Novel Reclassification of Adult Diabetes Is Useful to Distinguish Stages of β-Cell Function Linked to the Risk of Vascular Complications: The DOLCE Study From Northern Ukraine

Abstract

BackgroundPresently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine.MethodsWe analyzed 2,140 patients with established diabetes from the DOLCE study (n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration.ResultsSevere autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually (p = 0.0001).ConclusionThe novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve β-cell function. Long-term diabetes cases with preserved β-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.

A novel diabetes typology: towards precision diabetology from pathogenesis to treatment

“…The resulting subgroups (subtypes) were designated as 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) [6] (Table 1). This concept has been replicated in cohorts from Europe, North America and Asia despite varying disease duration since diabetes diagnosis [26][27][28][29][30][31][32]. The SAID subgroup comprises people who are otherwise classified as having type 1 diabetes (including those previously termed latent autoimmune diabetes of adults), whereas SIDD, SIRD, MOD and MARD represent novel entities of type 2 diabetes.…”

Characterisation of type 2 diabetes subgroups and their association with ethnicity and clinical outcomes: a UK real-world data study using the East London Database

“… 16 First reported by Ahlqvist and colleagues in 2018, clusters related to T2DM included: ‘severe insulin deficient diabetes’, ‘severe insulin resistant diabetes’, MOD, and MARD. 4 These subgroups have been replicated across a number of settings including the Netherlands and Scotland, 7 Ukraine, 17 China, 18 and India. 5 Only one included study was conducted in the UK; however, this was a cross-sectional hospital-based study of 33 children with type 1 diabetes.…”

Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes

“…Patients with diabetes and their first-degree relatives (parents, siblings, or children) were invited to participate. The recruitment started in November 2011 and ended in December 2014 ( Fedotkina et al, 2021b ). With the help of an endocrinologist and diabetes nurse, all participants completed a questionnaire covering their medical history, including the information on the family history of diabetes, anthropometric measurements (weight, height, and blood pressure), alcohol intake, smoking, medication for diabetes, hypertension, and hyperlipidemia.…”

“…A flowchart for the quality control and preparation of the DOLCE dataset for the statistical analysis is represented in Supplementary Figure 3 . All subsequent episodes of famine exposure in Ukraine were combined into decades of births before 1950 (exposed to famine) and after 1950 (unexposed) as previously described ( Fedotkina et al, 2021b ). To study the association of genetic variants and perinatal exposure to famine on the risk of PDR in adulthood, the interaction term between SNPs and famine exposure (year of birth before or after 1950) was fitted using generalized estimation equation using sex, age at visit, diabetes duration, and HbA1c as covariates, and corrected for family relationships (R-package “gee” version 4.13–19; defining families as clusters and correlation structure as exchangeable) ( VanderWeele and Knol, 2014 ; Carey and Ripley, 2019 ).…”