scholarly journals A Role for Intestinal Endocrine Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Peptide Release

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2038-2047 ◽  
Author(s):  
Zhi-Liang Chu ◽  
Chris Carroll ◽  
Jean Alfonso ◽  
Veronica Gutierrez ◽  
Hongmei He ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Oral Glucose ◽  
Hormone Release ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Incretin Hormone ◽  
Glucagon Like Peptide ◽  
Insulinotropic Peptide ◽  
G Protein Coupled

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic β-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9–39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic β-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.

scholarly journals Critical Role of Egr Transcription Factors in Regulating Insulin Biosynthesis, Blood Glucose Homeostasis, and Islet Size

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3040-3053 ◽  
Author(s):  
Isabelle Müller ◽  
Oliver G. Rössler ◽  
Christine Wittig ◽  
Michael D. Menger ◽  
Gerald Thiel
Keyword(s):  
Transcription Factors ◽  
Glucose Tolerance ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Size

Expression of early growth response protein (Egr)-1, a protein of the Egr family of zinc finger transcription factors, is stimulated in glucose-treated pancreatic β-cells and insulinoma cells. The purpose of this study was to elucidate the role of Egr transcription factors in pancreatic β-cells in vivo. To overcome the problem associated with redundancy of functions between Egr proteins, conditional transgenic mice were generated expressing a dominant-negative mutant of Egr-1 in pancreatic β-cells. The Egr-1 mutant interferes with DNA binding of all Egr proteins and thus impairs the biological functions of the entire Egr family. Expression of the Egr-1 mutant reduced expression of TGFβ and basic fibroblast growth factor, known target genes of Egr-1, whereas the expression of Egr-1, Egr-3, Ets-like gene-1 (Elk-1), and specificity protein-3 was not changed in the presence of the Egr-1 mutant. Expression of the homeobox protein pancreas duodenum homeobox-1, a major regulator of insulin biosynthesis, was reduced in islets expressing the Egr-1 mutant. Accordingly, insulin mRNA and protein levels were reduced by 75 or 25%, respectively, whereas expression of glucagon and somatostatin was not altered after expression of the Egr-1 mutant in β-cells. Glucose tolerance tests revealed that transgenic mice expressing the Egr-1 mutant in pancreatic β-cells displayed impaired glucose tolerance. In addition, increased caspase-3/7 activity was detected as a result of transgene expression, leading to a 20% decrease of the size of the islets. These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic β-cells in vivo.

scholarly journals Theoretical Modeling of Oral Glucose Tolerance Tests Guides the Interpretation of the Impact of Perinatal Cadmium Exposure on the Offspring’s Glucose Homeostasis

Toxics ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 30
Author(s):  
Alexandre Rocca ◽  
Eric Fanchon ◽  
Jean-Marc Moulis
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Least Square ◽  
Glucose Turnover ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Β Cells ◽  
Oral Glucose Tolerance Tests ◽  
Glucose Tolerance Tests ◽  
The Impact

Oral glucose tolerance tests, in which the concentration of glucose is monitored in the circulation over 2 h after ingesting a bolus, probe diabetic or pre-diabetic conditions. The resulting glucose curves inform about glucose turnover, insulin production and sensitivity, and other parameters. However, extracting the relevant parameters from a single complex curve is not straightforward. We propose a simple modeling method recapitulating the most salient features of the role of insulin-secreting pancreatic β -cells and insulin sensitive tissues. This method implements four ordinary differential equations with ten parameters describing the time-dependence of glucose concentration, its removal rate, and the circulating and stored insulin concentrations. From the initial parameter set adjusted to a reference condition, fitting is done by minimizing a weighted least-square residual. In doing so, the sensitivity of β -cells to glucose was identified as the most likely impacted function at weaning for the progeny of rats that were lightly exposed to cadmium in the perigestational period. Later in life, after young rats received non-contaminated carbohydrate enriched food, differences are more subtle, but modeling agrees with long-lasting perturbation of glucose homeostasis.

scholarly journals Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ionel Sandovici ◽  
Constanze M. Hammerle ◽  
Sam Virtue ◽  
Yurena Vivas-Garcia ◽  
Adriana Izquierdo-Lahuerta ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Chow Diet ◽  
Genome Wide Association Studies ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

scholarly journals Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR‐29 family

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Jing Li ◽  
Yujing Zhang ◽  
Yangyang Ye ◽  
Dameng Li ◽  
Yuchen Liu ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Pharmacological potential of methanol extract of Anacardium occidentale stem bark on alloxan-induced diabetic rats

2018 ◽  
Vol 5 (7) ◽  
pp. 2440-2454
Author(s):  
D. A. Omoboyowa ◽  
F. O. Afolabi ◽  
T. C. Aribigbola
Keyword(s):  
Blood Glucose ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Methanol Extract ◽  
Stem Bark ◽  
Tolerance Test ◽  
Diabetic Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Β Cells

Background: The anti-hyperglycemic potential of methanol stem bark extract of Anacardium occidentale (MSBEAO) was investigated using an alloxan-induced diabetic rat model. Alloxan administration induces the generation of free radicals which can affect antioxidant status resulting in the disruption of the β-cells of the pancreas. Therefore, this study examines the antioxidant potential of the plant extract and the ameliorating effect on the pancreas of alloxan-induced diabetic rats. Methods: Diabetes was induced by intraperitoneal injection of 150 mg/kg body weight of alloxan monohydrate. MSBEAO, at a concentration of 100 or 200 mg/kg b.w. was orally administered to alloxan-induced diabetic rats and normal rats. The hypoglycemic effect, oral glucose tolerance test, and biochemical assay of alloxan-induced diabetic rats were assayed using standard procedures. Results: Preliminary phytochemical screening of the extract revealed the presence of alkaloids, tannins, saponins, terpenoids, carbohydrates, and phenols at moderate concentrations. The lethality dose (LD50) of the plant extract was found to be equal to or less than 5000 mg/kg b.w. The hypoglycemic effect of the extract on the non-diabetic rats revealed a significant (p<0.05) decrease in the blood glucose concentration of animals administered with 1 g/kg b.w. of the extract, compared to normal control rats administered with normal saline. In the oral glucose tolerance test, the methanol extract exerted the highest response, similar to glibenclamide after 15 and 30 minutes of administration, compared to the control rats. The methanol extract yielded the highest blood glucose lowering effects after 9 days of treatment (p<0.05), compared to diabetic rats administered with normal saline and 0.3 mg/kg b.w. of glibenclamide. Administration of the extract at 200 mg/kg b.w. showed improved pancreas architecture and regeneration of the β-cells, compared with the pancreas of animals in the other groups. Conclusion: The results of this study suggest that MSBEAO is a potentially effective agent for the management of diabetes which might result from the antioxidant-generating capacity of the stem bark.

scholarly journals G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients

2018 ◽  
Vol 10 (1) ◽  
pp. 84-93 ◽  
Author(s):  
Hirotaka Watada ◽  
Masanari Shiramoto ◽  
Shin Irie ◽  
Yasuo Terauchi ◽  
Yuichiro Yamada ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
G Protein Coupled
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