Diabetes Types: The 5 Clusters of Type 2 Diabetes

Diabetes Clusters

Traditionally, there are four Diabetes Types: Type 1 Diabetes, Type 2 Diabetes, Gestational Diabetes, and LADA (latent autoimmune diabetes of adults).

Gestational diabetes develops during pregnancy and is otherwise similar to Type 2 Diabetes.

Type 1 Diabetes, Type 2 Diabetes, and LADA can be differentiated based on the degree of insulin production, insulin resistance, and the presence of autoantibodies against the beta islet cells.

Lately, scientists grouped patients with Type 2 Diabetes into 5 different clusters. These clusters have different glycemic profiles.

In addition, diabetes-associated complications especially kidney disease and diabetic retinopathy are more common in certain clusters than others.

Differentiating Between the Different Diabetes Types:

Historically, diabetes has been classified as either Type 1 diabetes which manifests at a younger age, and patients have positive autoantibodies against the pancreatic islet Beta cells.

Type 2 diabetes is usually diagnosed when autoantibodies are absent and the patients are usually older.

LADA (latent autoimmune diabetes of adults) is similar to type 2 diabetes at diagnosis but is indistinguishable from type 1 diabetes later on. Patients with LADA also have positive anti-glutamic acid decarboxylase antibodies.

A group of Swedish scientists classified type 2 diabetes into 5 different clusters based on the following 6 variables [Ref]:

  • glutamate decarboxylase antibodies,
  • age at diagnosis,
  • BMI,
  • HbA1c,
  • homeostatic model assessment 2 estimates
    of β-cell function and
  • Insulin resistance

3 Types of Diabetes were diagnosed:

  • Type 1 diabetes was defined when C-peptide levels were less than 0.3 mmol/L and GADA positive (glutamic acid decarboxylase antibodies)
  • LADA (latent autoimmune diabetes of adults) was defined as C-peptide levels of 0.3 mmol/L or more and GADA positive.
  • Type 2 Diabetes, with C-peptide higher than 0.3 mmol/L and GADA negative were further grouped into 5 clusters.

The 5 clusters of Type 2 Diabetes mellitus:

Diabetes types: The 5 clusters of diabetes type 2
Diabetes types: The 5 clusters of diabetes type 2

Patients with type 2 diabetes were further grouped into 5 clusters based on their glycemic profiles, insulin production, and insulin sensitivity.

SAID (Severe Autoimmune Diabetes): Cluster 1 characterized by:

  • Early-onset disease,
  • Relatively low BMI,
  • Poor metabolic control,
  • Insulin deficiency, and
  • the presence of GADA

SIDD (Severe Insulin Deficient Diabetes): Cluster 2 characterized by:

  • GADA negative (but otherwise similar to cluster 1)
  • Onset at a younger age
  • Low BMI
  • Insulin Deficiency, and 
  • Poor metabolic control

SIRD (Severe Insulin Resistant Diabetes): Cluster 3 characterized by:

  • Insulin resistance
  • High BMI

MOD (mild obesity-related diabetes): Cluster 4 characterized by:

  • Obesity
  • No insulin resistance

MARD (mild age-related diabetes) or MAD: Cluster 5 characterized by:

  • Older patients
  • No insulin resistance
  • Only modest metabolic derangements

Clinical Implications of the 5 Clusters of Type 2 Diabetes:

The 5 clusters of diabetes had significant variations in their diabetes profiles and associated complications.

The table below shows the clinical differences between the 5 clusters of diabetes:

Clinical Implication

Prevalence in different clusters

HbA1c at Diagnosis and KetoacidosisClusters 1 and 2 had higher HbA1c and more ketoacidosis at diagnosis compared to other clusters.
Non-Alcoholic Fatty Liver DiseaseCluster 3 had the highest prevalence of non-alcoholic fatty liver disease.
Autoantibodies (ZnT8A)ZnT8A autoantibodies were primarily seen in patients with SAID.
Insulin Prescription at RegistrationClusters 1 and 2 had higher proportions of patients prescribed insulin compared to clusters 3-5.
Metformin Use and Traditional ClassificationCluster 2 had the highest metformin use, cluster 1 was least likely to use metformin,

Cluster 3 had low metformin use despite the most expected benefits in this cluster.

Kidney Disease RiskCluster 3 had the highest risk of developing chronic kidney disease and diabetic kidney disease.
Diabetic RetinopathyEarly signs of diabetic retinopathy were more common in cluster 2 compared to other clusters.
Coronary Events and Stroke RiskNo significant difference between clusters in age-adjusted and sex-adjusted risk.
Genetic AssociationsDifferent genetic variants were associated with different clusters, indicating genetic heterogeneity.

Insulin prescription was predominantly observed in patients categorized within clusters 1 and 2, whereas clusters 3, 4, and 5 exhibited a lower likelihood of being prescribed insulin.

Patients belonging to cluster 2 demonstrated the briefest duration to administering a second oral diabetes treatment.

They concurrently exhibited the lengthiest period to achieve the treatment goal defined by an HbA1c level of less than 6.9%.

Clusters 1, 2, and 4 displayed the lowest incidence of coronary events and strokes.

The association of the TM6SF2 gene with SIRD, but not with MOD, implies a propensity for unhealthy obesity (specifically, metabolic syndrome) among individuals characterized by SIRD.


In Summary:

The 5 clusters of diabetes are summarized here in a table format:


Clinical Features


  • Higher HbA1C
  • Increased risk of DKA
  • Positive ZnT8A autoantibodies
  • Insulin use/ requirement is high
  • Least likely to be on metformin
  • Lowest events of coronary events and stroke


  • Higher HbA1C
  • Increased risk of DKA
  • Insulin use/ requirement is high
  • More likely were on metformin
  • Signs of diabetic retinopathy develop earlier
  • Require 2nd line oral anti-diabetic drug earlier
  • Takes a long time to achieve A1C goals
  • Lowest events of coronary events and stroke


  • Highest prevalence of NAFLD
  • Benefit most from metformin (but prescribed least likely
  • Highest risk of kidney disease
  • Lower likelihood of insulin requirement
  • TM6SF2 gene mutations positive

4. MOD

  • Least likely to require insulin
  • Lowest events of coronary events and stroke

5. MARD or MAD

  • Least likely to require insulin

SAID (severe autoimmune diabetes) overlapped with Type 1 diabetes and LADA.

SIDD (severe insulin-deficient diabetes) and SIRD (severe insulin-resistant diabetes) are two severe forms of type 2 diabetes.

Retinopathy was predominantly seen in SIDD (severe insulin-deficient diabetes) while kidney disease was strongly associated with severe insulin-resistant diabetes (SIRD).

Despite optimal glucose control, diabetic kidney disease developed in patients in cluster 3. Insulin resistance was the hallmark of cluster 3 and this association was thought to trigger kidney disease.

diabetes types: 5 clusters of diabetes type 2
diabetes types: 5 clusters of diabetes type 2

What do you think?

Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

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