BACKGROUND: This study aimed to investigate the impact of Vitamin A (VA) on intestinal glucose metabolic phenotypes.
METHODS: Male C57BL/6 mice were randomized assigned to a VA-normal diet (VAN) or a VA-deficient diet (VAD) for 12 weeks. After12 weeks, the VAD mice were given 30 IU/g/d retinol for 10 days and VAN diet (VADN) for 10 weeks. By using glucose tolerance tests, immunofluorescence staining, quantitative polymerase chain reaction, siRNA transduction, and enzyme-linked immunosorbent assay, the glucose metabolic phenotypes as well as secretory function and intracellular hormone changes of STC-1 were assessed.
RESULTS: VAD mice showed a decrease of glucose-stimulated insulin secretion and a loss of intestinal glucagon-like peptide-1 (GLP-1) expression. Through reintroducing dietary VA to VAD mice, the intestinal VA levels, GLP-1 expression and normal glucose can be restored. The incubation with retinol increased VA signaling factors expression within STC-1 cells, especially retinoic acid receptor β (RARβ). The activation of RARβ restored intracellular incretin hormone synthesis and secretory function.
CONCLUSIONS: VA deficiency leads to an imbalance of intestinal glucose metabolic phenotypes through a mechanism involving RARβ signaling pathway, suggesting a new method to achieve the treatment for VAD induced glucose metabolism impairment.

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental factors such as shift work, significantly increases the risk for the development of metabolic diseases, including type 2 diabetes and obesity. More recently, obesogenic feeding and its fatty acid components have also been shown to be potent disruptors of normal circadian biology. Two key hormones that are released in response to nutrient intake are the anti-diabetic incretin hormone glucagon-like peptide-1, from intestinal L cells, and insulin secreted by pancreatic β cells, both of which are required for the maintenance of metabolic homeostasis. This review will focus on the circadian function of the L and β cells and how both obesogenic feeding and the saturated fatty acid, palmitate, affect their circadian clock and function. Following introduction of the core biological clock and the hierarchical organization of the mammalian circadian system, the circadian regulation of normal L and β cell function and the importance of GLP-1 and insulin in establishing metabolic control are discussed. The central focus of the review then considers the circadian-disrupting effects of obesogenic feeding and palmitate exposure in L and β cells, while providing insight into the potential causative role in the development of metabolic disease.

This morphological and immunohistochemical study demonstrates that tumors currently known as \"middle ear adenomas\" are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.

The aim of this study was to investigate the underlying mechanism for the improvement of glucose tolerance following intake of high β-glucan barley (HGB) in terms of intestinal metabolism. C57BL/6J male mice were fed a fatty diet supplemented with HGB corresponding to 5% of dietary fiber for 83 days. An oral glucose tolerance test was performed at the end of the experimental period. The concentration of short-chain fatty acids (SCFAs) in the cecum was analyzed by GC-MS (gas chromatography-mass spectrometry). The mRNA expression levels related to L cell function in the ileum were measured by real-time PCR. Glucagon-like peptide-1 (GLP-1) levels in the portal vein and cecal content were assessed by enzyme-linked immunosorbent assay. GLP-1-producing L cells of the ileum were quantified by immunohistochemistry. HGB intake improved glucose tolerance and increased the cecal levels of SCFAs, acetate, and propionate. The number of GLP-1-positive L cells in the HGB group was significantly higher than in the control group. GLP-1 levels in the portal vein and cecal GLP-1 pool size in the HGB group were significantly higher than the control group. In conclusion, we report improved glucose tolerance after HGB intake induced by an increase in L cell number and subsequent rise in GLP-1 secretion.

Many types of endocrine cells have been identified in the gastroenteropancreatic system of vertebrates, which have subsequently been named with alphabet (s). L cells which secrete the glucagon-like peptide (GLP)-1 are scattered in the intestinal epithelium. This review discusses the morphological features of chicken L cells and GLP-1 secretion from intestinal L cells. L cells, identified using GLP-1 immunohistochemistry, are open-type endocrine cells that are distributed in the jejunum and ileum of chickens. GLP-1 co-localizes with GLP-2 and neurotensin in the same cells of the chicken ileum. Intestinal L cells secrete GLP-1 in response to food ingestion. Proteins and amino acids, such as lysine and methionine, in the diet trigger GLP-1 secretion from the chicken intestinal L cells. The receptor that specifically binds chicken GLP-1 is expressed in pancreatic D cells, implying that the physiological functions of chicken GLP-1 differ from its functions as an incretin in mammals.

Curcumin shows antiglycemic effects in animals. Curcumin is chemically unstable at physiological pH, and its oxidative degradation products were shown to contribute to its anti-inflammatory effects. Since the degradation products may also contribute to other effects, we analyzed their role in the antiglycemic activity of curcumin. We quantified curcumin-induced release of glucagon-like peptide 1 (GLP-1) from mouse STC-1 cells that represent enteroendocrine L-cells as a major source of this anti-diabetic hormone. Curcumin induced secretion of GLP-1 in a dose-dependent manner. Two chemically stable analogues of curcumin that do not readily undergo degradation, were less active while two unstable analogues were active secretagogues. Chromatographically isolated spiroepoxide, an unstable oxidative metabolite of curcumin with anti-inflammatory activity, also induced secretion of GLP-1. Stable compounds like the final oxidative metabolite bicyclopentadione, and the major plasma metabolite, curcumin-glucuronide, were inactive. GLP-1 secretion induced by curcumin and its oxidative degradation products was associated with activation of PKC, ERK, and CaM kinase II. Since activity largely correlated with instability of curcumin and the analogues, we tested the extent of covalent binding to proteins in STC-1 cells and found it occurred with similar affinity as N-ethylmaleimide, indicating covalent binding occurred with nucleophilic cysteine residues. These results suggest that oxidative metabolites of curcumin are involved in the antiglycemic effects of curcumin. Our findings support the hypothesis that curcumin functions as a pro-drug requiring oxidative activation to reveal its bioactive metabolites that act by binding to target proteins thereby causing a change in function.

Type II diabetes is a complex, chronic, and progressive disease. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released from the L cells which stimulate insulin secretion and promotes insulin gene expression and β-cell growth and differentiation. Elevated levels of hormones secreted by L cells are an essential reason for diabetes improvement. GLP-1 secretion has been reported to be regulated by farnesoid X receptor (FXR), a transcriptional sensor for bile acids which also acts on glucose metabolism. Herein, we attempted to evaluate the effect of FXR on GLP-1 secretion in mouse enteroendocrine L cell line, namely STC-1, and to investigate the underlying mechanism. FXR inversely regulated GLP-1 secretion in STC-1. A total of 24 nonredundant human proteins were shown to be related to FXR by BioGRID; KEGG pathway analysis revealed that FXR was related to glucagon signaling pathway, particularly with the transcriptional activators CREB, PGC1α, Sirt1, and CBP. CREB could positively regulate GLP-1 secretion in STC-1 cells. FXR combined with CREB to inhibit its transcriptional activity, thus inhibiting proprotein convertase subtilisin/kexin type 1 protein level and GLP-1 secretion. In the present study, we demonstrated a negative regulation of GLP-1 secretion by FXR in L cell line, STC-1; FXR exerts its function in L cells through interacting with CREB, a crucial transcriptional regulator of cAMP-CREB signaling pathway, to inhibit its transcriptional activity. Targeting FXR to rescue GLP-1 secretion may be a promising strategy for type II diabetes.

OBJECTIVE: Type II diabetes is a complex, chronic, and progressive disease. Glucagon-like peptide-1 (7-6) amide (GLP-1) is a gut hormone released from the L cells which stimulates insulin secretion, and promotes insulin gene expression and β-cell growth and differentiation. Elevated levels of hormone secreted by L cells are an important reason for diabetes improvement. GLP-1 secretion has been reported to be regulated by farnesoid X receptor (FXR), a transcriptional sensor for bile acids which also acts on glucose metabolism. Herein, we attempted to evaluate the effect of FXR on GLP-1 secretion in mouse enteroendocrine L cell lines, STC-1 and GLUTag, and to investigate the underlying mechanism.
METHODS: ELISA and Western blot assays were employed to examine the levels of GLP-1 and FXR, and the effect of FXR on GLP-1 secretion; online database, including BioGRID and KEGG were used to identify the potential interactions between FXR and proteins and involved pathways; GST pull-down and Co-Immunoprecipitation (Co-IP) assays were performed to validate FXR-CREB interaction; Luciferase reporter gene assays were used for CREB transcriptional activity determination.
RESULTS: FXR inversely regulated GLP-1 secretion in the mouse enteroendocrine L cell lines, GLUTag and STC-1. A total of 24 nonredundant human proteins were shown to be related to FXR by BioGRID; KEGG pathway analysis showed that FXR was related to glucagon signaling pathway, particularly with the transcriptional activators CREB, PGC1α, Sirt1 and CBP. CREB could positively regulate GLP-1 secretion in GLUTag and STC-1 cells. FXR combined with CREB to inhibit its transcriptional activity, thus inhibiting proprotein convertase subtilisin/ kexin type 1 (PCSK1) protein level and GLP-1 secretion.
CONCLUSIONS: In the present study, we demonstrated a negative regulation of GLP-1 secretion by FXR in L cell lines, GLUTag and STC-1; FXR exerts its function in L cells through interacting with CREB, a crucial transcriptional regulator of cAMP-CREB signaling pathway, to inhibit its transcriptional activity. Targeting FXR to rescue GLP-1 secretion may be a promising strategy for type II diabetes.

Chronic exposure to lipopolysaccharide (LPS) contributes to metabolic abnormalities, but there has been no study to evaluate plasma LPS levels after ileal transposition (IT). We examined the effect of IT on gut hormone secretion and plasma LPS levels and their correlation with metabolic parameters.
Sprague-Dawley rats underwent either IT or sham operation. After 4 weeks, oral glucose tolerance tests (OGTT) were performed and fasting plasma LPS and gut histology were analyzed.
Compared with the sham group, food intake and body weight decreased, and insulin sensitivity increased in the IT group. During the OGTTs, glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY) were significantly higher in the IT group than the sham group. The villi length, muscle thickness, and the density of GLP-1 and glucose-dependent insulinotropic polypeptide co-expressing cells (K/L-cells) increased in the transposed ileum compared with the ileum of the sham group. Fasting plasma LPS levels were lower in the IT group than the sham group (5.6 ± 0.2 vs. 6.8 ± 0.1 EU/ml, P = 0.002) and significantly correlated with insulin resistance (r = 0.755, P < 0.001). Plasma LPS levels were negatively correlated with PYY secretion (r = -0.710, P = 0.001), and GLP-2 secretion (r = -0.561, P = 0.019).
IT surgery decreased plasma LPS levels in a non-obese non-diabetic rat model, which was associated with improved insulin sensitivity and increased L-cell secretion.