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The historical subclassification of diabetes into predominantly types 1 and 2 is well appreciated to inadequately capture the heterogeneity seen in patient presentations, disease course, response to therapy and disease complications. This review summarises proposed data-driven approaches to further refine diabetes subtypes using clinical phenotypes and/or genetic information. We highlight the benefits as well as the limitations of these subclassification schemas, including practical barriers to their implementation that would need to be overcome before incorporation into clinical practice.

Aim/hypothesisFive subgroups were described in European diabetes patients using a data driven machine learning approach on commonly measured variables. We aimed to test the applicability of this phenotyping in Indian individuals with young-onset type 2 diabetes.MethodsWe applied the European-derived centroids to Indian individuals with type 2 diabetes diagnosed before 45 years of age from the WellGen cohort (n = 1612). We also applied de novo k-means clustering to the WellGen cohort to validate the subgroups. We then compared clinical and metabolic-endocrine characteristics and the complication rates between the subgroups. We also compared characteristics of the WellGen subgroups with those of two young European cohorts, ANDIS (n = 962) and DIREVA (n = 420). Subgroups were also assessed in two other Indian cohorts, Ahmedabad (n = 187) and PHENOEINDY-2 (n = 205).ResultsBoth Indian and European young-onset type 2 diabetes patients were predominantly classified into severe insulin-deficient (SIDD) and mild obesity-related (MOD) subgroups, while the severe insulin-resistant (SIRD) and mild age-related (MARD) subgroups were rare. In WellGen, SIDD (53%) was more common than MOD (38%), contrary to findings in Europeans (Swedish 26% vs 68%, Finnish 24% vs 71%, respectively). A higher proportion of SIDD compared with MOD was also seen in Ahmedabad (57% vs 33%) and in PHENOEINDY-2 (67% vs 23%). Both in Indians and Europeans, the SIDD subgroup was characterised by insulin deficiency and hyperglycaemia, MOD by obesity, SIRD by severe insulin resistance and MARD by mild metabolic-endocrine disturbances. In WellGen, nephropathy and retinopathy were more prevalent in SIDD compared with MOD while the latter had higher prevalence of neuropathy.Conclusions /interpretationOur data identified insulin deficiency as the major driver of type 2 diabetes in young Indians, unlike in young European individuals in whom obesity and insulin resistance predominate. Our results provide useful clues to pathophysiological mechanisms and susceptibility to complications in type 2 diabetes in the young Indian population and suggest a need to review management strategies.

Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes. Four T2D subtypes were previously identified: severe insulin deficient, severe insulin resistant, mild obesity-related, and mild age-related diabetes. Here, the authors show that these subtypes can be translated to an Arabic population and identify distinct subtype-specific metabolic and proteomic signatures.

Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease. Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci. Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.

Aims/hypothesisGalectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects.MethodsParticipants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study–Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10−11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort.ResultsGalectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10−89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10−3).Conclusions/interpretationGalectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.

Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82–0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer.

Background The Generalized Anxiety Disorder 7-item scale (GAD-7) could provide currently lacking data on anxiety levels among adolescents and young adults in Sweden. However, psychometric assessments of the scale are scarce in this population. Additionally, the structural validity of the scale needs to be examined further, given conflicting findings in other populations. The aim of this study was to psychometrically evaluate the GAD-7 among 15–29-year-olds using Rasch analysis and confirmatory factor analysis in a Swedish, general population sample. In addition, an iterative process explored if revised versions of the scale could be identified that fit the Rasch model in this sample. Methods A random, age- and sex-stratified sample of 15–29-year-olds from the Swedish population register was drawn, from which stratified groups were randomly invited to participate. Data ( n  = 590) were collected through a study-specific app. Rasch analyses included investigation of item fit, local independence, principal components analysis of standardized Rasch model residuals, response category functioning, measurement invariance, scale-to-sample targeting, and reliability. In addition, confirmatory factor analyses (CFA) were conducted and interpreted using dynamic, data-adaptive cutoffs. An exploratory, iterative process was undertaken aiming at scale refinement based on results for the GAD-7. Results No Rasch analyses provided support for the unidimensionality of the GAD-7, which also displayed issues with disordered response categories and measurement invariance. The CFA found substantial misfit for the one-factor model. The exploratory scale refinement resulted in two abbreviated scales warranting further investigation: Items 1–3 fit the Rasch model as a unidimensional scale and demonstrated acceptable to good reliability. Items 5–7 had good fit after merging the two highest response categories, although demonstrated poor reliability. Conclusions No analyses provided support for the unidimensionality of the GAD-7 among 15–29-year-olds in Sweden. While these findings do not support the use of a single sum score, they require confirmation in independent samples. Future research should evaluate whether the abbreviated, candidate scale comprising items 1–3 could be useful to assess anxiety in this population, including examination of criterion validity and the potential benefits of adding a response category to enhance both reliability and scale-to-sample targeting.

Diabetes increases the risk of bacterial infections. We investigated whether common genetic variants associate with infection susceptibility in Finnish diabetic individuals. We performed genome-wide association studies and pathway analysis for bacterial infection frequency in Finnish adult diabetic individuals (FinnDiane Study; N = 5092, Diabetes Registry Vaasa; N = 4247) using national register data on antibiotic prescription purchases. Replication analyses were performed in a Swedish diabetic population (ANDIS; N = 9602) and in a Finnish non-diabetic population (FinnGen; N = 159,166). Genome-wide data indicated moderate but significant narrow-sense heritability for infection susceptibility (h 2  = 16%, P = 0.02). Variants on chromosome 2 were associated with reduced infection susceptibility (rs62192851, P = 2.23 × 10 –7 ). Homozygotic carriers of the rs62192851 effect allele (N = 44) had a 37% lower median annual antibiotic purchase rate, compared to homozygotic carriers of the reference allele (N = 4231): 0.38 [IQR 0.22–0.90] and 0.60 [0.30–1.20] respectively, P = 0.01). Variants rs6727834 and rs10188087, in linkage disequilibrium with rs62192851, replicated in the FinnGen-cohort (P < 0.05), but no variants replicated in the ANDIS-cohort. Pathway analysis suggested the IRAK1 mediated NF-κB activation through IKK complex recruitment-pathway to be a mediator of the phenotype. Common genetic variants on chromosome 2 may associate with reduced risk of bacterial infections in Finnish individuals with diabetes.

Aims/hypothesisEvidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.MethodsGIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer–Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.ResultsIn meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10−5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD.Conclusions/interpretationIn two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5–9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

Purpose Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. Methods Analyses were based on Swedish case–control data comprising incident cases of LADA ( n  = 465) and T2D ( n  = 1528) with matched, population-based controls ( n  = 1789; n  = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. Results Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07–1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA- DQB1 and - DRB1 genotypes yielded OR 8.05 (95% CI 4.86–13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32–0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. Conclusion Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.