Subtypes of Type 2 Diabetes Mellitus and their implications for clinical practice

 Corresponding author: A. Manov Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Subtypes of Type 2 Diabetes Mellitus and their implications for clinical practice Andre Emanuilou Manov 1, * and Sarah Shahnaz 2 1 Internal Medicine and Transitional Year Residency Program at Mountain View Hospital, Las Vegas, Nevada. 2 Sunrise Health GME Consortium, Las Vegas, Nevada. World Journal of Advanced Research and Reviews, 2025, 27(02), 042-045 Publication history: Received on 22 June 2025; revised on 29 July 2025; accepted on 01 August 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.27.2.2837 Abstract The goal of this review article is to describe the four subtypes or clusters of Type 2 DM. We believe that differentiating these subtypes based on clinical and laboratory characteristics—such as glutamic acid decarboxylase antibodies (GAD), age at onset of Type 2 DM, HbA1c, body mass index (BMI), and measures of insulin resistance and insulin secretion— can help characterize them. The main purpose of defining these clusters is to understand how to tailor treatment and prevent complications that vary among these groups. The severe insulin-deficient group at diagnosis resembles Type 1 diabetes mellitus but lacks autoantibodies against beta cells and has different genetic markers. Microvascular complications like diabetic neuropathy and retinopathy are most common in this subtype, as well as cardiovascular complications. Insulin treatment should be started early in this group. The insulin-resistant subtype is linked to the highest rate of diabetic nephropathy. Efforts to decrease insulin resistance and protect kidney function are essential in this cluster. The mild obesity-related subtype and the mild age-related subtype generally have a lower risk of complications and respond well to lifestyle changes and weight loss. Identifying these subtypes of Type 2 DM allows for a personalized approach to disease management. Keywords: Type 2 Diabetes Mellitus; subtypes of type 2 DM; HOMA-IR; HOMA-IS; C-peptide 1. Introduction Until 2017, type 2 diabetes mellitus was seen as a condition marked by insulin resistance and initially, relative insulin deficiency, progressing to full insulin deficiency. It was viewed as a progressive disease that ultimately required insulin treatment. In the past seven years, four subtypes or groups of type 2 diabetes mellitus (T2DM) have been identified, each with distinct risk profiles and causes at diagnosis. This creates an opportunity to personalize treatments based on the main underlying mechanisms of each subtype [1,2,3]. Additionally, the complications associated with different T2DM groups vary, enabling tailored care approaches. Clinical and laboratory markers indicate different pathways involved in disease development. Six parameters—such as glutamic acid decarboxylase antibodies (GAD), age at diagnosis, HbA1c, body mass index (BMI), and measures of insulin resistance and secretion—can be used to distinguish these groups. 2. Subtypes of type 2 DM Type 2 DM is a complex disease with diverse presentations. The risk of developing insulin deficiency and complications varies among patients. The idea of classifying type 2 DM into subtypes has been rarely explored so far. In Western countries, including both white and black populations, many patients with type 2 DM are obese. In contrast, Asian patients with type 2 DM often do not appear obese. Understanding different subtypes of type 2 DM is essential because the underlying factors are varied and involve a wide range of predispositions. World Journal of Advanced Research and Reviews, 2025, 27(02), 042-045 43 In 2018, a study was conducted on patients with type 2 diabetes mellitus (DM) in Sweden. It was an observational cohort study called the New Diabetes in Scania (ANDIS) and included a cohort of 8980 patients. The study used six diabetesrelated variables: age at diagnosis, insulin secretory capacity measured by homeostatic model assessment of insulin secretion (HOMA-IS), insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR), body mass index (BMI), HbA1c, and GAD antibodies. Four subtypes of type 2 DM were identified based on these six variables [4,5]. Another paper in 2020 by Kahkoska et al. validated these subtypes of Type 2 DM [5]. Together, these findings identified four subtypes of Type 2 DM at diagnosis. The subtypes or clusters are listed as follows [6]. Subtype A: Severe insulin-deficient type 2 DM (SIDD); symptoms are quite severe, and GAD antibodies are negative. Patients typically have poor carbohydrate tolerance without insulin treatment. Usually, the BMI is normal with minimal or no insulin resistance. The later age at onset of Diabetes Mellitus and different genetic factors distinguish this subtype from type 1 DM without autoantibodies, which is very rare. This subtype accounts for 24% of patients with type 2 DM. Subtype B: Severe insulin-resistant type 2 DM (SIRD). This subtype has elevated beta-cell function, about 150-250% higher than normal. Patients usually have a high BMI. Their blood glucose levels increase later as pancreatic beta-cell function declines. This subtype accounts for 15% of type 2 DM cases. Subtype C: Mild obesity-related type 2 DM (MOD), where patients exhibit moderate insulin resistance and moderately increased beta cell function, approximately 100-150% of normal, and respond well to weight loss. The typical age at diagnosis is 45-55. It accounts for 22% of type 2 DM cases. Subtype D: Mild age-related type 2 DM (MARD) is characterized by moderate insulin resistance and minimal increase in pancreatic beta cell function. The typical age at diagnosis for these patients is over 65 years old. It is effectively managed through weight loss and physical activity. This subtype accounts for 39% of patients with type 2 DM. Related to these subtypes, Dennis et al. replicated them in the clinical trials of ADOPT (n=4351) and RECORD (n=4447) [7,8], finding similar data to the ANDIS cohort study. Additionally, these four subtypes of type 2 DM were confirmed in 2,316 Chinese patients and 972 Indian patients with type 2 DM [6,9]. An important question was whether these subtypes at diagnosis and after a longer duration of type 2 DM remain the same, and to what extent patients might shift from one subtype to another. One of the few studies addressing this was the German Diabetes Study (GDS), which showed that after 5 years, 23% of patients might change their subtype classification at diagnosis. However, the generalizability of these results is uncertain, given that it was a selected cohort study based on only 367 patients [10]. 3. Clinical importance of subtyping of patients with type 2 DM The clinical significance of subtyping relates to the complications associated with each subtype of type 2 DM and managing diabetes in the different subtypes with various antidiabetic medications. Type A – the SIDD subtype usually presents with very high HbA1c at diagnosis, diabetic ketoacidosis, and rapid progression to insulin treatment compared to other subtypes [6]. These patients are generally younger and have a lower BMI. This subtype of type 2 DM has the highest prevalence of diabetic retinopathy, with 23% experiencing at least mild retinopathy shortly after diagnosis. The German Diabetes Study (GDS) further examined this group, confirming the low C-peptide secretory capacity of SIDD through an intravenous glucose tolerance test [10]. In GDS, SIDD patients also showed the highest rates of diabetic sensorimotor neuropathy and cardiac autonomic neuropathy at diagnosis, along with an increased risk of cardiovascular events compared to other subtypes. Although glucose homeostasis was achieved at 5 years, neuropathy remained irreversible in these patients. These findings indicate that patients with SIDD should receive early, intensive insulin therapy, regular monitoring for complications, and continuous glucose monitoring (CGM). Based on patients with type 1 diabetes mellitus, many clinicians believe that microangiopathic complications such as diabetic retinopathy, neuropathy, and nephropathy also occur in patients with type 2 DM. However, while diabetic retinopathy and neuropathy tend to cluster in patients with SIDD, the Severe Insulin-Resistant Diabetic Patients (SIRD), which form the type B cluster, have the highest prevalence of diabetic kidney disease (DKD) [10]. SIRD patients have the lowest estimated glomerular filtration rate (eGFR) at diagnosis. They also have the highest incidence of developing chronic kidney disease (CKD), macroalbuminuria, and end-stage renal disease (ESRD). In the SIRD subgroup, the incidence of CKD and macroalbuminuria was twice as high, and the incidence of ESRD was five times higher after adjusting for age and sex than in mild age-related diabetic (MARD) patients. The increased incidence of DKD in SIRD World Journal of Advanced Research and Reviews, 2025, 27(02), 042-045 44 patients was also observed in GDS [10]. The relationship between DKD and insulin resistance is complex, and insulin resistance is a common feature in patients with CKD and ESRD [4,11]. Additionally, patients with SIRD exhibit the highest incidence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) [4]. These patients benefit from early interventions such as lifestyle changes, weight loss, and the use of glucagon-like peptide-1 receptor agonists (GLP1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) [12]. Furthermore, in the ADOPT and RECORD trials, an insulin sensitizer (thiazolidinedione) was used, showing the strongest effect in reducing HbA1c in SIRD patients [7]. The C cluster-mild obesity-related diabetes (MOD) subtype responds very well to lifestyle changes. In these patients, if weight loss is achieved, the HbA1c decreases more easily due to weight loss and improved insulin resistance. Additionally, GLP1-RAG, along with lifestyle interventions, might play a role in treatment [12]. Microvascular complications in this subtype are less common than in the first two subtypes. In the D cluster – mild age-related Diabetes (MARD) subtype, weight loss and increasing muscle mass help improve diabetes management. These patients face only mild blood sugar control issues and have fewer microvascular complications. 4. Discussion This article aims to describe the heterogeneity of patients with type 2 DM using clinical and laboratory parameters. We have identified four subtypes of the disease based on recent trials. These four subtypes have been confirmed in various studies and across different populations of patients with type 2 DM [4-10]. An essential laboratory component to measure is the C-peptide [3]. Estimating HOMA-IR and HOMA-IS helps identify different subtypes of patients with Type 2 DM. This allows clinicians to differentiate between patients with SIDD, SIRD, and milder forms like MARD. These subtypes might initially receive similar treatments. Early identification of the SIDD subtype emphasizes the need for early intensive treatment targeting insulin deficiency and monitoring for microvascular and macrovascular complications. In MARD, treatment mainly aims to reduce insulin resistance and protect kidney function. In MOD, managing obesity becomes the primary focus, and type 2 DM tends to be milder than in patients with SIDD. This subclassification offers clinicians a unique opportunity to tailor treatment strategies and monitor for specific complications linked to each of the four subtypes. We believe this personalized approach could lead to better understanding, enhanced treatment, and improved outcomes for patients with Type 2 DM. 5. Conclusion Describing the four subtypes of type 2 DM discussed in this article is essential for physicians. This is because, instead of a one-size-fits-all approach to the disease, clinicians can adopt a more pathophysiologic perspective. Doing so can improve the quality of care and outcomes for patients with different subtypes of type 2 DM, which was previously viewed as a single, uniform disease with a standard treatment pathway. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclsoed. Disclaimer This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare Affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily reflect the official views of HCA Healthcare or any affiliated entities. References [1] Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 2014; 383: 1084–1094 10.1016/S0140-6736(13)62219-9. [2] Pearson, E.R. Type 2 diabetes: a multifaceted disease. 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