How Does Type 1 Diabetes Develop? T1D Etiopathogenesis

Often, I hear people say that a certain event caused them to develop Type 1 diabetes, such as an accident, a stressful time in their lives, or pregnancy, but in fact the actual disease process begins far before such an event, perhaps years before. Another misconception that I hear often is that the autoantibodies destroy the pancreatic beta cells, but it is actually killer T cells. Type 1 diabetes is characterized by immune-mediated destruction of pancreatic beta cells in genetically predisposed individuals, which results in severe insulin deficiency and the need for exogenous insulin to sustain life.  In Type 1 autoimmune diabetes, the healthy insulin-producing beta cells of the pancreas are destroyed by T-cells of the immune system, which mistake the beta cells as “foreign” and attack them. Here are the sequential steps in the development of Type 1 diabetes:

Step 1: Genetic Predisposition

People genetically predisposed to Type 1 diabetes have either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both [Footnote 1].  Some HLA epitopes protect against the development of Type 1 diabetes; the presence of resistance HLA epitopes has been correlated with a later age of onset (adult-onset Type 1 diabetes) [Footnote 2].

Step 2: Immune Activation/Environmental Trigger

It is still not known what triggers the immune-mediated destruction of the beta cells, but it is related to environmental factors that are still poorly defined [Footnote 3]. Type 1 diabetes was first described in detail in about 100 C.E. by Aretaeus of Cappadocia [Footnote 4], so whatever the environmental factors are, they have been present for thousands of years.

Step 3: Immune Response/Development of Autoantibodies

During the immune activation and immune response involved in Type 1 diabetes, the immune system mistakenly attacks beta cells in the pancreas and destroys them over time, ultimately resulting in insulin deficiency. This process leads to the production of islet-specific autoantibodies (GAD, ICA, IA-2, IAA, and ZnT8); the autoantibodies are not pathogenic, but they represent biomarkers of the pathogenesis [Footnote 5].  Or put another way, diabetes autoantibodies are proteins that mark insulin-producing beta cells for destruction, but the autoantibodies are not believed to be directly pathological.

Step 4: Triggering Event

The triggering event is any event that stresses the body, such as illness, accident, or even pregnancy.  The stressful event means that the body requires additional insulin for proper functioning, but the ongoing destruction of the beta cells means that insufficient insulin is secreted in response to the stressor. This event is a tipping point or “the straw that broke the camel’s back,” but it is not causal.

Step 5: Development of Overt Type 1 Diabetes

Type 1 Diabetes TrialNet has identified three stages of progression in Type 1 diabetes. In stage 1, a person tests positive for autoantibodies, blood sugar levels remain normal, and the individual is asymptomatic. In Stage 2, individuals are autoantibody positive, there is a loss of beta cells, blood sugar levels are abnormal, and typically there are no symptoms. In stage 3, Type 1 diabetes symptoms are present due to significant beta cell loss. Common symptoms include increased thirst and urination, extreme hunger, unexplained rapid weight loss, blurred vision, and extreme fatigue. Exogenous insulin is necessary to sustain life. Note that in adults with slowly progressive Type 1 diabetes, symptoms may be far milder, which often leads to adults with new-onset T1D being misdiagnosed as having Type 2 diabetes (an altogether different disease).

Footnote 1: The majority of studies of HLA association with Type 1 diabetes have used Caucasian subjects.

Footnote 2:  Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility.  CL Roark et al. Diabetes 2014 Jan; 63(1): 323-331.

Footnote 3:  American Diabetes Association (ADA) Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020; 43 (Suppl 1): S14-S31.

Footnote 4: Aretaeus of Cappadocia, “Diabetes is a remarkable affliction, not very frequent among men… The course is the common one, namely, the kidneys and the bladder; for the patients never stop making water, but the flow is incessant, as if from the opening of aqueducts… The nature of the disease, then, is chronic, and it takes a long period to form; but the patient is short-lived, if the constitution of the disease be completely established; for the melting is rapid, the death speedy. Moreover, life is disgusting and painful; thirst, unquenchable; excessive drinking, which, however, is disproportionate to the large quantity of urine, for more urine is passed; and one cannot stop them either from drinking or making water. Or if for a time they abstain from drinking, their mouth becomes parched and their body dry; the viscera seems as if scorched up; they are affected with nausea, restlessness, and a burning thirst; and at no distant term they expire. They thirst, as if scorched up with fire … But if it increases still more, the heat is small indeed, but pungent, and seated in the intestines; the abdomen is shriveled, the veins protuberant, and there is general emaciation, when the quantity of urine and the thirst have already increased; and when, at the same time, the sensation appears at the extremity of the member, the patients immediately make water. Hence, the disease appears to me to have got the name diabetes as if from the Greek word διαβήτης (which signifies a siphon), because the fluid does not remain in the body, but uses the man’s body as a ladder, whereby to leave it. They survive not for long, for they pass urine with pain, and the emaciation is dreadful; nor does any great portion of the drink get into the system, and many parts of the flesh pass out along with the urine”. From Adams F (ed), 1856.The extant works of Aretaeus the Cappadocian. The Sydenham Society, London.

Footnote 5: If a single islet autoantibody or multiple islet autoantibodies are detected in a person diagnosed with diabetes (fasting blood sugar greater than 125 mg/dl), the diagnosis of Type 1 autoimmune diabetes is confirmed.