Insulin-Deficient Mouseβ-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.

miRNA‑770‑5p expression is upregulated in patients with type 2 diabetes and miRNA‑770‑5p knockdown protects pancreatic β‑cell function via targeting BAG5 expression

“…Insulin serves an important role in the balance of blood sugar levels in the human body, whereby insufficiency results in hyperglycemia, DM and DM complications (46). Previous studies have reported that miRNAs can regulate the synthesis and secretion of insulin (47,48) and regulate the blood sugar balance in the human body (49). miRNAs not only promote insulin synthesis and secretion, but also serve a negative regulatory role in insulin synthesis and secretion (50)(51)(52).…”

Recovery of isolated pancreatic isletsderived from gut leak-induced diabetes type ii mouse model

“…In contrast, MafA, Ins1, and Ins2 were expressed throughout culture periods, which are involving in β-cells function and insulin secretion (Hang et al, 2014;Nishimura et al, 2015;Ramzy et al, 2017). The Isl1 was also greatly expressed on day 5 which is working on controlling the development of islets by regulating the transcription of β-cells differentiation.…”