Milicic, Tanja (24073432600)Tanja (24073432600)MilicicJotic, Aleksandra (13702545200)Aleksandra (13702545200)JoticLalic, Katarina (13702563300)Katarina (13702563300)LalicLukic, Ljiljana (24073403700)Ljiljana (24073403700)LukicMacesic, Marija (26967836100)Marija (26967836100)MacesicStanarcic Gajovic, Jelena (56089716900)Jelena (56089716900)Stanarcic GajovicStoiljkovic, Milica (57215024953)Milica (57215024953)StoiljkovicMilovancevic, Mina (57236937100)Mina (57236937100)MilovancevicRafailovic, Djurdja (58144091500)Djurdja (58144091500)RafailovicBozovic, Aleksandra (59452932300)Aleksandra (59452932300)BozovicLalic, Nebojsa M. (13702597500)Nebojsa M. (13702597500)Lalic2025-06-122025-06-122025https://doi.org/10.3390/jcm14041109https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218869768&doi=10.3390%2fjcm14041109&partnerID=40&md5=7d8b7fd198ec03ba7da9e047bc814c76https://remedy.med.bg.ac.rs/handle/123456789/628Background/Objectives: Previous studies reported impairments in insulin secretion during different stages of type 1 diabetes (T1D), while data regarding insulin sensitivity and immunological changes are still controversial. We analyzed the following: (a) insulin secretion, (b) insulin sensitivity, and (c) pro-inflammatory interleukin-17 (IL-17) levels in peripheral blood in 17 healthy first-degree relatives in stage 1 (FDRs1) (GAD+, IA2+), 34 FDRs in stage 0 (FDRs0) (GAD−, IA2A−), 24 recent-onset T1D (R-T1D) patients in the insulin-requiring state (IRS), 10 in clinical remission (CR), and 18 healthy unrelated controls (HC). Methods: Insulin secretion was evaluated by an IVGTT and a glucagon stimulation test, expressed as a first-phase insulin response (FPIR) and a basal/stimulated C-peptide. Insulin sensitivity was tested by the euglycemic hyperinsulinemic clamp, expressed as an M value. Results: FDRs1 had a lower FPIR than FDRs0 (p < 0.05) and HC (p < 0.001) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01). Moreover, FDRs1 had lower basal/stimulated C-peptide than FDRs0 (p < 0.01/p < 0.05) and HC (p < 0.001/p = 0.001) but higher levels than RT1D-IRS (p < 0.001/p < 0.001). However, the M value was similar among FDRs1, FDRs0, and HC (p = 1.0) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01), while RT1D-IRS and RT1D-CR had lower M than HC (p < 0.001; p < 0.001; respectively). FDRs1 had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.05). RT1D-IRS had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.001), which was similar to RT1D-CR vs. FDRs0 (p < 0.001) and HC (p < 0.05). Conclusions: Early changes in pre-T1D might involve an initial decline of insulin secretion associated with a pro-inflammatory attack, which does not influence insulin sensitivity, whereas later, insulin sensitivity deterioration seems to be associated with the prominent reduction in insulin secretion. © 2025 by the authors.insulin secretioninsulin sensitivityinterleukin-17pre-stage 3 type 1 diabetesrecent-onset type 1 diabetes