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How Do We Move Type 1 Diabetes Immunotherapies Forward During the Current COVID-19 Pandemic?
Michael J. Haller, Laura M. Jacobsen, Amanda L. Posgai and Desmond A. Schatz
doi : 10.2337/dbi20-0045
Diabetes 2021 May; 70(5): 1021-1028.
Research-based immunotherapy trials seeking to prevent or reverse a number of autoimmune diseases, including type 1 diabetes, have seen near universal suspension due to the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diabetes and hyperglycemia are now appreciated as significant risk factors for COVID-19 morbidity and mortality; however, the vast majority of studies have reported on adults. Recent data in children and adolescents with type 1 diabetes suggest no increased risk of COVID-19. Even with immense appreciation for COVID-19 morbidity and mortality, we believe compelling arguments exist to carefully and thoughtfully resume certain type 1 diabetes phase 2–3 immunotherapy trials. In this Perspective, we consider the experience of trials that never halted or have resumed in the oncology and rheumatology fields, and advocate for staged type 1 diabetes immunotherapy trial resumption. With this, we present recommendations to achieve equipoise and mitigate risks for SARS-CoV-2 infection in the weeks surrounding infusion. Given the fact that the COVID-19 pandemic is expected to persist for some time, it is in the best interest of our patients that we find ways to safely move our field forward.
A Key to T1D Prevention: Screening and Monitoring Relatives as Part of Clinical Care
Carla J. Greenbaum
doi : 10.2337/db20-1112
Diabetes 2021 May; 70(5): 1029-1037.
The 2019 report of a randomized, placebo-controlled clinical trial demonstrating that immune therapy can delay the onset of clinical type 1 diabetes (T1D) in antibody-positive relatives by a median of 2 years stands out as a landmark in the decades-long effort to prevent T1D. With this important step achieved, it is now time to consider what is needed to bring disease-modifying therapy for prevention or delay of T1D to clinical use from this point. Long considered a chicken and egg problem (why screen for T1D risk when we have no therapy, and how can we develop therapies without more screening), we now have the opportunity to break this impasse. The purpose of this article is to place this clinical trial result in context, highlighting key foundational studies leading to this accomplishment, addressing the current gaps, and suggesting that a key next step for prevention of T1D is to screen and monitor relatives for T1D risk in the context of clinical care.
Altered ?-Cell Prohormone Processing and Secretion in Type 1 Diabetes
Teresa Rodriguez-Calvo, Yi-Chun Chen, C. Bruce Verchere, Leena Haataja, Peter Arvan, Pia Leete, Sarah J. Richardson, Noel G. Morgan, Wei-Jun Qian, Alberto Pugliese, Mark Atkinson, Carmella Evans-Molina and Emily K. Sims
doi : 10.2337/dbi20-0034
Diabetes 2021 May; 70(5): 1038-1050.
Analysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.
Pancreatic Pseudoislets: An Organoid Archetype for Metabolism Research
Mollie S.H. Friedlander, Vy M. Nguyen, Seung K. Kim and Romina J. Bevacqua
doi : 10.2337/db20-1115
Diabetes 2021 May; 70(5): 1051-1060.
Pancreatic islets are vital endocrine regulators of systemic metabolism, and recent investigations have increasingly focused on understanding human islet biology. Studies of isolated human islets have advanced understanding of the development, function, and regulation of cells comprising islets, especially pancreatic ?- and ?-cells. However, the multicellularity of the intact islet has stymied specific experimental approaches—particularly in genetics and cell signaling interrogation. This barrier has been circumvented by the observation that islet cells can survive dispersion and reaggregate to form “pseudoislets,” organoids that retain crucial physiological functions, including regulated insulin and glucagon secretion. Recently, exciting advances in the use of pseudoislets for genetics, genomics, islet cell transplantation, and studies of intraislet signaling and islet cell interactions have been reported by investigators worldwide. Here we review molecular and cellular mechanisms thought to promote islet cell reaggregation, summarize methods that optimize pseudoislet development, and detail recent insights about human islet biology from genetic and transplantation-based pseudoislet experiments. Owing to robust, international programs for procuring primary human pancreata, pseudoislets should serve as both a durable paradigm for primary organoid studies and as an engine of discovery for islet biology, diabetes, and metabolism research.
Obesity and COVID-19 in Adult Patients With Diabetes
Peihua Cao, Ying Song, Zian Zhuang, Jinjun Ran, Lin Xu, Yan Geng, Lefei Han, Shi Zhao, Jing Qin, Daihai He, Fengfu Wu and Lin Yang
doi : 10.2337/db20-0671
Diabetes 2021 May; 70(5): 1061-1069.
Obesity has caused wide concerns due to its high prevalence in patients with severe coronavirus disease 2019 (COVID-19). Coexistence of diabetes and obesity could cause an even higher risk of severe outcomes due to immunity dysfunction. We conducted a retrospective study in 1,637 adult patients who were admitted into an acute hospital in Wuhan, China. Propensity score–matched logistic regression was used to estimate the risks of severe pneumonia and requiring in-hospital oxygen therapy associated with obesity. After adjustment for age, sex, and comorbidities, obesity was significantly associated with higher odds of severe pneumonia (odds ratio [OR] 1.47 [95% CI 1.15–1.88]; P = 0.002) and oxygen therapy (OR 1.40 [95% CI 1.10–1.79]; P = 0.007). Higher ORs of severe pneumonia due to obesity were observed in men, older adults, and those with diabetes. Among patients with diabetes, overweight increased the odds of requiring in-hospital oxygen therapy by 0.68 times (P = 0.014) and obesity increased the odds by 1.06 times (P = 0.028). A linear dose-response curve between BMI and severe outcomes was observed in all patients, whereas a U-shaped curve was observed in those with diabetes. Our findings provide important evidence to support obesity as an independent risk factor for severe outcomes of COVID-19 infection in the early phase of the ongoing pandemic.
Virgin ?-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly
Sharon Lee, Jing Zhang, Supraja Saravanakumar, Marcus F. Flisher, David R. Grimm, Talitha van der Meulen and Mark O. Huising
doi : 10.2337/db20-0679
Diabetes 2021 May; 70(5): 1070-1083.
Proliferation of pancreatic ?-cells has long been known to reach its peak in the neonatal stages and decline during adulthood. However, ?-cell proliferation has been studied under the assumption that all ?-cells constitute a single, homogenous population. It is unknown whether a subpopulation of ?-cells retains the capacity to proliferate at a higher rate and thus contributes disproportionately to the maintenance of mature ?-cell mass in adults. We therefore assessed the proliferative capacity and turnover potential of virgin ?-cells, a novel population of immature ?-cells found at the islet periphery. We demonstrate that virgin ?-cells can proliferate but do so at rates similar to those of mature ?-cells from the same islet under normal and challenged conditions. Virgin ?-cell proliferation rates also conform to the age-dependent decline previously reported for ?-cells at large. We further show that virgin ?-cells represent a long-lived, stable subpopulation of ?-cells with low turnover into mature ?-cells under healthy conditions. Our observations indicate that virgin ?-cells at the islet periphery can divide but do not contribute disproportionately to the maintenance of adult ?-cell mass.
The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses ?- to ?-Cell Transdifferentiation
Xuehua Liang, Hualin Duan, Yahui Mao, Ulrich Koestner, Yiqiu Wei, Feng Deng, Jingshen Zhuang, Huimin Li, Cunchuan Wang, Luis R. Hernandez-Miranda, Weihua Tao and Shiqi Jia
doi : 10.2337/db20-0883
Diabetes 2021 May; 70(5): 1084-1097.
The allocation and specification of pancreatic endocrine lineages are tightly regulated by transcription factors. Disturbances in differentiation of these lineages contribute to the development of various metabolic diseases, including diabetes. The insulinoma-associated protein 1 (Insm1), which encodes a protein containing one SNAG domain and five zinc fingers, plays essential roles in pancreatic endocrine cell differentiation and in mature ?-cell function. In the current study, we compared the differentiation of pancreatic endocrine cells between Insm1 null and Insm1 SNAG domain mutants (Insm1delSNAG) to explore the specific function of the SNAG domain of Insm1. We show that the ?-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared with the control mice. We also show a less severe reduction of the ?-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in ?-, PP, and ?-cells in Insm1delSNAG and Insm1 null mutants. We further identified that the increased ?-cell number is due to ?- to ?-cell transdifferentiation. Mechanistically, the SNAG domain of Insm1 interacts with Lsd1, the demethylase of H3K4me1/2. Mutation in the SNAG domain of Insm1 results in impaired recruitment of Lsd1 and increased H3K4me1/2 levels at hematopoietically expressed homeobox (Hhex) loci that are bound by Insm1, thereby promoting the transcriptional activity of the ?-cell–specific gene Hhex. Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cell differentiation, particularly in the repression of ?- to ?-cell transdifferentiation.
Unique Human and Mouse ?-Cell Senescence-Associated Secretory Phenotype (SASP) Reveal Conserved Signaling Pathways and Heterogeneous Factors
Ayush Midha, Hui Pan, Cristian Abarca, Joshua Andle, Priscila Carapeto, Susan Bonner-Weir and Cristina Aguayo-Mazzucato
doi : 10.2337/db20-0553
Diabetes 2021 May; 70(5): 1098-1116.
The aging of pancreatic ?-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging ?-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to ?-cell failure. In this study, we defined the ?-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from mouse and human senescent ?-cells and a chemically induced mouse model of DNA damage capable of inducing SASP. These experiments revealed that the ?-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. Multiple SASP factors were transcriptionally upregulated in models of ?-cell senescence, aging, insulin resistance, and T2D. Single-cell transcriptomic analysis of islets from an in vivo mouse model of reversible insulin resistance indicated unique and partly reversible changes in ?-cell subpopulations associated with senescence. Collectively, these results demonstrate the unique secretory profile of senescent ?-cells and its potential implication in health and disease.
Single Molecule–Based fliFISH Validates Radial and Heterogeneous Gene Expression Patterns in Pancreatic Islet ?-Cells
Fangjia Li, Dehong Hu, Cailin Dieter, Charles Ansong, Lori Sussel and Galya Orr
doi : 10.2337/db20-0802
Diabetes 2021 May; 70(5): 1117-1122.
Single-cell RNA-sequencing (scRNA-Seq) technologies have greatly enhanced our understanding of islet cell transcriptomes and have revealed the existence of ?-cell heterogeneity. However, comparison of scRNA-Seq data sets from different groups have highlighted inconsistencies in gene expression patterns, primarily due to variable detection of lower abundance transcripts. Furthermore, such analyses are unable to uncover the spatial organization of heterogeneous gene expression. In this study, we used fluctuation localization imaging–based fluorescence in situ hybridization (fliFISH) to quantify transcripts in single cells in mouse pancreatic islet sections. We compared the expression patterns of Insulin 2 (Ins2) with Mafa and Ucn3, two genes expressed in ?-cells as they mature, as well as Rgs4, a factor with variably reported expression in the islet. This approach accurately quantified transcripts across a wide range of expression levels, from single copies to >100 copies/cell in one islet. Importantly, fliFISH allowed evaluation of transcript heterogeneity in the spatial context of an intact islet. These studies confirm the existence of a high degree of heterogeneous gene expression levels within the islet and highlight relative and radial expression patterns that likely reflect distinct ?-cell maturation states along the radial axis of the islet.
Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report
Andrea Lin, Jasmine A. Mack, Brittany Bruggeman, Laura M. Jacobsen, Amanda L. Posgai, Clive H. Wasserfall, Todd M. Brusko, Mark A. Atkinson, Stephen E. Gitelman, Peter A. Gottlieb, Matthew J. Gurka, Clayton E. Mathews, Desmond A. Schatz and Michael J. Haller
doi : 10.2337/db20-1103
Diabetes 2021 May; 70(5): 1123-1129.
Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [–0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (–0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.
Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline
Daniel C. Bittel, Adam J. Bittel, Arun S. Varadhachary, Terri Pietka and David R. Sinacore
doi : 10.2337/db20-0688
Diabetes 2021 May; 70(5): 1130-1144.
Two-thirds of people with type 2 diabetes mellitus (T2DM) have or will develop chronic kidney disease (CKD), which is characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promotes early frailty and mobility deficits that increase the risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental both in identifying those at high risk for functional decline and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-generation sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron transport, electron transport chain (ETC) complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3 CKD, with additional deficits in ETC respiration, enzymatic activity, and increased redox leak. Moreover, mitochondrial ETC function and coupling strongly relate to muscle performance and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits as primary mechanistic factors early in CKD progression in T2DM.
The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion
Gregor Sachse, Elizabeth Haythorne, Thomas Hill, Peter Proks, Russell Joynson, Raul Terrón-Expósito, Liz Bentley, Stephen J. Tucker, Roger D. Cox and Frances M. Ashcroft
doi : 10.2337/db20-0691
Diabetes 2021 May; 70(5): 1145-1156.
The ATP-sensitive K+ (KATP) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic ?-cells. E23K, a common polymorphism in the pore-forming KATP channel subunit (KCNJ11) gene, has been linked to increased risk of type 2 diabetes. Understanding the risk-allele-specific pathogenesis has the potential to improve personalized diabetes treatment, but the underlying mechanism has remained elusive. Using a genetically engineered mouse model, we now show that the K23 variant impairs glucose-induced insulin secretion and increases diabetes risk when combined with a high-fat diet (HFD) and obesity. KATP-channels in ?-cells with two K23 risk alleles (KK) showed decreased ATP inhibition, and the threshold for glucose-stimulated insulin secretion from KK islets was increased. Consequently, the insulin response to glucose and glycemic control was impaired in KK mice fed a standard diet. On an HFD, the effects of the KK genotype were exacerbated, accelerating diet-induced diabetes progression and causing ?-cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of ?-cell function in the early stages of diabetes progression.
Cell-Subtype-Specific Remodeling of Intrinsically Photosensitive Retinal Ganglion Cells in Streptozotocin-Induced Diabetic Mice
Wei-Yi Chen, Xu Han, Ling-Jie Cui, Chen-Xi Yu, Wen-Long Sheng, Jun Yu, Fei Yuan, Yong-Mei Zhong, Xiong-Li Yang and Shi-Jun Weng
doi : 10.2337/db20-0775
Diabetes 2021 May; 70(5): 1157-1169.
Recent evidence suggests that melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), a neuronal class regulating nonimage forming (NIF) vision and generally thought to be injury resistant, are dysfunctional in certain neurodegenerative diseases. Although disrupted NIF visual functions have been reported in patients and animals with diabetes, it remains controversial whether ipRGCs exhibit remodeling during diabetes and if so, whether such remodeling is variable among ipRGC subtypes. Here, we demonstrate that survival, soma-dendritic profiles, and melanopsin-based functional activity of M1 ipRGCs were unaltered in streptozotocin-induced 3-month diabetic mice. Such resistance remained at 6 months after streptozotocin administration. In contrast, M2/M3 ipRGCs underwent significant remodeling in diabetic mice, manifested by enlarged somata and increased dendritic branching complexity. Consistent with the unaltered melanopsin levels, the sensitivity of melanopsin-based activity was unchanged in surviving M2 cells, but their response gain displayed a compensatory enhancement. Meanwhile, the pupillary light reflex, a NIF visual function controlled by M2 cells, was found to be impaired in diabetic animals. The resistance of M1 cells might be attributed to the adjacency of their dendrites to capillaries, which makes them less disturbed by the impaired retinal blood supply at the early stage of diabetes.
Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing
Hua Qu, Tian Miao, Yuren Wang, Liang Tan, Bangliang Huang, Linlin Zhang, Xiufei Liu, Min Long, Rui Zhang, Xiaoyu Liao, Xiaoli Gong, Ju Wang, Xin Xiong, Junli Liu, Xi Li, Jiang Yu, Gangyi Yang, Zhiming Zhu, Hongting Zheng and Yi Zheng
doi : 10.2337/db20-1008
Diabetes 2021 May; 70(5): 1170-1184.
Cutaneous wound healing is a fundamental biologic and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify the pivotal role of dedicator of cytokinesis 5 (Dock5) in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration, and proliferation and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated reepithelialization and granulation tissue formation, and Dock5 overexpression–improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in reepithelialization, collagen deposition, ECM production, and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.
Pathogenesis Study Based on High-Throughput Single-Cell Sequencing Analysis Reveals Novel Transcriptional Landscape and Heterogeneity of Retinal Cells in Type 2 Diabetic Mice
Tian Niu, Junwei Fang, Xin Shi, Mengya Zhao, Xindan Xing, Yihan Wang, Shaopin Zhu and Kun Liu
doi : 10.2337/db20-0839
Diabetes 2021 May; 70(5): 1185-1197.
Diabetic retinopathy (DR) is the leading cause of acquired blindness in middle-aged people. The complex pathology of DR is difficult to dissect, given the convoluted cytoarchitecture of the retina. Here, we performed single-cell RNA sequencing (scRNA-seq) of retina from a model of type 2 diabetes, induced in leptin receptor–deficient (db/db) and control db/m mice, with the aim of elucidating the factors mediating the pathogenesis of DR. We identified 11 cell types and determined cell-type-specific expression of DR-associated loci via genome-wide association study (GWAS)-based enrichment analysis. DR also impacted cell-type-specific genes and altered cell-cell communication. Based on the scRNA-seq results, retinaldehyde-binding protein 1 (RLBP1) was investigated as a promising therapeutic target for DR. Retinal RLBP1 expression was decreased in diabetes, and its overexpression in Müller glia mitigated DR-associated neurovascular degeneration. These data provide a detailed analysis of the retina under diabetic and normal conditions, revealing new insights into pathogenic factors that may be targeted to treat DR and related dysfunctions.
Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes
Christian Herder, Haifa Maalmi, Klaus Strassburger, Oana-Patricia Zaharia, Jacqueline M. Ratter, Yanislava Karusheva, Mohamed A. Elhadad, Kálmán Bódis, Brenda W.C. Bongaerts, Wolfgang Rathmann, Sandra Trenkamp, Melanie Waldenberger, Volker Burkart, Julia Szendroedi, Michael Roden and for the GDS Group
doi : 10.2337/db20-1054
Diabetes 2021 May; 70(5): 1198-1208.
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 cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected P < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more 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.
