Student Pages

This lecture will cover:

Introduction to diabetes mellitus

The epidemiology and diagnosis of diabetes mellitus

The aetiology and pathophysiology of diabetes mellitus

Introduction to diabetes mellitus

What is diabetes?
Heterogenous clinical syndrome in which the central feature is a chronic elevation of the blood glucose concentration - this results in a range of pathologies.

Due to a deficiency of insulin (absolute) or a resistance to insulin (relative).

The chronic hyperglycaemia is associated with long term tissue damage, especially the blood vessels, nerves, heart, kidneys and eyes.

Normal blood glucose levels
Normal homeostatic mechanisms maintain blood glucose levels within a narrow range of 3.5-6.5 mmol/l

Insulin
- consists of two amino acid chains linked by two disulfide bridges
- proinsulin in pancreatic beta cell is cleaved to insulin and a connecting peptide (c-peptide levels can be used to measure amount of endogenous insulin production, as commercial insulin preparations do not have c-peptide)
- main stimulus for release is glucose, but release can also be triggered by amino acids, fatty acids and ketone bodies. Activation of beta2-adrenergic receptors in pancreas also stimulate release of insulin whereas stimulation of the alpha-adrenergic receptors in pancreas inhibit insulin release

- effects of insulin are anabolic - conservation of energy, promotes cell growth, suppresses gluconeogenesis and promotes glycogenolysis, promotes peripheral uptake of glucose – especially in skeletal muscle cells, encourages storage (as muscle glycogen)

Insulin receptors:
- The receptors for insulin are found on most mammalian cells – action of insulin is mediated through these receptors.
- Impaired action of insulin can result from defects in the receptors or defects in post-receptor events.

Deficiency of insulin:
- catabolic effects (breakdown of complex molecules) - these contribute to signs and symptoms of diabetes
- glycogen is broken down to glucose; proteins to amino acids; fats to glycerin and free fatty acid

- hyperglycaemia is promoted by increasing glycogenolysis and glycogenesis and a reduction in glucose utilisation

Classification of diabetes mellitus

Previous classification:
1. Juvenile onset diabetes/insulin dependent diabetes mellitus
2. Adult onset diabetes/non-insulin dependent diabetes mellitus

Now classified as:
1. Type 1: Immune mediated (could be in children with a more rapid onset (classic) or adults with a slower onset – LADA, ‘late autoimmune diabetes of adults’)
2. Type 2: Insulin resistant
3. Other specific types (eg certain genetic defects; drug induced; etc)
4. Gestational diabetes mellitus

Evolution and changes in the classification and diagnostic criteria have implications for the interpretation of epidemiological studies – a lot of important epidemiological work predated the most recent diagnostic criteria.

Online Resources:

Diagnosis and Classification of Diabetes Mellitus: New Criteria - full text article from the American Family Physician

New classification and criteria for diagnosis of diabetes mellitus - full text article from the Medical Journal of Australia

The epidemiology and diagnosis of diabetes mellitus

- Affects generally around 7% of the population in developed countries with large geographic and ethnic variations in incidence.
- Type 2 accounts for up to 85%-95% of cases of diabetes mellitus.

- In Australia, the prevalence of diabetes was 8% in men, 6.8% in women and is rising. The prevalence of impaired glucose tolerance was 17.4% in men and 15.4% in women.

Type 1:
- Registries widely used to record incidence
- Considerable geographic variability in incidence – rates are highest in Norway, Finland, Sweden, Canada; lowest in Japan, Chile, Mexico, China, South America.
Incidence is increasing.

Type 2:
- True prevalence not known.

- Type 2 accounts for up to 85%-95% of cases of diabetes mellitus.
- Up to 20% over age 80 have diabetes.
- Prevalence in Massachusetts, USA has increased from 0.9% in 1958 to 3% in 1995
- Increasing incidence of diabetes parallels increase in incidence of obesity.
- Epidemic in some countries.
- Lowest prevalence is in less developed countries and rural areas (up to 2% in China and Africa; >50% in Pima Indians in Arizona).

- Increasing incidence of obesity in children may be responsible for increased incidence of type 2 diabetes in children.

Diagnosis of diabetes mellitus:
Classical symptoms of hyperglycaemia - polyuria (excessive urination); polydipsia (thirst); nocturia (nocturnal urination); lethargy; weight loss

Criteria for diagnosis:
1. Classical symptoms plus a random plasma glucose concentration > 11.1mmol/l
or
2. Fasting plasma glucose > 7.0mmol/l (fasting is no food for > 8 hours)
or
3. 2 hour plasma glucose greater than 11.1mmol/l during oral glucose tolerance test (OGTT)

Impaired glucose tolerance (IGT):
• represents an intermediate category between normal and diabetes – an area of uncertainty
• at higher risk of developing type 2 diabetes and macrovascular disease (sometimes called ‘dysglycaemic macroangiopathy’)
• usually clinically asymptomatic
• not at increased risk for microvascular complications
• a small percent with IGT revert to normal glucose tolerance on subsequent tests
• the diagnostic levels for fasting blood glucose are considered to be at a level that there is an increased risk for microvascular disease and not at the assumed lower levels when there may be an increased risk for macrovascular disease

Online resources:

ePodiatry links to diabetes epidemiology articles

How should we respond to the world wide diabetes epidemic - full text article from Diabetes Care

The aetiology and pathophysiology of diabetes mellitus

Aetiology of Type 1
Due to selective destruction of pancreatic beta cells by an autoimmune process - assumed to occur following an environmental trigger in genetically susceptible individuals absolute insulin deficiency.

Aetiology - Type 1 - Genetics
Genetic susceptibility - HLA-DR3, -DR4, B8 and B15 predispose to diabetes (account for 40% of the genetic susceptibility). However, the majority of those who are genetically predisposed do not develop diabetes. Risk of developing diabetes when close relative has diabetes are 30% for identical twins, 5% for siblings and 6% for offspring.

Aetiology - Type 1 - Environment
Environmental - could be viral (several have been implicated - Coxsackie B4, retroviruses, rubella, cytomegalovirus, Epstein-Barr); diet (cow's milk has been implicated); stress
Viruses may initiate immune mediated damage to beta cells by direct destruction, by the generation of cytokines that can damage the beta cells or by molecular mimicry

Immune destruction
Markers of immune mediated damage include:
- islet cell autoantibodies (ICA)
- insulin autoantibodies (IAA)
- glutamic decarboxylase autoantibodies (GAD)
- tyrosinephosphatases autoantibodies (IA-2)

Individuals are insulin deficient (absolute insulin deficiency) - hyperglycaemia occurs when about 75% of beta cells are destroyed.

Clinical onset is generally acute, but destruction of beta cells had been progressive for many years prior to diagnosis – preclinical stage may be up to 5 – 7 years

Hypothetical Stages of Type 1
1. Genetic susceptibility
2. Triggering of immune response by environmental agent
3. Autoimmunity develops - antibodies detectable include ICA (islet cell antibodies), IAA (insulin autoantibodies) and anti-GAD.
4. Clinical diabetes
5. Remission (honeymoon phase)
6. Relapse - need insulin for survival

Aetiology - Type 2
- Insulin resistance creates a relative insulin deficiency. Insulin resistance can be due to a number of reasons - tends to occur in those that are obese.
- Consensus is that the aetiology is a multifactorial interaction of environmental and genetic factors

Aetiology - Type 2 - Genetics
- genetic predisposition for Type 2 diabetes is stronger than for Type 1
- concordance rates in monozygotic twins is almost 100%
- magnitude of genetic contribution is unknown
- probably involves several genes

Aetiology - Type 2 - Environment
i) Lifestyle:
- overeating, obesity and inactivity are a high risk for type 2
- most of type 2 patients are obese, but only a few obese people develop diabetes
ii) Malnutrition in utero
- retrospective analysis has shown an inverse relationship between weight at birth and type 2 diabetes in late adulthood
- suggested that malnutrition in utero may damage beta cell development
iii) Age
iv) Ethnicity

Thrifty genotype hypothesis:
A genetic trait that was important to survival (ability to go without food for extended period) is now detrimental due to abundant food supplies and reductions in physical activity. First proposed by Neel in 1962. Certain populations (largely indigenous populations) have developed what is considered a ‘thrifty gene’ that allows them to survive period of famine when food is in short supply – this ‘thrifty gene’ is associated with a metabolic efficiency that allows storage of calories as fat with minimal energy expenditure. However, when food is plentiful, as occurs in many of these cultures today (the ‘westernisation’ of diet), the ‘thrifty gene’ predisposes to obesity (especially central obesity) - this may account for the increased risk for development of diabetes

Insulin resistance
- Insulin resistance plays a central role - "the insulin resistance syndrome" (syndrome X, plurimetabolic syndrome, metabolic syndrome)
- clustering of conditions - type 2 diabetes, central obesity, hypertension & dyslipidaemia.

Insulin resistance is of two types - insulin insensitivity & insulin unresponsiveness

Can be due to:
1) Abnormality in insulin molecule
2) Defects in target cells/tissues (most common cause)
3) Excessive amounts of antagonists

Other aspects of type 2 pathophysiology
- No initial decrease in mass of beta cells, but later get amyloid deposits - role in pathogenesis is unclear.
- Eventually get failure of beta cell secretion of insulin.
- Endothelial dysfunction and leptin physiology also plays important roles in Type 2 diabetes.

Gestational Diabetes
- During pregnancy, sensitivity to insulin decreases (placental hormones affect glucose tolerance)
- beta cells may not be able to meet this increased need for insulin gestational diabetes
- occurs in up to 14% of pregnancies
- This increases subsequent risk of developing type 2 diabetes
- Increased risk for perinatal mortality and neonatal morbidity.

Clinical features - Type 1
- Onset is variable.
- Classically, in younger age groups, the onset is acute and insulin is needed for survival - generally present with a history of polyuria, polydipsia, lethargy and weight loss over a period of up to two weeks - many may present with ketoacidosis.
- Ketoacidosis - salt and water depletion; loss of skin turgor; tachycardia; hypotension; deep and sighing breath (usually smells of acetone).
- In older age groups onset is more insidious - residual beta cell function lessens risk of ketoacidosis at time of presentation.

Clinical features - type 2
- Usually occur in older age groups - especially obese (in 70%) (however, incidence in child is assumed to be increasing due to increased prevalence of childhood obesity).

- 50% have hypertension.
- Classical signs of thirst, polyuria, nocturia and weight loss are not always present in Type 2 - often start with fatigue and malaise
- Symptoms of hyperglycaemia are long standing and generally mild.

- Up to 20% may have one/some of the complications of diabetes present at time of diagnosis.

Other types of diabetes mellitus
Specific genetic/molecular defects have been identified in a minority of what were considered type 2 diabetes:

1) Genetic defects of function of beta cell
eg Hepatic nuclear factor 4 alpha - autosomal dominant condition of impaired insulin secretion; early onset and slowly progressive; MODY type 1 (mature onset diabetes of the young)
eg Mutation of mitochondrial DNA

2) Genetic defects in the action of insulin:
eg insulin receptor - (severe insulin resistance)
Lipoatrophic diabetes

Others….
Endocrine disorders
1) Diseases of the pancreas
eg pancreatitis, neoplasia, cystic fibrosis, haemochromatosis
2) Endocrinopathies
eg acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma

Drug/chemical induced
eg vacor, pentamidine, glucocorticoids, thiazides, dilantin
Infection
eg congenital rubella, cytomegalo virus

Immune mediated (uncommon)
eg Stiff man syndrome, anti-insulin receptor antibodies

Genetic syndrome associated with diabetes mellitus
eg Down syndrome, Turner syndrome, Freidreichs ataxia, Huntington's chorea, Porphyria, Prader-Willi syndrome

Link between hyperglycaemia and complications
There are several structural mechanisms in which the hyperglycaemia mediates tissue damage:

- Non-enzymatic glycation (glucose binds to proteins; eg limited joint mobility, HbA1c)
- Oxidative-reductive stress (more free radicals produced)
- Increased polyol pathway activity (sorbitol accumulates in cells)
- Intracellular myo-inositol depletion
- Increased protein kinase C activity

Functional consequences of hyperglycaemia
- Haemodynamic disturbances (eg increased capillary pressure)
- Haemorrheological abnormalities (eg increased blood viscosity; increased coagubility)
- Microvascular dysfunction
- Endothelial dysfunction

Online resources:

ePodiatry's links to articles on Diabetes physiology, Pathophysiology and Clinical aspects of diabetes

How Do We Diagnose Diabetes and Measure Blood Glucose Control? - full text article from Diabetes Spectrum

What You Should Know About Insulin Resistance Syndrome - full text article from Podiatry Today