Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob ( Ghrelin−/−: ob/ ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ ob mice ( Ghsr−/−: ob/ ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ ob mice did not affect the islet size; the average islet size of Ghsr−/−: ob/ ob mice is similar to that of ob/ ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

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Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00531.2011 ◽

2012 ◽

Vol 303 (6) ◽

pp. E752-E761 ◽

Cited By ~ 24

Author(s):

Kathryn D. Henley ◽

Kimberly A. Gooding ◽

Aris N. Economides ◽

Maureen Gannon

Keyword(s):

Insulin Secretion ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Cell Function ◽

Metabolic Stress ◽

Islet Function ◽

High Fat ◽

Β Cell ◽

Β Cell Function ◽

Bmp Pathway

Current endeavors in the type 2 diabetes (T2D) field include gaining a better understanding of extracellular signaling pathways that regulate pancreatic islet function. Recent data suggest that both Bmp and Wnt pathways are operative in pancreatic islets and play a positive role in insulin secretion and glucose homeostasis. Our laboratory found the dual Bmp and Wnt antagonist Sostdc1 to be upregulated in a mouse model of islet dysmorphogenesis and nonimmune-mediated lean diabetes. Because Bmp signaling has been proposed to enhance β-cell function, we evaluated the role of Sostdc1 in adult islet function using animals in which Sostdc1 was globally deleted. While Sostdc1-null animals exhibited no pancreas development phenotype, a subset of mutants exhibited enhanced insulin secretion and improved glucose homeostasis compared with control animals after 12-wk exposure to high-fat diet. Loss of Sostdc1 in the setting of metabolic stress results in altered expression of Bmp-responsive genes in islets but did not affect expression of Wnt target genes, suggesting that Sostdc1 primarily regulates the Bmp pathway in the murine pancreas. Furthermore, our data indicate that removal of Sostdc1 enhances the downregulation of the closely related Bmp inhibitors Ctgf and Gremlin in islets after 8-wk exposure to high-fat diet. These data imply that Sostdc1 regulates expression of these inhibitors and provide a means by which Sostdc1-null animals show enhanced insulin secretion and glucose homeostasis. Our studies provide insights into Bmp pathway regulation in the endocrine pancreas and reveal new avenues for improving β-cell function under metabolic stress.

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Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

10.2337/figshare.14666160.v1 ◽

2021 ◽

Author(s):

Casey J. Bauchle ◽

Kristen E. Rohli ◽

Cierra K. Boyer ◽

Vidhant Pal ◽

Jonathan V. Rocheleau ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Islet ◽

Glucose Homeostasis ◽

Cell Function ◽

Normal Glucose Tolerance ◽

Coupling Factor ◽

Β Cell ◽

Metabolic Coupling ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC to glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout mice and demonstrate these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme, cytosolic isocitrate dehydrogenase, Idh1, inhibited insulin secretion in wild type islets, but failed to impact β-cell function in β-cell CIC KO islets.<b> </b>Our data demonstrate that the mitochondrial citrate-isocitrate carrier is not required for glucose-stimulated insulin secretion, and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.

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Impaired glucose homeostasis in Shb−/− mice

Journal of Endocrinology ◽

10.1677/joe-09-0198 ◽

2009 ◽

Vol 203 (2) ◽

pp. 271-279 ◽

Cited By ~ 10

Author(s):

Björn Åkerblom ◽

Sebastian Barg ◽

Gabriela Calounova ◽

Dariush Mokhtari ◽

Leif Jansson ◽

...

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Blood Glucose ◽

Endothelial Cell ◽

Glucose Homeostasis ◽

Glucose Concentration ◽

Cell Function ◽

Blood Glucose Concentration ◽

Β Cell ◽

Islet Volume

Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of β-cell and endothelial cell function. We have recently obtained the Shb knockout mouse, and consequently, the aim of this study was to assess the effect of Shb deletion upon β-cell function and blood glucose homeostasis. Shb−/− mice display an elevated basal blood glucose concentration, and this increase is maintained during insulin challenge in insulin sensitivity tests. To assess glucose-induced insulin secretion, pancreata were perfused, and it was observed that Shb−/− first phase insulin secretion was blunted during glucose stimulation. Gene expression of Shb−/− islets shortly after isolation was altered, with increased pancreatic and duodenal homeobox gene-1 (Pdx1) gene expression and reduced expression of Vegf-A. Islet culture normalized Pdx1 gene expression. The microvascular density of the Shb−/− islets was reduced, and islet capillary endothelial cell morphology was changed suggesting an altered microvascular function as a contributing cause to the impaired secretory activity. Capacitance measurements of depolarization-induced exocytosis indicate a direct effect on the exocytotic machinery, in particular a dramatic reduction in readily releasable granules, as responsible for the insulin-secretory defect operating in Shb−/− islets. Shb−/− mice exhibited no alteration of islet volume or β-cell area. In conclusion, loss of Shb impairs insulin secretion, alters islet microvascular morphology, and increases the basal blood glucose concentration. The impaired insulin secretory response is a plausible underlying cause of the metabolic impairment observed in this mutant mouse.

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The role of ghrelin in the regulation of glucose homeostasis

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2016-0018 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 14

Author(s):

Bader N. Alamri ◽

Kyungsoo Shin ◽

Valerie Chappe ◽

Younes Anini

Keyword(s):

Insulin Resistance ◽

Insulin Release ◽

Glucose Homeostasis ◽

Energy Homeostasis ◽

Endocrine Pancreas ◽

Distinct Group ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor ◽

Glucose Plasma

AbstractGhrelin is a 28-amino acid (aa) stomach-derived peptide discovered in 1999 as the endogenous ligand for growth hormone secretagogue-receptor (GHS-R). Ghrelin-producing cells constitute a distinct group of endocrine cells dispersed throughout the gastric mucosa and to a lesser extent in the small intestine and the endocrine pancreas. Ghrelin plasma levels rise during fasting and chronic caloric restriction to stimulate food intake and fat storage and to prevent life-threatening falls in blood glucose. Plasma ghrelin levels decrease after a meal is consumed and in conditions of energy surplus (such as obesity). Ghrelin has emerged as a key player in the regulation of appetite and energy homeostasis. Ghrelin achieves these functions through binding the ghrelin receptor GHS-R in appetite-regulating neurons and in peripheral metabolic organs including the endocrine pancreas. Ghrelin levels are negatively correlated with body mass index (BMI) and insulin resistance. In addition, ghrelin secretion is impaired in obesity and insulin resistance. Several studies highlight an important role for ghrelin in glucose homeostasis. Genetic, immunological, and pharmacological blockade of ghrelin signaling resulted in improved glucose tolerance and insulin sensitivity. Furthermore, exogenous ghrelin administration was shown to decrease glucose-induced insulin release and increase glucose level in both humans and rodents. GHS-R was shown to be expressed in pancreatic β-cells and ghrelin suppressed insulin release via a Ca

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A crosstalk between E2F1 and GLP-1 signaling pathways modulates insulin secretion

10.1101/2021.04.16.440172 ◽

2021 ◽

Author(s):

Cyril Bourouh ◽

Emilie Courty ◽

Gianni Pasquetti ◽

Xavier Gromada ◽

Nabil Rabhi ◽

...

Keyword(s):

Insulin Secretion ◽

Signaling Pathways ◽

Glucose Homeostasis ◽

Transcriptional Activity ◽

Cell Function ◽

Cell Mass ◽

Mass Function ◽

Β Cell ◽

Cell Functions ◽

Β Cell Function

AbstractCompromised β-cell function contributes to type 2 diabetes (T2D) development. The glucagon like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential toward T2D treatment, notably by improving β-cell functions. Recent data have shown that the transcription factor E2f1, besides its role as a cell cycle regulator, is involved in glucose homeostasis by modulating β-cell mass, function and identity. Here, we demonstrate a crosstalk between the E2F1, phosphorylation of retinoblastoma protein (pRb) and Glp-1 signaling pathways. We found that β-cell specific E2f1 deficient mice (E2f1β−/−) presented with impaired glucose homeostasis and decreased glucose stimulated-insulin secretion mediated by exendin 4 (i.e., GLP1R agonist), which were associated with decreased expression of Glp1r encoding Glp-1 receptor (GLP1R) in E2f1β−/− pancreatic islets. Decreasing E2F1 transcriptional activity with an E2F inhibitor in islets from nondiabetic humans decreased GLP1R levels and blunted the incretin effect of exendin 4 on insulin secretion. Conversely, overexpressing E2f1 in pancreatic β cells increased Glp1r expression associated with enhanced insulin secretion mediated by GLP1R agonist. Interestingly, kinome analysis of mouse islets demonstrated that an acute treatment with exendin 4 increased pRb phosphorylation and subsequent E2f1 transcriptional activity. This study suggests a molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways that modulates insulin secretion and glucose homeostasis.

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Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

10.2337/figshare.14666160 ◽

2021 ◽

Author(s):

Casey J. Bauchle ◽

Kristen E. Rohli ◽

Cierra K. Boyer ◽

Vidhant Pal ◽

Jonathan V. Rocheleau ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Islet ◽

Glucose Homeostasis ◽

Cell Function ◽

Normal Glucose Tolerance ◽

Coupling Factor ◽

Β Cell ◽

Metabolic Coupling ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

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β Cell GHS-R Regulates Insulin Secretion and Sensitivity

International Journal of Molecular Sciences ◽

10.3390/ijms22083950 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3950

Author(s):

Geetali Pradhan ◽

Chia-Shan Wu ◽

Daniel Villarreal ◽

Jong Han Lee ◽

Hye Won Han ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Pancreatic Islets ◽

Glucose Homeostasis ◽

Fluorescent Protein ◽

Therapeutic Potential ◽

Fasting Blood Glucose ◽

Β Cell ◽

Growth Hormone Secretagogue ◽

Isolated Pancreatic Islets

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

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Phenolic-enriched blueberry-leaf extract attenuates glucose homeostasis, pancreatic β-cell function, and insulin sensitivity in high-fat diet–induced diabetic mice

Nutrition Research ◽

10.1016/j.nutres.2019.09.005 ◽

2020 ◽

Vol 73 ◽

pp. 83-96 ◽

Cited By ~ 5

Author(s):

Hua Li ◽

Hye-Mi Park ◽

Hyeon-Seon Ji ◽

Jisu Han ◽

Sang-Kyum Kim ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Leaf Extract ◽

Cell Function ◽

Pancreatic Β Cell ◽

Diabetic Mice ◽

High Fat ◽

Β Cell ◽

Β Cell Function

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Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22052397 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2397

Author(s):

Chrysostomos Charalambous ◽

Tereza Havlickova ◽

Marek Lapka ◽

Nina Puskina ◽

Romana Šlamberová ◽

...

Keyword(s):

Conditioned Place Preference ◽

Fixed Ratio ◽

Place Preference ◽

Self Administration ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor ◽

Addiction Therapy ◽

Significant Efficacy ◽

Lever Pressing

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

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