Type 2 diabetes is a heterogeneous disease and requires reclassification. What does it mean? When a doctor writes a diagnosis of type 2 diabetes on a specialist report and marks it with E11 in one person, and then writes the same diagnosis in another person – it does not mean that the first and the second person have the same disease! It is not worth discussing and comparing their therapy and sugar measurements. The reason is that there are several subtypes of the same disease, but there are still no different codes for the subtypes.
Why is it important to determine the subtype of type 2 diabetes?
One reason is therapeutic. Everyone is talking about the individualization of therapy. This means that medications should be tailored according to the pathophysiological disorder present in the individual.
Another reason is to enable individuals with a higher risk of developing complications to be identified at the time of diagnosis. This initially changes the therapeutic approach.
What data are needed to determine the subtype of type 2 diabetes?
Data from 5 epidemiological studies identified the markers which would help in the new classification of type 2 diabetes. These are:
- years of age,
- presence of autoAb (glutamate decarboxylase antibody – GAD AB),
- body mass index (BMI),
- HbA1c and
- c-peptide, HOMA2 -B and HOMA2-R indices (calculated upon c-peptide).
By determining these parameters, in epidemiological studies, the subgroups of type 2 diabetes which had different patient characteristics and different risks of developing complications were noticed. Defining a subtype is always important in order to predict and monitor the course of the disease. Subjects were followed through All New Diabetics in Scania (ANDIS, n = 14652), Scania Diabetes Registry (SDR, n = 1466), All New Diabetics in Uppsala (n = 844) and Diabetes Registry Vaasa (n = 3485) during 4.1 to 11 years. In all of these groups, type 1 diabetes, latent adult autoimmune diabetes (LADA), and secondary diabetes were identified. They were not monitored, but only type 2 diabetes, divided into the proposed subtypes. For example, in the ANDIS cohort from Sweden, which included newly diagnosed people with diabetes, there were 1.5% type 1, 5.3% LADA and 1.3% secondary diabetes. About 3.8% of people could not be classified because analyzes were missing, and the remaining 12,112 people were followed.
What are the proposed subtypes of type 2 diabetes?
These are: 1. Mild age related diabetes, 2. Mild obesity related diabetes, 3. Severe autoimmune diabetes, 4. Severe insulin deficient diabetes and 5. Severe insulin resistant diabetes.
Mild age related diabetes is the most common subtype of type 2 diabetes. Old age is defined when a person is 65 and older. This subtype of type 2 diabetes has a moderate metabolic disorder that is complicated by the presence of a geriatric syndrome. Metabolic changes occur due to a decrease in insulin secretion, which is independent of peripheral insulin resistance, body weight and waist circumference. This subtype of diabetes should be treated with simple therapeutic combinations, especially if it is for people older than 75 years. It is often necessary to introduce a small dose of insulin, which causes resistance. If this resistance is overcome, the older person will feel stronger and have a better quality of life.
Mild obesity related diabetes is the second most common type 2 diabetes. There is no pronounced insulin resistance in this subtype. It is characterized by a moderate metabolic disorder with normal HOMA2-IR index. Patients with this subtype benefit from physical activity and agents that lead to weight loss. The prognosis is especially good if there is more subcutaneous fat and less visceral fat. This can be determined through body composition analysis. Unfortunately, this subtype of type 2 diabetes also occurs in very young people. In the case of people under the age of 65, the medication of choice for weight loss would be Mysimba. If diabetes lasts for a shorter period, normalization of body weight could lead to remission in type 2 diabetes, as there is no development of insulin resistance. That is why it is very important to detect this subtype of diabetes on time! If this subtype of diabetes lasts longer, which is often the case, it is necessary to provide therapeutic cardio and renal protection with new medications. The medication of choice is weekly GLP-1RA, such as Trulicity or Ozempic. Then, these patients have a good prognosis.
Severe autoimmune type 2 diabetes is characterized by an early onset of the disease, normal to lower BMI, uncertain metabolic control, presence of GAD Antibodies and decreased insulin secretion (low HOMA2-B index). It may be initially presented as ketoacidosis. However, when ketoacidosis is regulated, it is noticed that these people need a very small dose of insulin. C-peptide is normal, or slightly lowered. Clinically, in the case of young people, this type is replaced with type 1 and the patient is often told that he/she has type 1, but that he/she is in the “honeymoon” phase now. However, the course of Severe autoimmune type 2 diabetes is different from type 1, as the therapy is different. People with this subtype, although young, often only have basal insulin therapy. They rarely have hypoglycemia. Their daily insulin requirements are less than 0.5 unit/kg BW. If they take care, they can stay on small doses of insulin for a long time. Thus, they differ from type 1 diabetes, which requires basal and bolus insulin in therapy and where the daily needs are around 0.7 unit/kg BW. The presence of GAD Ab requires considering existence of other antibodies and other autoimmune diseases. Knowing this may burden the patients burden.
Severe insulin deficient diabetes is similar to autoimmune diabetes, but GAD Antibodies are not present. This subtype of type 2 diabetes is often misdiagnosed as type 1 or LADA diabetes. Type 1 diabetes is defined by positive GAD AB and c-peptide that is lower than 0.3 nmol/l. LADA is defined by positive GAD AB and c-peptide higher than 0.3 nmol/l. Severe insulin deficient diabetes is characterized by negative GAD AB and c-peptide lower than 0.3 nmol/l. It is important to recognize this subtype since it allows usage of some oral antihyperglycemic medications. Sulfonylurea derivatives are not indicated. Metformin is indicated, although doctors are commonly reluctant to prescribe it. Usually, the total daily dose of insulin is less, than the dose in type 1 diabetes. This subtype is the most difficult to solve therapeutically. Ketoacidosis is not rare. Basal-bolus insulin therapy is often required, but with lower total daily dose than 0.7 unit/kg BW. Retinopathy develops most rapidly in this subgroup.
Severe insulin resistant diabetes is characterized by high BMI and HOMA2-IR index. This subtype usually develops fatty liver, which complicates the treatment. Acanthosis is often seen – on the neck, or in the armpits. This subtype requires the highest dose of insulin, metformin and pioglitazone. Diabetic kidney disease develops in this subtype very early. In general, this subtype of type 2 diabetes has the highest mortality.
In which subtype are cardiovascular diseases most common?
Cardiovascular diseases were the rarest in Severe autoimmune diabetes, Severe insulin deficient diabetes and Mild obesity related diabetes. Determining the subtype of type 2 diabetes at the time of diagnosis is of great preventive importance, since it identifies patients who are at risk of developing diabetic complications. Thus, it helps in the therapeutic decision. For example, SGLT2 inhibitors should not be given to persons prone to ketoacidosis. It is interesting that the subtypes remain the same and there is no transition from one to another. The subtypes of diabetes do not represent different stages of the same disease – type 2 diabetes.