Insulin-Deficient Mouse β-Cells Do Not Fully Mature but Can Be Remedied Through Insulin Replacement by Islet Transplantation.

Abstract

Insulin receptor (IR) insufficiency in β-cells leads to impaired insulin secretion and reduced β-cell hyperplasia in response to hyperglycemia. Selective IR deficiency in β-cells in later embryological development may lead to compensatory β-cell hyperplasia. Although these findings suggest insulin signaling on the β-cell is important for β-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 β-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 β-cells, including muscoloaponeurotic fibrosarcoma oncogene homolog A, homeodomain transcription factor 6.1, and glucose transporter 2. Ins1-/-Ins2-/-β-cells expressed progenitor factors associated with stem cells or dedifferentiated β-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 β-cells. Short-term insulin glargine (Lantus®) injections partially rescued the β-cell phenotype, whereas long-term replacement of insulin by isogenic islet transplantation supported the formation of more mature β-cells. Our findings suggest that tightly regulated glycemia, insulin species, or other islet factors are necessary for β-cell maturation.

• Authors: Adam Ramzy, Majid Mojibian, Timothy J Kieffer
• Journal: Endocrinology (Endocrinology) Vol. 159 Issue 1 Pg. 83-102 (01 01 2018) ISSN: 1945-7170 [Electronic] United States
• PMID: 29029025 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Endocrine Society.

Chemical References

• Biomarkers
• Ins1 protein, mouse
• Ins2 protein, mouse
• Insulin
• Insulin Glargine

Topics

• Animals
• Animals, Newborn
• Biomarkers (metabolism)
• Cell Differentiation (drug effects)
• Cell Size (drug effects)
• Female
• Fibrosis
• Gene Expression Regulation, Developmental (drug effects)
• Hormone Replacement Therapy (adverse effects)
• Hyperglycemia (drug therapy, etiology, pathology, surgery)
• Injections, Subcutaneous
• Insulin (deficiency, genetics, metabolism)
• Insulin Glargine (administration & dosage, adverse effects, therapeutic use)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Islets of Langerhans Transplantation
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Tissue Culture Techniques