Aims/hypothesis: The term prediabetes is used for individuals who have impaired glucose metabolism whose glucose or HbA_1c levels are not yet high enough to be diagnosed as diabetes. Prediabetes may already be associated with an increased risk of chronic ‘diabetes-related’ complications. This umbrella review aimed to provide a systematic overview of the available evidence from meta-analyses of prospective observational studies on the associations between prediabetes and incident diabetes-related complications in adults and to evaluate their strength and certainty. Methods: For this umbrella review, systematic reviews with meta-analyses reporting summary risk estimates for the associations between prediabetes (based on fasting or 2 h postload glucose or on HbA_1c) and incidence of diabetes-related complications, comorbidities and mortality risk were included. PubMed, Web of Science, the Cochrane Library and Epistemonikos were searched up to 17 June 2021. Summary risk estimates were recalculated using a random effects model. The certainty of evidence was evaluated by applying the GRADE tool. This study is registered with PROSPERO, CRD42020153227. Results: Ninety-five meta-analyses from 16 publications were identified. In the general population, prediabetes was associated with a 6–101% increased risk for all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, heart failure, atrial fibrillation and chronic kidney disease, as well as total cancer, total liver cancer, hepatocellular carcinoma, breast cancer and all-cause dementia with moderate certainty of evidence. No associations between prediabetes and incident depressive symptoms and cognitive impairment were observed (with low or very low certainty of evidence). The association with all-cause mortality was stronger for prediabetes defined by impaired glucose tolerance than for prediabetes defined by HbA_1c. Conclusions/interpretation: Prediabetes was positively associated with risk of all-cause mortality and the incidence of cardiovascular outcomes, CHD, stroke, chronic kidney disease, cancer and dementia. Further high-quality studies, particularly on HbA_1c-defined prediabetes and other relevant health outcomes (e. g. neuropathy) are required to support the evidence. Graphical

Aims/hypothesis: No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes. Methods: This cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL. Results: DSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA_1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures. Conclusions/interpretation: Our findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN. Graphical

Previous meta-analyses have shown an improved survival with higher blood 25-hydroxyvitamin D (25(OH)D) concentrations in patients with colorectal cancer (CRC). However, a number of much larger studies have been published since then. We provide an updated meta-analysis to synthesize current evidence. PubMed and Web of Science databases were systematically searched for eligible studies. The dose-response relationships and pooled hazard ratios for overall and CRC-specific survival comparing the highest versus the lowest categories of blood 25(OH)D concentrations were assessed. Subgroup analyses based on study geographic location, year of publication, sample size, length of follow-up time and stage were conducted to explore potential sources of heterogeneity. Overall, 11 original studies with a total of 7718 CRC patients were included. The dose-response meta-analysis showed an improvement in survival outcomes with increasing blood 25(OH)D concentrations. Pooled hazard ratios (95% confidence intervals) comparing highest versus lowest categories were 0.68 (0.55–0.85) and 0.67 (0.57–0.78) for overall and CRC-specific survival, respectively. Associations were more prominent among studies conducted in Europe, with larger sample sizes, and including stage I–IV patients. This updated meta-analysis reveals robust evidence of an association between higher blood 25(OH)D concentrations and better survival in CRC patients. The potential for enhancing prognosis of CRC patients by vitamin D supplementation should be explored by randomized trials.

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.

Inflammatory processes have been implicated in the development of chronic kidney disease (CKD). We investigated the association of a large panel of inflammatory biomarkers reflecting aspects of immunity with kidney function and CKD incidence. We used data from two independent population-based studies, KORA F4 (discovery, n = 1110, mean age 70.3 years, 48.7% male) and ESTHER (replication, n = 1672, mean age 61.9 years, 43.6% male). Serum levels of biomarkers were measured using proximity extension assay technology. The association of biomarkers with estimated glomerular filtration rate (eGFR) at baseline and with incident CKD was investigated using linear and logistic regression models adjusted for cardiorenal risk factors. Independent results from prospective analyses of both studies were pooled. The significance level was corrected for multiple testing by false-discovery rate (P_FDR < 0.05). In the KORA F4 discovery study, 52 of 71 inflammatory biomarkers were inversely associated with eGFR based on serum creatinine. Top biomarkers included CD40, TNFRSF9 and IL10RB. Forty-two of these 52 biomarkers were replicated in the ESTHER study. Nine of the 42 biomarkers were associated with incident CKD independent of cardiorenal risk factors in the meta-analysis of the KORA (n = 142, mean follow-up 6.5 years) and ESTHER (n = 103, mean follow-up 8 years) studies. Pathway analysis revealed the involvement of inflammatory and immunomodulatory processes reflecting cross-communication of innate and adaptive immune cells. Novel and known biomarkers of inflammation were reproducibly associated with kidney function. Future studies should investigate their clinical utility and underlying molecular mechanisms in independent cohorts.

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