Impaired Glucose-Stimulated Insulin Secretion, Enhanced Intraperitoneal Insulin Tolerance, and Increased β-Cell Mass in Mice Lacking the p110γ Isoform of Phosphoinositide 3-Kinase

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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Bioactive Phytochemicals Isolated from Akebia quinata Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1

Plants ◽

10.3390/plants9091087 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1087

Author(s):

Dahae Lee ◽

Jin Su Lee ◽

Jurdas Sezirahiga ◽

Hak Cheol Kwon ◽

Dae Sik Jang ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Experimental Studies ◽

Pancreatic Β Cell ◽

Β Cell ◽

Etoh Extract ◽

Chemical Structures ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion ◽

Phosphoinositide 3 Kinase

Chocolate vine (Akebia quinata) is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of A. quinata, a phytosterol glucoside stigmasterol-3-O-β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of A. quinata (AKQU). The chemical structures of isolates 1–7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1–7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3-O-β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3-O-β-d-glucoside (1) isolated from the fruits of A. quinata can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.

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Exocytosis proteins as novel targets for diabetes prevention and/or remediation?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00002.2017 ◽

2017 ◽

Vol 312 (5) ◽

pp. R739-R752 ◽

Cited By ~ 12

Author(s):

Arianne Aslamy ◽

Debbie C. Thurmond

Keyword(s):

Insulin Secretion ◽

Glucose Uptake ◽

Cell Mass ◽

Β Cell ◽

Protein Levels ◽

Receptor Complexes ◽

Metabolic Dysregulation ◽

Protein Receptor ◽

The Us ◽

Glucose Stimulated Insulin Secretion

Diabetes remains one of the leading causes of morbidity and mortality worldwide, affecting an estimated 422 million adults. In the US, it is predicted that one in every three children born as of 2000 will suffer from diabetes in their lifetime. Type 2 diabetes results from combinatorial defects in pancreatic β-cell glucose-stimulated insulin secretion and in peripheral glucose uptake. Both processes, insulin secretion and glucose uptake, are mediated by exocytosis proteins, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, Sec1/Munc18 (SM), and double C2-domain protein B (DOC2B). Increasing evidence links deficiencies in these exocytosis proteins to diabetes in rodents and humans. Given this, emerging studies aimed at restoring and/or enhancing cellular levels of certain exocytosis proteins point to promising outcomes in maintaining functional β-cell mass and enhancing insulin sensitivity. In doing so, new evidence also shows that enhancing exocytosis protein levels may promote health span and longevity and may also harbor anti-cancer and anti-Alzheimer’s disease capabilities. Herein, we present a comprehensive review of the described capabilities of certain exocytosis proteins and how these might be targeted for improving metabolic dysregulation.

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Spontaneous restoration of functional β-cell mass in obese SM/J mice

10.1101/2020.05.19.104588 ◽

2020 ◽

Author(s):

Mario A Miranda ◽

Caryn Carson ◽

Celine L St Pierre ◽

Juan F Macias-Velasco ◽

Jing W Hughes ◽

...

Keyword(s):

Insulin Secretion ◽

Mitotic Index ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Physiological Mechanisms ◽

Β Cell Function ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion ◽

Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

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Anti-Diabetic Activities of Gastrodia elata Blume Water Extracts Are Mediated Mainly by Potentiating Glucose-Stimulated Insulin Secretion and Increasing β-Cell Mass in Non-Obese Type 2 Diabetic Animals

Nutrients ◽

10.3390/nu8030161 ◽

2016 ◽

Vol 8 (3) ◽

pp. 161 ◽

Cited By ~ 10

Author(s):

Hye Yang ◽

Min Kim ◽

Dae Kwon ◽

Da Kim ◽

Young Lee ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Mass ◽

Β Cell ◽

Gastrodia Elata ◽

Water Extracts ◽

Gastrodia Elata Blume ◽

Glucose Stimulated Insulin Secretion ◽

Type 2 Diabetic

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Retinoic acid receptor signaling is required to maintain glucose‐stimulated insulin secretion and β‐cell mass

The FASEB Journal ◽

10.1096/fj.14-256743 ◽

2014 ◽

Vol 29 (2) ◽

pp. 671-683 ◽

Cited By ~ 21

Author(s):

Pierre‐Jacques Brun ◽

Ambar Grijalva ◽

Richard Rausch ◽

Elizabeth Watson ◽

Jason J. Yuen ◽

...

Keyword(s):

Insulin Secretion ◽

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Cell Mass ◽

Receptor Signaling ◽

Β Cell ◽

Acid Receptor ◽

Glucose Stimulated Insulin Secretion

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Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. E352-E362 ◽

Cited By ~ 15

Author(s):

Monika M. Gadhia ◽

Anne M. Maliszewski ◽

Meghan C. O'Meara ◽

Stephanie R. Thorn ◽

Jinny R. Lavezzi ◽

...

Keyword(s):

Amino Acids ◽

Insulin Secretion ◽

Amino Acid ◽

Cell Mass ◽

Late Gestation ◽

Insulin Content ◽

Acid Mixture ◽

Β Cell ◽

Fetal Sheep ◽

Glucose Stimulated Insulin Secretion

Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10–14 days during late gestation to target a 25–50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group ( P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) ( P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group ( P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell.

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