Transcript cardiovascular disease in diabetes

DIABETES
Arshia Panahloo
Consultant Diabetologist
St. George's Hospital , London
www.addison.ac.uk
Topics to be covered:
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Diagnosis
Classification
Epidemiology and Pathogenesis
Complications
Diagnosis
Diagnosis
• Hyperglycaemia central to the diagnosis
• Diagnostic confusion
• 1985 WHO criteria,based on an oral
glucose tolerance test
• American Diabetes Association set their
own criteria in 1997
• WHO revised in 1998
WHO 1985 Diagnostic Criteria
Glucose concentration (mmol/l)
Plasma
Whole blood
Venous
Cap’ll
Venous
Cap’ll
Diabetes
fasting
2hr -OGTT
IGT
fasting
2hr -OGTT
 7.8
 11.1
 7.8
 12.2
 6.7
 10.0
 6.7
 11.1
< 7.8
7.8 -11.0
< 7.8
8.9 - 12.1
< 6.7
6.7 - 9.9
< 6.7
7.8 - 11.0
ADA 1997 Diagnostic Criteria
Glucose concentration (mmol/l)
plasma
whole blood
venous
venous
cap’ll
Diabetes
fasting or
 7.0
 6.1
 6.1
2hr OGTT
 11.1
 10.0
 11.1
IGT
fasting &
< 7.0
< 6.1
< 6.1
2hr OGTT  7.8, <11.1  6.7, <10.0  7.8, < 11.1
IFG
fasting
 6.1, < 7.0  5.6, < 6.1  5.6, < 6.1
2hr OGTT
< 7.8
< 6.7
< 7.8
Diagnosis
In the presence of symptoms:
(polyuria, polydipsia,weight loss)
– Random plasma glucose  11.1 mmol/l
OR
– Fasting plasma glucose  7.0 mmol/l
OR
– 2 hour plasma glucose  11.1 mmol/l, 2hrs
after a 75g oral glucose tolerance test
Diagnosis
In the absence of symptoms
• Diagnosis should not be based on a
single sample
• Two samples on separate days, either:
– fasting
– random
– 2 hour post load
Diagnosis IGT and IFG
• IGT (Impaired Glucose Tolerance)
– Fasting plasma glucose < 7.0 mmol and 2
hour OGT value 7.8 -11.1
• IFG (Impaired Fasting Glycaemia)
– fasting plasma glucose 6.1 - 7.0 mmol/l
• IGT and IFG are not clinical entities in
their own right but risk categories for
cardiovascular disease (IGT) and/or
future diabetes (IFG)
Diagnosis
• The diagnosis of diabetes has important
legal and medical implications
• Diagnosis should NOT be made on:
– Glycosuria
– Finger prick blood glucose
– HbA1c
• A venous plasma sample is needed in
an accredited laboratory
Classification
Aetiological Classification
WHO 1998
• Type 1
 b cell destruction
• Type 2
– insulin resistance +/- insulin deficiency
– due to b cell dysfunction
• Gestational diabetes
Classification
• Other specific types
– genetic defects (b cell)
– genetic defects (insulin)
– exocrine pancreas
– endocrinopathies
– drug / chemical induced
– infections
– immune-mediated
– other genetic syndromes
Classification
• Diabetes due to other endocrine
disease:
– Cushing’s syndrome
– Acromegaly
– Thyrotoxicosis
– Phaeochromocytoma
– Hyperaldosteronism
– Glucagonoma
Classification
• Diabetes due drugs and chemicals:
– Glucocorticoids
– Diuretics
– B-Blockers
– B2-agonists
– Phenytoin
– Cyclosporin
– Nicotinic acid
Classification
• Diabetes associated with genetic
syndromes
– DIDMOAD (Wolfram) syndrome
– Myotonic dystrophy and other muscular
disorders
– Lipoatrophic diabetes
– Type-1 glycogen storage disease
– Cystic fibrosis
Epidemiology and
Pathogenesis of
Type-1 Diabetes
Type-1 Diabetes
• Develops predominantly in children and
young adults
• Can occur in all age groups
• Occurs in all continents
• Marked geographical variation
– Finland and Sardinia highest, 30-35 cases
per 100,000 children aged up to 14 years
– oriental populations lowest, <1 per 100,000
Geographical variation
• Variability is unexplained:
– genetic factors
– environmental factors
– Incidence in childhood in increasing
– ‘outbreaks’ suggest infectious agents
– seasonal variation, highest in autumn and
winter when viral infections more prevalent
Presentation
• Peak age of onset 11-13 years
• 10% of diabetic patients over 60 years
are insulin dependent
• In UK the prevalence of type-1 DM is
1% (20% of total DM patients)
• 20% of typical type-2 DM display
evidence of autoimmunity
Natural History of Type-1 DM
• Commonest cause is autoimmune
destruction of B-cells
• Interaction between genetic factors and
environment
• Onset is abrupt, but B-cell antigens may
be present for many years
• Pre-diabetic state mild abnormalities of
insulin secretion and glucose tolerance
can be detected
‘Honeymoon period’
• After starting insulin, some patients
need very small amounts
• Last 2-12 months
• Improvement in B-cell function once
‘glucose toxicity’ removed
• True remission rare
• Research into preserving B-cell function
Genetic Factors (1)
• Account for a third of the susceptibility
to type-1 DM
• 36% concordance for monozygotic
twins
• Over 20 regions of the human genome
show some linkage with type-1 DM
• Strongest linkage is with HLA genes
within the MCH region on chrom. 6
Genetic Factors (2)
• HLA haplotypes DR3 and DR4
predispose to type-1 DM
• linkage disequilibrium with true
susceptibility loci
• HLA class II antigens on the cell surface
present foreign and self antigens to Tlymphocytes and initiate the autoimmune response
Genetic Factors (3)
• Strong linkage between HLA-DR and
DQ regions
• Polymorphisms of the DQB1 gene
resulting in amino acid substitution in
class II antigens may determine B-cell
damage
• Region of the insulin gene on chrom. 11
is linked to type-1 DM, insulin or precursors can act as B-cell autoantigens
Environmental Factors
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Viruses
Dietary components
Stress
Drugs and toxins
Viruses
• Viruses can directly destroy B-cells or
indirectly by an autoimmune response
• Mumps
– Occasionally precedes IDDM
– autoimmune B-cell destruction
– islet cell antibodies develop
– can induce interleukin production and HLA
hyperexpression in B-cells
Viruses
• Coxsackie B
– IgM anti-coxsackie B antibodies in newly
diagnosed type-1 DM
– Antigen identified in islets post-mortem
– Direct cytotoxic action on B-cells
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Retroviruses
Rubella
CMV
Epstein-Barr
Nutrients
• ? Nitrosamines in diet
• Breast feeding
– short duration associated with increased
risk of adult Type-1 diabetes in some
studies
– Antibodies to cow’s milk protein found in
higher titres in children with recent onset
type-1 diabetes
Epidemiology and
Pathogenesis of
Type-2 Diabetes
Diabetes prevalence (thousands)
Incidence of type 2 diabetes
rapidly increasing
3000
Type 1
Type 2
3 million in the UK by 2010
2500
2000
1500
1000
500
0
1995
Amos AF et al. Diabet Med 1997;14(Suppl 5);S1–S85
2000
2010
Geographical variation
• Large variation
• Highest in some native American tribes
(Pima Indians) in Arizona (50%) and
South Pacific Islands
• Low prevalence in least developed rural
communities
• Prevalence is closely associated with
BMI
Type-2 Diabetes in the UK
• Prevalence:
– 1-2% for the white population
– 11% for Indian
– 9% for African-Caribbeans
• Compared to white patients Indian
patients have younger age of onset of
type-2 diabetes and earlier protinuria
and renal disease, and excess CHD.
Type-2 Diabetes
• Accounts for 85% of the diabetic population
• Patients do not require insulin to remain
alive, although 20% are treated with insulin
to control blood glucose
• Peak age of onset is 60 years, younger age
of onset seen with MODY
Type-2 Diabetes
• Is characterized by variable combinations of
insulin resistance and insulin deficiency
• Insulin deficiency is less severe than type-1
diabetes and insulin levels remain high
enough to prevent excess lipolysis and
ketoacidosis
• Patients are C-peptide positive
Genetic and/or
Environmental
Factors
Insulin
resistance
Genetic and/or
Environmental
Factors
b-cell
dysfunction
Compensation
Hyperinsulinaemia
maintains
Normoglycaemia
Inadequate insulin
response
Hyperglycaemia
IGT
Diabetes
Insulin Resistance
Inability of insulin to produce its usual
biological effects at circulating
concentrations that are effective in
normal subjects.
Acquired causes of insulin resistance
1)
Obesity
– truncal obesity (visceral fat) is related to insulin
resistance
– BMI >35 have 40 x risk of developing DM
compared with those with BMI < 23
– visceral fat is especially susceptible to lipolysis
and hence raised NEFA
– truncal obesity is associated with increased
proportion of white muscle fibres which are
more insulin resistant than red fibres
2)
Reduced physical activity
– exercise increases :
• insulin sensitive red fibres
• fat oxidative enzymes
• tissue (white adipose) sensitivity to catecholamines
and enhancing lipolysis
– hence exercise increases insulin sensitivity &
increased utilisation of fat as fuel
3)
Malnutrition in foetal/early infant life
– low birth wt. assoc with metabolic syndorme X
in later life (obesity,insulin resistance & DM,
hypertension, dyslipidaemia, atherosclerosis)
Management of Type II Diabetes
Aims :• Abolish symptoms and acute complications
of hyperglycaemia
• Reduce threat of chronic complications
• Increase life expectancy
• Restore quality of life
Genetics of Type II Diabetes
• High rate of concordance (60-100%) for the
disease in identical twins
• Familial aggregation
• Different prevalence in ethnic groups
• Polygenic trait with environmental factors
• MODY (0.3% type-2) mutations in
glucokinase gene
• Mutations in mitochondrial DNA (rare)
Complications
Complications of Diabetes
• Microvascular:
• Nephropathy
• Retinopathy
• Neuropathy
• Macrovascular
• Coronary heart disease / Stroke /lipids
• Peripheral vascular disease
• Blood pressure
Retinopathy
• Type-1:
• Rare less than 5 years of diabetes
• With increasing prevalence the incidence rises
to a peak at 15-20 years
• Severe proliferative retinopathy also increases
with diabetes duration, >20yrs
• Type-2:
• Can be present at diagnosis
• Increased incidence of macular oedema
Retinopathy
• Risk Factors:
• Poor glycaemic control
• Genetic factors
• Blood pressure
• Smoking
Nephropathy
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Type-1
Associated with the duration of DM
Peak incidence after 15-20 years, followed
by a steady decline after 30-40 years
Higher incidence in men
Higher incidence in patients who develop
DM prior to age of 15 years
Nephropathy
• Risk Factors:
• Age at onset
• Poor glycaemic control
• Genetic factors
• Blood pressure
• Smoking
Neuropathy
• Symmetrical sensory neuropathy
• Affects 20-30% diabetics, prevalence
rises with duration and severity of
diabetes
• Autonomic neuropathy
• Acute mononeuropathy (femoral or
oculomotor)
• Pressure palsies (median and ulnar nerve)