Type 2 diabetes
Type 2 diabetes refers to a group of metabolic disorders that result from an inability to produce and/or reduced sensitivity to insulin.
Diabetes mellitus is a chronic, multi-system disease, with profound biochemical and structural sequelae. It can be classified into four main groups:
- Type 1 diabetes mellitus: characterised by an inability to produce/secrete insulin due to autoimmune destruction of the beta-cells (production site of insulin) in the pancreatic islets of Langerhans.
- Type 2 diabetes mellitus: characterised by a combination of peripheral insulin resistance and inadequate secretion of insulin. It is strongly associated with obesity and the metabolic syndrome.
- Gestational diabetes mellitus: new onset of diabetes in pregnancy. It is associated with both maternal and foetal complications and as such patients are managed as part of a multi-disciplinary team in both antenatal and diabetic clinics. Patients with GDM have a higher risk of developing both GDM in future pregnancies and overt diabetes mellitus.
- Other: These can be divided into genetic and acquired disease. Genetic causes refer to monogenic diabetes (i.e caused by mutation to a single gene). They are rare and collectively termed ‘mature-onset diabetes of the young’ (MODY). Acquired causes may be secondary to medications or pathological conditions. Common causes include corticosteroids, pancreatitis and pancreatic tumours.
Type 2 diabetes is a condition caused by a combination of insulin resistance and deficiency. It is the most common form of diabetes and is responsible for a huge amount of morbidity and mortality in the UK.
T2DM is a complex, polygenic disease that is strongly associated with obesity.
Development of the condition is dependent on the interaction between the genetic make-up of the patient and their environment. Approximately 80% of the risk for developing T2DM is due to obesity.
T2DM is a worldwide public health concern with over 500 million people expected to suffer from the condition by 2030, over half being unaware of their condition.
T2DM has been shown to have a genetic basis. The risk of developing the condition is as high as 75% if both parents have suffered from the condition. Moreover, in monozygotic twins, there is a 50-90% concordance for developing the condition.
Importantly, T2DM is considered a polygenic disease with numerous genetic variants contributing to overall disease risk. Certain ethnicities (e.g. Asian/African) have a 2-4x increased risk of developing the condition.
Environmental risk factors have a significant impact on the development of T2DM. Obesity and inactivity account for the majority of this risk (80-85%). Obesity is associated with insulin resistance and the metabolic syndrome.
Other major environmental risk factors include:
- Poor dietary habit (low fibre, high glycemic index diet)
- Low birth weight
- Polycystic ovarian syndrome
- History of GDM
The two principle mechanisms involved in the development of T2DM are peripheral insulin resistance and inadequate insulin secretion.
It has long stood that peripheral insulin resistance was at the centre of T2DM. The importance of reduced insulin secretion and beta-cell dysfunction in the pathophysiology is now acknowledged.
During normal control of glucose homeostasis, the release of insulin following ingestion of a meal leads to the uptake of glucose into cells (peripheral muscle).
Insulin is able to bind to insulin receptors on the cell surface. Binding leads to a number of downstream responses including effects on lipid metabolism, protein metabolism and cellular growth. In general, these are anabolic effects that:
- Inhibit proteolysis and lipolysis
- Inhibit hepatic gluconeogenesis
- Promotes hepatic glycogen synthesis
Activation of the insulin receptor also initiates translocation of the glucose receptor GLUT-4 (found in the cytosol of adipose and striated muscle) to the cell surface. This allows movement of glucose intracellularly.
Resistance to insulin causes disruption of these metabolic processes. Hyperglycaemia develops due to failed glucose uptake and there are catabolic effects on lipids (increased lipolysis), protein (increased proteolysis) and hepatic tissue (increased hepatic gluconeogenesis and reduced hepatic glycogen synthesis). The exact mechanism involved in insulin resistance is poorly characterised.
An inability of peripheral tissue to respond to insulin leads to hyperglycaemia, which in turn causes hyperinsulinaemia. In the early stages of insulin resistance, abnormal regulation of glucose occurs following a meal in the post-prandial state. This is termed impaired glucose tolerance (IGT). IGT is a major risk for the future development of frank diabetes and cardiovascular disease.
High levels of glucose during the fasting state (between meals) can also occur with insulin resistance, which is termed impaired fasting glucose (IFG). IFG itself is another risk factor for the development of frank diabetes. IFG and IGT are often collectively referred to as ‘pre-diabetes’ as they are significant markers for the future development of the condition if no intervention occurs to reduce risk (e.g. lifestyle and diet modifications).
A reduction in insulin secretion is now central to the pathogenesis of T2DM with the development of beta cell dysfunction and gradual loss of beta cell mass.
As hyperglycaemia develops, the beta cells within the Islets of Langerhans must secrete more insulin to deal with the increase in glucose leading to hyperinsulinaemia. These high levels of insulin are still inadequate to restore glucose homeostasis. It is thought that high glucose levels (and lipids) are toxic to beta cells leading to a depletion in their cellular mass. This is termed glucotoxicity. During autopsy, patients with T2DM have shown to have deposition of amyloid within islet cells supporting the idea of beta cell depletion.
As a significant proportion of the beta cell mass is depleted, insulin levels begin to decline and there is secretary failure. This may progress toward absolute insulin deficiency, loss of glucose control, and requirement of insulin. The time frame for the development of beta cell dysfunction to absolute insulin deficiency is highly variable among patients.
Patients may complain of lethargy, polyuria, polydipsia, weight loss, and recurrent infections (e.g. thrush, balanitis) or be picked up on routine testing.
NOTE: Diabetes mellitus is a chronic, multi-system disease that has profound biochemical and structural sequelae. In patients with established chronic disease, it is important to consider clinical features associated with the variety of microvascular and macrovascular complications that can develop. These are discussed further below.
Investigations & diagnosis
The major diagnostic tool in T2DM is the measurement of glycated haemoglobin (HbA1c).
Other tests that can be used in the diagnosis and assessment of T2DM include random plasma glucose levels, fasting plasma glucose levels and an oral glucose tolerance test (OGTT).