Impact of Epidemiology on Diabetes Mellitus

Echo Lecture from

Thelma D. Crisostomo,MD

Epidemiology of Diabetes Mellitus Type II

Global – 2000 AD

1990 2000

Developing countriesDeveloped countries

60 million20 million

120 million40 million

Total 80 million 160 million

Figure 1. Diabetes-the global situation. It is estimated that in the year 2000 the number of diabetic patients will reach 160 million

Total Number of People with Diabetes

Year 2000

171 Million

Year 2030

366 Million

Developing Countries Most Affected In This Global

Diabetes Epidemic

Certain Ethnic Groups Who Have Experienced

Rapid Modernization Of Lifestyle

Demonstrate The Greatest Susceptibility To Type 2 DM

Epidemiology

Studies distribution and determinants of disease

PURPOSETo understand natural history, cause of the disorder and pathogenesis.For appropriate diagnostic investigation and clinical management.For creation of scientifically based program for prevention and health care.

The First Step Of Epidemiologic Research Begins With Measuring

IncidenceNumber of new cases discovered for a specific time and place.Used to identify epidemics.Used to search for etiology

PrevalenceTotal number of cases old and new occurring in a specified time and place.Tool for determining public health needs.

Is There An Epidemic Of Type 2 Diabetes Mellitus?

Epidemic – Definition The occurance in a community of a disease, infectious or chronic (e.g. diabetes mellitus), occurring at a greater frequency than usually expected.

Does this apply to Type 2 DM?Yes, particularly in developing and newly industrialized nations.

Type 2 DM: A Public Health Prospective

Type 2 DM is among the top 7 cause of death in most countries.Cardiovascular complications are major cause of morbidity and mortality: This results in the impact of type 2 DM being underestimated from death certificates.There is an excessive frequency of coronary artery and peripheral vascular disease and strokes.

Type 2 DM: A Public Health Prospective

Type 2 DM is the most common cause of adult blindness and a common cause of renal failure and amputation.Results in disability, reduced life expectancy and enormous health cost for any society.

Cause of Death in Type 2 DM

myocardial infarction

strokegangrene

kidney failure

diabetic coma

infections

tuberculosis

neoplasm

accident/suicide

other causes

unspecified

myocardial infarction

stroke

gangrene

kidney failure

diabetic coma

infections

tuberculosis

neoplasm

accident/suicide

other causes

unspecified

The true cost of treating T2DM is not the cost of oral

hypoglycemics. The true cost come from treating

complications with non-OADs and other forms of treatment

Cost Associated with Type 2 Diabetes

Etiologic Classification of Diabetes Mellitus

I. Type 1 Diabetes (B-cell destruction, usually leading absolute insulin deficiency).

a. Immune mediated b. Idiopathic

II. Type 2 Diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance).

Etiologic Classification of Diabetes Mellitus

III. Other specific typesa. Genetic defects of B-cell functionb. Genetic defects in insulin actionc. Disease of the exocrine pancreasd. Endocrinopathies e. Drug – or – chemical – induced f. Infectionsg. Uncommon forms of immune-mediated

diabetesh. Other genetic syndromes sometimes

associated with diabetes IV. Gestational diabetes mellitus (GDM)

Ratio of Diagnosed / Undiagnosed Type 2 DM

United States 1:1Western Europe

1:1

Other Countries

1:7

Prevalence of NIDDM in Selected Populations in the Age Range 30–64

Years

Prevalence of DM Worldwide

Year 2000

2.8%

Year 2030

4.8%

Global Diabetes Prevalence by Age and Sex for 2000

List of Countries with the Highest Numbers of Estimated Cases of Diabetes for 2000 and

2030

Estimated Number of Adults with Diabetes by Age-Group, Year, and Countries for the Developed and

Developing Categories and for the World.

Estimated Number of Adults with Diabetes by Age-Group, Year, and Countries for the Developed and

Developing Categories and for the World.

Prevalence of DM (Philippines)1982 - 1983

General Population 4.17%

Rural Areas 2.5%

Urban Areas 6.8%

National Capital Region

8.4%

Prevalence of IGT (Philippines)1982 - 1983

General Population 4.5%

National Capital Region

7.3%

What is the Prevalence of Diabetes Mellitus in the Philippines?

A. 2 out of 100B. 4 out of 100C. 6 out of 100D. 8 out of 100E. 10 out of 100

5th National Nutrition SurveyFNRI, DOST Oct 1999N = 70, 000 99 areas

Diabetes

Genetics Environment

Aetiology of NIDDM: The Interaction of Genetic Susceptibility and Environment

Factors Heredity

Genetic Susceptibilit

y

Obesity Physical inactivity

Nutritional Factors

Aging Intrauterine Factors

Hyperinsulinemia Insulin Resistance

Beta-cell Failure

Type 2 DM

Collision

Hunter Gatherer Genes VS 20th Century Lifestyle

Type 2 DM

Thrifty Gene Hypothesis

Past populations subjected to cycles of feast/famine

Genes were adopted to store energy efficiently

Rapid Modernization

Famine rare. Abundant food stored efficiently

Results in Obesity, hyperinsulinemia and diabetes

‘Thrifty Genotype’(Hyperinsulinemia)

Hunter-gatherer society Modern society

FeastFeast + famine

Maximum metabolic efficiency

Hepatic gluconeogenesis

Hepatic lipogenesis Selective insulin

resistance in muscle

Insulin resistance

• diet energy dense, high saturated fat

• Physical inactivity• Obesity

B-cell exhaustion

Glucose intoleranceDyslipidemia

Hypertension

Survival

A proposal for the operation of the “thrifty genotype” in the pathogenesis of non-insulin dependent diabetes and other associated cardiovascular disease

risk factors in populations who have changed their life-style from hunter gatherer to modern.

0 10 20 30 40

Aust. Europids

Fijians

Western Samoans

Kiribati

Fiji Indians

Aust. Aborgines

Nauruans

Age-Standardized prevalence of diabetes in adults in “urban” pacific populations (25-74 years)

0

5

10

15

20

25

Prevalence (%)

Hindu Indian MuslimIndian

Creole Chinese

Males

Females

Prevalence of diabetes by ethnic groups in Mauritius (25-74 years). Age-standardized by direct method to total Mauritius population – 1986.

0

5

10

15

20

25

Prevalence (%)

Mainland China Singapore Mauritius

Males

Females

Prevalence of NIDDM in Chinese (30 – 64 years) in China, Singapore and Mauritius. Age-standardized by the direct method to Segi’s world population.

Stages in the Development of Type 2 DM

Genetic susceptibility

Hyperinsulinemia and/or insulin resistance

Impaired glucose tolerance

Non-insulin dependent diabetes

Development of Type 2 Diabetes

I II III IV V

Fasting Glucose

Hyperglycemia

Glucose Tolerance

Abnormal glucose tolerance

Insulin Sensitivity

Decreased insulin sensitivity

Insulin Secretion

Hyperinsulinemia, the -cell failure

Normal IGT Type 2 Diabetes

Development of Type 2 Diabetes

Insulin Sensitivity

Insulin Secretion

Macrovascular Disease

30%50%70%100%

50%70-100%

150%100%

50%40%10%0%

Type 2 Diabetes

IGT

Impaired Glucose Metabolism

Normal Glucose Metabolism

Macrovascular disease is closely linked to Insulin Resistance

Groop Etiology of non-insulin-dependent diabetes mellitus.Hormone Res. 1997; 22:131-156

Studies that Confirm the Strong Genetic Basis of Type 2 DM

Twin studiesFamilial aggregation High prevalence population Genetic Admixture studies Prevalence in different ethnic groups in same environment MODY/Nauruans/Pimas – autosomal dominant inheritance

Genetic Factor

Type 2 DM – 100% Concordance in Identical Twins

Type 1 DM – 30-50% in Concordance in

Identical Twins

Impaired Glucose Tolerance Worsening to Diabetes in Siblings

Overall Occurrence Rate

Diabetes 12%

Impaired Glucose Tolerance12%

IGT Worsening to Diabetes

Filipino Siblings

50% Conversion in 8 years

Conversion rate: 9.3 per 100 cases/year

IGT Conversion Rate

PIMA Indians

9.3 cases per 1000/year

Filipino Siblings

Impaired Glucose Tolerance (IGT)Natural History

10 yr

Follow up

Subjects with IGT

Major Behavioral, Environmental and Social Risk Factors for Type 2

DM These may vary within and between

populations and include:AgeNutritional factorsObesity (central)Physical inactivityDegree of modernization Intra-uterine environment ? Stress, ? others

Hunter gatherers Peasant agriculturalist Western man

Fat15 to 20%

Starch50 to 70%

Protein15 to 20%

Fat10 to 15%

Starch60 to 75%

Protein10 to 15%

Sugar 5%

Fat40+%

Starch23 to 30%

Protein12%

Sugar 20%

Changes in Component of the Diet that Have Been Seen in the Change From Hunter Gatherer to the Modern

“Western” Diet

High Fat, High Simple Sugar Low Complex Carbohydrate Diet

in westernized Societies are contributing to the excess

Obesity and NIDDM

Environmental Determinant of Type 2 DM

Obesity

If there were no obesity, the prevalence of diabetes would

be greatly reduced

Central Distribution of Body Fats as Risk Factor for NIDDM

Implicated in:

Europids (Sweden)Mexican Americans Native AmericansMicronesians (Nauruans)Asian Indians (Hindu and Muslim)CreolesChineseJapanese Americans

Insulin Resistance in Obesity

0

50

100

150

200

0 30 60 120 180

0

50

100

0 30 60 120 180Minutes

Plasma glucose response (mg/dl)

Plasma glucose response (U/dl)

Normal weight (mean 66.1kg) Moderately obese (mean 91.1kg)

Reaven et al.: Diabetes 32, 600,1 983

Environmental Determinant of Type 2 DM

Intrauterine Factor

Low Birth Weight-Risk Factor for NIDDM

Impaired Development of Endocrine Pancreas

Physical Inactivity Risk Factor for Diabetes

Possible Explanation Insulin Resistance

0

5

10

15

20

25

30

35

Prevalence %

low medium high0

5

10

15

20

25

30

35

Prevalence %

low medium high

0

5

10

15

20

Prevalence %

low medium high0

5

10

15

20

Prevalence %

low medium high

Prevalence of abnormal glucose tolerance by body mass index and physical activity (Mauritius) 1997

BMI Tertile

BMI Tertile

inactive

active

New NIDDM

IGT

Higher Prevalence in Urban Than Rural Environment

Explanation:

Change in lifestylePhysical ActivityMore Refined Diet Greater Occurrance of Obesity

Major Behavioral, Environmental and Social Risk Factors for Type 2

DMThese may vary within and between

populations and include:

Age Nutritional factorsObesity (central)Physical inactivity Degree of modernization Intra-uterine environment ? Stress; ? Others

Preventing Type 2 DM

Evidence that it is possible

Primate studies of Type 2 DMPrevention of coronary artery diseaseReversion to traditional life-styleRural-urban studies of risk factorsInfluence of physical activity Type 2 DM prevalence and incidence

Marked Improvement in Fasting Metabolic Parameters in Ten Australian Aborigines with

7 Week Reversion to Traditional Lifestyle

Parameter Before after

Plasma glucose (mm/l) Plasma insulin (mU/ml) Plasma cholesterol (mm/l) Plasma triglycerides (mm/l) Weight (kg)

11.623.05.654.0281.9

6.6 **12.0 *4.98

1.15 **73.8

* P < 0.005 ** p < 0.001

Interventional Strategies

1. Weight Reduction 2. Dietary composition 3. Exercise 4. Pharmacologic therapy

People at High Risk of Developing Type 2 DM

Impaired glucose tolerance (IGT).Certain ethic groups such as Pacific Islanders, Australians Aborigines, migrant Asian Indians, American Indians, Black and Hispanics who show high diabetes prevalence.Positive family history of Type 2 DM in first degree relatives (parents, siblings or children).Obesity especially in women with a past history of gestational diabetes or large babies.

People at High Risk of Developing Type 2 DM

Age greater than 50 years in Europids and lower ages (30 to 40 years) in high prevalence groups.History of previous abnormality of glucose tolerance, particularly in pregnancy.Hypertension, macrovascular disease or dyslipidemia.

Epidemiology of Type I DM

Type 1

Genetics Environment

Aetiology of Type 1 DM

VirusesGenetic

susceptibility (HLA – DQ)

? Chemicals? Nutrition

Autoimmune Process

Beta-cell destruction

Insulin-dependent diabetes mellitus (Type 1 DM)

Modified from Schoffling, K.: Diabetologic in Klinik und Praxis, Thieme, 37-41 1984

Features of Type 1 DM

Occurs at any ageProneness to ketoacidosis Low insulin and C peptide levels

Specific associations with the HLA complex Islet cell antibodiesHigh frequency of insulin auto antibodies

Comparison of Characteristics of Type 1 DM and Type 2 DM

IDDM NIDDM

Prevalence in population 0.5% 3 – 5 %

Age of onset Usually < 40 yrs

Usually < 40 yrs*

Autoimmune aetiology Yes No

ICA, anti-GAD Yes No

HLA association Yes No

Twin Studies (monozygotic) concordance

30% 90%

Insulin therapy Invariable 20 – 30 %

Association with obesity Infrequently 80%

* Can vary significantly depending on population

Incidence of Childhood Onset

Type 1 DM (1998 - 1990) European

Study

Standardized Incidence RatesAge 0 – 14 years

DenmarkFinland

SardiniaSicily

Incidence Rate of Type 1 DM in

Children less than 15 yrs old

Incidence Rate / 100,000

Geographic and Ethnic Variation

Markeded Variations are Reflections of Difference in:

Environment Genetic Susceptibility

Environmental Factors

Nature of these factors are still obscurePossible cause1. Viral infections

RubellaCoxsackle BMumps

2. ChemicalsRodernticidesAlloxanStreptozocin

3. Changes in breast feeding habits

Early cow’s milk exposure may be an

important determinant of subsequent Type 1 Diabetes and may

increase the risk – 1.5 times

Cow’s Milk Consumption and Type 1 DM Incidence

Region Cow’s milk consumption IDDM I Incidence

PortugalGreeceSicilyLazioLuxebourgLombardyBelgiumSardinia FranceIsrael SpainNetherlandsU.K.DenmarkAustriaNorwayFinland

62.066.768.177.878.680.681.183.286.390.0

104.9120.9135.0145.5148.7222.1224.9

7.59.3

10.06.5

12.46.89.8

30.27.85.5

10.611.016.521.57.7

20.842.9

Cow’s milk consumption measured in liters/ person / yearIDDM incidence per 100,00 / year in those 0 – 14 years

Type 1 DM

Genetic Factors Concordance rate

Monozygotic twins : 25 – 30%Dizygotic twins : 5 – 10%Siblings : 5%Offspring : 2 – 3 % (if mother is

diabetic) 5 – 6 % (if father is

diabetic)

HLA System in Type 1 Diabetes Mellitus

Genes Conferring Susceptibility

Class II Allele : HLA – DR, -DQ, -DP LOGI

European : DR3, DR4 (5-8x risk): DR3/DR4 (20 – 40x risk): HLA – DR3 DQW2: HLA – DR4 DQW8: DOA1*0501, DQB1*0302

Genes Conferring Protection: HLA-DR2: HLA DQB1*0602

HLA System

HLA A B C Antigens

HLA DR Antigens

Function (HLA - DR)

-

-

-

Present in all body cells

Restricted to B Lymphocytes, Macrophages, endothelial cells

Defense against aggressive environmental factors and involved in autoreactive self recognition of tissue antigens.

Reports of Diabetes Mellitus and ICA Associated with Known Virus

Infection

References Virus Islet-Cell Antibodies

IgG CF

Yoon et. al 1979 (33)Helmke et. al; 1980 (42)Ilonen et. al 1980 (43)Gamble et. al 1980 (unpublished)Champsaur et. al 1982 (44)

Cox B4MumpsMumpsMumps

InfluenzaCoxB5

++++

+

Not done+++

< 1:20

CF = complement fixing

Type 1 DM – Immunological Factors

Not yet well definedInitiating autoantigens identified through studies on:

Islet Cell Cytoplasmic AntibodiesInsulin AutoantibodiesAnti-GADAntibodies to Pancreatic B Cell Surface Protein p69

Immune phenomena decline rapidlyShown by rapid disappearance ICA (Type 1A) 85 – 90% (Viral Etiology)

Immune phenomenon may persist(Type 1B) 10 – 15% characteristics of primary autoimmune endocrine disorder.

The Known an Unknown Immunological Phenomena Possibly Involved in the Recognition and Subsequent

Damage of Pancreatic Beta Cells

Complement

Natural killer cell Insulin Cell

Cytotoxic Thymphocyte

cell

Killer cell

??

HLA-A, -B, -C histocompatibility antigens

• virus or modified (tumour) antigens

Onset of Type 1 DM

Protracted Prodromal PeriodOver hyperglycemia occurs many years after islet cell antibodies and insulin autoantibodies are detected.

Seasonal Distribution of Onset of Type I Diabetes

0

20

40

60

80

100

J F M A M J J A S O N D

Num

ber

of

Pati

ents

UK

Num

ber o

f Patie

nts C

hile

J A S O N D J F M E M J

10

20

30

40

50

Combined data from studies carried out in the UK and Chile (38, 41). Approximately 1500 cases have been analyzed (age of onset: UK: 0-15 year; Chile 0-30 years). Major peeks are seen in autumn and winter and this pattern have been confirmed in a number of

countries in the northern hemisphere.

Pattern of Age Onset of Type 1 Diabetes

Rela

tive F

requency

%

Total

Males

Females

Age (Years)Combined data from studies out in Denmark, Chile, USA and Canada. The relative frequency of

Type 1 diabetes up to age 28 years is shown. Diabetes can occur in the first months of life and its frequency increase abruptly at about 9 months of age, rising to a major peak at puberty. This peak

is earlier in girls than boys.

Causes of Death in Type 1 DM(Age < 30 years)

myocardial infarction, 26.00%

stroke, 7.00%

kidney failure , 31.00%

infections, 9.00%

accident, 1.00%

others and unknown,

12.00%

Neoplasm, 4.00%

hypoglycemia, 5%

suicide, 3.00%

ketoacidosis, 2%

myocardial infarction

stroke

Neoplasm

kidney failure

infections

accident

others and unknown

suicide

hypoglycemia

ketoacidosis

The Natural History of Insulin-dependent diabetes mellitus*

Onset of diabetes

Environmental factors

e.g. viral infection cow’milk nutrition

Genetic Susceptibilit

y e.g. certain HLA types

ICA +IAA +Anti-GAD +

Hyperglycemia insulin dependency

Complications

Disability

Retinopathy Nephropathy Atherosclerosis Neuropathy

BlindnessRenal failure Coronary heart diseaseAmputation

DEA

TH

* HLA, Human Leukocyte Antigen: ICA, Islet-Cell Cytoplasmic Antibodies; IAA, Insulin Autoantibodies; anti-GAD, antibodies to glutamate Decarboxylase

Can Type 1 DM be Prevented?

Cow’s milk Exclusion

Nicotinamide

Insulin Prophylaxis

Dual Parameter

ModelFH +

ICA +> 20JDFu

Loss of FPIRIAA

IAA etc.ICA +Genetic

s Markers

FH -

Baseline Risk

The decision tree representation of prediction Type 1 DM with intervention trials planned in 1994

Insulin Therapy for End Stage Prediabetes State

Rationale:

Improve cell function to delay onset of Diabetes. Initiating active insulin substitution rapidly may save as many cells as possible.

Thank you!

Classification of Diabetes Mellitus and Other Categories of Glucose

Intolerance* Clinical classes

Diabetes mellitus Insulin-dependent (IDDM)Non-insulin dependent (NIDDM)

Non-obese Obese

Malnutrition related (MRDM)Other types

Pancreatic Endocrine Drug-induced, etc.

Classification of Diabetes Mellitus and Other Categories of Glucose

Intolerance*Other categories

Impaired glucose tolerance (IGT)Gestational Diabetes Mellitus (GDM)

* WHO Study Group on Diabetes Mellitus - 1995

NIDDM – A Public Health Perspective

NIDDM is amongst the top 7 causes of death most countries.Cardiovascular complications are a major cause of morbidity and mortality. This results in the impact if NIDDM being underestimated from death certificates.There is an excessive frequency of coronary artery and peripheral vascular disease and strokes.NIDDM is the most common cause of adult blindness and a common cause of renal failure and amputations.

Results in disability, reduced life expectancy and enormous health cost for any society

Studies of Diabetes Epidemiology

1. Modernization of Lifestyle in situ

2. Rural-Urban comparisons

3. Migration studies

4. Several ethnic groups living in same location

Thrifty Genotype

How does a genetic disorder, such as Diabetes, with adverse

impact on fertility and mortality, survive with such a high

prevalence within population?

The New World Syndrome

Non-insulin-dependent diabetes mellitusCentral obesityDyslipidemia Hyperinsulinemia Hypertension

NIDDM – A Spectrum Ranging from Hyperinsulinemia to

Hypoinsulinemia

Hyperinsulinemia / insulin resistance

Insulinemia deficiency

Preventing NIDDM

Evidence that it is possible:

Primate studies of NIDDMPrevention of coronary artery diseaseReversion to traditional life-style Rural-urban studies of risk factors Influence of physical activity on NIDDM prevalence and incidence

Primary Prevention

The promotion of health by personal and community-wide

efforts, e.g. improving nutritional status, physical

fitness etc.

NIDDM

HyperinsulinemiaInsulin resistance

Dyslipidemia Central obesity

hypertension

NIDDM is the “tip of the iceberg” of a cluster cardiovascular disease risk factors.

Why is Diabetes Mellitus Important?

Many people have the disease.Those who have the disease are at greater risk of dying.Those who have the disease puts a burden on health care cost because of the complications that develop.

0

5

10

15

20

Prevalence %

Fiji Indian Fiji Malenesian Wallis(Polynesian)

Inactive

Active

Prevalence if diabetes of diabetes by usual physical activity level (males > 20 years; age-standardized).

0

10

20

30

40

White Black Mexican-American

Pima Indians

Prevalence (% )

Prevalence of NIDDM Adults 25 years and Over in the USA

Harris MI, et al: Diabetes 36, 523-534, 1978

Dietary Factors DeterminingIGT and NIDDM

High fat intake contributes to risk of glucose intolerance.

Fish, potatoes, vegetables, legumes may have protective effects.Vitamin C and Antioxidants may have protective effects.

Finnish and Dutch Study Diabetes Care August 1995

Total Number of People With Diabetes is Increasing Due to:

1. Population growth 2. AGING3. URBANIZATION 4. Increasing prevalence of obesity and

physical inactivity