BACKGROUND: Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment. METHODS: Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models. RESULTS: Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin ( OMD ), apolipoprotein A4 ( APOA4 ), and insulin like growth factor binding protein 6 ( IGFBP6 ) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells. CONCLUSIONS Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD , APOA4 , and IGFBP6  may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders.
Machine Learning ; Humans ; Computational Biology/methods* ; Biomarkers/metabolism* ; Diabetes Mellitus, Type 2/genetics* ; Animals ; Mice ; Gluconeogenesis/physiology* ; Gene Expression Profiling ; Transcriptome/genetics* ; Gene Regulatory Networks/genetics* ; Clinical Relevance

Objective:To observe the effect of the combination therapy of Qingtong formula and Dapagliflozin on the renal function of diabetic mice.Methods:A total of 24 10-week-old diabetic model（db/db）mice were selected and divided into four groups with six db/db mice in each group by random number table method：db/db mice（control group），db/db mice + Dapaglifozin（western medicine group），db/db mice + Dapagliflozin + Qingtong formula［traditional Chinese medicine（TCM）combined with western medicine group］，and db/db mice + Qingtong formula（TCM group）. The changes of urine creatinine and urinary albumin / creatinine（ACR）before and after treatment were compared，and the levels of serum creatinine and urea nitrogen after treatment were also compared.Results:After treatment，the serum creatinine level in the TCM combined with western medicine group showed a downward trend compared with that of the control group and significantly decreased compared with the western medicine group and the TCM group，and the difference was statistically significant（ P < 0.01）. There was no significant difference in urea nitrogen level among all groups（ P > 0.05）. After treatment，urinary creatinine level in the TCM combined with western medicine group was significantly higher than those in other three groups，with statistical significance differences（ P < 0.05 or P < 0.01）. There was no significant difference in urinary ACR level among groups before and after treatment（ P > 0.05）. Conclusion:The combination therapy of Qingtong formula and Dapaglifozin can significantly increase urine creatinine excretion of db/db mice，lower the level of serum creatinine，thus improving renal function.

Objective:To observe the effect of the combination therapy of Qingtong formula and Dapagliflozin on the renal function of diabetic mice.Methods:A total of 24 10-week-old diabetic model（db/db）mice were selected and divided into four groups with six db/db mice in each group by random number table method：db/db mice（control group），db/db mice + Dapaglifozin（western medicine group），db/db mice + Dapagliflozin + Qingtong formula［traditional Chinese medicine（TCM）combined with western medicine group］，and db/db mice + Qingtong formula（TCM group）. The changes of urine creatinine and urinary albumin / creatinine（ACR）before and after treatment were compared，and the levels of serum creatinine and urea nitrogen after treatment were also compared.Results:After treatment，the serum creatinine level in the TCM combined with western medicine group showed a downward trend compared with that of the control group and significantly decreased compared with the western medicine group and the TCM group，and the difference was statistically significant（ P < 0.01）. There was no significant difference in urea nitrogen level among all groups（ P > 0.05）. After treatment，urinary creatinine level in the TCM combined with western medicine group was significantly higher than those in other three groups，with statistical significance differences（ P < 0.05 or P < 0.01）. There was no significant difference in urinary ACR level among groups before and after treatment（ P > 0.05）. Conclusion:The combination therapy of Qingtong formula and Dapaglifozin can significantly increase urine creatinine excretion of db/db mice，lower the level of serum creatinine，thus improving renal function.

The Fibulin family is a kind of secreted glycoprotein,belonging to the extracellular matrix protein.A total of 7 family members are widely distributed in basement membrane,elastic fiber and loose connective tissue.The Fibulin family is widely involved in the regulation of cell morphology,growth and adhesion.When Fibulin is disturbed,it can cause a range of diseases,such as skin laxity,tooth hypoplasia and various tumors.The researches show that Fibulin-1 is expressed abnormally in fibrosarcoma,gastric cancer and liver cancer,and the expression of Fibulin-2 is down-regulated in breast cancer and up-regulated in lung cancer.The other members of the family also show abnormal expression in various tumor tissues,which indicates the members of the Fibulin family play important roles in the genesis and development of tumors.