New Research Points to Multiple Adult Forms of Type 1 Diabetes

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A Bluesky post in English says researchers now believe type 1 diabetes may exist in several forms, with meaningful differences in how it begins, how it progresses, and how it may be treated. That does not change the broader work already underway on immune-system retraining or on transplanting beta cells protected from immune attack, but it does suggest doctors may need to recognize and manage distinct subtypes.

Adult-onset type 1 diabetes exhibits substantial heterogeneity. We aimed to investigate whether this variability reflects distinct disease entities or different temporal stages of a shared autoimmune process.

In this prospective cohort study, we analysed data from adults (aged 18–69 years) in the German Diabetes Study who had clinically diagnosed type 1 diabetes within the preceding 12 months, and from individuals who were positive for glutamic acid decarboxylase antibody (GADA) but had originally been diagnosed with type 2 diabetes. We used unsupervised machine learning based on GADA status, fasting C-peptide, glucose, triglycerides, and HDL cholesterol to characterise clinical and metabolic type 1 diabetes subtypes. The resulting subtypes were compared for aetiological traits (polygenic risk scores for type 1 diabetes and type 2 diabetes, partitioned type 2 diabetes polygenic risk scores, human leukocyte antigen [HLA] profiles, and islet-directed autoantibodies), insulin sensitivity, glucagon-stimulated C-peptide trajectories as a measure of residual β-cell function, and complications during prospective follow-up. Reproducibility was assessed in adults with type 1 diabetes from the German Diabetes Prospective Follow-up Registry (Diabetes-Patienten-Verlaufsdokumentation [DPV]).

Analysed participants in the German Diabetes Study cohort were recruited between June 27, 2005, and Jan 20, 2025 (n=600), and were followed up for a mean of 6·1 (SD 4·7) years. We identified three type 1 diabetes subtypes: two GADA-positive subtypes, and one GADA-negative subtype. A similar clinical and metabolic subtype structure was observed in the DPV cohort, whose participants were recruited between 2000 and 2025 (n=483) and were followed up for a mean of 3·1 (SD 5·0) years. One GADA-positive subtype was characterised by lower BMI, higher insulin sensitivity, and severe β-cell dysfunction (classic type 1 diabetes), whereas the second showed higher BMI, lower insulin sensitivity, and better β-cell function (mixed type 1 diabetes). The two GADA-positive subtypes did not differ in autoimmunity or type 1 diabetes polygenic risk scores, whereas the GADA-negative subtype had lower genetic type 1 diabetes risk, despite no clear subtype-specific differences in HLA risk haplotypes. Longitudinal modelling indicated that the mixed type 1 diabetes group was positioned 6·1 years (95% CI 4·6–7·8) earlier along the β-cell function decline trajectory compared with the classic type 1 diabetes group. The risks of hypoglycaemia (log-rank p=0·0019), retinopathy (mixed type 1 diabetes vs classic type 1 diabetes: adjusted hazard ratio 4·93 [95% CI 1·71–14·24]), and cardiovascular autonomic neuropathy (log-rank p=0·028) differed across the groups.

Type 1 diabetes is a chronic autoimmune disease characterised by progressive immune-mediated loss and dysfunction of pancreatic β cells, leading to insulin deficiency. Although type 1 diabetes was traditionally considered a uniform disease, this view has been increasingly challenged by recent evidence highlighting marked heterogeneity in its genetic, immunological, and clinical presentation.^1–3 However, it remains unclear whether and how this heterogeneous presentation translates to differences in progression rates, risk of complications, and therapeutic responses.

At the genetic level, both human leukocyte antigen (HLA) class II genotypes and non-HLA loci contribute to disease susceptibility, with varying effect across individuals and populations. Polygenic risk scores and genome-wide association studies have revealed substantial interindividual heterogeneity.

The article goes on to cite related studies on diabetes subtypes, endotypes, and cohort research, reinforcing the idea that the disease is more complex than a single uniform condition.

References from This Paper

Herder, C ∙ Roden, M

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

Diabetologia. 2022; 65:1770-1781

The current classification of diabetes, based on hyperglycaemia, islet-directed antibodies and some insufficiently defined clinical features, does not reflect differences in aetiological mechanisms and in the clinical course of people with diabetes. This review discusses evidence from recent studies addressing the complexity of diabetes by proposing novel subgroups (subtypes) of diabetes. The most widely replicated and validated approach identified, in addition to severe autoimmune diabetes, four subgroups designated severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes and mild age-related diabetes subgroups. These subgroups display distinct patterns of clinical features, disease progression and onset of comorbidities and complications, with severe insulin-resistant diabetes showing the highest risk for cardiovascular, kidney and fatty liver diseases.

Redondo, MJ ∙ Morgan, NG

Heterogeneity and endotypes in type 1 diabetes mellitus

Nat Rev Endocrinol. 2023; 19:542-554

Despite major advances over the past decade, prevention and treatment of type 1 diabetes mellitus (T1DM) remain suboptimal, with large and unexplained variations in individual responses to interventions. The current classification schema for diabetes mellitus does not capture the complexity of this disease or guide clinical management effectively. One of the approaches to achieve the goal of applying precision medicine in diabetes mellitus is to identify endotypes (that is, well-defined subtypes) of the disease each of which has a distinct aetiopathogenesis that might be amenable to specific interventions. Here, we describe epidemiological, clinical, genetic, immunological, histological and metabolic differences within T1DM that, together, suggest heterogeneity in its aetiology and pathogenesis. We then present the emerging endotypes and their impact on T1DM prediction, prevention and treatment.

Szendroedi, J ∙ Saxena, A ∙ Weber, KS ∙ et al., the GDS Group

Cohort profile: the German Diabetes Study (GDS)

Cardiovasc Diabetol. 2016; 15:59

The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities.

The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity.

You, L ∙ Ferrat, LA ∙ Oram, RA ∙ et al., the Type 1 Diabetes TrialNet Study Group

Identification of type 1 diabetes risk phenotypes using an outcome-guided clustering analysis

Diabetologia. 2024; 67:2507-2517

Although statistical models for predicting type 1 diabetes risk have been developed, approaches that reveal the heterogeneity of the at-risk population by identifying clinically meaningful clusters are lacking. We aimed to identify and characterise clusters of islet autoantibody-positive individuals who share similar characteristics and type 1 diabetes risk.

Methods: We tested a novel outcome-guided clustering method in initially non-diabetic autoantibody-positive relatives of individuals with type 1 diabetes, using the TrialNet Pathway to Prevention study data (n=1123). The outcome of the analysis was the time to development of type 1 diabetes, and variables in the model included demographic characteristics, genetics, metabolic factors and islet autoantibodies. An independent dataset (the Diabetes Prevention Trial of Type 1 Diabetes Study) (n=706) was used for validation.

Results: The analysis revealed six clusters with varying type 1 diabetes risks, categorised into three groups based on the hierarchy of clusters.

Torabi, F ∙ Vadakekolathu, J ∙ Wyatt, R ∙ et al.

Differential expression of genes controlling lymphocyte differentiation and migration in two distinct endotypes of type 1 diabetes

Diabet Med. 2023; 40, e15155

Morphological studies of pancreas samples obtained from young people with recent-onset type 1 diabetes have revealed distinct patterns of immune cell infiltration of the pancreatic islets suggestive of two age-associated type 1 diabetes endotypes that differ by inflammatory responses and rates of disease progression. The objective of this study was to investigate whether these proposed disease endotypes are associated with pathological differences in immune cell activation and cytokine secretion by applying multiplexed gene expression analysis to pancreatic tissue from recent-onset type 1 diabetes cases.

RNA was extracted from samples of fixed, paraffin-embedded pancreas tissue from type 1 diabetes cases characterised by endotype and from controls without diabetes. Expression levels of 750 genes associated with autoimmune inflammation were determined by hybridisation to a panel of capture and reporter probes and these were counted as a measure of gene expression. Normalised counts were analysed for differences in expression between 29 type 1 diabetes cases and 7 controls without diabetes, and between the two type 1 diabetes endotypes.

Ten inflammation-associated genes, including INS, were significantly under-expressed in both endotypes and 48 genes were more highly expressed. A different set of 13 genes associated with the development, activation and migration of lymphocytes was uniquely overexpressed in the pancreas of people developing diabetes at younger age.

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