27th May 2025

Aetiology

T1DM is caused by autoimmune destruction of pancreatic beta cells which results in absolute insulin deficiency. Although the cause of the immune mediated destruction is not fully understood, a number of genetic and environmental factors are attributed. 

Genetic Factors 

Genetic factors that increase the risk of T1DM include different gene polymorphisms, specifically human leukocyte antigen (HLA) alleles HLA-D2 and HLA-DQ. The HLA-DQ2 genotype is often seen in T1DM and also associated with coeliac disease. Individuals with a close relative with T1DM are at an increased risk of developing the disease. 

People with T1DM have an increased chance of having other autoimmune disorders, for example: Addison’s disease, Hashimoto’s thyroiditis, vitiligo and systemic lupus erythematous (SLE).

Environmental Factors 

Environmental factors are thought to be involved in contributing to developing T1DM but no cause has been found. Suggested environmental factors include viral infections, cow’s milk intake, vitamin D deficiency, early introduction of cereals and nitrate concentration in drinking water.

Pathophysiology

T1DM develops from the autoimmune destruction of insulin-producing beta cells in the islets of Langerhans in the pancreas, which results in absolute insulin deficiency. T1DM is considered a type IV hypersensitivity autoimmune reaction; CD4+ T helper cells and CD8+ cytotoxic T cells attack pancreatic beta cells and over time stop insulin production. 

Destruction of pancreatic beta cells occurs sub-clinically for months to years as inflammation of beta cells (insulitis). Hyperglycaemia develops when around 90% of the beta cells have been destroyed. 

Patients that lack insulin are unable to use glucose in adipose tissue and peripheral muscle. This leads to secretion of counter-regulatory hormones including glucagon from overstimulation of pancreatic alpha cells, adrenaline, cortisol and growth hormone. These hormones, particularly glucagon, lead to gluconeogenesis, glycogenolysis and ketogenesis especially after meals; which lead to hyperglycaemia and metabolic acidosis (which presents as diabetic ketoacidosis).

Long term complications of T1DM is explained by chronic hyperglycaemia which leads to chronic microvascular  and macrovascular damage. Vascular damage is caused by hyperglycaemia induced oxidative stress, glycosylation of proteins in tissues, free radical damage and sorbitol production. Oxidative stress causes damage to the vascular endothelium by neutralising nitric oxide, which leads to low-density lipoproteins entering the vessels and deposit into the vessel wall driving inflammation and atheroma formation.

Microvascular complications include retinopathy, nephropathy and neuropathy and macrovascular complications include cardiovascular, cerebrovascular and peripheral vascular disease.