Certain human leukocyte antigen (HLA)-DR/DQ gene polymorphisms, particularly HLA-DR and HLA-DQ alleles, increase susceptibility to, or provide protection from, the disease.[14] In susceptible individuals, environmental factors may trigger the immune-mediated destruction of pancreatic beta cells. Although the geographical variation in disease prevalence and increasing worldwide incidence of type 1 diabetes argue for a major environmental contribution to pathogenesis, the specific factors involved remain unknown.[15] Among viruses, the strongest associations have been found with human enteroviruses.[16][17][18] Among dietary factors, supplementation with vitamin D may be protective.[19][20] Further research is required to determine the effect of cow's milk, early introduction of cereals, or maternal vitamin D ingestion on type 1 diabetes risk.[21][22][23] Coeliac disease shares the HLA-DQ2 genotype with type 1 diabetes, and is more common among those with type 1 diabetes.[24][25] The incidence of type 1 diabetes may also be higher among those with coeliac disease, although a causal relationship is not suggested.[26]


Type 1 diabetes usually develops as a result of autoimmune pancreatic beta-cell destruction in genetically susceptible individuals.[15] Up to 90% of patients will have autoantibodies to at least one of three antigens: glutamic acid decarboxylase; insulin; and a tyrosine-phosphatase-like molecule, islet auto-antigen-2 (IA-2).[27] Over 25% of individuals without one of these or islet cytoplasmic autoantibodies will have positive antibodies to ZnT8, a pancreatic beta-cell-specific zinc transporter.[28] In addition, 10% of adults who have been classified as having type 2 diabetes may have circulating islet cell antibodies or antibodies to glutamic acid decarboxylase, indicating autoimmune destruction of beta cells.[29]

Beta-cell destruction proceeds sub-clinically for months to years as insulitis (inflammation of the beta cell). When 80% to 90% of beta cells have been destroyed, hyperglycaemia develops. Insulin resistance has no role in the pathophysiology of type 1 diabetes. However, with increasing prevalence of obesity, some patients with type 1 diabetes may be insulin resistant in addition to being insulin deficient.

Patients with insulin deficiency are unable to utilise glucose in peripheral muscle and adipose tissues. This stimulates the secretion of counter-regulatory hormones such as glucagon, adrenaline (epinephrine), cortisol, and growth hormone. These counter-regulatory hormones, especially glucagon, promote gluconeogenesis, glycogenolysis, and ketogenesis in the liver. As a result, patients present with hyperglycaemia and anion gap metabolic acidosis.

Long-term hyperglycaemia leads to vascular complications due to a combination of factors that include glycosylation of proteins in tissue and serum, production of sorbitol, and free radical damage. Microvascular complications include retinopathy, neuropathy, and nephropathy. Macrovascular complications include cardiovascular, cerebrovascular, and peripheral vascular disease. Hyperglycaemia is known to induce oxidative stress and inflammation. Oxidative stress can cause endothelial dysfunction by neutralising nitric oxide. Dysfunctional endothelium allows entry of low-density lipoprotein into the vessel wall, which induces a slow inflammatory process and leads to atheroma formation.[30]


World Health Organization (WHO) 2019

In an update to its previous classification systems, the WHO’s 2019 classification of diabetes no longer includes subtypes of type 1 diabetes.[1] A ‘hybrid’ category has been introduced to describe atypical cases with features of both type 1 and type 2 diabetes. 

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