Glucagon-like peptide-1(7-36NH2) (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5-2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100-1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05-0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the benefits of using metformin with dipeptidylpeptidase-IV inhibitors in patients with type 2 diabetes.

Metabolomics is the relatively new field in bioinformatics that uses measurements on metabolite abundance as a tool for disease diagnosis and other medical purposes. Although closely related to proteomics, the statistical analysis is potentially simpler since biochemists have significantly more domain knowledge about metabolites. This chapter reviews the challenges that metabolomics poses in the areas of quality control, statistical metrology, and data mining.

Aims/hypothesis Roof plate-specific spondin (R-spondin1; RSPO1) is a modulator of canonical Wg (wingless) plus Int1 (chromosomal integration site of mouse mammary tumour virus on mouse chromosome 15) (cWNT) signalling that induces cWNT target genes. We have demonstrated that Rspo1 is expressed in murine beta cells, and that it stimulates proliferation and insulin secretion, and inhibits cytokine-induced apoptosis, in mouse insulinoma (MIN6) and beta cells. We thus investigated the role of RSPO1 in beta cells in vivo using Rspo1 −/− mice. Methods The effects of Rspo1 deficiency were assessed by determination of cWNT signalling, glucose tolerance and beta cell mass. Results Rspo1−/− mice demonstrated an 82% reduction in RSPO1 transcripts and a 61% reduction in the signal detected by an RSPO1 antibody, as well as a 47% decrease in islet cWNT signalling. Despite no differences in body and pancreatic weights or in fasting glycaemia and insulinaemia compared with Rspo1 +/+ mice, Rspo1 −/− animals had improved glycaemic control after oral glucose challenge (p<0.05), with no difference in insulin sensitivity, but an enhanced insulin response over 30 min (p<0.05); glucagon responses were normal. Rspo1 deficiency also resulted in a twofold increase in beta cell mass (p<0.05) in association with 2-and 12-fold increases in the number of beta cells positive for antigen identified by monoclonal antibody Ki67 (Ki67) (p<0.01) and insulin-positive ductal cells (p<0.05), respectively. No change in the number of TUNEL-positive beta cells was detected. Islets isolated from Rspo1 −/− animals displayed no differences in glucose-induced insulin secretion or in glucose suppression of glucagon.Conclusions/interpretation The present study reveals an unexpected role for RSPO1 as a regulator of both beta cell proliferation and neogenesis in vivo, and reinforces the importance of cWNT signalling for the maintenance of normal pancreatic beta cell behaviour.

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Background: Radiation-associated sarcoma (RAS) occurs following ionizing radiation exposure from a therapeutic or environmental source. Because half of all cancer patients will receive radiation therapy (RT), there is a need to understand the etiology of radiation-induced sarcomas, as these cancers are thought to exhibit worse outcomes than their sporadic counterparts. Methods: A retrospective single-center analysis of sarcoma patients treated from 2013-2019 was conducted. Univariate and survival analyses were used to distinguish the characteristics of RAS and sporadic sarcoma (SS), and further assess differences in disease presentation, cancer treatment, and survival between the two groups. Results: The incidence of RAS during the study period was 6%. Breast (25%), prostate (25%) and colorectal (15%) cancers were the most common primary tumors associated with RAS development. There was substantial variation in the characteristics of the two groups, with noted differences in the histologic compositions, clinical stage at presentation, and overall survival (Table 1). The most frequent RAS histologies were angiosarcoma (30%), leiomyosarcoma (25%) and undifferentiated pleomorphic sarcoma (20%), while the most frequent SS subtypes were liposarcoma (15.5%), carcinosarcoma (13.5%) and leiomyosarcoma (11.9%). No patients with RAS had a known genetic cancer predisposition. A higher percentage of RAS patients presented at later clinical stages, as 75% of all RAS cases versus 41.9% of all SS cases were diagnosed at stage III/IV (p=0.004). RAS also exhibited overall worse outcomes, as the 5-year survival was significantly decreased compared to SS (32.6 vs 60.3%, p=0.027). Conclusion: Our study identifies marked differences in the disease characteristics and clinical outcomes of RAS and SS. Further research into cancer predisposition, biomarkers of risk, and molecular pathways of disease is essential to provide individualized care to patients with RAS. Table 1. Summary of Sporadic Sarcoma and Radiation-Associated Sarcoma Characteristics Sporadic Sarcoma Radiation-Associated Sarcoma P-Value Count 310 20 Median Age at Diagnosis (Years) 58.51 (0.02-87.74) 68.81 (48.09-84.19) 0.003 Location Trunk 109 (35.2%) Trunk 10 (50.0%) Lower Extremity 97 (31.3%) Lower Extremity 2 (10.0%) Head/Neck 36 ( 11.6%) Retroperitoneal 4 (20.0%) Other 68 (21.9%) Other 4 (20.0%) Histologic Subtype Liposarcoma 48 (15.5%) Angiosarcoma 6 (30.0%) Carcinosarcoma 42 (13.5%) Leiomyosarcoma 5 (25.0%) Leiomyosarcoma 37 (11.9%) UPS 4 (20.0%) Chondrosarcoma 36 (11.6%) Liposarcoma 3 (15.0%) Other 147 (47.4%) Other 2 (10%) Clinical Stage I & II 146 (47.1%) 4 (20.0%) 0.01 III & IV 130 (41.9%) 15 (75.0%) 0.004 Unknown 34 (11.0%) 1 (5.0%) Treatments Surgery 244 (78.7%) 12 (60.0%) 0.12 Radiation 91 (29.4%) 10 (50.0%) 0.95 Chemotherapy 105 (33.6%) 7 (35.0%) 0.35 Status at Follow-Up NED 139 (44.8% ) 6 (30.0%) AWD 74 (23.9%) 3 (15.0%) Deceased 97 (31.3%) 11 (55.0%) Five-Year Survival 60.3% 32.6% 0.027 Citation Format: Abigail Raynor, Amy Oh, Wen-I Chang, Joshua Honeyman. Radiation-associated sarcoma exhibits worse outcomes than sporadic sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5244.