The Three-stage Model for Type 1 Diabetes

The Three-Stage Model for T1D

This section will provide an overview of the three stages of Type 1 diabetes (T1D). As discussed in the first section, while T1D was previously considered a childhood disease, it can develop at any age. Although there is an uptick in diagnoses between ages 4-7 years and 10-14 years, nearly half of all cases of T1D are now diagnosed after the age of 30.

Historically, the onset of T1D has been compared to flipping an on/off switch to the "off" position: The body's immune system suddenly and erroneously attacks the beta cells of the pancreas, insulin production ceases, many symptoms appear — and a diagnosis of T1D is determined. Today, we have a much better understanding of the process by which T1D develops. Rather than being just like an on or off switch, it is more like a dimmer switch — with distinct, progressive stages between full-on to full-off.

Understanding and recognizing these stages provides Diabetes Care and Education Specialists (DCESs) and health care professionals (HCPs) with the opportunity to more appropriately intervene. Correctly staging and stratifying T1D offers intrinsic benefits for educating and treating people with the disease.

The American Diabetes Association's (ADA) Standards of Care in Diabetes includes the following key statements that explain screening for T1D before the onset of symptoms

"Multiple studies indicate that measuring islet autoantibodies in relatives of those with Type 1 diabetes… can effectively identify those who will develop Type 1 diabetes… Indeed, the risk of Type 1 diabetes increases as the number of relevant autoantibodies detected increases…" 

"A family history of autoimmune diabetes and a personal or family history of allergic diseases or other autoimmune diseases increase the risk of autoimmune diabetes compared with the general population." 

"Individuals who test autoantibody-positive should be provided with or referred for counseling about the risk of developing diabetes, diabetes symptoms, and DKA prevention and should be considered for additional testing as applicable to help determine if they meet criteria for intervention..." 

The Three Stages

The etiology of T1D can be broken down into three distinct stages. It is important to note, the rate of progression from one stage to the next is highly individualized and can last anywhere from months to decades. However, progression is generally more rapid in younger individuals.

Stage 1

Stage 1 (normoglycemia) is characterized by the presence of 2 or more autoantibodies that are known to contribute to the development of T1D: GAD 65 (glutamic acid decarboxylase), IA-2 (insulinoma-associated protein 2), ZnT8 (Zinc cotransporter 8), insulin antibodies and ICA (islet cell antibodies).

Stage 2 (dysglycemia) occurs after a damaging event, such as an acute illness, stress or physical trauma, triggers the release of antigens from the beta cells of the pancreas. In the presence of autoantibodies, these antigens activate T-cells within the islets to begin beta-cell destruction.

At this stage, insulin production is diminished to the point where glucose levels rise above normal but are not high enough to meet the criteria for T1D diagnosis. This is called dysglycemia. Glucose levels remain mostly below the renal threshold for glucose — the plasma glucose concentration above which significant glucosuria or the presence of glucose in the urine occurs. The normal threshold is 180mg/dL.

During dysglycemia, typical physical diabetes symptoms including the three Ps discussed in the previous section (polyuria, polydipsia, and polyphagia — excessive urination, thirst and hunger) and/or rapid weight loss are usually not yet present.

Stage 3

Stage 3 (dysglycemia with clinical symptoms of T1D) is reached when the beta cell function of the pancreas is mostly or completely extinguished so insulin is no longer being produced by the body.

When this happens, glucose levels become markedly elevated and the criteria for the diagnosis of T1D are met, including increased A1C in the blood or increased concentrations of glucose in venous plasma, as described in the ADA Standards. Common symptoms include rapid weight loss and lethargy, accompanied by excessive thirst, hunger, and urination. With a severe or complete insulin deficiency, the body's cells shift away from glucose and towards fat as a primary energy source.

Until a person begins taking insulin not produced by their own body (called exogenous insulin), ketoacids accumulate and diabetes-related ketoacidosis (DKA) can occur. In the U.S., DKA is present at T1D diagnosis in up to 60% of youth.

The Etiology of T1D Can Be Broken Down Into Three Distinct Stages

OGTT = oral glucose tolerance test

Intrinsic Benefits of Staging and Stratifying T1D

The detection of autoantibodies before the development of overt T1D offers several unique benefits:

• Individuals who test positive can be placed on a program of glucose monitoring per health care practitioner recommendations to quickly detect dysglycemia and hyperglycemia, and they can begin insulin treatment before DKA can develop. By lowering the likelihood of experiencing DKA at diagnosis, these metabolic and physical consequences of DKA can be mitigated:
• Lower residual beta cell function
• Higher A1C for at least 15 years
• Rare neurological trauma such as cerebral edema

• Affected individuals can prepare themselves and their families, emotionally and logistically, for an eventual T1D diagnosis — with your help.

• Various medical and behavior strategies may be put in place to delay the progression of beta cell loss and prolong the "honeymoon" phase after an eventual diagnosis. Also called a partial remission phase, the honeymoon phase typically takes place soon after insulin treatment begins. During this phase, a temporary uptick in endogenous insulin production results in near-normal glycemia, which can sometimes mean the individual suddenly needs less exogenous insulin. This reduces the initial self-management burden and the risk for severe hypoglycemia.

Key Takeaways

Correctly assessing and understanding an individual’s stage of T1D enables the DCES and other HCPs to:    

• Educate on the true etiology of T1D
• If <2 autoantibodies, recommend annual follow-up screening
• If ≥2 autoantibodies:
  • Schedule confirmatory screening within 6 weeks
  • Instruct on glucose self-monitoring (covered in section 4)
  • Provide list of symptoms indicative of progression to stage 3
  • Offer emotional support

The next section will review pre-clinical screening in detail.