Receptor Analogues Research Articles

Mineral bone disorders in chronic kidney disease.

As the GFR loss aggravates, the disturbed mineral metabolism worsens the bone microstructure and remodelling - scenario, which is known as CKD-mineral bone disease (MBD). CKD-MBD is characterized by : (i) abnormal metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; (ii) abnormalities in bone turnover, mineralization, volume linear growth or strength; (iii) soft-tissue calcifications, either vascular or extra-osseous. Uremic vascular calcification and osteoporosis are the most common complications related to CKD-MBD. Disregulated bone turnover by uremic toxin or secondary hyperparathyroidism disturbed bone mineralization and makes it difficult for calcium and inorganic phosphate to enter into bone, resulting in increased serum calcium and inorganic phosphate. Vascular calcification worsens by hyperphosphatemia and systemic inflammation. Since vitamin D deficiency plays an important role in renal osteodystrophy, supplement of nutritional vitamin D is important in treating uremic osteoporosis and vascular calcification at the same time. Its pleotropic effect improves the bone remodeling initiated by osteoblast and alleviates the risk factors for vascular calcification with less hypercalcemia than vitamin D receptor analogs. Therefore, nutritional vitamin D should be considered in managing CKDMBD.

A review on anti-adhesion therapies of bacterial diseases.

Infections caused by bacteria are a foremost cause of morbidity and mortality in the world. The common strategy of treating bacterial infections is by local or systemic administration of antimicrobial agents. Currently, the increasing antibiotic resistance is a serious and global problem. Since the most important agent for infection is bacteria attaching to host cells, hence, new techniques and attractive approaches that interfere with the ability of the bacteria to adhere to tissues of the host or detach them from the tissues at the early stages of infection are good therapeutic strategies. All available national and international databanks were searched using the search keywords. Here, we review various approaches to anti-adhesion therapy, including use of receptor and adhesion analogs, dietary constituents, sublethal concentrations of antibiotics, and adhesion-based vaccines. Altogether, the findings suggest that interference with bacterial adhesion serves as a new means to fight infectious diseases. Anti-adhesion-based therapies can be effective in prevention and treatment of bacterial infections, but further work is needed to elucidate underlying mechanisms.

Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2-related factor 2 nuclear translocation

Activation of endoplasmic reticulum (ER) stress is involved in the development of nonalcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) has been reported to reduce hepatic steatosis, but the underlying mechanism has not been fully elucidated. Here, we investigated whether exendin-4 (EX-4), a GLP-1 receptor analogue, improves hepatic steatosis through ER stress reduction. Furthermore, we explored which ER stress pathway is involved in this process, with a focus on the protein kinase RNA-like ER kinase (PERK)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway. EX-4 treatment reduced hepatic lipid accumulation by suppressing the expression of lipogenic genes and restoring the expression of β-oxidation genes in palmitate-treated HepG2 cells and high fat diet (HFD)-fed mice. In addition, EX-4 treatment suppressed hepatic ER stress activation in HFD-fed mice and tunicamycin-treated mice. In particular, EX-4 treatment restored HFD- and tunicamycin-induced Nrf2 nuclear translocation to control levels. Inhibition of Nrf2 by siRNA enhanced phosphorylation of PERK and eukaryotic translation initiation factor 2α (eIF2α), as well as other substrates of the PERK pathway. Nrf2 knockdown also inhibited the protective effects of EX-4 against lipid accumulation, ER stress activation, and cell death in palmitate-treated HepG2 cells. EX-4 treatment prevents hepatic steatosis and improves cell survival by regulating hepatic lipid metabolism and reducing ER stress activation, and Nrf2 plays an essential role in the protective effect of GLP-1 on hepatic steatosis.

Capacitive sensor for detection of benzo(a)pyrene in water

An affinity sensor based on capacitive transduction was developed to detect benzo(a)pyrene (BaP) in river water. Two types of recognition elements, the synthetic receptor analogues molecularly imprinted polymers (MIPs) and natural monoclonal antibody (mAb) were tested for this type of biosensor. Different polymerization strategies to obtain MIPs were compared. One approach comprised a preliminary batch synthesis of beads that were subsequently coupled covalently to an electrode surface. Another approach consisted of the in-situ synthesis of MIPs directly onto the electrode surface using electropolymerization. The latter approach provided the best results. To choose the optimal recognition element mAb and MIP-modified electrodes different sets were evaluated with regards to their sensitivity, selectivity, linear range and re-usability. The mAb-modified electrodes were considerably more sensitive toward BaP (ng L−1 range vs µg L−1 range for the MIP-modified one), and showed a broader linear working range than the MIP-modified electrodes. The latter revealed more suitable for group-selective determination of PAHs. The developed capacitive sensor was tested for the detection of BaP in naturally-contaminated water samples collected in different places of Ghent, Belgium. The results obtained with the sensor were coherent and reproducible, and were in a good agreement with the confirmation technique, HPLC-FlD.

Effect of the Combination Therapy of Liraglutide, a GLP-1 Receptor Analog, and IDegAsp in Patients with Type 2 Diabetes

Background: Diabetes care management aims to not only achieve good glycemic control but also maintain the quality of life (QoL). Basal insulin-treated patients frequently receive bolus insulin as a strengthening therapy; however, concerns exist about QoL due to the increasing number of injections. We examined the glycemic effect and QoL in patients treated with liraglutide (Lira) and insulin degludec/insulin aspart (IDegAsp). Methods: Patients with type 2 diabetes treated with basal-supported oral therapy (BOT) and DPP-4 inhibitor were enrolled in this observational study. Basal insulin was switched to IDegAsp at the same dose and DPP-4 inhibitor to Lira simultaneously; no titration protocol was used. We estimated the clinical and laboratory parameters and assessed the change in QoL within 12 weeks using the diabetes therapy-related QoL (DTR-QoL) questionnaire. The timing of dose up in regard to IDegAsp and Lira was also determined. Results: Fourteen patients were enrolled (male/female: 9/5, age (years): 63.6). The IDegAsp dose ranged from 9.1 to 13.7 U; all patients received 0.9 mg/day of Lira. The combination therapy significantly decreased HbA1c levels (8.7% vs. 7.1%, P=0.02), pre-breakfast glucose level (138.2 mg/dL vs. 108.9 mg/dL, P=0.044), bodyweight (62.9 kg vs. 60.3 kg, P=0.003), and BMI (24.6 vs. 23.5, P=0.004). The total DTR-QoL score at baseline was 61.6 and significantly improved to 73.2 (P=0.004). Significant improvement was also seen in D3 score (hypoglycemia; 63.6 vs. 81.4, P=0.036). D4 score (satisfaction with treatment) showed an increasing trend (59.0 vs. 78.2) and was negatively correlated with HbA1c levels (P=0.049). Conclusion: The change from BOT to the combination therapy of Lira and IDegAsp significantly improved glycemic control and reduced the bodyweight without deteriorating QoL in type 2 diabetes, although the treatment modality changed from one-injection to two-injection therapy. Disclosure M. Harada: None. M. Shinoda: None. R. Sakamoto: None. J. Suzuki: None. K. Takahashi: None. T. Yamakawa: None.

Cloning, Expression, Purification and Characterization of Oligomeric States of the Native 5HT2A G-Protein-Coupled Receptor.

The 5HT2A G-Protein Coupled Receptor (GPCR) is an important family of receptors involved in an array of neuromodulatory functions. Their dysregulation has been implicated in a number of psychiatric diseases. In spite of the importance of this GPCR, high resolution structure and mechanistic details of its function is unknown. Cholesterol plays an important role in the function of many receptors and reduced cholesterol levels can lead to disruption of serotonergic pathways. However, the role of cholesterol in the formation of GPCR oligomers has not been previously shown for this receptor. Given that receptor dimers have been shown to be the functional unit of this receptor, it is important to investigate the effect of cholesterol in the oligomeric state of 5HT2A receptor. The main objective of this work is to clone, over-express and purify the 5HT2A receptor and investigate the effect of cholesterol in its oligomer formation. The 5HT2A receptor (5HT2AR) DNA construct was subcloned into pFastBac-HT vector and the purified bacmid was used to transfect healthy Sf9 cells. After subsequent passages, a high titer baculovirus was used for over-expression in Sf9 cells. To verify whether the over-expressed receptor was localized in the membrane or cytosolic fraction, cells with and without baculoviral infection were analyzed by immunocytochemistry. Subsequently, the over-expression conditions required to obtain sufficient quantity of the receptor was optimized followed by the optimization of the purification conditions. Finally, the culture was scaled up and the receptor was purified by affinity chromatography. The over-expression of the receptor was checked by Western blotting and purity was analyzed by Coomassie stained SDS PAGE. Cryo-electron microscopy experiments were performed on the purified receptor in presence and absence of cholesterol and at multiple concentrations to rule out any concentration dependent effect on the oligomer formation. Immunocytochemistry experiments showed prominent nuclear staining; however, bright green staining along the cell membrane was observed only for the infected cells, suggesting appropriate trafficking of majority of the over-expressed receptors to the cell membrane. Results of cryoelectron microscopy show that the receptor with cholesterol had particles that were bigger in size (~11 - 12 nm) compared to the dimension of known GPCR homologs. In contrast, the receptor after removal of cholesterol revealed a uniform distribution of smaller particles (~5 - 6 nm) that is approximately half the size of 5HT2AR particles with cholesterol. Comparing the 2D average views of detergent-encapsulated 5HT2AR particles with the overall dimensions of other 5HT receptor analogs, we show that while a 5HT2AR dimer more closely matches the dimensions of particles with CHS, only a monomer can be fit to particles without CHS. Importantly, even at higher receptor concentration and particle density, the size for 5HT2AR particles without CHS remains the same, suggesting that dimerization is unlikely an effect of concentration. Our results indicated that 5HT2A receptor primarily forms a dimer in presence of cholesterol whereas it predominantly forms a monomer when cholesterol is removed.

Efficacy in metabolic control and weight loss of combined treatment with GLP-1 receptor analogues and SGLT-2 inhibitors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Computational analysis of the receptor binding specificity of novel influenza A/H7N9 viruses

BackgroundInfluenza viruses are undergoing continuous and rapid evolution. The fatal influenza A/H7N9 has drawn attention since the first wave of infections in March 2013, and raised more grave concerns with its increased potential to spread among humans. Experimental studies have revealed several host and virulence markers, indicating differential host binding preferences which can help estimate the potential of causing a pandemic. Here we systematically investigate the sequence pattern and structural characteristics of novel influenza A/H7N9 using computational approaches.ResultsThe sequence analysis highlighted mutations in protein functional domains of influenza viruses. Molecular docking and molecular dynamics simulation revealed that the hemagglutinin (HA) of A/Taiwan/1/2017(H7N9) strain enhanced the binding with both avian and human receptor analogs, compared with the previous A/Shanghai/02/2013(H7N9) strain. The Molecular Mechanics - Poisson Boltzmann Surface Area (MM-PBSA) calculation revealed the change of residue-ligand interaction energy and detected the residues with conspicuous binding preference.ConclusionThe results are novel and specific to the emerging influenza A/Taiwan/1/2017(H7N9) strain compared with A/Shanghai/02/2013(H7N9). Its enhanced ability to bind human receptor analogs, which are abundant in the human upper respiratory tract, may be responsible for the recent outbreak. Residues showing binding preference were detected, which could facilitate monitoring the circulating influenza viruses.

Prostatic inflammation: a potential treatment target for male LUTS due to benign prostatic obstruction.

The purpose of this narrative review is to evaluate the role of prostatic inflammation as a treatment target for lower urinary tract symptoms (LUTS) due to benign prostatic obstruction (BPO) and provide an update on the available therapies. An extensive literature search was conducted for studies on established and investigational treatments with anti-inflammatory mechanism of action that has been assessed for the management of male LUTS due to BPO. Data on phosphodiesterase 5 inhibitors, nonsteroidal anti-inflammatory drugs, vitamin D3 receptor analogs, phytotherapy, statins, and lifestyle changes have been reviewed and analyzed. Preclinical evidence has shown the anti-inflammatory effect of these treatments on prostate. However, there is a wide variation in the degree of mature of each therapy. In addition, there are significant differences between the studies in terms of design, number of patients, and duration of follow-up. Several drugs classes have been investigated for their impact on prostatic inflammation and improvement of male LUTS. The reviewed data support the rationale for use of agents that may alter and improve the inflammatory environment in the prostate in men with LUTS, but further high-quality long-term studies are required for the exact positioning of the new drugs in daily practice.

Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure.

Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.

Treatment strategies of low-risk myelodysplastic syndromes

The support treatment of low-risk myelodysplastic syndromes (MDS) patients whose revised international prognostic score system (IPSS-R) is defined as 3.5 points remains the main treatment. The erythropoiesis stimulating agent (ESA) is the best choice for patients with del(5q) MDS as long as the endogenous erythropoietin (EPO) level is less than 500 U/L (preferably < 200 U/L). The application of EPO for patients with treatment failure or relapsed after transfusion, chooses are immunosuppressant, transforming growth factor beta inhibitors and lenalidomide. Del(5q) syndrome could benefit from lenalidomide, and some patients after discontinuation of treatment still have been stable in peripheral blood. Thrombocytopenia caused serious hemorrhage rarely; thrombopoietin receptor analogs could reduce bleeding and improve the platelet count. These drugs can be used in patients with bone marrow blast counts of < 0.05. If treatment failed or advanced to high-risk MDS or transformed to acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation might be required. Combined with reports in the 59th American Society of Hematology (ASH) Annual Meeting, this article describes the treatment strategies for low-risk MDS. Key words: Myelodysplastic syndromes; Low-risk; Therapy

68Ga-somatostatin receptor analogs and 18F-FDG PET/CT in the localization of metastatic pheochromocytomas and paragangliomas with germline mutations: a meta-analysis.

Metastatic pheochromocytoma and paraganglioma (PCs/PGLs) show high germline mutation, and 18F-FDG and 68Ga-DOTA peptide positron emission tomography/computed tomography (PET/CT) imaging are recommended for the diagnosis of metastatic of PCs. However, there has been lack of direct comparison of the two modalities in the diagnosis of metastatic of PCs up to now. To evaluate and compare the value of localization of 68Ga-somatostatin receptor analogs and 18F-FDG in the diagnosis of metastatic PCs/PGLs. A comprehensive literature search of PubMed/MEDLINE, ScienceDirect, and Web of Science was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines published in August 2016. We critically reviewed all studies based on the PICOS criteria. QUADAS-2 was used to evaluate the quality of the methodology of the included studies. This meta-analysis included 17 studies (629 patients, average age [mean ± SD] = 42.7 ± 6.3 years). The pooled sensitivity and specificity of 18F-FDG and 68Ga peptides were 0.85 (95% confidence interval [CI] = 0.78-0.91) and 0.55 (95% CI = 0.37-0.73), and 0.95 (95% CI = 0.92-0.97) and 0.87 (95% CI = 0.63-0.96), respectively. The area under the sROC curves of the 18F-FDG and 68Ga peptides were 0.88 (95% CI = 0.85-0.91) and 0.78 (95% CI = 0.74-0.81), respectively. A subgroup analysis demonstrated that the difference at the per-lesion level and gene mutation level was significant. Compared to 18F-FDG PET/CT, the 68Ga-somatostatin receptor demonstrated good performance in the localization of metastatic PCs/PGLs, especially those with germline mutations. The use of the 68Ga-somatostatin receptor can be a new tool in the diagnosis of metastatic PCs/PGLs.

Hypoglycemia in the Elderly with Diabetes: A Growing Problem with Emerging Solutions

A1c = glycated hemoglobin A1c Gla-100 = glargine 100 U/mL Gla-300 = glargine 300 U/mL GLP-1 RA = glucagon-like peptide-1 receptor analogue.

Glycemic Control as Primary Prevention for Diabetic Kidney Disease.

Improving strategies to prevent the development and progression of CKD is a highly desirable outcome for all involved in the care of patients with diabetes. This is because CKD is a major factor contributing to morbidly and mortality in patients with diabetes. Furthermore, diabetes is the leading cause of ESRD in most developed countries. Although tight glucose control is now an established modality for preventing the development and progression of albuminuria, evidence is now accumulating to suggest that it can also ameliorate glomerular filtration rate loss and possibly progression to ESRD. These benefits of intensive glucose control appear to be most pronounced when applied to patients with the early stages of CKD. Recently, medications that belong to the sodium glucose cotransporter-type 2 inhibitor and the glucagon-like peptide-1 receptor analogue classes have been shown to reduce progression of CKD in patients with type 2 diabetes and relatively well-preserved kidney function. Here, we review the evidence from observational and interventional clinical studies that link good glucose control with the primary prevention of diabetic kidney disease with a focus on preventing early glomerular filtration rate loss.

Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: A pilot pharmacogenetics study.

Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide. We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5μg BID for 30days, or liraglutide, 3mg daily for 5weeks. Data were analyzed using the dominant genetic model and intention-to-treat analysis. There was a significant correlation between changes in weight and GE T1/2 (rs =-.382, P=.004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9±27.5 [SEM] minutes and 128.9±38.32minutes) compared to GG genotype (95.8±30.4minutes and 61.4±21.4minutes, respectively; P=.11). There was a non-significant difference in weight loss based on GLP1R rs6923761 genotype after 5weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype. The minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.

Toward an effective peripheral visceral analgesic: responding to the national opioid crisis.

This minireiew summarizes recent new developments in visceral analgesics. This promising field is important, as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors via biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor, or dual action on NOP and μ-opioid receptor, buprenorphine and morphiceptin analogs. Other compounds target nonopioid mechanisms, including cannabinoid (CB2), N-methyl-d-aspartate, calcitonin gene-related peptide, estrogen, and adenosine A2B receptors and transient receptor potential (TRP) channels (TRPV1, TRPV4, and TRPM8). Although current evidence is based predominantly on animal models of visceral pain, early human studies also support the evidence from the basic and animal research. This augurs well for the development of nonaddictive, visceral analgesics for treatment of chronic abdominal pain, an unmet clinical need.

Effective anti-adhesives of uropathogenic Escherichia coli.

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are among the most common infectious diseases in humans. Due to their frequent occurrence in the community and nosocomial settings, as well as the development of resistance to the commonly prescribed antimicrobial agents, an enormous financial burden is placed on healthcare systems around the world. Therefore, novel approaches to the prevention and treatment of UTIs are needed. Although UPEC may harbour a plethora of virulence factors, type I fimbriae and P pili are two of the most studied adhesive organelles, since the attachment to host cells in the urinary tract is a crucial step towards infection. Design of receptor analogues that competitively bind to UPEC surface adhesins placed at the top of pili organelles led to the development of anti-adhesive drugs that are increasingly recognized as important and promising alternatives to antibiotic treatment of UTIs.

Activation of amylin receptors attenuates alcohol-mediated behaviours in rodents.

Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut–brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol‐related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol‐induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward‐dependent memory consolidation. In addition, sCT pre‐treatment attenuated alcohol intake in low alcohol‐consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

Vitamin D shows in vivo efficacy in a placebo-controlled, double-blinded, randomised clinical trial on canine atopic dermatitis

Atopic dermatitis (AD) in dogs is among the most common skin diseases in small animal practice. It is an inflammatory disease based on a genetic predisposition to develop hypersensitivity against...

Glucagon receptor signaling in metabolic diseases

Glucagon is a peptide hormone secreted from the pancreatic alpha cells in response to hypoglycemia but in some patients with type 2 diabetes a paradoxical hypersecretion results from the intake of glucose. In rodent, antagonizing the actions of glucagon have been shown to be effective for lowering blood glucose levels and this has recently have been solidified in patients with type 2 diabetes. Although the reported increases of liver enzymes, hyperglucagonemia, and alpha cell hyperplasia resulting from glucagon receptor antagonism may potentially limit the clinical applicability of glucagon receptor antagonists, they may serve as an instrumental toolbox for delineating the physiology of glucagon. Agonizing glucagon receptor signaling may be relevant, in particular when combined with glucagon-like peptide-1 receptor analogues in the perspective of body weight lowering therapy. Here, we will focus on new conceptual aspects of glucagon biology and how this may led to new diagnostics and treatment of metabolic diseases.