β-catenin activation and illicit receptor expression in adrenocortical cells

Adrenal cortisol-producing tumors can express illicit membrane receptors such as luteinizing hormone (LH), glucose-dependent insulinotropic peptide (GIP) or type 4 and 7 serotonin (5-HT4/7) receptors. Abnormal expression of the LH receptor (LH-R) has been ascribed to activation of the Wnt/β-catenin signaling pathway in adrenocortical cells. In the present study, we have investigated whether β-catenin activation may also trigger illegitimate expression of GIP and 5-HT receptors. Three models of β-catenin activation in adrenocortical cells were used: an APC-mutated adrenocortical tumor, human transfected adrenocortical cells and genetically modified mouse adrenal glands. The methods employed included RT-qPCR, immunohistochemistry, and measurement of cortisol secretion by cultured tumor cells. Abnormal expression of the GIP, 5-HT7 and LH receptors was observed in the APC-mutated adrenocortical tumor tissue. In addition, GIP, 5-HT and hCG stimulated cortisol production from tumor cells in primary culture. Conversely, only the LHCGR was upregulated in human and mouse adrenocortical cells harboring activation of β-catenin. Moreover, LH-R immunoreactivity was detected in clusters of zona fasciculata cells in the β-catenin-activated mouse model. Our data indicate that activation of the β-catenin signaling pathway can promote illicit expression of functional LH receptors in adrenal zona fasciculata cells but does not favor abnormal expression of GIP and 5-HT receptors.

Abstract P196: Exacerbation Of Postural Tachycardia Syndrome After An Oral Glucose Challenge: Role Of Incretins

Postural Tachycardia Syndrome (POTS) is characterized by excessive upright tachycardia and disabling pre-syncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal. The purpose of this study is to investigate the effect of oral glucose on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. We studied 12 women with POTS and 13 age-matched controls, all subjects received 75-gr oral glucose and 20 mg/kg acetaminophen for nutrient absorption measurement. Hemodynamic, GI hormone secretion and acetaminophen levels were measured at different time-points up to 120-min post-ingestion and while supine and standing. POTS patients had significant upright tachycardia ( delta HR: 48.7 ± 11.2 vs. 23.3 ± 8.1 bpm, P=0.012) and norepinephrine levels (835.2 ± 368.4 vs. 356.9 ± 156.7 pg/mL, P= 0.004). After oral glucose, upright HR significantly increased in POTS (92±15.5 vs. 112± 26 bpm, P=0.002) with a concomitant decline in upright stroke volume (P=0.027); total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707). POTS patients had increased secretion of C-peptide (P=0.001), Glucose Dependent Insulinotropic Peptide (GIP) (P=0.001), peptide YY (P=0.016) and pancreatic polypeptide (P=0.04), but not GLP-1 (p=0.658) or Glucagon (P=0.836). Only GIP had a time-dependent association with the worsening upright tachycardia and SV fall, figure. Conclusions: Oral glucose exacerbated upright tachycardia in POTS, which was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, is being maximally secreted.

Medikamentöse Adipositastherapie – Chancen und Perspektiven

ZusammenfassungMedikamentöse Therapiestrategien sind dringend erforderlich, um Adipositas-assoziierte Begleiterkrankungen langfristig reduzieren und verhindern zu können. Mit einer Gewichtsabnahme um 10% kann bereits eine Reduktion kardiovaskulärer Endpunkte erreicht werden. Als medikamentöse Therapieoption stehen aktuell in Deutschland der Lipaseinhibitor Orlistat sowie der GLP-1 Rezeptor-Agonist (GLP-1RA) Liraglutid zur medikamentösen Langzeittherapie der Adipositas zur Verfügung. Perspektivisch könnten zukünftig noch weitere Therapieoptionen zur Verfügung stehen, mit denen eine effektive Gewichtsreduktion erzielt werden kann. Semaglutid ist bereits als GLP-1RA zur Therapie des Typ 2 Diabetes zugelassen und zeigt, neben einer effektiven HbA1c-Senkung, eine deutliche Gewichtsreduktion. Im Fokus aktueller Adipositasforschung stehen zudem die Multi-Agonisten auf GLP-1-Basis, die balanziert an Rezeptoren mehrerer gastrointestinaler Peptide binden. So zeigen klinische Studien bspw. mit einem dualen Agonisten aus GLP1 und GIP (Glucose-dependent insulinotropic peptide) vielversprechende Körpergewichts-reduzierende Effekte. Weitere Forschungsansätze medikamentöser Therapieoptionen zur Gewichtsreduktion basieren u. a. auf Glukagon-Analoga, PYY und Amylin, aber auch auf Kombinationstherapien wie Leucin-Metformin-Sildenafil. Neben einer Verringerung der Nahrungsaufnahme werden derzeit zudem Therapieansätze zur Steigerung des Energieumsatzes, z. B. über die Aktivierung des braunen Fettgewebes, intensiv beforscht. In diesem Übersichtsartikel werden aktuelle sowie mögliche zukünftige Therapieoptionen zur Gewichtsreduktion in der Therapie der Adipositas zusammengefasst.

Potential for Gut Peptide-Based Therapy in Postprandial Hypotension

Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.

DIFFERENTIAL EFFECTS OF BILE ACIDS ON THE POST-PRANDIAL SECRETION OF GUT HORMONES: a randomised crossover study

AIMS Bile acids (BA) regulate post-prandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The post-prandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effect of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on post-prandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon and ghrelin. METHODS Twelve healthy volunteers underwent a mixed meal test 60 minutes after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg) or no BA in a randomised cross-over study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin and fibroblast growth factor 19 were measured prior to BA administration at -60, 0 (just prior to mixed meal) and 15, 30, 60, 120, 180 and 240 minutes after the meal. RESULTS UDCA and CDCA provoked differential gut hormone responses: UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced post-prandial secretion of GIP, with an associated reduction in post-prandial insulin secretion. CONCLUSIONS Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmedin obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.

Co-Purification of Recombinant Modified Glucagon-Like and Glucose-Dependent Insulinotropic Peptide to Create a Two-Component Drug for the Treatment of Type 2 Diabetes Mellitus and Obesity

In addition to the previously developed recombinant modified human glucagon-like peptide 1 (rmglp1, Glypin), a recombinant modified human glucose-dependent insulinotropic peptide (RMGIP) has been obtained. A new universal reverse-phase HPLC technique has been proposed allowing quantitative analysis of rmGlp1 and rmGip separately and as part of a two-component preparation. The data show that the design of recombinant human rmGip according to the Glypine formula makes it possible to produce one-component and two-component preparations containing various rmGip and rmGlp1 protein ratios ranging from 1:0 to 20:1, using cell biomass samples mixed in predetermined proportions. Studies of human rmGip activity in a mouse model revealed reduced specific activity and signs of weak antagonistic effects. In this regard, there is a need for further study of human rmGip activity in a mouse model, including the use of alternative mouse or rat rmGip. type 2 diabetes mellitus; two-component drug, glucose-dependent insulinotropic peptide, glucagon-like peptide-1 The work was supported by the Internal Grant from National Research Center Kurchatov Institute.

Relationship Between GIP Receptor Gene Polymorphism rs10423928 and Bone Mineral Density in Postmenopausal Women in Shanghai

Background: GIP (glucose-dependent insulinotropic peptide) has been found to affect bone metabolism. GIPR single nucleotide polymorphism (SNP) is related to its activity, but the relationship between GIPR SNP and osteoporosis in postmenopausal women is still unclear. The Aim of this study was to investigate the association between GIPR SNP and bone mineral density (BMD) in postmenopausal women in Shanghai.Methods: GIP SNP rs10423928 was detected in 884 postmenopausal women in Shanghai. The correlation between GIPR SNP and BMD was further assessed.Results: There was a statistical difference between the dominant model of this site rs10423928 and the bone mineral density of the femoral neck (P = 0.035) and the Wards triangle area (P = 0.033). Conclusions: The rs10423928 of GIPR is related to the BMD of postmenopausal women in Shanghai, China.

Glucose-dependent insulinotropic peptide in the high normal range is associated with increased carotid intima-media thickness

<b>Objective:</b> While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide-1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease.. We investigated the associations between fasting and post-challenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by intima-media thickness in the common carotid artery (IMT_meanCCA), and intima-media thickness in the carotid bifurcation (IMT_maxBulb). <p><b>Research design and methods: </b>Participants at re-examination within the Malmö Diet and Cancer cardiovascular cohort study (n=3734, mean age 72.5 years; 59.3% women; 10.8% subjects with diabetes; fasting GIP available for 3342 subjects; fasting GLP-1 available for 3299 subjects) underwent oral glucose tolerance testing and carotid ultrasound. </p> <p><b>Results: </b>In linear regression analyses, each 1 SD increment of fasting GIP was associated with increased (per mm) IMT_meanCCA (β=0.010, p=0.010) and IMT_maxBulb (β=0.014; p=0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1 SD increment of fasting GLP-1 was associated with decreased IMT_maxBulb (per mm; β=-0.016, p=0.014). These associations remained significant when subjects with diabetes were excluded from analyses. </p> <p><b>Conclusion </b>In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMT_meanCCA, while GLP-1 is associated with decreased IMT_maxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.</p>