Diabetes mellitus
An overview
Dr.Prasad Katulanda MBBS, MD, Dphil
Consultant Endocrinologist/diabetologist
Senior Lecturer in Medicine
ASCEND 2011
Objectives
 Definition
 Magnitude of the problem & Epidemiology
 Clinical presentations
 Diagnosis
 Classification of Diabetes mellitus
 Natural History of Diabetes and Pre-diabetic states
 Characteristics of the Asian diabetes epidemic
Definition of Diabetes Mellitus
Definitions
Diabetes mellitus
Chronic hyperglycaemia
Acute metabolic
complications
Chronic organ dysfunction
and failure
Global pandemic of diabetes, 2010
285 million with diabetes
International Diabetes Federation, World Diabetes Atlas 2009
Prevalence (%) estimates of diabetes (20-79
years), 2030
438 million with diabetes
Prevalence (%) estimates of diabetes (20-79 years), 2010
South-East Asian Region
Regional estimates for diabetes, 2010
International Diabetes Federation, World Diabetes Atlas 2009
Number of people with diabetes (20-79
years), 2010 and 2030
International Diabetes Federation, World Diabetes Atlas 2009
Epidemic in South Asia
20
18
16
14
12
National
Urban
Rural
10
8
6
4
2
0
India
Sri Lanka
Ramachandran et al. lancet, 2009
Pakistan
Bangladesh
Asian Disease
Implications - multisystem disease
Impact of the disease
Western Data
 Commonest cause of ESRF
 Commonest cause of new onset blindness
 Commonest cause of non traumatic lower limb
amputation
 Stroke – adult disability
 Cardiovascular disease
Mortality Statistics - underestimate
Health Care Costs – unbearable to developing
nations
The most burdensome chronic
disease of the New millennium (WHO)
Diagnosis of Diabetes Mellitus
Prevalence of retinopathy according to plasma glucose and HBA1C levels
[● – 2 hr plasma glucose, ■ – fasting plasma glucose, ▲ – HBA1C.
Based on data from Pima Indians - adapted from Diabetologia (McCance et al., 1997)]
Diagnosis of Diabetes Mellitus
DIABETES
1. SYMPTOMS OF DIABETES PLUS CASUAL PLASMA GLUCOSE ≥ 11.1 MMOL/L (≥ 200MG/DL).
CASUAL REFERS TO ANY TIME OF THE DAY REGARDLESS OF THE RELATIONSHIP TO MEALS. CLASSIC
SYMPTOMS OF DIABETES INCLUDE POLYURIA, POLYDIPSIA AND WEIGHT LOSS.
OR
1. FASTING PLASMA GLUCOSE ≥ 7MMOL/L (≥ 126MG/DL). FASTING DEFINED AS NO CALORIC INTAKE
FOR MORE THAN 8 HOURS.
OR
1. 2 – HOUR PLASMA GLUCOSE ≥ 11.1 MMOL/L (≥ 200MG/DL) DURING AN OGTT.
IMPAIRED GLUCOSE TOLERANCE (IGT)
2 – HOUR PLASMA GLUCOSE ≥7.8 MMOL/L (140MG/DL) AND ≤ 11.1 MMOL/L (200 MG/DL) AND
FASTING GLUCOSE <7MMOL/L (IF MEASURED)
IMPAIRED FASTING GLUCOSE (IFG)*
FASTING PLASMA GLUCOSE 5.6 – 6.9MMOL/L (100 – 125MG/DL) AND 2 – HOUR PLASMA GLUCOSE
< 7.8 MMOL/L (IF PERFORMED)
ADA 1997 , WHO 1998. If no symptoms need repeating
Diabetes mellitus
Diagnosis of categories of glucose intolerance
Fasting plasma
glucose
≥7 mmol/l
Diabetes mellitus
Impaired fasting
glycaemia
2-Hour PG plasma
glucose
≥11 mmol/l
Prediabetes
Normal
<5.6 mmol/l
Diabetes mellitus
Impaired glucose
tolerance
Normal
<7.8 mmol/l
Importance of pre-diabetes
 Higher percentage progress to diabetes
mellitus
 Theoretically – should be able to prevent
progression to diabetes
 High risk of cardiovascular disease
Risk of progression to hyperglycaemia
≈ 5-10%
progress to
diabetes on an
annual basis
(0.7% in Nl)
Gerstein HC et al Diabetes Res Clin Pract 2007; 78: 305-12
Glycaemia and CVD risk
DECODE Study. Diabetes Care 2003; 26: 688-96
Clinical Presentations
 Asymptomatic
 Acute symptoms
 Subacute presentation
 Presentation with complications
Acute presentation
 Brief history – over 2-4 weeks
 Classic triad – polyuria, polydipsia, weight loss
 Ketoacidosis
Especially seen in Type 1 Diabetes
Sub-acute presentation
 Symptoms over several months
 Non specific symptoms – lack of energy, visual
blurring
 Polyuria, Nocturia
 Pruritus vulvae, balanitis
Type 2 diabetes commonly presents like this
Presentation with chronic complications
T2DM
Microvascular
Nephropathy
Neuropathy
Retinopathy
Macrovascular
IHD, Stroke, PVD
Other
Infections – Staphylococcal skin sepsis, wound
infection, fungal infections
Types of Diabetes Mellitus
1.
Type 1
2.
Type 2
3.
Other specific types
4.
Gestational Diabetes Mellitus
Type 1 Diabetes Mellitus
 Immune mediated destruction of beta cells
 Absolute insulin deficiency
 Autoantibodies can be detected
 Associated with other autoimmune disease
 Leads to Keto-acidosis
 Younger onset <30 years
 Usually lean patients
 Genetic association less than for type 2
Type 1 Diabetes – evidence for an
autoimmune basis
 HLA associations – HLA DR3/DR4 & DQ B
increases the risk. HLA DR2 protective
 Presence of auto antibodies
• Islet cell antibodies (ICAs)
• Anti GAD antibodies
• Anti insulin antibodies
 Association with other autoimmune disease
Pernicious anaemia, Autoimmune thyroid disease, Addisons’
diasease
 Immune suppression therapy can delay the
onset
 Presence of T cell infiltration - insulitis
Type 2 Diabetes Mellitus
(90 – 95% of all Diabetes)
 Previously called NIDDM
 Due to variable degrees of relative insulin deficiency







and insulin resistance at tissue levels
Usually seen in obese patients
C peptide persist even at late stage
Keto acidosis rare
No specific HLA associations
Strong genetic predisposition
Can be asymptomatic until complications arise
No insulitis
Risk factors for type 2 diabetes mellitus
Non modifiable
Age
Genetic factors
Risk factors for type 2 diabetes
Modifiable
IGTI
FG
Are you at risk of T2DM?
1.
2.
3.
4.
5.
6.
7.
8.
9.
Have you got a first degree relative?
Are you from a high risk ethnic group?
Are you obese?
Are you spending a sedentary lifestyle?
Do you eating high calory fatty foods?
Do you a smoke?
Have you got hypertension?
Are you always stressed?
Did you have a low birth weight?
How many risk factors you have got?
Other specific types of DM
A.
Genetic defects of Beta cell function
B.
MODY type 1-3, Mitochondrial DNA diasease
C.
Genetic defects in Insulin action
D.
Diseases of exocrine pancreas
E.
Other endocrinopathies
F.
Drug induced
G.
Infective
H.
Other genetic syndromes sometimes associated with
DM
Gestational diabetes mellitus
 Diabetes occuring during pregnacy
 Associated with adverse maternal and foetal
outcomes
 Can be a risk factor for development of Type 2
diabetes later in life
Risk factors for diabetes in Sri
Lanka
 Age
 High triglycerides
 Physical inactivity
 Hypertension
 Obesity
 Province of
 Gestational diabetes
residence
 Overseas
employment
 Acanthosis nigricans
 Family history
 Low HDL cholesterol
Katulanda et al
Pathogenesis of type 2 diabetes
Genetic predisposition
At risk environment - foetal to
adulthood
Excess calory intake
Physical inactivity
Obesity (visceral)
Excess FFA
β cell Lipotoxicity
Compensatory
Insulin resistance
hyperinsulinaemia
β cell Glucotoxicity
Hyperglycaemia
(T2DM)
Beta cell secretory
failure
How can we face this challenge?
Natural History of
Type 2 Diabetes
“Pre-diabetes”
Normal
IGT
IFG
Preclinical
state
Primary
prevention
“Clinical-diabetes”
Type 2
Diabetes
Clinical
disease
Secondary
prevention
Complications
Complications
Tertiary
prevention
Disability
Death
Primary prevention of T2DM
Lifestyle modification
The Finnish Diabetes Prevention Study (DPS)
Intensive lifestyle intervention in 577 with IGT
Weight reduction >5%
Reduced fat intake <30%
Reduced saturated fats <10%
Increased fiber content >15g/1000kCal
Physical Exercise >30 min/day
Type 2 diabetes reduced by 58%
No new type 2 diabetes if all goals
achieved
N Eng J Med 344: 1343-1350, 2001
Lifestyle and Drugs
Diabetes Prevention Program – DPP
In USA in people with IGT
Intensive Lifestyle Modification –
58% reduction
Metformin – 31% reduction
N Eng J Med 344: 1343-1350, 2001
Drugs in primary prevention
(?prevention)
STOP-NIDDM Trial
Acarbose
32% relative risk
reduction
Diabetes Care 21:1720-1725, 1998
DREAM study
Rosiglitazone
Xendos – Orlistat
62% relative risk
reduction
2002Lancet (2006); 368: 1096-105
56% relative risk
reduction
Diabetes 51:2796-2803,
Practical approaches
1. Population based approach
‘ Small changes in many people’
2. High risk approach
‘ Bigger changes in small groups’
Lifestyle intervention
in prevention of
T2DM

Overview of Management
Aims of management
 Cure
 Relieve symptoms
 Prevent or delay long term complications
 Control other risk factors
 Patient Education and self management
 Reduce disability due to complications
 Improve quality of life
Specific aspects
Glycaemic control
Diet
Exercise
Oral hypoglycaemic agents/ Insulin
Screening for complications
Reduction of the cardiovascular risk
Promotion of self care
Mutlidisciplinary teamwork approach
Glycaemic Control
Glycaemic control
Tight control – near normal
Good evidence – DCCT & UKPDS trials – reduce and
prevent microvascular complications + some
positive effect on macrovascular Cx
Reduction of the cardiovascular risk
Promotion of self care
Mutlidisciplinary teamwork approach
Glycaemic control
UKPDS
Hypertension control
When to optimise therapy?
 UKPDS post study monitoring – glycaemic
memory
 Accord – high mortality esp if rapidly
optimised in old and CVD pts
 ADVANCE – better if slow and steady
UKPDS – post study monitoring
UKPDS – post study monitoring
UKPDS – post study monitoring
UKPDS – post study monitoring
UKPDS – post study monitoring
UKPDS – post study monitoring
DCCT trial
Diabetes in Asia
 Asia has undergone marked economic and
demographic transition in recent decades
 Increasingly aging populations, globalization and
industrialization are seen in most Asian Societies
 Changes seen in food supply and dietary patterns
 All these leading to epidemiological transition with
diabetes, obesity, dyslipidaemia and related CVD
morbidity and mortality becoming major public
health concerns
Impact of migration
Characteristics of the
Asian Diabetes
Epidemic
South Asia – rapid increase in prevalence
Kun-Ho Yoon et al
Lancet.com Vol 368
November 11, 2006
Age and diabetes
V.U. Menon et al. /Diabetes Research and Clinical Practice 74 (2006) 289–294
Number of Persons With Diabetes in Different Age Groups
Different Regions of the World in 2007
Chan, J. C. N. et al. JAMA 2009;301:2129-2140.
South Asian Diabetes – occurs at lower level of obesity
Kun-Ho Yoon et al
Lancet.com Vol 368
November 11, 2006
Urbanisation and diabetes
Economic development and diabetes in Asia
Lancet
DOI:10.1016/S014
0-6736(09)60937-5
India
China
Malaysia
Singapore
BMI and diabetes - Caucasians
Body mass index at 16 yr follow-up and relative risk for type 2 diabetes in participants in nurses'
health study. Ann Intern Med 1995;122:481-6
South Asians have higher adiposity
Identical BMI, but differences in body fat according to DEXA.
Lifestyle, genetics or intrauterine factors?
BMI and diabetes – Sri Lankans
Diabetes prevalence according to BMI
25%
20%
19.30%
19.00%
23.0 - 27.4
>=27.5
15%
9.80%
10%
5%
4.20%
4.40%
<16
16.0 - 18.4
0%
18.5 - 22.9
Sri Lanka Diabetes and CVD study
Aetiology
 Insulin resistance
 Age
 Obesity
 Physical inactivity
 Urbanisation
 Genetics – ethnicity
 Other
Biochemical attributes of different ethnic
groups living in Singapore
Dickinson S, Colagiuri S, Faramus E, Petocz P, Brand-Miller JC. Postprandial
hyperglycemia and insulin sensitivity differ among lean young adults of different
ethnicities. J Nutr. 2002;132(9):2574-2579.
Fasting and OGTT Insulin in different
ethnicities
700
600
500
pmol/l
400
Insulin (F)
Insulin (2hr)
Increment
300
200
100
0
Caucasian SE Asian
Chinese
Indian
Arabic
Dickinson S et al Postprandial hyperglycemia and insulin sensitivity differ among lean young
adults of different ethnicities. J Nutr. 2002;132(9):2574-2579.
Insulin resistance in different ethnicities
25
HOMA
IR
20
15
10
5
0
Caucasian
Chinese
Indian
Arabic
Dickinson S et al Postprandial hyperglycemia and insulin sensitivity differ among lean young
adults of different ethnicities. J Nutr. 2002;132(9):2574-2579.
Genetics - GWAs
PPARG
KCNJ11
TCF7L2
SCL30A8
CDKL1
HHEX
IGF2BP2
CDKN2A
CDKN2B
FTO
Genetics
•Most variants confer similar risk as in
Caucasians
•Interethnic differences in allele frequency
(TCF7L2)
•Presence of other variants within the same
gene
•Differences in the population attributable risks
• Need to conduct Asian relevant genetic studies
If not genes then what?
 Environmental pollution?
 Infections?
 Epigenetics?
Phenotypes of Asian
Diabetes Epidemic
Aetiology – Insulin requiring diabetes
4%
Insulin
Non-insulin
Katulanda et al, Diabet Med, 25, 1062–69
Aetiological subtypes of diabetes among
young adults
100
88.8
80
60
40
20
0
0.9
2.1
MIDD
Type 1
3.3
4.9
LADA GAD -ve Type 2
T1
Katulanda, et al. Diabet Med, 25, 370-4.
Societal impact
Number of Deaths Attributable to Diabetes in Different
Regions of the World in 2007
Chan, J. C. N. et al. JAMA 2009;301:2129-2140.
Number of deaths attributable to diabetes,
2010
International Diabetes Federation, World Diabetes Atlas 2009
Mean health expenditure per person with
diabetes (USD), R=2, 2010
International Diabetes Federation, World Diabetes Atlas 2009
Summary
 World especially Asia is facing a large
epidemic of diabetes
 The diabetes prevalence is higher despite
lower levels of obesity and income compared
to the NA and Europe
 Diabetes most often affects people in Asia 10
years younger than in the West
 Despite lower level of income obesity is rapidly
increasing in the South Asia
Implications of the diabetes epidemic
 Epidemic of diabetes related chronic
complications – blindness, renal failure, foot
amputations
 Epidemic of CVD
 Consequences for affected individuals,
families, health care services, the economy
and society
Summary
 Glycaemic control is of paramount
importance
 Tight blood pressure control saves lives
 Weight reduction and moderate exercise
have multiple beneficial effects
 Optimise early – start even at pre-diabetes
stage
 Comprehensive CVD risk reduction is vital
Future of diabetes in Asia
 Urgent public health interventions to stem the tide of
diabetes
 Modification of the health care systems to tackle
diabetes and obesity related morbidity – micro and
macro vascular disease
 Further research
• Pathogenesis and specific genetic variants
• Practical and cost effective methods for early
detection and prevention of diabetes