Marshall Z Schwartz

Glucagonlike peptide-2 enhances small intestinal absorptive function and mucosal mass in vivo

PURPOSEnGlucagonlike peptide-2 (GLP-2) is a 33-amino acid peptide that appears to be highly tissue specific for the intestine. This study was designed to examine the effect of systemically administered GLP-2 on intestinal absorptive function and mucosal mass, and determine the in vivo dose-response curves for this new peptide.nnnMETHODSnTwenty-five young adult male Sprague-Dawley rats had placement of jugular venous catheters connected to subcutaneously placed osmotic minipumps. The rats were divided into five groups based on the contents in the osmotic pump: group 1 (control, n = 5) normal saline and groups 2, 3, 4, and 5 (n = 5 each) were given GLP-2 at 5, 50, 250, and 500 microg/kg/d, respectively. After a 14-day infusion, [C14] galactose and [C14] glycine absorption were measured in a 10-cm segment of midsmall intestine using an in vivo closed-recirculation technique. Mucosal DNA content and protein content of the same small bowel segment were also determined for each group. Statistical analysis was performed by analysis of variance (ANOVA).nnnRESULTSnGLP-2 significantly increased galactose absorption at a dose of 50 (P<.01), 250 (P<.01), and 500 (P<.05) microg/kg/d and glycine absorption at a dose of 50, 250, and 500 microg/kg/d (P<.01). GLP-2 also significantly increased mucosal DNA content at a dose of 50 (P<.01) and 250 (P<.05) microg/kg/d and protein content at a dose of 50 and 250 microg/kg/d (P<.01).nnnCONCLUSIONSnThese data demonstrate that GLP-2 can enhance normal rat small intestine mucosal mass and absorption in vivo with the maximum effect seen at 50 microg/kg/d.

Enhancement of intestinal adaptation by hepatocyte growth factor

BACKGROUND/PURPOSEnHepatocyte growth factor (HGF) was originally shown to enhance hepatocyte DNA synthesis. Recently, the expression of HGF and its receptor (c-met) were observed in the intestinal tract. In a previous study, we demonstrated that HGF can increase normal rat intestinal epithelial mass and function in vivo. This study was designed to determine if HGF, given either systemically or luminally, can enhance intestinal epithelial mass and function beyond the normal adaptive response after massive small bowel resection.nnnMETHODSnTwenty young adult male Sprague-Dawley rats underwent an 80% small bowel resection. Seven days after resection, systemic infusion (via the jugular vein) or luminal perfusion (via the jejunum) were performed using subcutaneously placed osmotic minipumps. The rats were divided into four groups: group 1, systemic saline, (control, n=5); group 2, systemic HGF at 150 microg/kg/d (n=5); group 3, luminal saline, (control, n=5); and group 4, luminal HGF at 75 microg/kg/d (n=5). After a 14-day infusion, [C14] galactose and [C14] glycine absorption (micromol/cm2 intestine), mucosal DNA content (microg/mg mucosa) and protein content (microg/mg mucosa) were measured in the remaining small intestine of each rat.nnnRESULTSnSystemic infusion of HGF increased galactose absorption 68% (P<.05), glycine absorption 57% (P<.05), DNA content 17% (P<.01), and protein content 57% (P<.01), when compared with the appropriate control. Luminal perfusion of HGF also increased galactose absorption 114% (P<.01), glycine absorption 126% (P<.01), DNA content 32% (P<.01), and protein content 45% (P<.01), when compared with the appropriate control.nnnCONCLUSIONSnThese data demonstrate for the first time that HGF can significantly enhance intestinal epithelial cell function and mucosal mass beyond the normal adaptive response. Luminal administration appeared to produce a greater response when compared with systemic administration but was significant only for galactose absorption (P<.05). HGF may be clinically useful in patients with short bowel syndrome.

Hepatocyte growth factor up-regulates SGLT1 and GLUT5 gene expression after massive small bowel resection

BACKGROUND/PURPOSEnHepatocyte growth factor (HGF), originally known to stimulate hepatocyte DNA synthesis, also has been shown to stimulate growth of intestinal epithelial cells in vitro. The authors recently demonstrated that HGF can dramatically increase substrate absorption beyond the normal adaptive response after massive small bowel resection in the rat. However, the mechanism for this enhanced substrate absorption is unknown. This study was designed to determine if up-regulation of gene expression by HGF of the Na+/glucose cotransporter SGLT1 and the facilitative glucose transporter GLUT5 is a possible mechanism of action.nnnMETHODSnYoung adult Sprague-Dawley rats underwent an 80% small bowel resection and jejunostomy tube placement. Seven days later, an osmotic minipump was connected to the subcutaneously placed jejunostomy tube. The rats were divided into two groups based on the contents in the minipumps: group 1, saline (control, n = 5); and group 2, HGF at 75 microg/kg/d (n = 5). After a 14-day infusion, biopsy specimens of the small bowel mucosa were obtained. After total RNA extraction, Northern blot analysis was performed with SGLT1 and GLUT5 cDNA probes. Auto radiographs were quantitated by image analysis.nnnRESULTSnSGLT1 mRNA levels were significantly up-regulated in the HGF-treated animals (121% increase, P<.01) when compared with the control. Up-regulation of GLUT5 mRNA levels was also seen in the HGF-treated animals (96% increase, P < .01).nnnCONCLUSIONSnThese data, demonstrating that HGF upregulates intestine epithelial glucose transporter gene expression after massive small bowel resection, may elucidate a mechanism of action for the enhanced carbohydrate absorption after HGF administration. This growth factor may be useful for patients with short bowel syndrome.

Enteral glutamine does not enhance the effects of hepatocyte growth factor in short bowel syndrome

PURPOSEnThis study was designed to determine if luminally administered glutamine alone functions as a growth factor or is synergistic with hepatocyte growth factor (HGF) after massive small bowel resection (MSBR).nnnMETHODSnTwenty Sprague-Dawley rats underwent an 80% small bowel resection and jejunostomy tube placement. Seven days later the rats were divided into four groups: group 1, control, no further treatment (n = 5); group 2 received glutamine (4% of total food intake per day) via an orogastric tube (n = 5); group 3 received intraluminal HGF via a jejunostomy tube at 75 microg/kg/d (n = 5); and group 4 received glutamine and HGF at the same doses, respectively. After a 14-day HGF infusion, glutamine feeding, or both combined, [C14] glycine absorption (micromol/L/cm2 intestine) and mucosal DNA and protein content (microg/mg mucosa) were measured in the remaining small bowel.nnnRESULTSnGlutamine alone had no effect on substrate absorption and protein or DNA content. HGF increased galactose absorption (106% increase over control, P<.01), glycine absorption (95% increase over control, P<.05), protein content (44% increase over control, P<.01), and DNA content (32% increase over control, P<.01). The combination of glutamine and HGF did not prove to be synergistic.nnnCONCLUSIONSnThese data demonstrate that in this short bowel model, glutamine alone did not enhance intestinal function. Furthermore, glutamine is not synergistic with HGF. This study suggests that glutamine alone may not be useful clinically in patients with inadequate intestinal function.

Growth factor enhancement of intestinal function: Dramatic response but lack of synergism

BACKGROUND/PURPOSEnThe authors have shown that gastrin and epidermal growth factor (EGF) exert a trophic effect on intestinal epithelial cells. Because these peptides may have different mechanisms by which they stimulate these cells, this study was designed to determine the effect of gastrin and EGF on the intestinal epithelial cell and to evaluate their potential synergistic effect.nnnMETHODSnTwenty young adult male Sprague-Dawley rats underwent placement of jugular venous catheters that were connected to subcutaneously placed osmotic minipumps. The rats were divided into four groups based on the content of the osmotic pump: Group 1, saline (control, n = 5); Group 2, EGF at 150 microg/kg/d (n = 5); Group 3, gastrin at 13.5 nmol/kg/d (n = 5); and Group 4, EGF at 150 microg/kg/d plus gastrin at 13.5 nmol/kg/d (n = 5). After a 14-day intravenous infusion, [C14] galactose and [C14] glycine absorption (pmol/cm2 intestine), mucosal DNA content (microg/mg mucosa), and protein content (microg/mg mucosa) were measured in the small intestine of each rat.nnnRESULTSnThe galactose absorption, glycine absorption, DNA content, and protein content were significantly increased by EGF (69%, 28%, 64%, and 55%, respectively) and gastrin (72%, 60%, 93%, and 48%, respectively) when compared with control. Combining EGF and gastrin also significantly increased these parameters (61%, 44%, 96%, and 70%, respectively) when compared with control. However, these data demonstrate no further enhancement than the effect of each peptide alone.nnnCONCLUSIONnEGF and gastrin individually may be useful for patients who have inadequate intestinal function, but when combined did not exert a synergistic benefit.

GROWTH FACTOR ENHANCEMENT OF INTESTINAL ADAPTATION AND FUNCTION FOLLOWING MASSIVE SMALL BOWEL RESECTION. • 719

GROWTH FACTOR ENHANCEMENT OF INTESTINAL ADAPTATION AND FUNCTION FOLLOWING MASSIVE SMALL BOWEL RESECTION. • 719