(A) Number of islets per pancreatic cryosection (n = 144 slides, 3 mice per genotype), (B) relative frequency plot of islet diameter comparing WT with Trpm7^R/R islets (n = 144 slides, 6 mice per genotype). (C) Pancreas weight of WT and Trpm7^R/R mice maintained on an HFD for approximately 16 weeks (n = 5 mice per genotype). (D) β Cell size (≥10 islets, at least 3 mice per genotype) and (E) percentage of Ki67-positive cells from the population (100%) of the insulin-positive cells per pancreatic islet in WT and Trpm7^R/R mice under the chow or HFD for 16 weeks (n = 20, 5 mice per genotype). (F) Confocal images of WT and Trpm7^R/R islets stained for DAPI (blue), insulin (green), and Ki67 (red). The scale bar represents 100 μm. (G) For RNA-Seq analysis, islet RNA was collected from Trpm7^R/R mice and the control littermates that had been maintained on an HFD for approximately 16 weeks (n = 3 mice per genotype, age: ~24 weeks). Volcano plot with downregulated and upregulated genes. Differentially expressed genes (DEGs) were identified (P < 0.05) by using EdgeR method. DEGs are expressed as log₂ fold change over control with an adjusted P value for each gene. (H) Assessment of the activity of the cell signaling molecules SMAD2, SMAD4, ERK1/2, and AKT using Bio-Plex assay and phospho-specific antibodies on lysates of isolated islets from WT and Trpm7^R/R mice (n = 10, measured in duplicates, 10 mice per genotype) under 16 weeks of HFD. Data are normalized to Tubulin content. Data show means ± SEM and statistical differences were assessed by Mann-Whitney test (A) or unpaired 2-tailed Student’s t test (B–E, and H). Circles in bar graphs represent single values. P values are shown above the bars.