| First Author | Ramzy A | Year | 2018 |
| Journal | Endocrinology | Volume | 159 |
| Issue | 1 | Pages | 83-102 |
| PubMed ID | 29029025 | Mgi Jnum | J:256398 |
| Mgi Id | MGI:6108102 | Doi | 10.1210/en.2017-00263 |
| Citation | Ramzy A, et al. (2018) Insulin-Deficient Mouse beta-Cells Do Not Fully Maturebut Can Be Remedied Through Insulin Replacementby Islet Transplantation. Endocrinology 159(1):83-102 |
| abstractText | Insulin receptor (IR) insufficiency in beta-cells leads to impaired insulin secretion and reduced beta-cell hyperplasia in response to hyperglycemia. Selective IR deficiency in beta-cells in later embryological development may lead to compensatory beta-cell hyperplasia. Although these findings suggest insulin signaling on the beta-cell is important for beta-cell function, they are confounded by loss of signaling by the insulinlike growth factors through the IR. To determine whether insulin itself is necessary for beta-cell development and maturation, we performed a characterization of pancreatic islets in mice with deletions of both nonallelic insulin genes (Ins1-/-Ins2-/-). We immunostained neonatal Ins1-/-Ins2-/- and Ins1+/+Ins2+/+ pancreata and performed quantitative polymerase chain reaction on isolated neonatal islets. Insulin-deficient islets had reduced expression of factors normally expressed in maturing beta-cells, including muscoloaponeurotic fibrosarcoma oncogene homolog A, homeodomain transcription factor 6.1, and glucose transporter 2. Ins1-/-Ins2-/-beta-cells expressed progenitor factors associated with stem cells or dedifferentiated beta-cells, including v-myc avian myolocytomatosis viral oncogene lung carcinoma derived and homeobox protein NANOG. We replaced insulin by injection or islet transplantation to keep mice alive into adulthood to determine whether insulin replacement was sufficient for the completed maturation of insulin-deficient beta-cells. Short-term insulin glargine (Lantus(R)) injections partially rescued the beta-cell phenotype, whereas long-term replacement of insulin by isogenic islet transplantation supported the formation of more mature beta-cells. Our findings suggest that tightly regulated glycemia, insulin species, or other islet factors are necessary for beta-cell maturation. |
