Over the last decades, the prevalence of obesity and related diseases has increased rapidly in the Western world. Obesity is a disorder of energy balance and is associated with hyper-insulinemia, insulin resistance, and abnormalities in lipid metabolism, and it is one of the most important risk factors in the development of Type II diabetes, cardiovascular disease, atherosclerosis, and certain cancers. Because of the lower frequency of these diseases in Asian countries, attention has been turned toward the Asian diet, which consists highly of soy and soy-based products. The health benefits associated with soy consumption have been linked to the content of isoflavones, the main class of the phytoestrogens. As a result of their structural similarities to endogenous estrogens, isoflavones elicit weak estrogenic effects by competing with 17beta-estradiol (E2) for binding to the intranuclear estrogen receptors (ERs) and exert estrogenic or antiestrogenic effects in various tissues. The estrogenic activities of soy isoflavones are thought to play an important role in their health-enhancing properties. Additionally, the isoflavones have been proved to exert non-ER-mediated effects through numerous other pathways. Genistein, daidzein, and glycitein are the principal isoflavones in soy. Genistein is the most thoroughly examined of these, because it is the most prevalent isoflavone in soy and the most active of these compounds, because of its higher binding affinity for the ER. Genistein and daidzein can be obtained in high levels in humans under certain nutritional conditions, and epidemiologic and laboratory data suggest that these compounds could have health benefits in human obesity. This review will focus on the latest results of research on isoflavones and their effect on obesity in cell cultures, rodents, and humans.
Aims/hypothesisGlucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion. The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1 on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn is dependent on glucose levels.MethodsWe used the perfused mouse pancreas model to investigate this hypothesis.ResultsWe found that, in this model, GLP-1 was able to significantly inhibit glucagon secretion from pancreatic alpha cells at all glucose levels tested: 6.0, 1.5 and 0.5 mmol/l (−27.0%, −37.1%, and −23.6%, respectively), and the decrease in glucagon secretion was invariably accompanied by an increase in somatostatin secretion (+286.8%, +158.7%, and +118.8%, respectively). Specific blockade of somatostatin receptor 2 increased glucagon secretion (+118.8% at 1.5 mmol/l glucose and +162.9% at 6.0 mmol/l glucose) and completely eliminated the inhibitory effect of GLP-1.Conclusions/interpretationWe have shown here that the glucagon-lowering effect of GLP-1 is entirely mediated through the paracrine actions of somatostatin in the perfused mouse pancreas. However, in this model, the inhibitory effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists.
The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30–40% of all drug targets. During the last two decades, GPCR oligomerization has been extensively studied using methods like bioluminescence resonance energy transfer (BRET) and today, receptor–receptor interactions within the GPCR superfamily is a well-established phenomenon. Evidence of the impact of GPCR oligomerization on, e.g., ligand binding, receptor expression, and signal transduction indicates the physiological and pharmacological importance of these receptor interactions. In contrast to the larger and more thoroughly studied GPCR subfamilies A and C, the B1 subfamily is small and comprises only 15 members, including, e.g., the secretin receptor, the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality in family B1 GPCRs. One example of the functional effects of GPCR oligomerization is the facilitation of allosterism including cooperativity in ligand binding to GPCRs. Here, we review the currently available data on family B1 GPCR homo- and heteromerization, mainly based on BRET investigations. Furthermore, we cover the functional influence of oligomerization on ligand binding as well as the link between oligomerization and binding cooperativity.
In mice, the GLP-1 metabolite is eliminated within a few minutes owing to endoproteolytic cleavage by NEP 24.11. Therefore, accurate measurement of GLP-1 secretion in mice requires assays for NEP 24.11 metabolites. Conventional sandwich ELISAs are inadequate because of endoproteolytic cleavage of the dipeptidyl peptidase-4-generated metabolite.
Wewer Albrechtsen NJ, Kuhre RE, Windeløv JA, Ørgaard A, Deacon CF, Kissow H, Hartmann B, Holst JJ. Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes. Am J Physiol Endocrinol Metab 311: E302-E309, 2016. First published May 31, 2016 doi:10.1152/ajpendo.00119.2016.-Glucagon is a metabolically important hormone, but many aspects of its physiology remain obscure, because glucagon secretion is difficult to measure in mice and rats due to methodological inadequacies. Here, we introduce and validate a low-volume, enzyme-linked immunosorbent glucagon assay according to current analytical guidelines, including tests of sensitivity, specificity, and accuracy, and compare it, using the BlandAltman algorithm and size-exclusion chromatography, with three other widely cited assays. After demonstrating adequate performance of the assay, we measured glucagon secretion in response to intravenous glucose and arginine in anesthetized mice (isoflurane) and rats (Hypnorm/midazolam). Glucose caused a long-lasting suppression to very low values (1-2 pmol/l) within 2 min in both species. Arginine stimulated secretion 8-to 10-fold in both species, peaking at 1-2 min and returning to basal levels at 6 min (mice) and 12 min (rats). D-Mannitol (osmotic control) was without effect. Ketamine/xylazine anesthesia in mice strongly attenuated (P Ͻ 0.01) ␣-cell responses. Chromatography of pooled plasma samples confirmed the accuracy of the assay. In conclusion, dynamic analysis of glucagon secretion in rats and mice with the novel accurate sandwich enzyme-linked immunosorbent assay revealed extremely rapid and short-lived responses to arginine and rapid and profound suppression by glucose.␣-cell; islet biology; immunoassay; enzyme-linked immunosorbent assay GLUCAGON REGULATES BLOOD GLUCOSE by stimulating hepatic glucose production (3). Importantly, elevated fasting and postprandial glucagon levels in patients with type 2 diabetes contribute to the hyperglycemia of these patients as demonstrated clearly using specific antagonists of the glucagon receptor (13). However, regulation of glucagon secretion has only been incompletely characterized, due partly to technical limitations with regard to its quantification (volume requirements, inadequate specificity, and accuracy) using current immune-based detection methods: radioimmunoassay (RIA) and enzyme-linked immunosorbent assays (ELISA) (7,8,16,18,22).Here, we introduce a novel low-volume sandwich ELISA that exclusively detects fully processed pancreatic glucagon, corresponding to proglucagon-(33-61) (see Fig. 1), and use it to characterize the dynamics of glucagon secretion in mice and rats in response to intravenous injections of L-arginine, D-glucose, and D-mannitol. By extensive assay validation, we conclude that the applied assay is reliable for measurements of glucagon in small plasma volumes. Because of this technical advance, we were able to make reliable real-time estimates of glucagon secretion (in vivo) in mice and rats. Our...
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