The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)^1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies^3,4,5,6,7, large-scale genome-wide association studies (GWAS) of fasting BCF^8,9 or functional islet studies on T2D risk variants^{10,11,12,13,14}. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size^15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells^17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.

Aging has been associated with a changed composition and function of the gut microbiota (GM). Here, we investigate the effects of the multi-strain probiotic HOWARU^® Restore on GM composition and function in seniors. Ninety-eight healthy adult volunteers aged ≥75 years were enrolled in a randomised, double-blinded intervention (NCT02207140), where they received HOWARU Restore (10¹⁰ CFU) or the placebo daily for 24 weeks, with 45 volunteers from each group completing the intervention. Questionnaires monitoring the effects on gastro-intestinal discomfort and bowel movements were collected. Faecal samples for GM characterisation (qPCR, 16S rRNA gene amplicon sequencing) and metabolomics (GC-FID, ¹H NMR) were collected at the baseline and after 24 weeks. In the probiotic group, self-reported gastro-intestinal discomfort in the form of flatulence was significantly decreased during the intervention. At the baseline, 151 ‘core species’ (present in ≥95% of samples) were identified. Most core species belonged to the Lachnospiraceae and Ruminococcaceae families. Neither alpha diversity nor beta diversity or faecal metabolites was affected by probiotic intake. On the contrary, we observed high intra-individual GM stability, with ‘individual’ accounting for 72–75% of variation. In conclusion, 24 weeks of HOWARU Restore intake reduced gastro-intestinal discomfort in the form of flatulence in healthy seniors without significantly influencing GM composition or activity.

Context Insulin sensitivity (IS) is an important factor in type 2 diabetes (T2D) and can be estimated by many different indices. Objective We aimed to compare the genetic components underlying IS indices obtained from fasting and oral glucose-stimulated plasma glucose and serum insulin levels. Methods We computed 21 IS indices, classified as fasting, OGTT_0,120, and OGTT_0,30,120 indices, using fasting and oral glucose tolerance test (OGTT) data in 2 cohorts. We used data from a family cohort (n = 313) to estimate the heritability and the genetic and phenotypic correlations of IS indices. The population cohort, Inter99 (n = 5343), was used to test for associations between IS indices and 426 genetic variants known to be associated with T2D. Results Heritability estimates of IS indices ranged between 19% and 38%. Fasting and OGTT_0,30,120 indices had high genetic (ρG) and phenotypic (ρP) pairwise correlations (ρG and ρP: 0.88 to 1) The OGTT_0,120 indices displayed a wide range of pairwise correlations (ρG: 0.17-1.00 and ρP: 0.13-0.97). We identified statistically significant associations between IS indices and established T2D-associated variants. The PPARG rs11709077 variant was associated only with fasting indices and PIK3R rs4976033 only with OGTT_0,30,120 indices. The variants in FAM63A/MINDY1, GCK, C2CD4A/B, and FTO loci were associated only with OGTT_0,120 indices. Conclusion Even though the IS indices mostly share a common genetic background, notable differences emerged between OGTT_0,120 indices. The fasting and OGTT-based indices have distinct associations with T2D risk variants. This work provides a basis for future large-scale genetic investigations into the differences between IS indices.