Baseline b-cell mass is established during the early postnatal period when b-cells expand. In this study, we show that heterozygous ablation of Insm1 decreases baseline b-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an ob/ob background, glucose intolerance was more severe in Insm1 +/lacZ mice compared with Insm1 +/+ mice, although no further decrease in the b-cell mass was detected. In islets of early postnatal Insm1 +/lacZ mice, the cell cycle was prolonged in b-cells due to downregulation of the cell cycle gene Ccnd1. Although Insm1 had a low affinity for the Ccnd1 promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the Ccnd1 promoter after downregulation of Insm1 expression. Furthermore, downregulation of Ccnd1 resulted in a prolonged cell cycle, and overexpression of Ccnd1 rescued cell cycle abnormalities observed in Insm1-deficient b-cells. We conclude that decreases in Insm1 interfere with b-cell specification during the early postnatal period and impair glucose homeostasis during metabolic stress in adults. Insm1 levels are therefore a factor that can influence the development of diabetes.Pancreatic b-cell mass is regulated both during development and in the adult. Lineage tracing in animals indicates that embryonic b-cells mainly differentiate from pancreatic progenitor cells (1), whereas postnatal increases in b-cell mass arise through self-renewal (2,3). b-Cell replication slows considerably in adults, although variations in insulin demand can lead to adaptive changes in b-cell mass (4). Sufficient b-cell mass is essential for normal regulation of blood glucose levels. Loss of b-cell mass by an immune attack or metabolic stressors results in type 1 and type 2 diabetes, respectively. In addition, although b-cell mass varies in individuals, low b-cell mass is a risk factor for prediabetes and diabetes (5). At least two factors contribute to total b-cell mass: replication capacity and baseline b-cell mass. The replication rate of adult b-cells is low, and massive efforts have been made to restore diabetic b-cell loss by enhancing b-cell replication. In contrast, the establishment of the baseline b-cell mass is not well investigated, and it is not yet fully understood how postnatal b-cell expansion varies in different individuals.The baseline b-cell mass is established in the early postnatal period in both mice and humans (2,6-8). Recent identified factors that modulate the postnatal b-cell expansion regulate the metabolic pathways or the cell cycle (9-11). The cyclin genes Ccnd1 and Ccnd2 are essential for postnatal b-cell growth and regulate the progression through G 1 through interaction with . Heterozygous mutations in Ccnd1 combined with complete knockout of Ccnd2 have dose-dependent effects on b-cell mass (14). Cell cycle inhibitors are another group of essential regulators in the postnatal b-cell mass expansion. p16 INK4a is a b-cell replication inhibi...

The allocation and specification of pancreatic endocrine lineages are tightly regulated by transcription factors. Disturbances in differentiation of these lineages contribute to the development of various metabolic diseases, including diabetes. The insulinoma-associated protein 1 (Insm1), which encodes a protein containing one SNAG domain and five zinc fingers, plays essential roles in pancreatic endocrine cell differentiation and in mature β-cell function. In the current study, we compared the differentiation of pancreatic endocrine cells between Insm1 null and Insm1 SNAG domain mutants (Insm1delSNAG) to explore the specific function of the SNAG domain of Insm1. We show that the δ-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared with the control mice. We also show a less severe reduction of the β-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in α-, PP, and ε-cells in Insm1delSNAG and Insm1 null mutants. We further identified that the increased δ-cell number is due to β- to δ-cell transdifferentiation. Mechanistically, the SNAG domain of Insm1 interacts with Lsd1, the demethylase of H3K4me1/2. Mutation in the SNAG domain of Insm1 results in impaired recruitment of Lsd1 and increased H3K4me1/2 levels at hematopoietically expressed homeobox (Hhex) loci that are bound by Insm1, thereby promoting the transcriptional activity of the δ-cell–specific gene Hhex. Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cell differentiation, particularly in the repression of β- to δ-cell transdifferentiation.