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Abbreviations: APO, apolipoprotein; CD36, cluster-of-differentiation 36; DFTT, duodenal fat tolerance test; FATP-4, fatty acid transfer protein-4; h(GLY 2 ) GLP-2, human glycine 2 -glucagon-like peptide-2; IE-IGF-1R, intestinal epithelial-insulin-like growth factor-1 receptor; KO, knockout; MTP, microsomal triglyceride transfer protein; OFTT, oral fat tolerance test; WD, Western diet. AbstractThe intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances the enterocyte chylomicron production. However, GLP-2 is known to require the intestinal-epithelial insulin-like growth factor-1 receptor (IE-IGF-1R) for its other actions to increase intestinal growth and barrier function. The role of the IE-IGF-1R in enterocyte lipid handling was thus tested in the GLP-2 signaling pathway, as well as in response to a Western diet (WD). IE-IGF-1R knockout (KO) and control mice were treated for 11 days with h(GLY 2 )GLP-2 or fed a WD for 18 weeks followed by a duodenal fat tolerance test with C 14 -labeled triolein. Human Caco-2BBE cells were treated with an IGF-1R antagonist or signaling inhibitors to determine triglyceride-associated protein expression. The IE-IGF-1R was required for GLP-2-induced increases in CD36 and FATP-4 in chow-fed mice, and for expression in vitro; FATP-4 also required PI3K/Akt. Although WD-fed IE-IGF-1R KO mice demonstrated normal CD36 expression, the protein was incorrectly localized 2h post-duodenal fat administration.IE-IGF-1R KO also prevented the WD-induced increase in MTP and decrease in APOC3, increased jejunal mucosal C 14 -fat accumulation, and elevated plasma triglyceride and C 14 -fat levels. Collectively, these studies elucidate new roles for the IE-IGF-1R in enterocyte lipid handling, under basal conditions and in response to GLP-2 and WD-feeding.

Background Trace elements' (TEs) contamination of parenteral nutrition (PN) solutions is an ongoing concern. The aims of this study were 1) to measure actual TE concentrations in PN admixtures compared with ordered concentrations and 2) compare TE intake with current recommendations. Methods PN admixtures from discarded bags were collected from patients receiving home PN and on inpatient wards. Samples were collected from 72 patients (39 inpatients, 33 receiving home PN). Age, percentage energy intake from PN, and PN orders were collected from patients' charts. PN samples were analyzed for TEs, including chromium (Cr) and manganese (Mn), and concentration measurements compared with ordered concentrations and current recommendations. Results Measured Cr and Mn concentrations were higher than ordered concentrations: 5.3 ± 1.7 vs 2.8 ± 1.5 µg/L; P < 0.0001 and 11.9 ± 5.9 vs 0.00 µg/L; P < 0.0001, respectively. Chromium contamination alone accounted for over 100% of current recommendations for patients 0–12 months and between 63% and 92% for children >1 year. Contamination of Mn provided all the measured Mn in PN admixtures, since Mn is excluded from PN orders at our institution. Between 70% and 120% of current Mn recommendations were met from contamination. Conclusions Cr should be excluded from PN admixtures for children 0–12 months and only one‐fourth the current recommendation should be added for pediatric patients >1 year. Manganese should also be excluded from PN admixture for pediatric patients but plasms monitoring 2–3 times per year is recommended for those on long‐term PN.

Background Short bowel syndrome (SBS) is characterized by malabsorption requiring parenteral nutrition. The intestinotrophic glucagon‐like peptide (GLP)‐2 receptor agonist, h[Gly2]GLP2, is used to treat patients with SBS. Evidence suggests that GLP‐1 receptor agonists such as exendin‐4 (Ex4) may be beneficial in SBS given their ability to increase intestinal growth and delay gastric emptying (GE). Methods Intestinal growth, body weight (BW), food intake (FI), GE, gastrointestinal (GI) transit, intestinal permeability, and glucose tolerance were investigated in male and female C57/BL6 mice following vehicle, h[Gly2]GLP2, or Ex4 treatment, alone or in combination at “low,” “medium,” and “high” doses (0.1, 0.5, 1.0 and 0.01, 0.05, 0.1 μg/g, respectively). Results Only the h[Gly2]GLP2 low/Ex4 high‐dose combination additively increased small intestinal (SI) weight compared with vehicle and both monoagonists (P < 0.01–0.001), via increased villus height (P < 0.01) and SI length (P < 0.05). This combination had no effects on BW; FI; and fat, liver, spleen, heart, and kidney weights but reduced GI transit (P < 0.001) versus low‐dose h[Gly2]GLP2 monotreatment and abrogated the inhibitory effects of high‐dose Ex4 on GE (P < 0.01) and of low‐dose h[Gly2]GLP2 on intestinal permeability (P < 0.05). Ex4‐induced improvements in glucose homeostasis were maintained upon combination with h[Gly2]GLP2 (P < 0.001). Conclusions These findings suggest that combining specific doses of GLP‐2‐ and GLP‐1 receptor agonists additively improves SI growth and GI transit without detrimental effects on BW, FI, GE, and glucose homeostasis, and may be useful for the treatment of patients with SBS.

The intestinal L-cell incretin, glucagon-like peptide-1 (GLP-1), exhibits a circadian pattern of secretion, thereby entraining diurnal insulin release. Secretagogin (Scgn), an actin-binding regulatory protein, is essential for the temporal peak of GLP-1 secretion in vitro. To interrogate the role of Scgn in diurnal GLP-1 secretion in vivo, peak and trough GLP-1 release were evaluated in knockout mice (Scgn−/−, Gcg-CreERT2/+; Scgnfl/fl and Vil-CreERT2/+; Scgnfl/fl), and RNA sequencing (RNA-Seq) was conducted in Scgn knockdown L-cells. All 3 knockout models demonstrated loss of the diurnal rhythm of GLP-1 secretion in response to oral glucose. Gcg-CreERT2/+; Scgnfl/fl mice also lost the normal pattern in glucagon secretion, while Scgn−/− and Vil-CreERT2/+; Scgnfl/fl animals demonstrated impaired diurnal secretion of the related incretin, glucose-dependent insulinotrophic polypeptide. RNA-Seq of mGLUTag L-cells showed decreased pathways regulating vesicle transport, transport and binding, and protein-protein interaction at synapse, as well as pathways related to proteasome-mediated degradation including chaperone-mediated protein complex assembly following Scgn knockdown. Scgn is therefore essential for diurnal L-cell GLP-1 secretion in vivo, likely mediated through effects on secretory granule dynamics.