Fig. 6: α-Ketoglutarate supplementation mitigates endogenous glutamine wastage and insulin resistance in Atm-KO mice.

a Diagram illustrates the metabolic fates of α-KG or glutamine. Expression level changes in genes involved in the key metabolic reactions in human A-T cerebellar tissues (from GSE61019) compared to non-diseased controls. Values presented in brackets represent Log₂(fold change) followed by Log₁₀(adjusted p-values). b Schematics of ¹³C₅-U-glutamine and 1,2,3,4-¹³C₄-α-KG carbon flow. c Isotopologue analysis of GABA, succinate, citrate, and OAA in acute ex vivo cerebellar cultures. The relative distributions of heavy isotopologues over the total amount of the respective metabolite are depicted (n = 8, two-tailed unpaired t-test for all except for “M + 4 citrate” where two-tailed Mann-Whitney test was used). d Tissue ammonia levels in acute ex vivo cerebellar cultures (n = 8, two-tailed unpaired t-test). e Schematics of a dietary regimen involving CaAKG supplementation (2% w/w) or vehicle alongside a standard laboratory diet. f Survival analysis throughout the treatment paradigm (n = 20, two-way ANOVA). g Representative mouse images depicting body length differences and their quantifications after the treatment paradigm (n = 16, one-way ANOVA). h Summary of the average wet weights of major skeletal muscles (n = 8, one-way ANOVA). i Chronological variations in indirect calorimetry readings demonstrating alterations in respiratory quotient. Overview of changes between light and dark cycles (n = 26, two-tailed Mann-Whitney test for all except for WT-V where two-tailed unpaired t-test was used). j Outcomes of IGTT (n = 26, two-way ANOVA) and calculations of the AUCs (n = 26, one-way ANOVA). k Assessment of plasma insulin levels after overnight fast and at 2 h after the IGTT (n = 26, two-way ANOVA). Calculation of the HOMA-IR index shown on the right (n = 26, one-way ANOVA). l, m Overview of behavioral performances in the l open-field and m rotarod paradigms (n = 26, Kruskal-Wallis test). Correlations between the HOMA-IR index and performances (n = 78, Pearson’s correlation). n Representative images of cerebellar vermis anterior (L3) and posterior (L8) lobes. Quantifications of IP3R1+ Purkinje cell numbers per mm² area is shown (n = 12, one-way ANOVA for all except for L6 where Kruskal-Wallis test was used). Values represent the mean ± s.d. N presents biological replicates. Source data are provided as a Source Data file.