Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate secretion.

Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To determine whether this effect was due to systemic hyperinsulinemia or to reduced endogenous insulin production, we examined the effect of hyperglycemia on secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were created in six dogs. After 30 minutes of equilibration, a computer-assisted hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150 mg/dL above basal in clamp animals; control animals received volume- and rate-matched infusions of 0.9% saline. One hour after beginning the clamp period, intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not differ between groups. INS and GLU levels in clamp animals were significantly elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods. For the same periods, HCO3 secretion was not significantly changed despite profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback regulation on the pancreas, we propose that suppression of endogenous INS secretion mediates the previously reported inhibitory response.

Increasing membrane-bound MCSF does not enhance OPGL-driven osteoclastogenesis from marrow cells.

Macrophage colony-stimulating factor (MCSF) and osteoprotegerin ligand (OPGL), both produced by osteoblasts/stromal cells, are essential factors for osteoclastogenesis. Whether local MCSF levels regulate the amount of osteoclast formation is unclear. Two culture systems, ST-2 and Chinese hamster ovary-membrane-bound MCSF (CHO-mMCSF)-Tet-OFF cells, were used to study the role of mMCSF in osteoclast formation. Cells from bone marrow (BMM) or spleen were cultured with soluble OPGL on glutaraldehyde-fixed cell layers; osteoclasts formed after 7 days. Osteoclast number was proportional to the amount of soluble OPGL added. In contrast, varying mMCSF levels in the ST-2 or CHO-mMCSF-Tet-OFF cell layers, respectively by variable plating or by addition of doxycycline, did not affect BMM osteoclastogenesis: 20-450 U of mMCSF per well generated similar osteoclast numbers. In contrast, spleen cells were resistant to mMCSF: osteoclastogenesis required > or = 250 U per well and further increased as mMCSF rose higher. Our results demonstrate that osteoclast formation in the local bone environment is dominated by OPGL. Increasing mMCSF above basal levels does not further enhance osteoclast formation from BMMs, indicating that mMCSF does not play a dominant regulatory role in the bone marrow.