Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after adjustment (model 2) for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (SAID, 21%), severe insulin-deficient diabetes (SIDD, 3%), severe insulin-resistant diabetes (SIRD, 9%), mild obesity-related diabetes (MOD, 32%) and mild age-related diabetes (MARD, 35%). In model 1, 23 biomarkers showed ≥1 pairwise difference between subgroups (Bonferroni-corrected p<0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with ≥1 of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g. lower CASP8, EN-RAGE and IL-6 in SIDD vs. all other subgroups, all p<0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.

Download Full-text

Differences in the prevalence of erectile dysfunction between novel subgroups of recent-onset diabetes

Diabetologia ◽

10.1007/s00125-021-05607-z ◽

2021 ◽

Author(s):

Haifa Maalmi ◽

Christian Herder ◽

Gidon J. Bönhof ◽

Klaus Strassburger ◽

Oana-Patricia Zaharia ◽

...

Keyword(s):

Erectile Dysfunction ◽

Autoimmune Diabetes ◽

High Sensitivity ◽

Cross Sectional Study ◽

Contributing Factors ◽

Cross Sectional ◽

Recent Onset ◽

Insulin Resistant ◽

Onset Diabetes ◽

Age Related

Abstract Aims/hypothesis In men with diabetes, the prevalence of erectile dysfunction increases with advanced age and longer diabetes duration and is substantially higher in men with type 2 diabetes than those with type 1 diabetes. This study aimed to evaluate the prevalence of erectile dysfunction among the five novel subgroups of recent-onset diabetes and determine the strength of associations between diabetes subgroups and erectile dysfunction. Methods A total of 351 men with recent-onset diabetes (<1 year) from the German Diabetes Study baseline cohort and 124 men without diabetes were included in this cross-sectional study. Erectile dysfunction was assessed with the International Index of Erectile Function (IIEF) questionnaire. Poisson regression models were used to estimate associations between diabetes subgroups (each subgroup tested against the four other subgroups as reference) and erectile dysfunction (dependent binary variable), adjusting for variables used to define diabetes subgroups, high-sensitivity C-reactive protein and depression. Results The prevalence of erectile dysfunction was markedly higher in men with diabetes than in men without diabetes (23% vs 11%, p = 0.004). Among men with diabetes, the prevalence of erectile dysfunction was highest in men with severe insulin-resistant diabetes (SIRD) (52%), lowest in men with severe autoimmune diabetes (SAID) (7%), and intermediate in men with severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) (31%, 18% and 29%, respectively). Men with SIRD had an adjusted RR of 1.93 (95% CI 1.04, 3.58) for prevalent erectile dysfunction (p = 0.038). Similarly, men with SIDD had an adjusted RR of 3.27 (95% CI 1.18, 9.10) (p = 0.023). In contrast, men with SAID and those with MARD had unadjusted RRs of 0.26 (95% CI 0.11, 0.58) (p = 0.001) and 1.52 (95% CI 1.04, 2.22) (p = 0.027), respectively. However, these associations did not remain statistically significant after adjustment. Conclusions/interpretation The high RRs for erectile dysfunction in men with recent-onset SIRD and SIDD point to both insulin resistance and insulin deficiency as major contributing factors to this complication, suggesting different mechanisms underlying erectile dysfunction in these subgroups. Graphical abstract

Download Full-text

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

Diabetologia ◽

10.1007/s00125-021-05625-x ◽

2022 ◽

Author(s):

Christian Herder ◽

Michael Roden

Keyword(s):

Clinical Features ◽

Autoimmune Diabetes ◽

Routine Care ◽

Insulin Resistant ◽

Open Questions ◽

Age Related ◽

The Stability ◽

Mild Obesity ◽

Insight Into

AbstractThe 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. While it has been suggested that people in these subgroups would benefit from stratified treatments, RCTs are required to assess the clinical utility of any reclassification effort. Several methodological and practical issues also need further study: the statistical approach used to define subgroups and derive recommendations for diabetes care; the stability of subgroups over time; the optimal dataset (e.g. phenotypic vs genotypic) for reclassification; the transethnic generalisability of findings; and the applicability in clinical routine care. Despite these open questions, the concept of a new classification of diabetes has already allowed researchers to gain more insight into the colourful picture of diabetes and has stimulated progress in this field so that precision diabetology may become reality in the future. Graphical abstract

Download Full-text

Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation

10.2337/figshare.15782064.v1 ◽

2021 ◽

Author(s):

Jacqueline M. Ratter-Rieck ◽

Haifa Maalmi ◽

Sandra Trenkamp ◽

Oana-Patricia Zaharia ◽

Wolfgang Rathmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Cell ◽

Autoimmune Diabetes ◽

Cell Types ◽

Recent Onset ◽

Insulin Resistant ◽

Cell Counts ◽

Age Related

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4+ T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4+ regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4+ T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4+ regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

Download Full-text

The Identification of Diabetes Mellitus Subtypes Applying Cluster Analysis Techniques: A Systematic Review

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17249523 ◽

2020 ◽

Vol 17 (24) ◽

pp. 9523

Author(s):

Antonio Sarría-Santamera ◽

Binur Orazumbekova ◽

Tilektes Maulenkul ◽

Abduzhappar Gaipov ◽

Kuralay Atageldiyeva

Keyword(s):

Diabetes Mellitus ◽

Systematic Review ◽

Cluster Analysis ◽

Autoimmune Diabetes ◽

Insulin Resistant ◽

Age Related ◽

Mild Obesity ◽

Diabetes Patients

Diabetes Mellitus is a chronic and lifelong disease that incurs a huge burden to healthcare systems. Its prevalence is on the rise worldwide. Diabetes is more complex than the classification of Type 1 and 2 may suggest. The purpose of this systematic review was to identify the research studies that tried to find new sub-groups of diabetes patients by using unsupervised learning methods. The search was conducted on Pubmed and Medline databases by two independent researchers. All time publications on cluster analysis of diabetes patients were selected and analysed. Among fourteen studies that were included in the final review, five studies found five identical clusters: Severe Autoimmune Diabetes; Severe Insulin-Deficient Diabetes; Severe Insulin-Resistant Diabetes; Mild Obesity-Related Diabetes; and Mild Age-Related Diabetes. In addition, two studies found the same clusters, except Severe Autoimmune Diabetes cluster. Results of other studies differed from one to another and were less consistent. Cluster analysis enabled finding non-classic heterogeneity in diabetes, but there is still a necessity to explore and validate the capabilities of cluster analysis in more diverse and wider populations.

Download Full-text

Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation

10.2337/figshare.15782064 ◽

2021 ◽

Author(s):

Jacqueline M. Ratter-Rieck ◽

Haifa Maalmi ◽

Sandra Trenkamp ◽

Oana-Patricia Zaharia ◽

Wolfgang Rathmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Cell ◽

Autoimmune Diabetes ◽

Cell Types ◽

Recent Onset ◽

Insulin Resistant ◽

Cell Counts ◽

Age Related

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4+ T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4+ regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4+ T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4+ regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

Download Full-text

Aetiological differences between novel subtypes of diabetes derived from genetic associations

10.1101/2020.09.29.20203935 ◽

2020 ◽

Author(s):

Dina Mansour Aly ◽

Om Prakash Dwivedi ◽

Rashmi B Prasad ◽

Annemari Karajamaki ◽

Rebecka Hjort ◽

...

Keyword(s):

Insulin Secretion ◽

Family History ◽

Autoimmune Diabetes ◽

Genetic Risk Score ◽

Strong Association ◽

Genetic Associations ◽

Insulin Resistant ◽

Age Related ◽

Patients With Diabetes ◽

History Of

Background: Type 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.1 In this study we use genetic information to investigate if these subtypes have distinct underlying genetic drivers. Methods: Genome-wide association (GWAS) and genetic risk score (GRS) analysis was performed in Swedish (N=12230) and Finnish (N=4631) cohorts. Family history was recorded by questionnaires. Results: Severe insulin-deficient diabetes (SIDD) and mild obesity-related diabetes (MOD) groups had the strongest family history of T2D. A GRS including known T2D loci was strongly associated with SIDD (OR per 1 SD increment [95% CI]=1.959 [1.814-2.118]), MOD (OR 1.726 [1.607-1.855]) and mild age-related diabetes (MARD) (OR 1.771 [1.671-1.879]), whereas it was less strongly associated with severe insulin-resistant diabetes (SIRD, OR 1.244 [1.157-1.337]), which was similar to severe autoimmune diabetes (SAID, OR 1.282 [1.160-1.418]). SAID showed strong association with the GRS for T1D, whereas the non-autoimmune subtype SIDD was most strongly associated with the GRS for insulin secretion rate (P<7.43x10-9). SIRD showed no association with variants in TCF7L2 or any GRS reflecting insulin secretion. Instead, only SIRD was associated with GRS for fasting insulin (P=3.10x10-8). Finally, a T2D locus, rs10824307 near the ZNF503 gene was uniquely associated with MOD (ORmeta=1.266 (1.170-1.369), P=4.3x10-9). Conclusions: New diabetes subtypes have partially different genetic backgrounds and subtype-specific risk loci can be identified. Especially the SIRD subtype stands out by having lower heritability and less involvement of beta-cell related pathways in its pathogenesis.

Download Full-text

Are the Different Diabetes Subgroups Correlated With All-Cause, Cancer-Related, and Cardiovascular-Related Mortality?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa628 ◽

2020 ◽

Vol 105 (12) ◽

pp. e4240-e4251

Author(s):

Peng-Fei Li ◽

Wei-Liang Chen

Keyword(s):

Cancer Mortality ◽

Autoimmune Diabetes ◽

Primary Outcome Measure ◽

Nhanes Iii ◽

P Value ◽

Data Set ◽

Insulin Resistant ◽

Age Related ◽

Hazard Ratios ◽

Related Mortality

Abstract Context Numerous studies have shown that cardiovascular disease (CVD) represents the most important cause of mortality among people with diabetes mellitus (DM). However, no studies have evaluated the risk of CVD-related mortality among different DM subgroups. Objective We aimed to examine all-cause, CVD-related, and cancer-related mortality for different DM subgroups. Design, Setting, Patients, and Interventions We included participants (age ≥ 20 years) from the National Health and Nutrition Examination Survey III (NHANES III) data set. We evaluated the risks of all-cause and cause-specific (CVD and cancer) mortality among 5 previously defined diabetes subgroups: 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). Primary Outcome Measure The hazard ratios (HRs) for all-cause and cause-specific (CVD and cancer) mortality were measured for each of the 5 DM subgroups. We also evaluated the odds ratios (ORs) for retinopathy and nephropathy in each subgroup. Results A total of 712 adults were enrolled and the median follow-up time was 12.71 years (range, 0.25-18.08 years). The number of deaths in the 5 subgroups (SAID, SIDD, SIRD, MOD, and MARD) were 50, 75, 64, 7, and 18, respectively, and the number of CVD-related deaths in the 5 subgroups was 29, 30, 26, 2, and 11, respectively. Compared to the MOD subgroup, the adjusted HRs and 95% CIs of CVD-related mortality for the SAID, SIDD, SIRD, and MARD subgroups were 3.23 (95% CI, 0.77-13.61), 2.87 (95% CI, 0.68-12.06), 2.23 (95% CI, 0.53-9.50), and 4.75 (95% CI, 1.05-21.59), respectively (the HR for the MARD subgroup had a P value of .04). In addition, compared to the MARD subgroup, the adjusted ORs and 95% CIs for retinopathy in the SAID and SIDD groups were 2.38 (95% CI, 1.13-5.01, P = .02) and 3.34 (95% CI, 1.17-6.88, P = .001), respectively. The ORs for nephropathy were nonsignificant. Conclusions Our study of patients from the NHANES III data set indicated that among the different DM subgroups, the MARD subgroup tended to have a higher CVD-related mortality than the MOD subgroup. The all-cause and cancer-related mortality rates were similar across the different diabetes subgroups. In addition, compared to the MARD subgroup, the SAID and SIDD subgroups had a higher retinopathy risk, but there was no difference in nephropathy among the subgroups.

Download Full-text

MON-649 Application of the New Cluster-Based Classification of Adult Onset Diabetes in a South Texas Veteran Population

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1629 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jonathan Trejo ◽

Lyan Gondin Hernandez ◽

Lucy M A Esteve ◽

Libia Vasquez ◽

Sheila Pinkson ◽

...

Keyword(s):

Autoimmune Diabetes ◽

Microvascular Complications ◽

South Texas ◽

Adult Onset ◽

Insulin Deficiency ◽

Diabetes Clinic ◽

C Peptide ◽

Onset Diabetes ◽

Adult Onset Diabetes

Abstract Recently a cluster-based classification of disease phenotypes has been developed as a tool to aid in improved characterization and management of diabetes. The majority of these studies have been completed in European populations, but it is unclear if these are applicable to other populations. Using these cohorts, we categorized patients in a South Texas VA diabetes clinic to evaluate if these phenotypes apply to that population. A retrospective cohort study was completed from August 2019 through October 2019, in which 120 patients’ records in the Audie Murphy VA Diabetes Clinic were reviewed for presence of macro and microvascular complications, type of anti-diabetic medication, lipid profile and HbA1c levels, and fasting C-peptide and GADab status. 86 patients who had anti-GADab and C-Peptide levels measured were then stratified into diabetic phenotype cohorts as defined by Ahlqvist et al. 2018, based on presence of diabetes associated autoantibodies, fasting C-peptide level, insulin use >200 U/day, BMI, and age >65. Six subjects belonged to the Severe Autoimmune Diabetes (SAID) cohort, with average GADab 713±301IU; 66% of the cohort had nephropathy, 33% had retinopathy. The Severe Insulin Deficiency (SIDD) cohort had 9 patients, with average fasting C-peptide of 0.58±0.08ng/ml, 44% of the cohort had retinopathy, nephropathy and CAD as complications. The Severe Insulin Resistant (SIRD) cohort had 26 patients; fasting C-peptide was 4.94±0.43ng/ml, 73% had nephropathy, 38% retinopathy and 46% CAD. The Mild Obesity Related (MOD) cohort had 35 patients with average BMI of 35±0.6 kg/m2 and average A1c 7.9±0.2%. Nephropathy was the most prevalent complication, present in 49% of the cohort. The Mild Age Related (MARD) cohort had 10 patients, with average age of 71±1.0 years, with nephropathy and CAD present in 66% of the cohort. The highest gross prevalence of nephropathy was in the SIRD cohort, whereas highest prevalence of retinopathy was in the SIDD cohort, both of which are concordant with the recently reported study, although not statistically significant (p=0.28 and 0.65, respectively). There was no difference in prevalence of CAD between the different categories of diabetes. These findings in a South Texas VA diabetes clinic population reflect agreement in diabetes associated complications in clusters of diabetes based on insulin resistance and insulin deficiency. Targeted intensification of therapy based on the major underlying pathophysiologic abnormalities may delay or prevent micro and macrovascular complications. 1. Ahlqvist E, et al. Novel Subgroups of Adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Endocrinology and Diabetes. 2018;6: 361-369.

Download Full-text