What are the distinct subgroups in the newer classification of diabetes mellitus?

Newer Classification of Diabetes Mellitus

The newer classification of diabetes identifies five distinct subgroups based on clinical and pathophysiological characteristics: severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which differ substantially in their risk profiles for complications and treatment responses. 1, 2

The Five Distinct Subgroups

1. Severe Autoimmune Diabetes (SAID)

• Characterized by presence of islet autoantibodies (GAD, IA-2, IAA, ZnT8) and autoimmune β-cell destruction leading to absolute insulin deficiency 1
• Includes latent autoimmune diabetes in adults (LADA) 3
• Presents with younger age at diagnosis, lower BMI (<25 kg/m²), and often requires insulin treatment 1
• Highest risk for diabetic ketoacidosis (DKA) among all subgroups 4
• Increased risk of diabetic retinopathy compared to MARD subgroup 5, 6

2. Severe Insulin-Deficient Diabetes (SIDD)

• Marked by severe β-cell dysfunction with low C-peptide levels but absence of autoantibodies 2, 7
• Presents with high HbA1c at diagnosis and poor glycemic control 1, 2
• Highest risk of diabetic retinopathy among all subgroups 1, 5
• Shows particular benefit from insulin glargine therapy with 13% decreased occurrence of hyperglycemia compared to standard care 7
• More likely to develop cardiovascular disease, stroke, and diabetic peripheral neuropathy 4

3. Severe Insulin-Resistant Diabetes (SIRD)

• Defined by marked insulin resistance with elevated BMI and high fasting insulin/C-peptide levels despite preserved β-cell function 2, 7
• Carries the highest risk for diabetic kidney disease among all subgroups, with HR 2.25 for chronic kidney disease stage 3B and HR 1.56 for macroalbuminuria compared to MARD 7, 6
• Highest risk for cardiovascular disease, fatty liver disease, and metabolic syndrome 1, 2, 4
• Independent risk factor for diabetic kidney disease even after adjusting for other risk factors 6

4. Mild Obesity-Related Diabetes (MOD)

• Characterized by obesity (elevated BMI) with moderate insulin resistance but relatively preserved β-cell function 2, 4
• Younger age at diagnosis with features of metabolic syndrome 1, 4
• Highest prevalence of non-alcoholic fatty liver disease (NAFLD) 4
• Lower cardiovascular mortality risk compared to other subgroups 5

5. Mild Age-Related Diabetes (MARD)

• Presents at older age with modest metabolic derangements and relatively preserved β-cell function 2, 7
• Most common subgroup in some populations (23% in Eastern China cohort) 4
• Paradoxically shows higher cardiovascular-related mortality (HR 4.75) compared to MOD subgroup despite milder metabolic profile 5
• More likely to develop cardiovascular disease and diabetic peripheral neuropathy 4

Clinical Utility and Implementation

Diagnostic Approach Using AABBCC Framework

The American Diabetes Association recommends the AABBCC clinical tool for distinguishing diabetes subtypes 1:

• Age: <35 years suggests type 1/SAID
• Autoimmunity: Personal/family history of autoimmune disease
• Body habitus: BMI <25 kg/m² suggests SAID/SIDD; elevated BMI suggests MOD/SIRD
• Background: Family history of type 1 diabetes
• Control: Inability to achieve glycemic goals on non-insulin therapies
• Comorbidities: Immune checkpoint inhibitor therapy can cause acute autoimmune diabetes

Laboratory Testing for Subgroup Classification

• Autoantibody testing (GAD, IA-2, IAA, ZnT8) to identify SAID 1, 3
• C-peptide measurement (fasting, when glucose ≤220 mg/dL) to assess endogenous insulin production: low levels indicate SIDD, high levels suggest SIRD 3, 7
• HOMA2 estimates of β-cell function and insulin resistance 6
• HbA1c and BMI at diagnosis 2, 7

Important Clinical Caveats

Overlapping Features

• A diagnosis of type 1 diabetes does not preclude features of type 2 diabetes (insulin resistance, obesity), and patients may require treatment approaches for both conditions 1, 3
• Misdiagnosis occurs in 40% of adults with new type 1 diabetes, often misclassified as type 2 diabetes 1
• MODY patients are frequently misdiagnosed as type 1 diabetes 1

Staging of Type 1 Diabetes

The American Diabetes Association defines three distinct stages of type 1 diabetes 1:

• Stage 1: Multiple islet autoantibodies with normoglycemia, presymptomatic
• Stage 2: Islet autoantibodies with dysglycemia (FPG 100-125 mg/dL, 2-h PG 140-199 mg/dL, or A1C 5.7-6.4%), presymptomatic
• Stage 3: Overt hyperglycemia meeting diabetes criteria, symptomatic

Validation Across Populations

• These five subgroups have been validated in multiethnic cohorts including Europeans, Latin Americans, and East Asians 7, 6
• Distribution varies by population: Eastern China showed 44% SIDD, 23% MARD, 20% MOD, 8% SIRD, and 4% SAID 4
• Subgroups exhibit similar baseline characteristics and complication risks across ethnic groups 7

Treatment Implications

• SIDD patients show superior response to insulin glargine versus standard care 7
• SIRD patients require aggressive management of cardiovascular and renal risk factors given highest complication rates 2, 7
• MOD patients benefit from weight loss interventions and metabolic syndrome management 4