Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet β-cells

Insulin receptor substrate 2 (IRS-2) plays a critical role in pancreatic β-cells. Increased IRS-2 expression promotes β-cell growth and survival, whereas decreased IRS-2 levels lead to apoptosis. It was found that IRS-2 turnover in rat islet β-cells was rapid, with mRNA and protein half-lives of ∼90 min and ∼2 h, respectively. However, this was countered by specific glucose-regulated IRS-2 expression mediated at the transcriptional level. Glucose (≥6 mM) increased IRS-2 mRNA and protein levels in a dose-dependent manner, reaching a maximum 4-fold increase in IRS-2 mRNA and a 5-6-fold increase in IRS-2 protein levels at ≥12 mM glucose (p ≤ 0.01). Glucose (15 mM) regulation of islet β-cell IRS-2 gene expression was rapid, with a significant increase in IRS-2 mRNA levels within 2 h that reached a maximum 4-fold increase by 4 h. IRS-2 protein expression in β-cells followed that of IRS-2 mRNA. Glucose metabolism was necessary for increased IRS-2 expression in β-cells. Moreover, inhibition of a glucose-induced rise in islet β-cell cytosolic [Ca²⁺] _i prevented an increase in IRS-2 expression, indicating this was Ca²⁺-dependent. The glucose-induced rise in IRS-2 levels correlated with increased IRS-2 tyrosine phosphorylation and downstream activation of protein kinase B. These data indicate that fluctuations of glucose in the normal physiological range (5-15 mM) promote β-cell survival via regulation of IRS-2 expression and a subsequent parallel protein kinase B activation. Given that the onset of type-2 diabetes is marked by loss of β-cells, these data further the idea that controlled IRS-2 expression in β-cells could be a therapeutic means to promote β-cell survival and delay the onset of the disease.