scholarly journals Amylin-mediated regulation of LRP1 by miR-103/107 induces cerebral microvascular dysfunction and impairs β-amyloid efflux

2020 ◽  
Author(s):  
Gopal Velmurugan ◽  
Han Ly ◽  
Savita Sharma ◽  
Nirmal Verma ◽  
Sanda Despa ◽  
...  
Keyword(s):  
Cell Monolayer ◽  
Amyloid Β ◽  
Microvascular Dysfunction ◽  
Blood Levels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Cerebral Microvessels ◽  
In Vitro Bbb Model ◽  
Human Amylin

Abstract Background: The cerebral small blood vessels of individuals with Alzheimer’s Disease (AD) often have deposits of amylin, an amyloid-forming protein secreted in the blood by pancreatic β-cells. To determine whether systemic pancreatic amylin dyshomeostasis impairs amyloid β (Aβ) efflux across the blood-brain barrier (BBB), we studied cerebral microvessels in humans and rats with pancreatic expression of amyloidogenic human amylin, and evaluated the effect of human amylin in an in vitro BBB model. Methods: Brain sections from AD and cognitively unimpaired individuals were co-stained with anti-Aβ and anti-amylin antibodies. In vivo analyses of Aβ efflux across the BBB were carried out in aged rats that express amyloid-forming human amylin in pancreatic β-cells and littermates expressing non-amyloidogenic rat amylin. We also used an in vitro BBB model of Aβ transcytosis in which the endothelial cell monolayer was exposed to amylin-mediated stress to determine whether amylin stress downregulates LRP1, the Aβ efflux transporter. This allowed us to use pharmacology to rescue the endothelial LRP1. Results: In human AD brains, Aβ accumulation within the perivascular space frequently co-localized with deposits of amylin in the vessel wall. In rats with pancreatic expression of amyloid-forming human amylin, the high blood levels of human amylin promoted amylin deposition in brain capillaries, increased brain Aβ level, lowered plasma-to-brain Aβ ratio and suppressed expression of LRP1 protein. In vitro BBB model experiment revealed that amylin-induced stress downregulates LRP1 in endothelial cells through a miRNA-based translational repression mechanism. Conclusions: High blood human amylin levels cause cerebral microvascular dysfunction and interfere with Aβ efflux across the BBB through miRNA-mediated LRP1 downregulation. Lowering the blood amylin level in early AD could improve Aβ clearance from the brain.

scholarly journals GLP1-derived nonapeptide GLP1(28–36)amide protects pancreatic β-cells from glucolipotoxicity

2012 ◽  
Vol 213 (2) ◽  
pp. 143-154 ◽  
Author(s):  
Zhengu Liu ◽  
Violeta Stanojevic ◽  
Luke J Brindamour ◽  
Joel F Habener
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Secretion ◽  
Islet Cells ◽  
Blood Levels ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions

Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic β-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote β-cell survival via its actions on its G-protein-coupled receptor on β-cells. Here, we report that a nonapeptide, GLP1(28–36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 β-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 β-cells. We propose that GLP1(28–36)amide might be useful in alleviating β-cell stress and might improve β-cell functions and survival.

scholarly journals Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Yaser Albadr ◽  
Andrew Crowe ◽  
Rima Caccetta
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

scholarly journals Treatment With Naringenin Elevates the Activity of Transcription Factor Nrf2 to Protect Pancreatic β-Cells From Streptozotocin-Induced Diabetes in vitro and in vivo

2019 ◽  
Vol 9 ◽  
Author(s):  
Rashmi Rajappa ◽  
Dornadula Sireesh ◽  
Magesh B. Salai ◽  
Kunka M. Ramkumar ◽  
Suryanarayanan Sarvajayakesavulu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Streptozotocin Induced Diabetes

A novel standardized in vitro islet model system for efficacy and toxicity testing in pancreatic β-cells

2016 ◽  
Vol 258 ◽  
pp. S158
Author(s):  
B. Yesildag ◽  
A. Neelakandhan ◽  
S. Messner ◽  
W. Moritz
Keyword(s):  
Toxicity Testing ◽  
Model System ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Protein Kinase CK2 Controls CaV2.1-Dependent Calcium Currents and Insulin Release in Pancreatic β-cells

2020 ◽  
Vol 21 (13) ◽  
pp. 4668
Author(s):  
Rebecca Scheuer ◽  
Stephan Ernst Philipp ◽  
Alexander Becker ◽  
Lisa Nalbach ◽  
Emmanuel Ampofo ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Calcium Currents ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Voltage Dependent ◽  
Regulatory Impact ◽  
Kinase Ck2

The regulation of insulin biosynthesis and secretion in pancreatic β-cells is essential for glucose homeostasis in humans. Previous findings point to the highly conserved, ubiquitously expressed serine/threonine kinase CK2 as having a negative regulatory impact on this regulation. In the cell culture model of rat pancreatic β-cells INS-1, insulin secretion is enhanced after CK2 inhibition. This enhancement is preceded by a rise in the cytosolic Ca2+ concentration. Here, we identified the serine residues S2362 and S2364 of the voltage-dependent calcium channel CaV2.1 as targets of CK2 phosphorylation. Furthermore, co-immunoprecipitation experiments revealed that CaV2.1 binds to CK2 in vitro and in vivo. CaV2.1 knockdown experiments showed that the increase in the intracellular Ca2+ concentration, followed by an enhanced insulin secretion upon CK2 inhibition, is due to a Ca2+ influx through CaV2.1 channels. In summary, our results point to a modulating role of CK2 in the CaV2.1-mediated exocytosis of insulin.

scholarly journals Tracing phenotypic reversibility of pancreatic β-cells in vitro

2010 ◽  
Vol 1 (6) ◽  
pp. 242-251 ◽  
Author(s):  
Kohtaro Minami ◽  
Kazumasa Miyawaki ◽  
Manami Hara ◽  
Shuichi Yamada ◽  
Susumu Seino
Keyword(s):  
Β Cells ◽  
Pancreatic Β Cells

Pannexin-2-deficiency sensitizes pancreatic β-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo

2017 ◽  
Vol 448 ◽  
pp. 108-121 ◽  
Author(s):  
Lukas A. Berchtold ◽  
Michela Miani ◽  
Thi A. Diep ◽  
Andreas N. Madsen ◽  
Valentina Cigliola ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Induced Apoptosis

scholarly journals Generation of Functional Human Pancreatic β Cells In Vitro

Cell ◽  
2014 ◽  
Vol 159 (2) ◽  
pp. 428-439 ◽  
Author(s):  
Felicia W. Pagliuca ◽  
Jeffrey R. Millman ◽  
Mads Gürtler ◽  
Michael Segel ◽  
Alana Van Dervort ◽  
...  
Keyword(s):  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Fructose-1,6-Bisphosphatase Regulates Glucose-Stimulated Insulin Secretion of Mouse Pancreatic β-Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4688-4695 ◽  
Author(s):  
Ye Zhang ◽  
Zhifang Xie ◽  
Guangdi Zhou ◽  
Hai Zhang ◽  
Jian Lu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Specific Inhibitor ◽  
Physiological Role ◽  
Glucose Sensing ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Fructose 1,6 Bisphosphatase ◽  
Glucose Stimulated Insulin Secretion

Pancreatic β-cells can precisely sense glucose stimulation and accordingly adjust their insulin secretion. Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme, but its physiological significance in β-cells is not established. Here we determined its physiological role in regulating glucose sensing and insulin secretion of β-cells. Considerable FBPase mRNA was detected in normal mouse islets and β-cell lines, although their protein levels appeared to be quite low. Down-regulation of FBP1 in MIN6 cells by small interfering RNA could enhance the glucose-stimulated insulin secretion (GSIS), whereas FBP1-overexpressing MIN6 cells exhibited decreased GSIS. Inhibition of FBPase activity in islet β-cells by its specific inhibitor MB05032 led to significant increase of their glucose utilization and cellular ATP to ADP ratios and consequently enhanced GSIS in vitro. Pretreatment of mice with the MB05032 prodrug MB06322 could potentiate GSIS in vivo and improve their glucose tolerance. Therefore, FBPase plays an important role in regulating glucose sensing and insulin secretion of β-cells and serves a promising target for diabetes treatment.

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