Objective · To screen the differentially expressed genes (DEGs) and pathways in the islet tissues of lipoprotein lipase (Lpl) gene heterozygous knockout (Lpl+/-) mice and wild type (WT) mice, and explore the molecular mechanism of pathogenesis of type 2 diabetes mellitus (T2DM) mediated by lipotoxicity. Methods · The islets of Lpl+/- mice and WT mice were isolated and purified. DEGs were screened by gene microarray analysis. Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were performed. The expressions of key genes were verified by quantitative real-time PCR (qPCR). Results · A total of 187 DEGs were identified. GO functional analysis and KEGG pathway analysis showed that DEGs were mainly involved in the biological processes such as immune cell proliferation and differentiation, inflammatory signaling pathways and cell adhesion. Among the top 10 DEGs screened from Lpl+- mice and WT mice, gremlin 1 (Grem1) gene was closely related to the function of islet β cells, while the result of qPCR was consistent with that of gene microarray analysis. Conclusion · Multiple signaling pathways are involved in the process of T2DM mediated by lipotoxicity, which may lead to the dysfunction of islet β cells by inhibiting Grem1 expression.