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

2017 ◽  
Vol 312 (5) ◽  
pp. R739-R752 ◽  
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.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

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.

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

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.

Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 β-cells

2004 ◽  
Vol 286 (2) ◽  
pp. E304-E310 ◽  
Author(s):  
Jianhua Shao ◽  
Liping Qiao ◽  
Jacob E. Friedman
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Late Pregnancy ◽  
Inhibitory Effect ◽  
Late Gestation ◽  
Intracellular Camp ◽  
Β Cell ◽  
Protein Levels ◽  
Glucose Stimulated Insulin Secretion ◽  
Camp Levels

Islet cells undergo major changes in structure and function to meet the demand for increased insulin secretion during pregnancy, but the nature of the hormonal interactions and signaling events is incompletely understood. Here, we used the glucose-responsive MIN6 β-cell line treated with prolactin (PRL), progesterone (PRG), and dexamethasone (DEX, a synthetic glucocorticoid), all elevated during late pregnancy, to study their effects on mechanisms of insulin secretion. DEX alone or combined with PRL and PRG inhibited insulin secretion in response to 16 mM glucose-stimulating concentrations. However, in the basal state (3 mM glucose), the insulin levels in response to DEX treatment were unchanged, and the three hormones together maintained higher insulin release. There were no changes of protein levels of GLUT2 or glucokinase (GK), but PRL or PRG treatment increased GK activity, whereas DEX had an inhibitory effect on GK activity. α-Ketoisocaproate (α-KIC)-stimulated insulin secretion was also reduced by DEX alone or combined with PRL and PRG, suggesting that DEX may inhibit distal steps in the insulin-exocytotic process. PRL treatment increased the concentration of intracellular cAMP in response to 16 mM glucose, suggesting a role for cAMP in potentiation of insulin secretion, whereas DEX alone or combined with PRL and PRG reduced cAMP levels by increasing phosphodiesterase (PDE) activity. These data provide evidence that PRL and to a lesser extent PRG, which increase in early pregnancy, enhance basal and glucose-stimulated insulin secretion in part by increasing GK activity and amplifying cAMP levels. Glucocorticoid, which increases throughout gestation, counteracts only glucose-stimulated insulin secretion under high glucose concentrations by dominantly inhibiting GK activity and increasing PDE activity to reduce cAMP levels. These adaptations in the β-cell may play an important role in maintaining the basal hyperinsulinemia of pregnancy while limiting the capacity of PRL and PRG to promote glucose-stimulated insulin secretion during late gestation.

scholarly journals Markers of Islet Endothelial Dysfunction Occur in Male B6.BKS(D)-Leprdb/J Mice and May Contribute to Reduced Insulin Release

Endocrinology ◽  
2016 ◽  
Vol 158 (2) ◽  
pp. 293-303 ◽  
Author(s):  
Meghan F. Hogan ◽  
Amy W. Liu ◽  
Michael J. Peters ◽  
Joshua R. Willard ◽  
Zaheen Rabbani ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Secretion ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
High Fat ◽  
Advanced Glycation ◽  
Β Cell ◽  
Protein Levels ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Abstract Islet endothelial cells produce paracrine factors that support β-cell function and growth. Endothelial dysfunction underlies diabetic microvascular complications; thus, we hypothesized that in diabetes, islet endothelial cells become dysfunctional, which may contribute to β-cell secretory dysfunction. Islets/islet endothelial cells were isolated from diabetic B6.BKS(D)-Leprdb/J male (db/db) mice, treated with or without the glucose-lowering agent phlorizin, or from C57BL/6J mice fed a high-fat diet for 18 weeks and appropriate controls. Messenger RNA (mRNA) and/or the protein levels of the cell adhesion molecule E-selectin (Sele), proinflammatory cytokine interleukin-6 (Il6), vasoconstrictor endothelin-1 (Edn1), and endothelial nitric oxide synthase (Nos3; Nos3) were evaluated, along with advanced glycation end product immunoreactivity. Furthermore, an islet endothelial cell line (MS-1) was exposed to diabetic factors (glucose, palmitate, insulin, and tumor necrosis factor-α) for six days. Conditioned media were collected from these cells, incubated with isolated islets, and glucose-stimulated insulin secretion and insulin content were assessed. Islet endothelial cells from db/db mice exhibited increased Sele, Il6, and Edn1 mRNA levels, decreased Nos3 protein, and accumulation of advanced glycation end products. Phlorizin treatment significantly increased Nos3 protein levels but did not alter expression of the other markers. High-fat feeding in C57BL/6J mice resulted in increased islet Sele, Il6, and Edn1 but no change in Nos3. Exposure of islets to conditioned media from MS-1 cells cultured in diabetic conditions resulted in a 50% decrease in glucose-stimulated insulin secretion and 30% decrease in insulin content. These findings demonstrate that, in diabetes, islet endothelial cells show evidence of a dysfunctional phenotype, which may contribute to loss of β-cell function.

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

2014 ◽  
Vol 29 (2) ◽  
pp. 671-683 ◽  
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

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

2013 ◽  
Vol 304 (4) ◽  
pp. E352-E362 ◽  
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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