Comprehensive validation of fasting- and oral glucose tolerance test-based indices of insulin secretion against gold-standard measures

Background and aims With prediabetes and diabetes increasingly recognized as heterogenous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on OGTT- and fasting-measurements in comparison with gold standard methods. Materials and methods The hyperglycaemic clamp extended with GLP-1 infusion and IVGTT, as well as OGTT, was performed in two well-phenotyped cohorts. The gold-standard-derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearson’s and Spearman’s correlation coefficients. The insulin- and C-peptide-based indices were analysed separately in different groups of glucose tolerance and the entire cohorts. Results The highest correlation coefficients were found for AUC (I0-30)/AUC (G0-30), first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycaemic clamp. AUC (I0-30)/AUC (G0-30), first-phase Stumvoll, AUC (I0-120)/AUC (G0-120) and BIGTT-AIR0-60-120 demonstrated the strongest association with incretin-stimulated insulin response. Conclusion We have identified glucose- and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold-standard measures and could be potentially used in future researches and clinical practice. ### Competing Interest Statement Outside of the current work, R.W. does report lecture fees from Novo Nordisk and Sanofi. He served on the advisory board of Akcea Therapeutics, Daiichi Sankyo, Sanofi and NovoNordisk. Outside of the current work, A.F. reports lecture fees and advisory board membership from Sanofi, Novo Nordisk, Eli Lilly, and AstraZeneca. Outside of the current work, M.H. reports research grants from Boehringer Ingelheim and Sanofi (both to the University Hospital of Tuebingen), advisory board for Boehringer Ingelheim, and lecture fees from Boehringer Ingelheim, Sanofi, Novo Nordisk, Eli Lilly and Merck Sharp & Dohme. None of the other authors report a conflict of interest. ### Funding Statement This work was supported in part by grant 01GI0925 from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocols were approved by the Ethical Committee of the Medical Faculty of the University of Tuebingen. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets analyzed during the current study are not publicly available owing to ethical regulations, but are available from the corresponding author on reasonable request.