Stimulation of pancreatic β-cell proliferation by growth hormone is glucose- dependent : signal transduction via Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling

Mitogenic signal-transduction pathways have not been well defined in pancreatic β-cells. In the glucose-sensitive rat β-cell line, INS-1, glucose (6–18 mM) increased INS-1 cell proliferation (" 20-fold at 15 mM glucose). Rat growth hormone (rGH) also induced INS-1 cell proliferation, but this was glucose-dependent in the physiologically relevant concentration range (6–18 mM glucose). The combination of rGH (10 nM) and glucose (15 mM) was synergistic, maximally increasing INS-1 cell proliferation by " 50-fold. Moreover, glucose-dependent rGH-induced INS-1 cell proliferation was increased further by addition of insulin-like growth factor 1 (IGF-1; 10 nM) to " 90-fold at 12 mM glucose. Glucose metabolism and phosphatidylinositol-3«-kinase (PI3«K) activation were necessary for both glucoseand rGH-stimulated INS-1 cell proliferation. Glucose (" 3 mM) independently increased tyrosine-phosphorylation-mediated recruitment of growth-factor-bound protein 2 (Grb2)}murine sons of sevenless1 protein (mSOS) and PI3«K to insulin receptor substrate (IRS)-1 and IRS-2, as well as SH2-containing protein (Shc) association with Grb2}mSOS and downstream activation of mitogen-