Insulin deficient mouse β-cells do not fully mature but can be remedied through insulin replacement by islet transplantation.

3 years ago

Insulin deficient mouse β-cells do not fully mature but can be remedied through insulin replacement by islet transplantation.

Kieffer, Mojibian, Ramzy

Insulin receptor insufficiency in β-cells leads to impaired insulin secretion and reduced β-cell hyperplasia in response to hyperglycemia. Selective insulin receptor deficiency in β-cells in later embryological development may lead to compensatory β-cell hyperplasia. Though these findings suggest insulin signaling on the β-cell is important for β-cell function, they are confounded by loss of signaling by the IGFs through the insulin receptor. To determine if insulin itself is necessary for β-cell development and maturation, we performed a characterization of pancreatic islets in mice with deletions of both non-allelic insulin genes (Ins1-/-Ins2-/-). We immunostained neonatal Ins1-/-Ins2-/- and Ins1+/+Ins2+/+ pancreas and performed qPCR on isolated neonatal islets. Insulin deficient islets had reduced expression of factors normally expressed in maturing β-cells including muscoloaponeurotic fibrosarcoma oncogene homolog A (MAFA), homeodomain transcription factor 6.1 (NKX6.1), and the glucose transporter 2 (GLUT2). 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 (L-MYC), and homeobox protein NANOG. We replaced insulin by injection or islet transplantation to keep mice alive into adulthood to determine if 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, and/or other islet factors are necessary for β-cell maturation.

Publisher URL: http://doi.org/10.1210/en.2017-00263

DOI: 10.1210/en.2017-00263