The NERP-4-SNAT2 axis regulates pancreatic β-cell maintenance and function

Insulin secretion from pancreatic β cells is regulated by multiple stimuli, including nutrients, hormones, neuronal inputs, and local signalling. Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. The granin protein VGF has dual roles in β cells: regulating secretory granule formation and functioning as a multiple peptide precursor. A VGF-derived peptide, neuroendocrine regulatory peptide-4 (NERP-4), increases Ca2+ influx in the pancreata of transgenic mice expressing apoaequorin, a Ca2+-induced bioluminescent protein complex. NERP-4 enhances glucose-stimulated insulin secretion from isolated human and mouse islets and β-cell-derived MIN6-K8 cells. NERP-4 administration reverses the impairment of β-cell maintenance and function in db/db mice by enhancing mitochondrial function and reducing metabolic stress. NERP-4 acts on sodium-coupled neutral amino acid transporter 2 (SNAT2), thereby increasing glutamine, alanine, and proline uptake into β cells and stimulating insulin secretion. SNAT2 deletion and inhibition abolish the protective effects of NERP-4 on β-cell maintenance. These findings demonstrate a novel autocrine mechanism of β-cell maintenance and function that is mediated by the peptide-amino acid transporter axis.</p

Additional file 2: of Comparison of fluid balance and hemodynamic and metabolic effects of sodium lactate versus sodium bicarbonate versus 0.9% NaCl in porcine endotoxic shock: a randomized, open-label, controlled study

Study design. During preparation period, all animals received 25 mL/kg 0.9% NaCl to prevent hypovolemia. When all preparations were completed, a 30-min period was allowed to stabilize the measured variables. Measurements were taken over a 5-h period. All animals were administered 5 μg/kg/min Escherichia coli lipopolysaccharide (LPS) (serotype 055:B5; Sigma Chemical Co., St. Louis, MO, USA). If MAP fell below 65 mmHg, 2.5 mL/kg infusion of NaCl 0.9% was given as rescue therapy every 15 min. We studied three groups receiving 450 mL (from T30 to T300) of different fluids as follows: 11.2% hypertonic sodium lactate AP-HP® (AGEPS, Paris, France) (SL group), 0.9% NaCl (NC group), and 8.4% hypertonic sodium bicarbonate (SB group). In order to inject an equivalent energy supply, 5% glucose solution (Baxter SAS, Guyancourt, France) was perfused in the NC and SB groups. Finally, in order to maintain the same fluid intake in the three groups, the SL group received 780 mL sterile water for injection (Baxter SAS, Guyancourt, France) in place of 5% glucose solution from T30 to T300. SL, Sodium lactate group; SB, sodium bicarbonate group; NC, NaCl 0.9% group; MAP, mean arterial pressure; HR, heart rate; BP, blood pressure; PBP, pulmonary blood pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SvO2, mixed venous oxygen saturation; CI, cardiac index; SDF, sidestream dark field; NIRS, near-infrared spectroscopy; A-VBG, arterial and venous blood gas. (PDF 48 kb