In humans, α cells appear to be more capable of proliferation than β cells in response to disease or injury of the islets. Glucagon receptor antagonist I is a competitive antagonist of the glucagon receptor (GCGR; IC 50 = 181 nM). Therapeutic strategies might involve treatment of diabetic individuals with a combination of glucagon receptor antagonists and small molecules that target alpha cells and suppress the expression of the transcription factor Arx, and/or increase the expression of Pax4. In addition, GLP-1 levels are increased, which have a beneficial effect on treating DM. The anorectic effects of central administrations of OXM are abolished by co-administration of the GLP1R antagonist, exendin(9–39), and are not observed in Glp1r−/− mice, suggesting that the acute central effect of OXM on food intake is mediated by the GLP1R [30,54,55]. Rat islets from dorsal glucagon-rich pancreas have a better insulin response than islets taken from the ventral lobe [38]. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways. 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]. As previously mentioned, the differential neuronal activation observed following OXM, GLP-1 and glucagon administration seems to support a dissociation between the effects of oxyntomodulin and those of GLP-1 and glucagon [33–36]. Unson et al., 1987; Unson et al., 1989; Zechel et al., 1991; Dharanipragada et al., 1993; Unson, 1994; Azizeh et al., 1995; 1996; Sturm et al., 1997). The conclusion [34] is that “the exquisite responsiveness of intact islets is not only dependent on the process of glucose recognition, but also on the presence of a certain threshold of intra-islet glucagon concentration which results in activation of glucagon receptors on β cells”. The islet cells retain normal cytologic appearance and arrangement within the islet, but they may be enlarged (hypertrophy). (1972) has been substantially improved for much greater sensitivity in measuring cAMP accumulation in response to glucagon agonists (Van Tine et al., 1996). This does not constitute invasion and should not be used as a criterion of malignancy. Aspartic acid is crucial at this position and cannot be replaced even by the closely related diacid glutamic acid. Betatrophin stimulates β-cell proliferation and may represent a natural hormone regulator of β-cell mass. Glucagon-containing a-cells potently regulate glucose homeostasis, but the developmental biology of a-cells in adults remains poorly understood. How these findings with glucagon might apply to mammalian eyes requires further research. Proliferation of islet cells can be demonstrated using proliferation markers, such as Ki-67. 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). Mitoses are not common. During a mouse hyperglycemic clamp, OXM infusion reduced the exogenous glucose required to maintain the hyperglycemic levels in Glp1r−/− vs. Gcgr−/− and wild-type mice despite increased plasma insulin levels. The neoplastic cells are usually uniform and normal appearing or enlarged. Recent studies in mice suggest that excessive glucagon signaling might be more diabetogenic than has heretofore been appreciated. 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. Pancreatic Islet cell carcinoma with anaplastic cells arranged in irregular cords. In general, the chemically induced models of islet cell injury are not associated with β-cell proliferation/regeneration; however, transdifferentiation and neogenesis of islet cells are often reported. 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. Since study results are meaningfully positive, a follow-up phase-3 randomized clinical trial would be expected. 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. 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. Loranne Agius BSc, DPhil, DSc, in Best Practice & Research Clinical Endocrinology & Metabolism, 2007, Hepatic glycogenolysis and gluconeogenesis are the two main metabolic pathways that sustain the fasting plasma glucose concentration. 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. 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. Extension of this amphiphilic helix, which could have an important effect on the binding properties of glucagon, has been investigated in several ways. Some time ago, Collins et al. 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. These findings are consistent with increased glucose production observed in mice treated with OXM during a hyperinsulinemic-euglycemic clamp [49]. The glucagon receptor antagonist RVT-1502, at the high dose 15 mg per day, lowered A1c by 1.0% without severe hypoglycemia. 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]. Correct spatial orientation of the imidazole side chain is important for hydrogen bonding or an electrostatic interaction as has been shown by the report that [dHis1]glucagon amide lost over 90% of its binding and showed a considerably reduced cyclase activity relative to the natural L-His1 molecule (Hruby et al., 1986b). A sophistication (which may turn into pathology) of this system is that an excess of PKA activation by cyclic AMP may phosphorylate Raf-1 isoform in an inadequate manner decreasing the activity of the pathway instead of increasing it. Addition of a glucagon receptor antagonist in human islets not only blunts the glucagon-induced but also the glucose-induced insulin release [34]. The “bihormonal hypothesis” for diabetes mellitus postulates glucagon to have an important role on the metabolic disorders of this disease (Ungar, 1978). In summary, G6Pase has two limitations as a therapeutic target for glycaemic control in type-2 diabetes: (1) low concentrations of inhibitor that cause a mild lowering of blood glucose result in marked perturbation of the expression of various genes involved in lipogenesis, with consequent development of fatty liver29,31; and (2) high concentrations of inhibitor may cause severe hypoglycaemia because G6Pase activity is essential for hepatic glucose production by both gluconeogenesis and glycogenolysis. Figure 35.13. Whether better tolerability reflects gastrointestinal tachyphylaxis to sustained GLP-1 receptor agonism or differences in pharmacokinetics remains to be ascertained.96, GLP-2 is a 33–amino acid peptide cosecreted with GLP-1, oxyntomodulin, and glicentin from enteroendocrine cells in a nutrient-dependent manner. 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. 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. It is interesting to note that, if GLP-1 regulates insulin release via its incretin effect, it does not seem to share with glucagon its action on glucose competence, since this parameter is preserved in islets with disrupted GLP-1 receptors [41]. Several GLP-1 receptor agonists are suitable for once weekly administration (exenatide once weekly, albiglutide, dulaglutide); all of these agents are associated with weight loss or prevention of weight gain in randomized clinical trials of subjects with type 2 diabetes.94 The principal side effects associated with the use of GLP-1 receptor agonists are gastrointestinal, predominantly nausea. Explore approaches to reduce, but not eliminate, glucagon signaling, which is counter-regulatory to insulin signaling, leading to improved glycemic control in individuals with type 2 diabetes. The hormone betatrophin has been isolated from the liver and fat of mice with chemically induced DM. 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. It also is possible to use perfused liver slices to examine the various biological activities related to glucagon (and insulin) action (Smith et al., 1986; McKee et al., 1988). 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, Boorman's Pathology of the Rat (Second Edition). Alpha cell hyperplasia also occurs in response to the impairment of glucagon signaling, both in mice and humans. Also, ablation of the glucagon receptor gene produces alteration in islet development and differentiation [36]. The loss of both the imidazole nitrogen and an aromatic ring as in [Pro1]glucagon amide reduced binding affinity to merely 10% that of the parent hormone and abolished all cyclase activity. Figure 35.8. • Glucagon receptor antagonists have the potential for use as monotherapy or in combination with other oral anti-hyperglycemic medications 29 Conclusions. However, the receptors involved in the body-lowering action of OXM are not fully delineated. Therapeutic strategies might involve treatment of diabetic individuals with a combination of, The forgotten members of the glucagon family, Metabolic Syndrome: Removing Road Blocks to Therapy. 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. 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. It is possible that differences interspecies may further complicate the interpretation of the mechanisms involved in the effects of OXM. There is a strong interest in therapies that will permit recovery of β-cell mass. 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. In response to extreme injury of beta cells alpha cells can transform (transdifferentiate) into functioning beta cells. Initial studies using semisynthetic [des-His1]glucagon, and later with a totally synthetic analog, as well as the presence of the negatively charged functional group of Asp9, led to speculations that an interaction of the negative Asp9 with positive His1 may constitute a part of the triggering mechanism at the molecular level (Unson et al., 1987). Some of the regenerative α cells may be positive immunohistochemically for both insulin and glucagon. From: Encyclopedia of Endocrine Diseases, 2004. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. As GLP-1 increases the proliferation and cytoprotection of beta cells, intra-islet paracrine signaling between injured beta cells and alpha cells might be a process designed to repair and regenerate beta cells that are reduced in diabetes. 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). The hyperplasia begins as β-cell hyperplasia, with increased fibrosis over time, eventually replacing much of the islet architecture. Hyperplasia of pancreatic islets occurs in old rats and hyperinsulinism may result, despite the fact that insulin secretion by individual cells is reduced. 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. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). Extensive structure–activity studies have been done on glucagon during the past 25 years (most recently reviewed by Hruby et al., 1986). Pancreatic Islet cell adenoma with cells arranged in cords or ribbons. Central role of ERK in β-cell regulation by glucagon and insulin. For example, activation of the expression of the prohormone convertase PC1/3 so as to preferentially form GLP-1 by the cleavage of proglucagon thereby promoting beta cell regeneration. Proliferation may decrease with age, but islet cell proliferation can still occur in aged rodents. Glucagon is a hormone produced by the pancreas that stimulates the liver to produce glucose (sugar). Taken together, these data suggest that OXM may engage additional receptors but that additional downstream pathways aside from cAMP may be involved [31]. In view of the recent cloning of the human glucagon receptor (vidé supra), it is likely that binding and in vitro cAMP assays with rat membranes will be supplemented or replaced using membranes containing the stably transfected human receptor. 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. Investigations from different laboratories using rodent models of islet cell injury report variable degrees of β-cell regeneration with similar or dissimilar mechanisms. These findings illustrate the essential importance of endogenous GLP-1 in the control of islet hormone secretion and gut motility. Die unten aufgezeichnete Sequenzierung erschloss 1956 William Wallis Bromer. Therefore, dopamine or dopamine receptor antagonists will increase prolactin secretion. GLP-2 exhibits trophic actions in the small intestine and colon (see Fig. Figure 35.12. 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. form deprivation, minus lens wear) and increased by conditions inhibiting eye growth (i.e. Glucose 6-phosphatase (G6Pase) catalyses the final reaction in hepatic glucose production by both gluconeogenesis and glycogenolysis, and has been proposed as a potential target for antihyperglycaemic drugs for type-2 diabetes.21,22 G6Pase gene expression is induced by both insulin deficiency and by hyperglycaemia.23 Accordingly, its expression is expected to increase in type-2 diabetes. Liraglutide appears to be slightly more effective in controlling blood glucose, compared with twice-daily exenatide, lixisenatide, or albiglutide.95 Most once-weekly GLP-1 receptor agonists appear to be better tolerated than the shorter-acting agonists. Pancreatic Islet cell adenoma with cells arranged in solid clusters. Chronic treatment with OXM resulted in superior body weight lowering and comparable glucose-lowering to equimolar amounts of OXMQ3E [46]. The corresponding d-amino acid replacements, however, resulted in virtually 90% loss of binding affinity and consequently adversely affected the cyclase activity. OXM also delayed gastric emptying in humans [53] but not in mice [48] adding a layer of complexity in interpreting receptors activated by OXM. When present, the metastases are usually in the liver or lung. 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. A recent report [57] demonstrated in rats that intracerebroventricular glucagon administration improves whole-body glucose metabolism. Spontaneous islet cell neoplasms are uncommon in the aging rat. 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. The physiologic importance of glucagon action has been examined after genetic or transient interruption of glucagon receptor expression. 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. Glucagon receptor antagonists are novel molecules that have demonstrated a reduction of plasma glucose and hemoglobin A1c in patients with type 2 diabetes in mid-stage clinical trials. Additional DPP-IV inhibitors, as well as DPP-IV-resistant analogs and naturally occurring incretin mimetics are being investigated in clinical trials.78. 4. Accumulations of hemosiderin-laden macrophages may accompany the fibrosis. Purified β-cells separated from α cells have a poor secretory response to glucose [39]. Recently, two publications [45,46] expanded the initial findings on the mechanism of action of OXM and demonstrated that OXM has glycogenolytic properties in perfused mice liver [46]. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. There are no definitive morphological criteria that accurately identify the biological nature of proliferative lesions of the islets of Langerhans, except for overt evidence of malignancy such as invasion and metastasis. However, Azizeh et al. Pancreatic islet cell adenoma with a few exocrine acini trapped near the periphery. 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. These neoplasms are discrete solitary nodules composed of interspersed, well-differentiated acinar cells and islet cells, often in nearly equal numbers (Figure 35.13). In der Vergangenheit wurde das Glucagon v. a. bei einem kardiogenen Schock angewende… 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. 3). Accordingly, a further major problem with G6Pase inhibitors is that they cause a large accumulation of glucose 6-phosphate.28–30 This perturbation of intracellular homeostasis of a pivotal allosteric regulator causes glycogen accumulation and induction of lipogenic genes, resulting in hepatic steatosis.29,31 G6Pase inhibition markedly increases the mRNA levels of various genes, including the Glut-2 transporter, glycogen synthase, the G6Pase catalytic subunit, and the T1 transporter, as well enzymes of glycolysis (pyruvate kinase) and lipogenesis (acetyl-coenzyme A carboxylase and fatty acid synthase), whilst suppressing glucokinase mRNA levels.28 These effects are most likely due to the role of glucose 6-phosphate in regulating gene expression.32 The induction of glycolytic and lipogenic enzymes predisposes to fatty liver. Thus, it appears that the complete or near complete glucagon sequence is needed for agonist and possibly for antagonist activities for glucagon. Islet cell hyperplasia, adenoma, and carcinoma comprise a morphological and biological continuum. Fig. Nevertheless these data are not conclusive as in the same study cpd A alone in feed resulted in significant body-weight reduction thereby limiting the interpretation of each receptor's contribution to the body weight-lowering effect of OXM [46]. G6Pase is located within the lumen of the endoplasmic reticulum, and transport of the substrate glucose 6-phosphate from the cytoplasm into the lumen is catalysed by a translocator (T1). 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. Eventually, enough β cells are lost in T2DM so that the animals develop insulin-dependent DM (IDDM). 1 Glucagon receptor antagonist I, at 50 mg/kg, reduces the increase in glucose levels observed after intraperitoneal administration of glucagon in humanized mice. It seems apparent that the side chain of position 9 is not directly involved in binding contacts but provides a major functional requirement for agonist activity. Glucagon receptor antagonists represent an avenue to decrease liver glucose production and lower the blood glucose of diabetic patients. 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. 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. Glucagon receptor antagonists are designed to lower plasma glucose levels by reducing the production of glucose by the liver. S9697 New: Semaglutide. Glucose competence may be restored by adding nM concentrations of glucagon [40]. Interestingly, though several earlier reports suggested that smaller fragments of glucagon could interact with the glucagon receptor to give agonist or partial antagonist activity (Hruby et al., 1986a), none of these earlier reports have held up to more recent critical scrutiny. Alpha cell hyperplasia also occurs in response to the impairment of glucagon signaling, both in mice and humans. Glucagon receptor antagonists are novel molecules that have demonstrated a reduction of plasma glucose and hemoglobin A1c in patients with type 2 … We use cookies to help provide and enhance our service and tailor content and ads. Unexpectedly, GLP-1, which, similarly to glucagon, stimulates cyclic AMP production, stimulates PKA and phosphorylates ERK, appears to skip the ERK step: Acute GLP-1 stimulation phosphorylates CREB in a non ERK-dependent manner, since the MEK inhibitor has no effect on CREB phosphorylation by GLP-1, while prolonged GLP-1 stimulation phosphorylates CREB in a β-arrestin-1-ERK-dependent manner. Of critical importance was the discovery of the importance of the Asp9 residue to glucagon activity when it was found that [des-His1, Glu9]glucagon and several related analogues (Unson et al., 1987, 1989) were antagonists, and that des-Phe6 analogues also were antagonists (Zechel et al., 1991). Spatially constrained histidine analogs, namely, containing 4,5,6,7-tetrahydro-1H-imidazo[c]pyridine-6-carboxylic acid (Tip), a constrained fused ring, show both reduced binding affinity and cyclase activity (Zechel et al., 1991). Glucagon receptor antagonists or antireceptor antibodies have the potential for treatment of T2DM due to their ability to decrease blood glucose and hepatic production of glucose. 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. As OXM agonizes GLP1R and GCGR in vitro [27–32] and because increases in heart rate and energy expenditure were reported following GCGR activation [56], the differential effect of OXM vs. GLP1 could be mediated by activation of the GCGR.
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