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Glucose is essential to the physiological processes of vertebrates. Mammalian physiological stability requires a relatively stable blood glucose level (~5 mM), whereas other vertebrates have greater flexibility in regulating blood glucose (0.5–25 mM). GCGR family receptors play an important role in vertebrate glucose regulation. Here, we examine the evolution of the GCGR family ligand-receptor systems in different species. Comparatively, we discover that the conserved sequences among GCG family ligands lead to the non-specific activation of ligands across species. In particular, we observe that glucagon-like peptide 1 receptor (GLP1R), glucagon-like peptide 2 receptor (GLP2R), and glucagon-like receptor (GCGLR, also called GCRPR) are arbitrarily activated by other members of the ligand family in birds. Moreover, we reveal that Gallus gallus GLP2 (gGLP2) effectively activates mammalian GLP1R and improves glucose tolerance in diabetic mice. Our study has important implications for understanding blood glucose stabilization in vertebrates and demonstrates that gGLP2 may be a potential drug for treating type 2 diabetes.

Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson's disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future. [ABSTRACT FROM AUTHOR]

Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.

Background: Teduglutide, a semisynthetic analogue of glucagon‐like peptide‐2 (sGLP‐2), increases intestinal absorption of fluids and nutrients, reducing the need for parenteral nutrition (PN). This report aims to describe our experience with sGLP‐2 in a cohort of adult patients with short‐bowel syndrome. Methods: This is a prospective observational study on adult patients initially evaluated in our specialized intestinal rehabilitation program that received sGLP‐2 from June 2014 to March 2020. Results: Autologous gastrointestinal reconstruction surgery (AGIRS) was performed in 108 patients; 68.5% (74 of 108) achieved intestinal sufficiency with standard medical therapy. Seventeen patients were treated with sGLP‐2; 66.5% (8 of 12) received treatment for a mean time of 25.8 weeks (3.4–54.0) and could suspend PN. One patient reinitiated treatment due to renal lithiasis and acute renal failure. Currently, 7 of 12 patients (53.8%) continue without PN for a mean time of 165.6 weeks. Volume, energy, and days of PN were reduced in all patients. No serious adverse events were registered. Four of 7 patients (57.1%) who discontinued PN could also discontinue sGLP‐2. Therefore, the use of sGLP‐2 increased the overall success rate of PN independency after AGIRS to 76% (82 of 108). Conclusion: This study confirmed that sGLP‐2 should be considered as part of the standard therapy for postsurgical medical rehabilitation treatment in patients with chronic intestinal failure. We add to the current knowledge that some patients can discontinue both PN and sGLP‐2 in the long term, achieving complete recovery of their quality of life. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Teduglutide has been used for patients with short bowel syndrome. Teduglutide can be a dose‐dependent triggering factor to increased amylase and lipase. Serum amylase and lipase levels should be monitored routinely for patients on teduglutide, and they should be screened before the initiation of treatment. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: This study characterized the glucagon-like peptide 2 receptor (GLP2R) gene of chickens because relatively little is known about the underlying mechanism of GLP2 actions in nonmammalian species. With the use of reverse transcription PCR, we first cloned the chicken GLP2R (cGLP2R) from adult intestine, which was predicted to encode a 529-amino acid receptor precursor. With the use of a pGL3-CRE luciferase reporter system, we demonstrated that cGLP2R expressed in Chinese hamster ovary cells could be potently activated by cGLP2 (half maximal effective concentration, 1.06nM) but not by its structurally related peptides, including the newly identified glucagon-like peptide, indicating that cGLP2R is a functional receptor specific to cGLP2. Reverse transcription PCR assay revealed that cGLP2R mRNA was widely expressed in adult chicken tissues, including pancreas and various parts of the gastrointestinal tract. With the use of quantitative real-time reverse transcription PCR assays, we further investigated the mRNA expression of cGLP2R and its potential downstream mediators, epidermal growth factor receptor (EGFR) ligands (heparin-binding EGF-like growth factor, epiregulin, and amphiregulin), in the distal duodenum of developing embryos. The mRNA expression levels of GLP2R and EGFR ligands (heparin-binding EGF-like growth factor and amphiregulin) were shown to increase (P < 0.05 or 0.01) during the late embryonic stages (E16 and E20), implying a potential coordinated action of GLP2 and EGFR ligands on embryonic intestine development. Taken together, our findings not only establish a molecular basis to explore the physiological roles of GLP2 in birds, but they also provide comparative insights into the roles of GLP2R and its ligand in vertebrates, such as its roles in embryonic intestine development. [Copyright &y& Elsevier]

XTEN, unstructured biodegradable proteins, have been used to extend the in vivo half-life of genetically fused therapeutic proteins and peptides. To expand the applications of XTEN technology to half-life extension of other classes of molecules, XTEN protein polymers and methods for chemical XTENylation were developed. Two XTEN precursors were engineered to contain enzymatically removable purification tags. The proteins were readily expressed in bacteria and purified to homogeneity by chromatography techniques. As proof-of-principle, GLP2-2G peptide was chemically conjugated to each of the two XTEN protein polymers using maleimide–thiol chemistry. The monodisperse nature of XTEN protein polymer enabled reaction monitoring as well as the detection of peptide modifications in the conjugated state using reverse phase-high performance liquid chromatography (RP-HPLC) and electrospray ionization mass spectrometry. The resulting GLP2-2G-XTEN conjugates were purified by preparative RP-HPLC to homogeneity. In comparison with recombinantly fused GLP2-2G-XTEN, chemically conjugated GLP2-2G-XTEN molecules exhibited comparable in vitro activity, in vitro plasma stability and pharmacokinetics in rats. These data suggest that chemical XTENylation could effectively extend the half-life of a wide spectrum of biologically active molecules, therefore broadening its applicability. [ABSTRACT FROM AUTHOR]

For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function [ABSTRACT FROM AUTHOR]

Abstract: Context: Anorexia nervosa, characterized by extreme low body weight due to reduced nutrient intake, is associated with severe bone loss. Peptide hormones, including amylin, GIP, and GLP2, are released immediately after nutrient intake and may be involved in the regulation of bone turnover. Objective: To investigate fasting levels of amylin, GIP, and GLP2 and their relationships with bone mineral density (BMD) in women with anorexia nervosa compared to healthy controls. Design: Cross-sectional. Setting: Clinical Research Center. Study participants: 15 women with anorexia nervosa and 16 healthy controls. Intervention: None. Main outcome measures: Fasting serum amylin, GIP, and GLP2, and BMD. Results: Women with anorexia nervosa had significantly lower fasting serum amylin and GIP levels than healthy controls. Fasting serum GLP2 levels were not significantly different between groups. Fasting amylin levels were positively associated with BMD and Z-score at the PA spine, total hip, and femoral neck. Fasting amylin levels were also positively associated with weight and percent fat; after controlling for these variables, amylin was still a significant predictor of BMD and Z-score at the femoral neck and of Z-score at the total hip. In the anorexia nervosa group, there was a trend toward an inverse association between amylin and C-terminal telopeptide (CTX) levels (R =−0.47, p =0.08). GIP and GLP2 levels did not predict BMD at any site. Conclusion: Decreased secretion of amylin may be a mechanism through which reduced nutrient intake adversely affects BMD in anorexia nervosa. [Copyright &y& Elsevier]

Background: Glucagon-like peptide 2 (GLP-2) agonists decrease the need for parenteral nutrition (PN) in short bowel syndrome (SBS); mechanisms evaluated to date have focused on the intestinotrophic effect of GLP-2 agonists such as increased absorptive capacity of the remnant intestine and increased citrulline levels. Other mechanisms may also play a role in effects of GLP-2 agonists., Aim: To measure effects of a GLP-2 agonist, teduglutide (TED), compared with placebo (PLA) on gastric emptying (GE), overall gut transit, fluid balance, intestinal monosaccharide absorption, and permeability in patients with SBS on home PN (HPN)., Materials and Methods: In 8 adults with SBS on HPN, we compared daily subcutaneous TED (0.05 mg/kg) and PLA (crossover design, each treatment 7 days with a 14-day washout) on gut transit, intestinal absorption, and permeability after oral mannitol (200 mg) and lactulose (1 g), as well as stool weight and urine volume over 8 hours. Analysis used the paired t test., Results: Of 8 patients, 4 were men, with a mean ± SD age of 54 ± 1 years, body mass index of 25 ± 4 kg/m 2 , residual small intestine of 63 ± 12 cm, and 25% ± 15% of residual colon. The overall gut transit (% emptied at 6 hours) was 53.4% ± 15% for TED vs 62.4% ± 15.2% for PLA (P = .075), with no effect on GE (P = .74). TED increased urine mannitol excretion at 0-2 hours (16.2 ± 3.6 mg TED vs 11.3 ± 2.2 mg PLA, P = .20) and 0-8 hours (32.7 ± 5.9 mg PLA vs 48.8 ± 8.9 mg TED, P = .17). There were no differences in urine lactulose excretion or lactulose/mannitol ratio (0.024 ± 0.005 TED vs 0.021 ± 0.005 PLA). Over 8 hours, TED (vs PLA) numerically reduced stool weight (mean ± SEM, 77 ± 18 g TED vs 106 ± 43 g PLA, P = .42) and increased urine volume (408.9 ± 52.2 mL TED vs 365.7 ± 57.3 mL PLA, P = .34)., Conclusion: Seven-day TED treatment in 8 participants suggests beneficial effects on fluid balance and monosaccharide absorption, and it retarded overall gut transit with no effects on GE or mucosal permeability. Larger, longer, mechanistic studies of TED in SBS are warranted. This trial was registered at clinicaltrials.gov as NCT02099084., (© 2015 American Society for Parenteral and Enteral Nutrition.)