glucagon-like-peptide-1 and Colorectal-Neoplasms

Ginseng-derived gintonin reportedly contains functional lysophosphatidic acids (LPAs) as LPA receptor ligands. The effect of the gintonin-enriched fraction (GEF) on in vitro and in vivo glucagon-like protein-1 (GLP-1) secretion, which is known to stimulate insulin secretion, via LPA receptor(s) remains unclear. Accordingly, we examined the effects of GEF on GLP-1 secretion using human enteroendocrine NCI-H716 cells. The expression of several of LPA receptor subtypes in NCI-H716 cells using qPCR and Western blotting was examined. LPA receptor subtype expression was in the following order: LPA6 > LPA2 > LPA4 > LPA5 > LPA1 (qPCR), and LPA6 > LPA4 > LPA2 > LPA1 > LPA3 > LPA5 (Western blotting). GEF-stimulated GLP-1 secretion occurred in a dose- and time-dependent manner, which was suppressed by cAMP-Rp, a cAMP antagonist, but not by U73122, a phospholipase C inhibitor. Furthermore, silencing the human LPA6 receptor attenuated GEF-mediated GLP-1 secretion. In mice, low-dose GEF (50 mg/kg, peroral) increased serum GLP-1 levels; this effect was not blocked by Ki16425 co-treatment. Our findings indicate that GEF-induced GLP-1 secretion could be achieved via LPA6 receptor activation through the cAMP pathway. Hence, GEF-induced GLP secretion via LPA6 receptor regulation might be responsible for its beneficial effects on human endocrine physiology.

Topics: Animals; Colorectal Neoplasms; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Secretion; Lysophospholipids; Male; Mice; Mice, Inbred ICR; Panax; Plant Extracts; Receptors, Lysophosphatidic Acid; Signal Transduction; Tumor Cells, Cultured

Evidence on the safety of the incretin-based drugs (glucagon-like peptide-1 [GLP-1] analogues and dipeptidyl peptidase-4 [DPP-4] inhibitors) with respect to colorectal cancer is contradictory. The objective of this study was to determine whether use of incretin-based drugs is associated with risk of incident colorectal cancer in patients with type 2 diabetes.. Using data from the UK Clinical Practice Research Datalink, we identified a cohort of 112,040 patients newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2015. We modeled use of GLP-1 analogues and DPP-4 inhibitors as time-varying variables and compared them with use of sulfonylureas. We lagged exposures by 1 year for latency and to reduce reverse causality and detection bias. We used time-dependent Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals of incident colorectal cancer associated with the use of GLP-1 analogues and DPP-4 inhibitors overall, by cumulative duration of use and by time since initiation.. During 388,619 person-years of follow-up, there were 733 incident colorectal cancer events (incidence rate: 1.9 per 1,000 person-years). Use of GLP-1 analogues was not associated with colorectal cancer incidence (hazard ratio: 1.0; 95% confidence interval = 0.7, 1.6), nor was use of DPP-4 inhibitors (hazard ratio: 1.2; 95% confidence interval = 1.0, 1.5). There was no evidence of a duration-response relation for either drug.. The results of this large population-based study indicate that use of incretin-based drugs is not associated with colorectal cancer incidence among patients with type 2 diabetes.

Topics: Aged; Colorectal Neoplasms; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Incretins; Longitudinal Studies; Male; Medical Audit; Middle Aged; Proportional Hazards Models; United Kingdom

Obesity and insulin resistance are associated with an increased risk of colorectal adenoma (CRA). Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis through its amplification of insulin secretion in response to oral nutrients; however, its role in human CRA remains unknown. We investigated oral glucose-mediated GLP-1 secretion in patients with adenoma.. We performed a case-control study of 15 nondiabetic patients with pathologically diagnosed CRA and 10 age-matched healthy controls without adenoma. Plasma concentrations of active GLP-1 were measured during a 75 g oral glucose tolerance test.. Mean waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR) values, the total areas under the curve (AUC) of glucose and insulin were significantly higher in patients with CRA than in controls. The total AUC of GLP-1 (p = 0.01) was lower in patients with CRA than in controls. Moreover, the total AUC of GLP-1 showed a negative correlation with WC, total AUC of glucose, and HOMA-IR. Multiple linear regression analyses revealed that the total AUC of GLP-1 was independently correlated with the number and maximum size of CRAs.. GLP-1 could actively participate in the development of CRA in humans, particularly in patients with metabolic syndrome.

Topics: Adenoma; Adult; Aged; Blood Glucose; Case-Control Studies; Colonoscopy; Colorectal Neoplasms; Comorbidity; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Metabolic Syndrome; Middle Aged