Type 1 diabete
Type 1 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 Langerhan.
- 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 1 diabetes is a condition caused by an inability to produce or secrete insulin. It is characterised by an absolute insulin deficiency, state of persistent hyperglycaemia with abnormalities in carbohydrate, fat and protein metabolism.
It accounts for 90-95% of diabetes in children, classically presenting with polyuria, polydipsia and weight loss. Insulin is central to management as is monitoring for and treating complications.
T1DM typically develops in children and adolescents.
The condition can develop at any age. It is estimated that over 370,000 adults are affected with T1DM within the UK and this is thought to represent about 10% of adults who suffer from diabetes. The incidence of T1DM is thought to be increasing.
Insulin is produced and secreted by beta cells within the pancreatic islets of Langerhan.
In T1DM, progressive beta-cell destruction leads to a decline in the amount of insulin that is able to be secreted. This continues until the relative deficiency in insulin is unable to maintain normal blood glucose leading to hyperglycaemia. This usually occurs when up to 90% of the beta-cell mass has been destroyed.
Although the precise mechanism is unknown, it is presumed that autoimmunity is the main factor leading to the destruction of beta-cells. It is thought that genetically susceptible individuals may develop autoantibodies that target the beta-cells in response to an external trigger (e.g. viral infection). Up to 85% of patients with T1DM are found to have circulating autoantibodies. The anti-glutamic acid decarboxylase (anti-GAD) antibody, an enzyme found within beta cells of the pancreas, is most commonly identified.
In T1DM, it is estimated that approximately 15% of patients will have a first-degree relative who has the condition, and there is 30-50% concordance in monozygotic twins. There is also a significant link with other autoimmune conditions. The prevalence of T1DM is higher in patients with autoimmune conditions such as Graves’ disease, autoimmune thyroiditis and Addison’s disease.
T1DM has also been linked to certain human leucocyte antigens (HLA). HLAs are the human form of the major histocompatibility complex (MHC) proteins key to cell-signalling. In particular, they are important for the immune system to be able to distinguish its own cells from pathogens (e.g. from bacteria). The MHC class 1 genes encode HLA-A, HLA-B and HLA-C, which are present on all cells within the body. The MHC class 2 genes encode proteins, which are predominantly found on antigen-presenting cells and immune cells (e.g. T-helper cells). They encode the human leucocyte antigens HLA-DP, HLA-DQ and HLA-DR. It is estimated that up to 95% of patients with T1DM have human leucocyte antigens HLA-DR3 or HLA-DR4.
Under normal physiological conditions, glucose metabolism is a tightly controlled process maintaining blood glucose levels between 3.5-8.0 mmol/L.
Insulin, an anabolic hormone that is essential for the synthesis of carbohydrate, fat and protein stores, is the principle hormone that controls glucose metabolism. Numerous hormones and enzymes are involved in glucose metabolism including glucagon and glucagon-like peptide.
Glucose & insulin during fasting
In normal fasting conditions, insulin concentrations are low as it acts locally on the liver to modulate glucose production. It does this by modulation of glycogenolysis (breakdown of the stored version of glucose termed glycogen) and gluconeogenesis. The latter describes the formation of glucose from non-carbohydrate carbon substrates including amino acids (alanine and glutamate), lactate and glycerol (derived from fatty acids).
Glucose & insulin post-prandial
Following a meal (post-prandial), insulin is released from the pancreas in large amounts. The release of insulin is enhanced by the release of other gut hormones including glucagon-like peptide (GLP). Insulin acts on the liver to reduce its glucose output, inhibiting glycogenolysis and gluconeogenesis. Insulin is also essential for the promotion of glucose uptake in peripheral tissues (e.g. muscle and adipose tissue).
In addition to this insulin:
- Decreases lipolysis, increases fatty acid and triacylglycerol synthesis.
- Increases glucose uptake in adipose tissue and muscle.
- Increases protein synthesis in a variety of tissues and prevents protein degradation.