Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis Type-2 Diabetes Mellitus rats

Gut dysbiosis contributes to type 2 diabetes (T2DM) progression according preclinical evidence. Alterations in gut microbiome, energy metabolism, and barrier function were observed in individuals with obesity and insulin resistance. However, it remains unclear whether therapeutic interventions can reverse these alterations. This study aimed to evaluate whether improvements of glucose homeostasis resulting from leptin administration can lead to changes in colonic epithelial metabolism and barrier function in male UC Davis Type 2 Diabetic Mellitus (UCD-T2DM) rats. Male UCD-T2DM rats (age: 173 ± 41 days) with 6 weeks post-onset of diabetes were randomized to receive daily subcutaneous injections of either PBS (control; n=12) or recombinant leptin (0.5 mg/kg; n=12) for four weeks. Metabolic and intestinal outcomes were assessed, including glucose tolerance, insulin sensitivity, GLP-1 levels, gut permeability, microbiota composition, short chain fatty acids (SCFA) content, epithelial hypoxia, intestinal morphology, and gene/protein expression. Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity without affecting body weight. No changes were observed in microbiome composition, gut permeability, or epithelial hypoxic gradients. Ileal villus height was decreased, while colonic crypt depth was not different between leptin-treated rats and control rats. Butyric, isocaproic, and valeric acids levels were increased in colonic content, colonic expression of <i>Pparg</i> and <i>Ldha</i> was downregulated, while PHD2 and Occludin protein levels were upregulated in leptin-treated compared with control. Despite improvements of glucose homeostasis, chronic leptin treatment did not modify gut microbiota or barrier function markers, and colonic metabolic gene expression showed no clear adaptive shift.