It’s important to note that the model of T1D development shown in Figure 1 is a simplified representation and does not fully capture the complexity of the condition [1, 18]. There is significant variation at every stage, which is not yet well understood. For example, there is variation in the starting β-cell mass and function, and genetic predisposition is now recognised as a stronger driver for immune abnormalities than initially thought. Other immunological abnormalities might appear before detectable autoantibodies, and β-cell loss can follow a relapsing or remitting pattern rather than a linear progression as shown in the original model. The rate of progression through the initial stages is also variable and likely influenced by immune, genetic, and environmental factors [1, 18].
In people with a high genetic risk for T1D, the first signs can appear very early in life, with the peak incidence of the first autoantibody appearance occurring before age two [29]. While many people with only one autoantibody will not develop T1D, progression to two or more serum autoantibodies in children is associated with an 84% risk of clinical T1D by the start of adulthood [29, 30]. This has led to the establishment of a new classification of the stages of T1D [1, 30, 31].
The preclinical Stage 1 is now defined as the ‘start of diabetes’ and is characterised by the presence of two or more autoantibodies but with normal blood glucose levels [1, 31]. As the disease advances through Stages 2 and 3, metabolic abnormalities will emerge, progressing from dysglycaemia without symptoms (Stage 2) to clinical onset (i.e., hyperglycaemia-related symptoms) and diagnosis (Stage 3) [1, 31].
Genetic Risk or Predisposition to T1D
T1D is a complex disease influenced by multiple genes 1, which is still under investigation [32]. Two specific gene types, known as human leukocyte antigen (HLA) class II haplotypes, HLA-DR3 and HLA-DR4, account for approximately 50% of the genetic risk and are common in white individuals with T1D [33]. In places like Scandinavia, where there is a high incidence of T1D, nearly 90% of children diagnosed with T1D have one or both of these haplotypes [28]. However, the mechanisms by which these HLA haplotypes affect T1D risk are not yet clear. Additionally, over 60 other non-HLA genetic locations, mostly linked to the immune system, have been associated with a higher risk of T1D [33].
Two important points should be noted regarding genetic risk or predisposition to T1D:
· Despite the known genetic factors, most people with T1D do not have a relative with the condition. The risk for siblings is only 6-7%, and the risk for children having a parent with T1D is 1-9% [28].
· It is generally accepted that an environmental trigger is needed to develop T1D [28]. However, as discussed below, this suggests there is more to the story than genetics.
Environmental Factors as Potential Triggers for T1D
Several environmental factors have been identified as potential triggers of islet autoimmunity or promoters of progression from autoimmunity to full-blown T1D [34]. These factors can occur before or after birth and include dietary factors. For instance, breastfeeding has been shown to protect against T1D development. On the other hand, early exposure to cow’s milk and gluten-containing cereals may increase the risk. However, correlation does not mean causation.
Other factors include vitamin D deficiency, early-life viral infections linked to islet inflammation (e.g., enteroviruses), and decreased gut microbiome diversity [34]. Additionally, obesity has been linked to an increased risk of progression in children who are autoantibody-positive relatives [35]. The exact immune, genetic, environmental, and physiological events and interactions that cause T1D initiation and progression are still not fully understood [1, 14].
Blood Glucose Balance: How Blood Glucose is Normally Regulated and the Role of Insulin
The body uses a tight feedback loop to keep blood glucose within the normal ‘euglycaemic’ range, typically between 70 and 140 mg/dL or 3.9-7.8 mmol/L in people without diabetes [36, 37]. This loop involves insulin and its opposing hormones: glucagon, epinephrine (adrenaline), norepinephrine (noradrenaline), cortisol, and growth hormone (Figure 2).
● Insulin: Produced by the β-cells in the pancreas, insulin plays a central role in regulating blood glucose levels. It is the only hormone with hypoglycaemic effects. It promotes the uptake of glucose by cells, particularly in the muscle, fat, and liver, and inhibits the production and secretion of glucose by the liver.
● Glucagon: Secreted by the α-cells in the pancreas, glucagon has the opposite effect of insulin. It stimulates the liver to release stored glucose (glycogen) into the bloodstream and promotes glucose production.
● Other Counterregulatory Hormones: Norepinephrine and epinephrine (also known as noradrenaline and adrenaline, respectively), cortisol, and growth hormone are also involved in blood glucose regulation. These hormones counteract the effects of insulin by promoting glucose production and inhibiting glucose uptake by cells.