Simultaneous pancreas‐kidney (SPK) transplantation has become a standard therapy for end‐stage diabetic nephropathy patients. This study aims to investigate serum microRNA (miRNA) profiles in patients with type 2 diabetic nephropathy after SPK and explored the mechanism of insulin resistance induced by relevant miRNAs.

Patients with type 2 diabetic nephropathy were recruited at our organ transplantation center from June 2018 to March 2019. Six patients were randomly selected, and miRNA microarray analysis was performed to assess serum miRNA expression levels. Target genes were predicted, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted.

The gene chip results revealed significant upregulation of miR‐320d, miR‐4701‐3p, and miR‐940 and significant downregulation of miR‐1229‐5p, miR‐125a‐3p, miR‐3614‐5p, miR‐6090, and miR‐6893‐5p. Target gene prediction and pathway analysis revealed that four miRNAs (miR‐125a‐3p, miR‐320d, miR‐940, and miR‐1229‐5p) form distinct signal regulatory networks.

Specific miRNA expression profiles are present in the serum of patients with diabetic nephropathy after simultaneous pancreas‐kidney transplantation. These specific miRNAs may be involved in the regulatory mechanism of restoring normoglycemia in diabetic nephropathy patients.