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

Authors: MARTINEZ-RUIZ, MANUEL - Arkansas Children'S Nutrition Research Center (ACNC); TABOR-SIMECKA, LESLIE - Arkansas Children'S Nutrition Research Center (ACNC); GRAHAM, JAMES - University Of California, Davis; RANDOLPH, CHRISTOPHER - Arkansas Children'S Nutrition Research Center (ACNC); FOX, RENEE - Arkansas Children'S Nutrition Research Center (ACNC); LAN, RENNY - Arkansas Children'S Nutrition Research Center (ACNC); PACK, LINDSAY - Arkansas Children'S Nutrition Research Center (ACNC); LEROITH, TANYA - Virginia Tech; STANHOPE, KIMBER - University Of California, Davis; Yeruva, Venkat; HAVEL, PETER - University Of California, Davis; PICCOLO, BRIAN - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2026
Publication Date: 3/16/2026
Citation: Martinez-Ruiz, M., Tabor-Simecka, L., Graham, J.L., Randolph, C., Fox, R., Lan, R., Pack, L., Leroith, T., Stanhope, K.L., Yeruva, V., Havel, P.J., Piccolo, B.C. 2026. Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis Type-2 Diabetes Mellitus rats. American Journal of Physiology - Gastrointestinal and Liver Physiology. 330(5):G549-G564. https://doi.org/10.1152/ajpgi.00412.2025.
DOI: https://doi.org/10.1152/ajpgi.00412.2025

Interpretive Summary: Background: People with obesity and insulin resistance often have imbalances in their microbiome (the bacteria that live and work in our guts) and may also have issues with gut cell health – including regulating the absorption of food and other substances, like pathogens and toxins. Preclinical evidence suggests that gut microbiota imbalances can contribute to the progression of type 2 diabetes – but treatment strategies to reverse these imbalances are not well known. Evidence indicates that leptin, a signaling hormone produced in fat cells and involved in appetite regulation among other functions, improves markers of glucose regulation and insulin resistance, independent of diet, in rats with type 2 diabetes. Findings: Scientists studied how leptin affects glucose regulation and insulin resistance in rats with type 2 diabetes – and examined how other indicators of gut cell health were affected. Giving male rats with diabetes leptin injections for four weeks, they measured glucose tolerance, insulin sensitivity, GLP-1 levels, gut permeability, microbiota composition, and other markers of gut cell health and inflammation. Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity, without affecting body weight. There were no differences in microbiome composition, gut permeability, or markers of gut cell function. Impact: Despite significant improvements of glucose regulation, leptin treatment did not affect gut microbiota or gut cell function.

Technical Abstract: Introduction: Preclinical evidence suggests that gut microbial dysbiosis contributes to the progression of type 2 diabetes (T2DM). Alterations in the gut microbiome, energy metabolism, and barrier function have been observed in individuals with obesity and insulin resistance. However, it remains unclear whether therapeutic interventions can reverse these disruptions. 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 diabetic male UC Davis Type 2 Diabetic Mellitus (UCD-T2DM) rats. Methods: Male UCD-T2DM rats (age: 173'±'41 days) with 6 weeks post-onset of diabetes were randomized to receive twice 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 (fecal and intestinal), SCFA content, epithelial hypoxia, intestinal morphology, and gene/protein expression in colonic tissue. Results: Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity as assessed be glucose and insulin responses during an OGTT, without affecting body weight. No differences were observed in microbiome composition, gut permeability, or epithelial hypoxic gradients. Ileal villus height was decreased significantly, while colonic crypt depth was not different between leptin treated rats and control rats. Levels of butyric, isocaproic, and valeric acids were increased in colonic content, colonic expression of Pparg and Ldha was downregulated, while Phd2 and occludin protein levels were upregulated in leptin-treated compared with control rats. Conclusion: Despite significant 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.