How these findings with glucagon might apply to mammalian eyes requires further research. Cpd-A, a potent and selective GCGR antagonist (GRA) was studied in preclinical models to assess its effects on alpha cells. Accumulations of hemosiderin-laden macrophages may accompany the fibrosis. A glucagon receptor antagonists which blocked glucagon action in experiments employing cell lines or primary cultures in vitro, or rodent studies in vivo as described in: Design and synthesis of glucagon partial agonists and antagonists. Supporting a potential role for glucagon in vision-dependent eye growth in chick, exogenous glucagon, a glucagon-related peptide and glucagon receptor agonists suppress form deprivation myopia; and a glucagon receptor antagonist inhibits the refractive shift and growth compensation to plus lens wear (Feldkaemper and Schaeffel, 2002; Vessey et al., 2005a,b). Indeed, as key residues have been modified, the more usual result has been a change from glucagon agonist activity to partial agonist or even antagonist activity. Glucagon excess represents one of the hallmark metabolic derangements that contribute to hyperglycemia in type 1 and type 2 diabetes.87 Conversely, increased glucagon secretion functions as the primary counterregulatory mechanism to restore normal levels of plasma glucose in the setting of hypoglycemia, and individuals who are prone to frequent episodes of hypoglycemia may use glucagon injections for emergency management of severe hypoglycemia. The adenomas are usually discrete, well-circumscribed, single nodules 1–10 mm in diameter that may compress the surrounding acinar tissue. To date it remains unknown whether these two transcription factors contribute to the genetic background of humans who develop diabetes. From: Encyclopedia of Endocrine Diseases, 2004, Kathleen M. Dungan, John B. Buse, in Endocrinology (Sixth Edition), 2010, Novel pharmaceutical agents, including glucagon receptor antagonists, inhibitors of gluconeogenic and glycogenolytic pathways, glucokinase activators, sodium-glucose cotransporter inhibitors, acetyl-CoA carboxylase inhibitors, selective PPAR-γ modulators, modifiers of lipid metabolism, and antiobesity agents are areas of early pharmaceutical development.78. The loss of glucagon actions in genetically manipulated mice prevents the development of diabetes in the complete absence of pancreatic insulin, a convincing demonstration of the potent diabetogenic actions of glucagon. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Among identified cells, these changes are prominent in glucagoncontaining amacrine cells (Fischer et al., 1999a). Glucagon-containing α-cells potently regulate glucose homeostasis, but the developmental biology of α-cells in adults remains poorly understood. These recent findings on the biology of alpha cells provide a compelling rationale for exploiting alpha cells as a means to generate new beta cells. OBJECTIVE Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. Interestingly, earlier it was shown that [Nim-2,4-dinitrophenylhistidine1, homoarginine12]glucagon was an antagonist (Bregman et al., 1980). However, the limitations of morphology must be considered when interpreting the results of toxicological studies that show a chemical-related increase in the incidence of proliferative lesions. Finally, in vivo it is important to examine in normal and diabetic animals such critical parameters as glucose levels, ketone bodies, blood pH, and so forth, and well-developed methods are available in most clinical laboratories for such studies. Oxyntomodulin administered three times daily for 4 weeks reduced body weight in overweight and obese human subjects.104 Although distinct G protein–coupled receptors for glucagon, GLP-1, and GLP-2 have been characterized, separate receptors that mediate the actions of glicentin and oxyntomodulin have not been identified, and the anorectic action of oxyntomodulin requires a functional GLP-1 receptor.105 Oxyntomodulin simultaneously activates both glucagon and GLP-1 receptors, and oxyntomodulin mimetics resulted in enhanced weight loss in preclinical models compared with the actions of GLP-1 receptor agonists alone.106 Multiple co-agonists targeting the glucagon, GLP-1, or GIP receptors exhibit enhanced activity on appetite and weight loss and are being explored for the treatment of human subjects with diabetes and obesity.55, Victor J. Hruby, Dinesh Patel, in Peptides: Synthesis, Structures, and Applications, 1995. The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. A major target for ERK is the transcription factor CREB (cyclic AMP response element binding protein) which controls expression of genes implicated in many cell functions. National Library of Medicine. Shortly thereafter, the first potent glucagon antagonist, THG-glucagon, was reported (Bregman et al., 1980) which was shown to lower blood glucagon levels in diabetic rats (Johnson et al., 1982), presumably by blocking the effect of endogenous glucagon. Inhibition of enzymes involved in gluconeogenesis and/or glycogenolysis therefore constitutes an alternative approach to GRAs to suppress hepatic glucose production and lower fasting plasma glucose. Sections of pancreatic tissue may contain one hyperplastic islet (Figure 35.5) or most islets may be affected. This might be related to the different timing of actions of the three regulators, glucagon having plenty of time (the interprandial state) to produce in-depth regulation of CREB-dependent mechanisms, and, thus ‘preparing’ the ß-cell to respond to glucose, as compared to GLP-1 which acts, as an incretin, shortly before glucose reaches the islets. Among the most widely used are the following: Receptor binding assays using purified rat liver plasma membranes (Pohl et al., 1971) and [125I]glucagon in competitive binding experiments (Lin et al., 1975). Glucagon Receptor Antagonist. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Hyperplastic islets attain a diameter of up to 500 µm or more, but islets are not usually affected to the same degree. Fig. β-cell regeneration from the three potential mechanisms has been demonstrated in rodents and rodent models of β-cell injury, but the mechanisms and relevance are still controversial in humans. Unlike hyperplastic islets, cells containing glucagon or somatostatin are usually randomly distributed in the neoplasms. Indeed, CREB phosphorylation by glucagon is suppressed by addition of a MEK (MAP kinase–kinase) inhibitor. The corresponding d-amino acid replacements, however, resulted in virtually 90% loss of binding affinity and consequently adversely affected the cyclase activity. The ERK pathway exists in the β-cell as shown by the effect of low glucose in the absence and in the presence of glucagon on ERK activation by double phosphorylation in the MIN6 β-cell line [42]. Figure 35.13. Animals with experimental DM treated with functional or structural glucagon receptor antagonists and glucagon receptor knockout mice develop α-cell hyperplasia with prominent hyperglucagonemia. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. Chronic treatment with OXM resulted in superior body weight lowering and comparable glucose-lowering to equimolar amounts of OXMQ3E [46]. The discovery that the aspartic acid in position 9 was the locus of uncoupling and coupling resulted in the design and synthesis of potent glucagon antagonists (Unson et al., 1990, 1991). Figure 35.7. Addition of a glucagon receptor antagonist in human islets not only blunts the glucagon-induced but also the glucose-induced insulin release [34]. None demonstrated invasive growth or metastasis. Prolactin secretion is inhibited by dopamine. The close vicinity between the two types of cells allows mutual interactions. The acinar cells may be hypertrophic. Results obtained from such sequence modifications suggest that the backbone conformation in the 9 to 12 region is crucial for the correct fit of the message sequence 1–5 to the active site of the receptor (Hruby et al., 1993a). In Sprague–Dawley rats, spontaneous age-related islet changes may be observed in males and females as young as 3.5 and 14 months, respectively. In contrast to the clearly opposite nature of glucagon towards insulin recalled above, the relationship between the two hormones inside their production site, the islets of Langerhans, are much more complex. Replacement of histidine with other aromatic derivatives lacking an α-amino group (4-imidazoleacetic acid; 3-indoleacetic acid; Nα-2,4-difluorobenzoic acid) led to high-binding analogs that were all partial agonists. Though this analogue was useful in examining the possibility of two separate signal-transduction systems for glucagon (Wakelam et al., 1986), it subsequently was shown to be a weak partial agonist in some systems (Hruby et al., 1981; Corvera et al., 1984; Garcia-Saint et al., 1986; Hruby et al., 1996). Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways. Thus far, though a few residues can be removed from the N- or C-terminal with maintenance of some agonist activity, in general the potency is greatly reduced, and even [des-His1]glucagon was shown to be a weak partial agonist/antagonist (Lin et al., 1975: Hruby et al., 1976). In the cytoplasm, glucose-activated ERK phosphorylates proteins which have been proposed to be implicated in insulin granule exocytosis, such as Fak, paxillin, and synapsin-1 [43–45]. Adomeglivant (LY2409021) is a potent and selective antagonist of glucagon receptor that is used as a chronic treatment for type 2 diabetes. 4. Replacement of His1 with singularly charged amino acids also resulted in a significant loss of binding affinity, whereas reversal of the charge had a similar effect. It appears that essentially the entire glucagon(1-29) sequence is necessary for potent agonist activity at the glucagon receptor (Frandsen et al., 1981; Hruby et al., 1986). This does not constitute invasion and should not be used as a criterion of malignancy. Our potent, novel compound, LGD-6972, has demonstrated significant and consistent glucose lowering activity and a desirable safety profile in animal models and in Phase 1 clinical trials. Recently, the classical cAMP accumulation assay of Brown et al. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose‐lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects. Thus, it appears that the complete or near complete glucagon sequence is needed for agonist and possibly for antagonist activities for glucagon. The way is now open to obtain pure, potent glucagon receptor antagonists for investigating in detail the role of glucagon alone and in conjunction with insulin in normal and diabetic states in more detail and with more clarity than has hitherto been possible. Pancreatic islet cell adenomas occur more frequently than carcinomas. This is possible thanks to the presence of authentic glucagon receptors at the surface of the insulin-secreting cells [32–34]. Of course, it also is possible to study the activity of the various enzymes in the cascade since they might be of interest to some specific downstream function one is examining. Fig. It is also in recognition of a growing number of already available therapeutic choices, some of which have a proven longstanding safety record when used appropriately and low cost. Glucagon Receptor Antagonist I | C20H30N2OS - PubChem. By Uday Suresh March 6, 2018 No Comments. Related terms: Gluconeogenesis; Glucose; Diabetes Mellitus; Beta Cell; Peptide; Glucagon; Insulin; Glucagon Receptor In the complete absence of glucagon receptor signaling in mice diabetes does not develop even in the near absence of insulin. Figure 35.6. A mixed ductal-squamous-islet cell carcinoma has been described following treatment with a tobacco-specific nitrosamime. They increase insulin and suppress postprandial glucagon secretion but do not produce changes in gastrointestinal motility, satiety, or body weight.94,102 Incretin signaling is necessary for the glucose lowering of DPP-4 inhibitors.103, In contrast to GLP-1 and GLP-2, the biologic actions of the proglucagon-derived peptides glicentin and oxyntomodulin are less well established. In isolated hepatocytes, inhibitors of the T1 translocator inhibit both basal and glucagon-stimulated glucose production.26 In animal studies, acute administration of an inhibitor of the T1 translocator caused a rapid lowering of blood glucose that correlated with the accumulation of the compound in the liver. Criteria that are useful in distinguishing hyperplasia from neoplasia are listed in Table 35.1. Since study results are meaningfully positive, a follow-up phase-3 randomized clinical trial would be expected. Glucagon receptor antagonists are designed to lower plasma glucose levels by reducing the production of glucose by the liver. S9697 New: Semaglutide. A recent report [57] demonstrated in rats that intracerebroventricular glucagon administration improves whole-body glucose metabolism. Oxyntomodulin was shown to inhibit pancreatic secretion through the nervous system in rats [58]. Although, Structure–Function Studies of Peptide Hormones: An Overview, Peptides: Synthesis, Structures, and Applications, Following a combination of systematic modifications of the primary sequence in positions 3–5, a number of, Best Practice & Research Clinical Endocrinology & Metabolism, β-cell development and perspectives for treatment, The alpha cells of the pancreatic islets, long recognized for their production of glucagon, a diabetogenic hormone that regulates hepatic glucose production to maintain plasma glucose levels during fasting, has become a focus of attention as a potential target for the treatment of diabetes. OXM inhibits food intake and stimulates energy expenditure in rodents and in human subjects [37–40]. Pancreatic islet hyperplasia develops more frequently in males than females and to a greater extent in rats fed ad libitum than those with dietary restrictions. The hyperplasia begins as β-cell hyperplasia, with increased fibrosis over time, eventually replacing much of the islet architecture. In humans, the glucagon receptor is encoded by the GCGR gene. Figure 35.8. Islet cell hyperplasia, adenoma, and carcinoma comprise a morphological and biological continuum. Although Mavash Disease is autosomal recessive and as such is a rare disease, consideration of the disease is indicated in the absence of glucagonoma syndrome, abdominal pain, occasional hypoglycemia, extremely elevated plasma glucagon levels, pancreatic hypertrophy, and the identification of alpha cell nesidioblastosis upon endoscopic biopsy of the panceas. LGD-6972 to be a foundational program for Metavant, a new company formed by Roivant to pursue the development of innovative therapies for cardiometabolic diseases. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo. If these data translate to higher species, it is possible that central GCGR signaling may contribute to the improvement of glucose metabolism in animals treated with OXM. Likewise, the transcription factor paired homeobox 4 (Pax4) is capable of regenerating ablated beta cells when conditionally expressed in alpha cells in mice. In such a model, glucagon would first interact nonspecifically with the cell membrane, following which the initial binding energy between the peptide and the membrane would be utilized to overcome the entropy requirements involved in the peptide–receptor interaction. Thusly, alpha cells play important roles in beta cell neogenesis and transdifferentiation. Glucagon Receptor Antagonist II - CAS 191034-25-0 - Calbiochem The Glucagon Receptor Antagonist II, also referenced under CAS 191034-25-0, controls the biological activity of Glucagon Receptor. When a capsule is present, it often contains atrophic acinar or ductular cells, suggesting that the capsule may be derived from the collapse or atrophy of surrounding exocrine pancreas. Hyperplasia of pancreatic islets occurs in old rats and hyperinsulinism may result, despite the fact that insulin secretion by individual cells is reduced. Treatment of BHK-GIPR or BHK-GLP2R rat cells with OXM had no effect on cAMP production, whereas BHK cells that express the rat GLP-1 or glucagon receptors exhibited significant increases in cAMP accumulation in response to treatment with OXM [30]. These compounds potently counteract the hyperglycaemic response to a glucagon challenge with a concomitant rise in plasma lactate.25 Because of the overriding role of elevated glucagon on hepatic glucose production10, the acute suppression of hyperglycaemia is more likely to be due to inhibition of G6Pase than to the insulin-mimetic properties of the compounds. Taken together, these results clearly demonstrated the critical importance of the His1, Phe6, Asp9, and Ser16 residues in receptor transduction and the important role also played by the residues Gly4, Thr5, Tyr10, Lys12, and Tyr13 in glucagon for agonist/antagonist activity. Taken together, these data suggest that OXM may engage additional receptors but that additional downstream pathways aside from cAMP may be involved [31]. Although morphological criteria for distinguishing hyperplasia from adenoma and adenoma from carcinoma are somewhat arbitrary, established criteria are necessary to provide a basis for comparison and interpretation of study results. Hyperplasic pancreatic islet. As previously discussed, all of the physiological actions of glucagon are thought to be mediated by the interactions of glucagon with its receptors on plasma membranes. 38-2) through stimulation of crypt cell proliferation and reduction of apoptosis within the crypt and villus compartments.97 GLP-2 also enhances intestinal epithelial barrier function and stimulates gut blood flow and intestinal nutrient absorption.98 Preclinical studies demonstrate that GLP-2 prevents injury and enhances repair, regeneration, and function in the gastrointestinal epithelium.98,99 Teduglutide, a degradation-resistant human GLP-2 receptor agonist, reduces requirements for parenteral nutrition support and is approved for treatment of human subjects with short bowel syndrome.100, The actions of GLP-1 and GLP-2 are transduced through distinct receptors, and both peptides are rapidly cleaved at the position 2 alanine by dipeptidyl peptidase 4 (DPP4). Adomeglivant is widely used in the research for type 2 … Because GLP-1 does not stimulate glucose absorption and an increase in hexose transport has been previously described for glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic peptide (GIP) [62,63], OXM could engage additional G-protein-coupled receptors (GPCR) of the secretin like (class B) family such as GLP-2 and GIP receptors [64,65]. Proliferation of islet cells can be demonstrated using proliferation markers, such as Ki-67. Victor J. Hruby, in Principles of Medical Biology, 1997. RESEARCH DESIGN AND METHODS The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral … When present, the metastases are usually in the liver or lung. Using an equipotent GLP1R agonist peptide obtained with a mutation of glutamine to glutamate (OXMQ3E) in position 3 that dials out activity on GCGR, researchers were able to demonstrate that OXM, not OXMQ3E, stimulated ketogenesis in wild-type mice and in Glp1r−/− mice, but not in Gcgr−/− mice [45]. Discover a means to specifically stimulate the production of GLP-1 in alpha cells. [27,28]. Hyperplasia typically affects a variable number of islets. In addition, GLP-1 levels are increased, which have a beneficial effect on treating DM. The growth pattern of islet cell adenomas varies and consists of nests, solid clusters, ribbons, or cords of islet cells separated by a fine fibrovascular stroma (Figures 35.6–35.8). Figure 35.11. Glucagon receptor antagonists are novel molecules that have demonstrated a reduction of plasma glucose and hemoglobin A1c in patients with type 2 … Although previous data have shown that the glucagon receptor is involved in the body weight and glucose lowering action of OXM in addition to GLP1R, OXM may activate additional receptors. Results Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Doch erst im Jahre 1953 konnte Anne-Marie Staub die Reinsubstanz gewinnen und isolieren. Glucagon receptor antagonists represent an avenue to decrease liver glucose production and lower the blood glucose of diabetic patients. Recently there has been a call for more rigorous testing of diabetes therapeutics prior to FDA approval.101 This was partly a reaction to perceived safety concerns of drugs that are approved solely on the basis of surrogate outcomes (A1C) instead of demonstrating a reduction in clinical endpoints. OXM also delayed gastric emptying in humans [53] but not in mice [48] adding a layer of complexity in interpreting receptors activated by OXM. GLP-2 inhibits both centrally induced antral motility and meal-stimulated gastric acid secretion. Area covered: Following … Despite type 2 diabetes (T2D) being recognized as a bihormonal pancreatic disease, current therapies are mainly focusing on insulin, while targeting glucagon has been long dismissed. Synthesis from [42–46]. National Center for Biotechnology Information. These recent findings on the biology of alpha cells provide a compelling rationale for exploiting alpha cells as a means to generate new beta cells. Studies in genetically manipulated mouse models have identified a transcription factor called aristalis (Arx) that when absent or severely reduced, prompts alpha cells to convert into functioning beta cells. Injury models include partial pancreatectomy, pancreatic duct ligation, cellophane wrapping, chemical injury (streptozotocin or alloxan), or genetically modified mice. have developed a pure, clean glucagon antagonist, [des-His1, des-Phe6, Glu9]glucagon (Azizeh et al., 1995; Van Tine et al., 1996), and subsequently other related analogues that are pure antagonists (Azizeh et al., 1997). Glucagon receptor knockout mice exhibit modest fasting hypoglycemia, pancreatic alpha cell hyperplasia, and markedly elevated levels of circulating glucagon and GLP-1.88 Similarly, reduction of hepatic glucagon receptor mRNA transcripts in rodents markedly lowers blood glucose, improves insulin secretion, and increases levels of circulating GLP-1 in rodents with experimental diabetes. The peptide hormone glucagon is produced in the pancreas and is involved in carbohydrate metabolism (Farah, 1983). Develop effective antagonists of glucagon actions so as to increase the numbers of alpha cells in islets to serve as substrates for their conversion into beta cells. Some time ago, Collins et al. The early work clearly established the importance of the His1 and Lys12 residues for developing antagonist activity in glucagon. The 19–27 sequence of glucagon readily forms an amphiphilic helix (Kaiser and Kezdy, 1983; Epand and Liepneks, 1983; Gysin and Schwyzer, 1984) which is considered to be important for the binding of glucagon to its receptor. While glucagon can depress pancreatic exocrine secretions in normal animals and humans, it is still unclear how glucagon exerts this effect [59]. Fig. The thiazolidinediones (such as rosiglitazone, troglitazone, and pioglitazone) are peroxisome proliferator activated receptor (PPAR)-γ agonists and have shown efficacy for preserving β cells, increasing insulin secretion, and protecting β cells from oxidative stress in the early stages of T2DM. The glucagon receptor antagonist BI-32169, recently isolated from Streptomyces sp., was described as a bicyclic peptide, although its primary structure comprises conserved elements of class I and class II lasso peptides. It is evident from the studies of Unson and co-workers (1993) that both positions 1 and 9 play an important role in transducing the hormonal signal. Among these were analogs that included the deletion of position 9 or the replacement of Asp9 by d-Asp, Asn, Glu, d-Glu, Gln, Glu-OMe, Gly, Nle, or Lys, each change being made in the presence or absence of His1. The absence or severe impairment of glucagon signaling in mice results in alpha cell hyperplasia that with age progresses to alpha cell nesidioblastosis and to the formation of pancreatic neuroendocrine tumors (pNETs) with complete penetrance and distant metastases. This receptor conformation is inherent in the primary sequence which allows for only a limited number of secondary and tertiary structures. In addition to its catalytic role in the final reaction of hepatic glucose production, G6Pase has an important regulatory function in buffering the cell content of glucose 6-phosphate27, which is an important regulator of glycogen metabolism and also of transcription of glycolytic and lipogenic genes. A clearly defined connective tissue capsule is present in only a minority of spontaneous adenomas and often a capsule is completely lacking. The alpha cells of the pancreatic islets, long recognized for their production of glucagon, a diabetogenic hormone that regulates hepatic glucose production to maintain plasma glucose levels during fasting, has become a focus of attention as a potential target for the treatment of diabetes.
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