impact of epidemiology on diabetes mellitus echo lecture from thelma d. crisostomo,md
TRANSCRIPT
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Impact of Epidemiology on Diabetes Mellitus
Echo Lecture from
Thelma D. Crisostomo,MD
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Epidemiology of Diabetes Mellitus Type II
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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
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Total Number of People with Diabetes
Year 2000
171 Million
Year 2030
366 Million
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Developing Countries Most Affected In This Global
Diabetes Epidemic
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Certain Ethnic Groups Who Have Experienced
Rapid Modernization Of Lifestyle
Demonstrate The Greatest Susceptibility To Type 2 DM
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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.
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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.
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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.
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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.
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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.
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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
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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
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Cost Associated with Type 2 Diabetes
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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).
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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)
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Ratio of Diagnosed / Undiagnosed Type 2 DM
United States 1:1Western Europe
1:1
Other Countries
1:7
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Prevalence of NIDDM in Selected Populations in the Age Range 30–64
Years
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Prevalence of DM Worldwide
Year 2000
2.8%
Year 2030
4.8%
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Global Diabetes Prevalence by Age and Sex for 2000
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List of Countries with the Highest Numbers of Estimated Cases of Diabetes for 2000 and
2030
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Estimated Number of Adults with Diabetes by Age-Group, Year, and Countries for the Developed and
Developing Categories and for the World.
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Estimated Number of Adults with Diabetes by Age-Group, Year, and Countries for the Developed and
Developing Categories and for the World.
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Prevalence of DM (Philippines)1982 - 1983
General Population 4.17%
Rural Areas 2.5%
Urban Areas 6.8%
National Capital Region
8.4%
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Prevalence of IGT (Philippines)1982 - 1983
General Population 4.5%
National Capital Region
7.3%
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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
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Diabetes
Genetics Environment
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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
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Collision
Hunter Gatherer Genes VS 20th Century Lifestyle
Type 2 DM
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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
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‘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.
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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)
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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.
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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.
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Stages in the Development of Type 2 DM
Genetic susceptibility
Hyperinsulinemia and/or insulin resistance
Impaired glucose tolerance
Non-insulin dependent diabetes
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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
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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
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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
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Genetic Factor
Type 2 DM – 100% Concordance in Identical Twins
Type 1 DM – 30-50% in Concordance in
Identical Twins
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Impaired Glucose Tolerance Worsening to Diabetes in Siblings
Overall Occurrence Rate
Diabetes 12%
Impaired Glucose Tolerance12%
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IGT Worsening to Diabetes
Filipino Siblings
50% Conversion in 8 years
Conversion rate: 9.3 per 100 cases/year
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IGT Conversion Rate
PIMA Indians
9.3 cases per 1000/year
Filipino Siblings
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Impaired Glucose Tolerance (IGT)Natural History
10 yr
Follow up
Subjects with IGT
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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
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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
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High Fat, High Simple Sugar Low Complex Carbohydrate Diet
in westernized Societies are contributing to the excess
Obesity and NIDDM
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Environmental Determinant of Type 2 DM
Obesity
If there were no obesity, the prevalence of diabetes would
be greatly reduced
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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
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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
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Environmental Determinant of Type 2 DM
Intrauterine Factor
Low Birth Weight-Risk Factor for NIDDM
Impaired Development of Endocrine Pancreas
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Physical Inactivity Risk Factor for Diabetes
Possible Explanation Insulin Resistance
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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
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Higher Prevalence in Urban Than Rural Environment
Explanation:
Change in lifestylePhysical ActivityMore Refined Diet Greater Occurrance of Obesity
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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
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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
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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
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Interventional Strategies
1. Weight Reduction 2. Dietary composition 3. Exercise 4. Pharmacologic therapy
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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.
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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.
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Epidemiology of Type I DM
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Type 1
Genetics Environment
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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
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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
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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
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Incidence of Childhood Onset
Type 1 DM (1998 - 1990) European
Study
Standardized Incidence RatesAge 0 – 14 years
DenmarkFinland
SardiniaSicily
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Incidence Rate of Type 1 DM in
Children less than 15 yrs old
Incidence Rate / 100,000
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Geographic and Ethnic Variation
Markeded Variations are Reflections of Difference in:
Environment Genetic Susceptibility
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Environmental Factors
Nature of these factors are still obscurePossible cause1. Viral infections
RubellaCoxsackle BMumps
2. ChemicalsRodernticidesAlloxanStreptozocin
3. Changes in breast feeding habits
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Early cow’s milk exposure may be an
important determinant of subsequent Type 1 Diabetes and may
increase the risk – 1.5 times
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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
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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)
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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
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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.
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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
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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.
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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
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Onset of Type 1 DM
Protracted Prodromal PeriodOver hyperglycemia occurs many years after islet cell antibodies and insulin autoantibodies are detected.
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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.
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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.
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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
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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
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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
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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.
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Thank you!
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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.
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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
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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
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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
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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?
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The New World Syndrome
Non-insulin-dependent diabetes mellitusCentral obesityDyslipidemia Hyperinsulinemia Hypertension
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NIDDM – A Spectrum Ranging from Hyperinsulinemia to
Hypoinsulinemia
Hyperinsulinemia / insulin resistance
Insulinemia deficiency
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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
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Primary Prevention
The promotion of health by personal and community-wide
efforts, e.g. improving nutritional status, physical
fitness etc.
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NIDDM
HyperinsulinemiaInsulin resistance
Dyslipidemia Central obesity
hypertension
NIDDM is the “tip of the iceberg” of a cluster cardiovascular disease risk factors.
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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.
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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).
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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
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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
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Total Number of People With Diabetes is Increasing Due to:
1. Population growth 2. AGING3. URBANIZATION 4. Increasing prevalence of obesity and
physical inactivity