Type 2 diabetes mellitus (T2D) causes gastroparesis, delayed intestinal transit, and constipation, for unknown reasons. Complications are predominant in women than men (particularly pregnant and postmenopausal women), suggesting a female hormone-mediated mechanism. Low G-protein coupled estrogen receptor (GPER) expression from epigenetic modifications may explain it. We explored sexually differentiated GPER expression and gastrointestinal symptoms related to GPER alterations in wild-type (WT) and T2D mice (db/db). We also created smooth muscle-specific GPER knockout (GPER KO) mice to phenotypically explore the effect of GPER deficiency on gastrointestinal motility. GPER mRNA and protein expression, DNA methylation and histone modifications were measured from stomach and colon samples of db/db and WT mice. Changes in gut motility were also evaluated as daily fecal pellet production patterns. We found that WT female tissues have the highest GPER mRNA and protein expressions. The expression is lowest in all db/db. GPER downregulation is associated with promoter hypermethylation and reduced enrichment of H3K4me3 and H3K27ac marks around the GPER promoter. We also observed sex-specific disparities in fecal pellet production patterns of the GPER KO mice compared to WT. We thus, conclude that T2D impairs gut GPER expression, and epigenetic sex-specific mechanisms matter in the downregulation.

For many patients, diabetes Mellitus and Malignancy are frequently encountered comorbidities. Diabetes affects approximately 10.5% of the global population, while malignancy accounts for 29.4 million cases each year. These troubling statistics indicate that current treatment approaches for these diseases are insufficient. Alternative therapeutic strategies that consider unique signaling pathways in diabetic and malignancy patients could provide improved therapeutic outcomes. The G-protein-coupled estrogen receptor (GPER) is receiving attention for its role in disease pathogenesis and treatment outcomes. This review aims to critically examine GPER’ s comparative role in diabetes mellitus and malignancy, identify research gaps that need to be filled, and highlight GPER’s potential as a therapeutic target for diabetes and malignancy management. There is a scarcity of data on GPER expression patterns in diabetic models; however, for diabetes mellitus, altered expression of transport and signaling proteins has been linked to GPER signaling. In contrast, GPER expression in various malignancy types appears to be complex and debatable at the moment. Current data show inconclusive patterns of GPER expression in various malignancies, with some indicating upregulation and others demonstrating downregulation. Further research should be conducted to investigate GPER expression patterns and their relationship with signaling pathways in diabetes mellitus and various malignancies. We conclude that GPER has therapeutic potential for chronic diseases such as diabetes mellitus and malignancy.

Type 1 diabetes (T1D) affects gastrointestinal (GI) motility, favoring gastroparesis, constipation, and fecal incontinence, which are more prevalent in women. The mechanisms are unknown. Given the G-protein-coupled estrogen receptor’s (GPER) role in GI motility, we investigated sex-related diabetes-induced epigenetic changes in GPER. We assessed GPER mRNA and protein expression levels using qPCR and Western blot analyses, and quantified the changes in nuclear DNA methyltransferases and histone modifications (H3K4me3, H3Ac, and H3K27Ac) by ELISA kits. Targeted bisulfite and chromatin immunoprecipitation assays were used to evaluate DNA methylation and histone modifications around the GPER promoter by chromatin immunoprecipitation assays in gastric and colonic smooth muscle tissues of male and female control (CTR) and non-obese diabetic (NOD) mice. GPER expression was downregulated in NOD, with sex-dependent variations. In the gastric smooth muscle, not in colonic smooth muscle, downregulation coincided with differences in methylation ratios between regions 1 and 2 of the GPER promoter of NOD. DNA methylation was higher in NOD male colonic smooth muscle than in NOD females. H3K4me3 and H3ac enrichment decreased in NOD gastric smooth muscle. H3K4me3 levels diminished in the colonic smooth muscle of NOD. H3K27ac levels were unaffected, but enrichment decreased in NOD male gastric smooth muscle; however, it increased in the NOD male colonic smooth muscle and decreased in the female NOD colonic smooth muscle. Male NOD colonic smooth muscle exhibited decreased H3K27ac levels, not female, whereas female NOD colonic smooth muscle demonstrated diminished enrichment of H3ac at the GPER promoter, contrary to male NOD. Sex-specific epigenetic mechanisms contribute to T1D-mediated suppression of GPER expression in the GI tract. These insights advance our understanding of T1D complications and suggest promising avenues for targeted therapeutic interventions.