiopathicIdiopathic

American Diabetes Association. Diabetes Care. 2003;26:S33–S50.

Inflammation

T cell

TNF IFNFasL

Autoimmune ReactionMacrophage

Beta cell

CD8+ T cell

TNF

IL-1

NO

Class IMHC

Dendritic cell

Beta cell Destruction

Class IIMHC

Atkinson MA and Eisenbarth GS. Lancet. 2001;358:221–229.

Progression of Type 1 Progression of Type 1 DiabetesDiabetes

Beta Cell Mass

Genetic predisposition

Normal insulin release

Precipitating event

Progressive loss of insulin releaseAntibody

formation

Glucose normal

C-peptide present

No C-peptide present

Overt diabetes

Time

BetaBeta Cell Dysfunction and Cell Dysfunction and Insulin Resistance Produce Insulin Resistance Produce Hyperglycemia in Type 2 Hyperglycemia in Type 2 DiabetesDiabetes

Pancreas

Insulin Resistance

Liver

HyperglycemiaHyperglycemia

Islet Beta Cell Degranulation;Reduced Insulin Content

Muscle Adipose Tissue

Decreased Glucose Transport and Activity

(expression) of GLUT4

Increased Lipolysis

↑GlucoseProduction

↓GlucoseUptake

ReducedPlasma Insulin

Increased Glucose Output

Beta Cell Dysfunction

Elevated Plasma FFA

Elevated Plasma FFA

Setter S, et al. In: Herfindal T, Gourley D, eds. Textbook of Therapeutics:Drug and Disease Management. 7th ed. 2000;377–406.

Prevalence of Prevalence of DiabetesDiabetes

Magnitude of the DiseaseMagnitude of the Disease

AgeAge Adjusted Total Prevalence of Adjusted Total Prevalence of Diabetes in People Aged 20 Years or Diabetes in People Aged 20 Years or Older, by Race/Ethnicity—United States, Older, by Race/Ethnicity—United States, 20022002

Source: 1999-2001 National Health Interview Survey and 1999-2000 National Health and Nutrition Examination Survey estimates projected to year 2002. 2002 outpatient database of the Indian Health Service.

American Indians/Alaskan Natives

Hispanic/Latino Americans

Non-Hispanic African Americans

Non-Hispanic Caucasians

Percent0 10 20 25155

Prevalence of Diabetes at Prevalence of Diabetes at Age 45 to 74 YearsAge 45 to 74 Years

How and why diabetes How and why diabetes affects major affects major physiologic systemsphysiologic systems

Objective 3Objective 3

Metabolic Metabolic Complication PathwaysComplication Pathways

Advanced Glycosylation Advanced Glycosylation EndproductsEndproducts

Sorbitol (polyol) PathwaySorbitol (polyol) Pathway

Advanced Advanced Glycosylation Glycosylation Endproducts (AGE’s)Endproducts (AGE’s) Circulation glucose attaches to Circulation glucose attaches to

various proteins via a process various proteins via a process called glycosylationcalled glycosylation

Glucose attaches to the amino Glucose attaches to the amino terminus of the protein forming terminus of the protein forming aldimine (Schiff base) which later aldimine (Schiff base) which later irreversibly changes through an irreversibly changes through an amadori reaction to AGE’s amadori reaction to AGE’s

AGE’sAGE’s

AGE’s are found in both AGE’s are found in both extracellular and intracellular sites.extracellular and intracellular sites.

These AGE’s then form irreversible These AGE’s then form irreversible protein-protein crosslinks with other protein-protein crosslinks with other amino groups, that permanently amino groups, that permanently attach to macromolecules such as attach to macromolecules such as arterial wall collagenarterial wall collagen

AGE’s – sites affectedAGE’s – sites affected

Other sites affected by AGE’s are Other sites affected by AGE’s are macrophages, endothelial cells, macrophages, endothelial cells, and smooth muscle.and smooth muscle.

AGE’s accumulate over the life of AGE’s accumulate over the life of the patient.the patient.

AGE’s in arterial walls can AGE’s in arterial walls can increase binding for LDL increase binding for LDL cholesterolcholesterol

AGE’s – sites affectedAGE’s – sites affected

AGE formation also causes the AGE formation also causes the thickening of capillary basement thickening of capillary basement membranes.membranes.

This process is thought to be This process is thought to be responsible for the microvascular responsible for the microvascular complications in the eye, kidney, complications in the eye, kidney, and nerve cellsand nerve cells

Sorbitol pathwaySorbitol pathway

Some cells are not dependent on Some cells are not dependent on insulin for entry of glucose (brain insulin for entry of glucose (brain and eye)and eye)

Glucose enters these cells and is Glucose enters these cells and is enzymaticaly converted to enzymaticaly converted to sorbitol and fructosesorbitol and fructose

Sorbitol pathway-Sorbitol pathway-complicationscomplications Elevated glucose levels within the Elevated glucose levels within the

cell leads to an increase in cell leads to an increase in formation of sorbitol and fructose. formation of sorbitol and fructose. These two sugars accumulate These two sugars accumulate within the cell and create a within the cell and create a hyperosmolar state. This increases hyperosmolar state. This increases the amount of water being pulled the amount of water being pulled within the cell which leads to within the cell which leads to swelling and cell damage.swelling and cell damage.

Sorbitol pathway - Sorbitol pathway - complicationscomplications The cellular damage as a result of The cellular damage as a result of

this process is what leads to this process is what leads to damage of the fine blood vessels damage of the fine blood vessels in the retina and peripheral in the retina and peripheral nervous system. nervous system.

Complications of Complications of DiabetesDiabetes

DiabetesDiabetes

AmputationAmputation

BlindnessBlindnessRenal Renal failurefailure

Nerve Nerve damagedamage

CardiovascularCardiovascularcomplicationscomplications

http://www.cdc.gov/diabetes/pubs/factsheet.htm#contents. Accessed 2/10/04.

Chronic ComplicationsChronic Complications

Complications due to chronic Complications due to chronic hyperglycemia are microvascular, hyperglycemia are microvascular, macrovascular, and neuropathicmacrovascular, and neuropathic

Microangiopathy – damage to Microangiopathy – damage to smaller arteries by diffuse smaller arteries by diffuse thickening of the capillary thickening of the capillary basement membranesbasement membranes

Macroangiopathy – damage to Macroangiopathy – damage to larger blood vesselslarger blood vessels

Physiologic systems Physiologic systems affectedaffected Vascular systemVascular system

– The three major types of macrovascular The three major types of macrovascular disease complications in diabetes are CAD disease complications in diabetes are CAD (responsible for 50%-60% of deaths), (responsible for 50%-60% of deaths), cerebrovascular disease, and peripheral cerebrovascular disease, and peripheral vascular disease (PVD).vascular disease (PVD).

Accelerated atherosclerosis in the Accelerated atherosclerosis in the major arteries increase risk of MI, major arteries increase risk of MI, cerebral stroke, aortic aneurysms, and cerebral stroke, aortic aneurysms, and gangrene of lower extremitiesgangrene of lower extremities

Physiologic systemsPhysiologic systems

Diabetic nephropathy Diabetic nephropathy (microangiopathy)(microangiopathy)– Found in 20% - 30% or patients with Found in 20% - 30% or patients with

diabetesdiabetes– Renal failure accounts for many deaths in Renal failure accounts for many deaths in

both type 1 and type 2 patientsboth type 1 and type 2 patients– Symptom include – microalbuminuria, Symptom include – microalbuminuria,

proteinuria, chronic renal failure, and HTNproteinuria, chronic renal failure, and HTN– ACE inhibitors help prevent this damage in ACE inhibitors help prevent this damage in

addition to tight glucose controladdition to tight glucose control

Physiologic systemsPhysiologic systems

Ocular complications (microvascular)Ocular complications (microvascular)– Proliferative and nonproliferative Proliferative and nonproliferative

retinopathy, cataracts and glaucomaretinopathy, cataracts and glaucoma– Damage due to weakened blood vesselsDamage due to weakened blood vessels– Osmotic damage can also occur to the lens Osmotic damage can also occur to the lens

of the eye and certain neurons, by the of the eye and certain neurons, by the sorbitol pathway metabolism of glucose.sorbitol pathway metabolism of glucose.

– Risk factors – poor blood glucose control, Risk factors – poor blood glucose control, high blood pressure, hyperlipidemiahigh blood pressure, hyperlipidemia

Physiologic systemsPhysiologic systems Neuropathy (neurologic/microvascular)Neuropathy (neurologic/microvascular)

– Classified as somatic and autonomicClassified as somatic and autonomic– Affect 50% of patientsAffect 50% of patients– May affect nearly every system of the bodyMay affect nearly every system of the body– Occurs due to accumulation of sorbitol, and Occurs due to accumulation of sorbitol, and

decrease in myoinositol, nerve glyosylation, decrease in myoinositol, nerve glyosylation, SomaticSomatic

– The most common. The most common. – Lead to decreased sense of touch, position, Lead to decreased sense of touch, position,

and vibration sensations. Painful sensations and vibration sensations. Painful sensations also occur such as tingling, pin pricks also occur such as tingling, pin pricks (parasthesias), burning, stabbing, tearing, even (parasthesias), burning, stabbing, tearing, even crushing paincrushing pain

– Sweat glands also affected. Decreased Sweat glands also affected. Decreased moisture/dry skin moisture/dry skin

Neuropathy cont.Neuropathy cont.

AutonomicAutonomic– Affects the involuntary nerves of Affects the involuntary nerves of

the autonomic nervous systemthe autonomic nervous system– Complications occur include Complications occur include

gastroparesis, diarrhea, gastroparesis, diarrhea, constipation, urinary tract constipation, urinary tract dysfunction, sexual dysfunction, and dysfunction, sexual dysfunction, and cardiac abnormalities.cardiac abnormalities.

Physiologic systemsPhysiologic systems

InfectionsInfections– Decreased ability to fight infectionsDecreased ability to fight infections– Prolonged healing timesProlonged healing times– Due to impaired leukocyte function Due to impaired leukocyte function

and poor circulationand poor circulation– Infections in the mouth can lead to Infections in the mouth can lead to

gum diseasegum disease

Frequent Symptoms of Frequent Symptoms of Diabetes Diabetes May be May be

asymptomatic asymptomatic at in type 2at in type 2

3 P’s: 3 P’s: – polyuria, polyuria, – polydipsia, polydipsia, – PolyphagiaPolyphagia

KetoacidosisKetoacidosis

Weakness/Weakness/fatiguefatigue

GlycosuriaGlycosuria Dry, itchy skin Dry, itchy skin Visual changesVisual changes Skin and mucous Skin and mucous

membrane membrane infectionsinfections

Normal Plasma glucose Normal Plasma glucose rangerange Normal fasting plasma glucose is Normal fasting plasma glucose is

70-110 mg/dl 70-110 mg/dl Diagnostic criteria for diabetesDiagnostic criteria for diabetes

Fasting plasma glucose of Fasting plasma glucose of > > 126mg/dl or a 2 126mg/dl or a 2 hour postload glucose of hour postload glucose of >> 200mg/dl. Must 200mg/dl. Must be confirmed on a different day.be confirmed on a different day.

Diagnostic criteria for pre-diabetesDiagnostic criteria for pre-diabetes Fasting plasma glucose of 100-125mg/dl or Fasting plasma glucose of 100-125mg/dl or

a 2 hour postload glucose of 140-199 mg/dla 2 hour postload glucose of 140-199 mg/dl

Importance of Importance of Postprandial Glucose Postprandial Glucose (PPG) — Conclusions (PPG) — Conclusions

Even in nondiabetic individuals, Even in nondiabetic individuals, postprandial hyperglycemia carries a higher postprandial hyperglycemia carries a higher risk of death than elevated fasting evidence risk of death than elevated fasting evidence shows that elevated PPG levels increases shows that elevated PPG levels increases the risk for cardiovascular diseasethe risk for cardiovascular disease

Earlier detection and management of Earlier detection and management of postprandial hyperglycemia is crucial in postprandial hyperglycemia is crucial in reducing the risk of deathreducing the risk of death

Gerich J. Arch Int Med. Jun 2003;163:1306-1316

ConclusionsConclusions Approximately 13 million patients in the United States Approximately 13 million patients in the United States

have diabetes, with another 5.2 million people have diabetes, with another 5.2 million people undiagnosedundiagnosed

US health care costs associated with diabetes are US health care costs associated with diabetes are $132 billion each year $132 billion each year

Kidney failure, cardiovascular disease, blindness, and Kidney failure, cardiovascular disease, blindness, and amputations are major complications of diabetesamputations are major complications of diabetes

Intensive insulin therapy is effective in reducing the Intensive insulin therapy is effective in reducing the risk of several diabetic complicationsrisk of several diabetic complications

Use of intensive insulin therapy is steadily increasingUse of intensive insulin therapy is steadily increasing

Risk factors associated Risk factors associated with development of with development of Type 2 diabetesType 2 diabetes Family historyFamily history

– Children of individuals with type 2 diabetes have a Children of individuals with type 2 diabetes have a 15% chance of developing the disease and 30% 15% chance of developing the disease and 30% risk of developing IGTrisk of developing IGT

– > 90% concordance in twins> 90% concordance in twins Obesity Obesity >> 120% of ideal body weight 120% of ideal body weight Age Age >> 45yo 45yo RaceRace History of gestational diabetesHistory of gestational diabetes Hypertension Hypertension HyperlipidemiaHyperlipidemia Polycystic ovary diseasePolycystic ovary disease

HbA1cHbA1c Hemoglobin is a protein in circulating Hemoglobin is a protein in circulating

red blood cells. The level of red blood cells. The level of glycosylation to HbA1c of this protein glycosylation to HbA1c of this protein is directly proportional to the level of is directly proportional to the level of glucose in the blood. Because glucose in the blood. Because gylcosylation is irreversible and the life gylcosylation is irreversible and the life span of a red blood cell is 120 days, span of a red blood cell is 120 days, measuring the level can tell us how measuring the level can tell us how well blood sugar has been controlled well blood sugar has been controlled over the past 3 to 4 months.over the past 3 to 4 months.

Should be <6.5%Should be <6.5%

Approximate Comparison Approximate Comparison of HbA1c to Blood of HbA1c to Blood GlucoseGlucose

Glucose mg/dlGlucose mg/dl

6060 9090121200

151500

181800

212100

242400

272700

303000

333300

44 55 66 77 88 99 1010 1111 1212 1313

HbA1c %HbA1c %

Blood glucose test vs. Blood glucose test vs. urine glucose testurine glucose test Blood glucose testing tells you what Blood glucose testing tells you what

your blood sugar is at that time. your blood sugar is at that time. The kidney only spills glucose into The kidney only spills glucose into the urine when blood glucose levels the urine when blood glucose levels exceed 180mg/dl. So urine testing exceed 180mg/dl. So urine testing is not very accurate and the results is not very accurate and the results only approximate what your blood only approximate what your blood sugar level was at an earlier time.sugar level was at an earlier time.

High blood sugar. >200 mg/dlHigh blood sugar. >200 mg/dl Symptoms include:Symptoms include:

Extreme thirstExtreme thirst Frequent urinationFrequent urination Dry skinDry skin HungerHunger Blurred visionBlurred vision DrowsinessDrowsiness NauseaNausea

If not corrected can lead to diabetic If not corrected can lead to diabetic ketoacidosisketoacidosis

HyperglycemiaHyperglycemia

HypoglycemiaHypoglycemia

Low blood sugar <60-70 mg/dl Low blood sugar <60-70 mg/dl (depends)(depends)

Symptoms include:Symptoms include: Shaky, light-headed or weakShaky, light-headed or weak Sweaty or clammy skinSweaty or clammy skin Fast heartbeatFast heartbeat IrritabilityIrritability ConfusionConfusion Sudden extreme hungerSudden extreme hunger HeadacheHeadache Fast heartbeatFast heartbeat

Treatment of Treatment of hypoglycemiahypoglycemia ““Rule of 15’s”Rule of 15’s”

If blood sugar is low eat or drink 15 grams of If blood sugar is low eat or drink 15 grams of carbohydratecarbohydrate

Wait 15 minutesWait 15 minutes Check blood sugar againCheck blood sugar again If blood glucose is normal and your next meal is If blood glucose is normal and your next meal is

more than 60 to 90 minutes away eat a snackmore than 60 to 90 minutes away eat a snack If not back to normal then treat, wait and check If not back to normal then treat, wait and check

again. If not back to normal after 3 tmts. Call again. If not back to normal after 3 tmts. Call 911911

HypoglycemiaHypoglycemia

15 grams of carbohydrate15 grams of carbohydrate– 4 glucose tablets4 glucose tablets– 1 tube glucose gel1 tube glucose gel– 1/3 to ½ cup of fruit juice1/3 to ½ cup of fruit juice– 1 cup skim milk1 cup skim milk– 1/3 to ½ cup of regular soda1/3 to ½ cup of regular soda– 6 small sugar cubes6 small sugar cubes– 1 tbsp honey1 tbsp honey– 5 lifesavers5 lifesavers