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Objective Proteomic profiling can identify useful biomarkers. Monozygotic(MZ) twins, discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well characterised cohorts. Research Design and Methods A broad, multiplex analysis of 4068 proteins in sera from MZ twins concordant (n=43) and discordant for type 1 diabetes (n=27) identified major differences which were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n=39) and discordant (n=42) for type 1 diabetes, individuals at-risk (n=195) and with type 1 diabetes (n=990), as well as with non-insulin requiring adult-onset diabetes diagnosed as either autoimmune (n=96) or type 2 (n=291). Results Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite strong correlation between twins, whether concordant or discordant for type 1 diabetes (p Conclusions Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and non-genetically determined factors. Exocrine/endocrine interactions are important under-investigated factors in type 1 diabetes.

Aims/hypothesis We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations. Methods A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants. Results Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16–25 and 26–35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p p = 1.60 × 10−7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans. Conclusions/interpretation The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.

Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood. Electronic supplementary material The online version of this article (10.1007/s00125-019-05016-3) contains peer-reviwed but unedited supplementary material, which is available to authorised users.

Aims: It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes (T1D) and non-autoimmune type 2 diabetes (T2D). Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune T1D, but the clinical value of GADA by current standard radio-binding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes. Methods: Two cohorts of individuals recently diagnosed with diabetes at ≥20 years of age were analyzed including 771 patients 30-70 years olds from the Action LADA study and 2,063 patients 20-45 year olds from the Diabetes in Young Adults (DiYA) study. Clinical characteristics including requirement of early insulin treatment, BMI, and development of multiple islet autoantibodies were analyzed according to the status of RBA-GADA and ECL-GADA, respectively. Results: GADA was the most prevalent and predominant autoantibody, >90% in both cohorts with any positive autoantibody. GADA positivity by either RBA or ECL assay significantly discriminated clinical T1D from T2D. However, patients with ECL-GADA in both cohorts were at greatest risk of insulin treatment, multiple islet autoantibodies and lower BMI (all p Conclusion: The ECL-GADA assay offers advantages over the RBA-GADA in identification of adult-onset diabetes patients at higher risk of early insulin dependency. Disclosure X. Jia: None. L. Yu: None. R. D. Leslie: None. The action lada consortium: n/a. The diabetes in young adults (diya) study group: n/a. Y. Gu: None. T. Vartak: None. D. Miao: None. F. Dong: None. S. T. Jerram: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. A. Ferrara: None. J. M. Lawrence: None. Funding JDRF (2-SRA-2019-695-S-B); National Institutes of Health (DK32083); 5th Framework Program of the European Union; Centers for Disease Control and Prevention (1U18DP006289)

T1DM results from the interaction of genetic and environmental factors; the classical phenotype has been based largely on people of European background. However, Africa is a continent of enormous genetic diversity and extreme environmental conditions; do these differences have an impact on the T1DM phenotype? A consecutive series of recently diagnosed insulin-dependent diabetic subjects (n=236, ≤35 years) and controls (n=200), were recruited from the ethnic Amhara of rural NW Ethiopia. We assessed their demographic and socio-economic characteristics, measured non-fasting C-peptide, diabetes-associated autoantibodies, and HLA-DRB1 alleles. With genome-wide genotyping we performed principal component analysis (PCA) and a genome-wide association study (GWAS), and calculated a T1DM genetic risk scores (GRS) to compare their genetic background with known European T1DM determinants. Patients presented with low BMI, stunted growth, and were insulin sensitive; only 15.3% had diabetes onset ≤15 years. C-peptide levels were low but not absent (P=0.03). With clinical diabetes onset at ≤15, 16-25, and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had GADA as a single antibody; the prevalence of IA-2A and ZnT8A was low in all age groups. PCA showed that the Amhara genomes falls between those of ancestral European and ancestral African genomes. HLA-DRB1*03:01 and HLA-DRB1*04 were positively associated with diabetes while HLA-DRB1*15 was protective (P Thus, insulin-dependent diabetes in rural Ethiopia does have the immunogenetic characteristics of T1DM. The phenotypic differences between T1DM in rural Ethiopia and the industrialized world could be due, at least in part, to chronic undernourishment. Disclosure E.R. Trimble: None. S.A. Balcha: None. A.G. Demisse: None. D.L. Cousminer: None. R. Mishra: Employee; Self; GlaxoSmithKline plc. B.F. Voight: None. K. Lorenz: None. T. Vartak: None. S.T. Jerram: None. K.M. Hodge: None. S. Schwartz: Advisory Panel; Self; Intarcia Therapeutics, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Salix Pharmaceuticals. A. Holmes: None. A. Gamper: Stock/Shareholder; Self; GlaxoSmithKline plc., Unilever. H.F. Wilson: None. A.J. Williams: None. R.D. Leslie: None. S.F. Grant: None. D.I.W. Phillips: None. Funding American Diabetes Association (1-17-PDF-077 to D.L.C.); Association of Physicians of Great Britain and Ireland; National Institutes of Health (1K99HD099330-01, R01DK085212); Diabetes UK

Renal microvascular disease associated with diabetes [Diabetic kidney disease - DKD] is the leading cause of chronic kidney disease. In DKD, glomerular basement membrane thickening, mesangial expansion, endothelial dysfunction, podocyte cell loss and renal tubule injury contribute to progressive glomerulosclerosis and tubulointerstitial fibrosis. Chronic inflammation is recognized as a major pathogenic mechanism for DKD, with resident and circulating immune cells interacting with local kidney cell populations to provoke an inflammatory response. The onset of inflammation is driven by the release of well described proinflammatory mediators, and this is typically followed by a resolution phase. Inflammation resolution is achieved through the bioactions of endogenous specialized pro-resolving lipid mediators (SPMs). As our understanding of SPMs advances ‘resolution pharmacology’ based approaches using these molecules are being explored in DKD.