The Ins and Outs of Secretion from Pancreatic β-Cells: Control of Single-Vesicle Exo- and Endocytosis

Physiology ◽  
2007 ◽  
Vol 22 (2) ◽  
pp. 113-121 ◽  
Author(s):  
Patrick E. MacDonald ◽  
Patrik Rorsman
Keyword(s):  
Plasma Membrane ◽  
Plasma Glucose ◽  
Secretory Vesicles ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Single Vesicle

Exocytosis of insulin-containing secretory vesicles in pancreatic β-cells is crucial to maintenance of plasma glucose levels. They fuse with the plasma membrane in a regulated manner to release their contents and are subsequently recaptured either intact or through conventional clathrin-mediated endocytosis. Here, we discuss these mechanisms in β-cells at the single-vesicle level.

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.

Protective effect of 4,6-O-ethylidene glucose against the cytotoxicity of streptozotocin in pancreatic β cells in vivo: indirect evidence for the presence of a glucose transporter in β cells

1987 ◽  
Vol 112 (3) ◽  
pp. 375-378 ◽  
Author(s):  
J. Kawada ◽  
M. Okita ◽  
M. Nishida ◽  
Y. Yoshimura ◽  
K. Toyooka ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Glucose Transporter ◽  
Indirect Evidence ◽  
Tolerance Test ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
In Vivo Experiments ◽  
Glucose Transport System

ABSTRACT Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic β cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect β cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by (1) their blood glucose levels, (2) response in a glucose-tolerance test, and (3) insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in β cells and also the transport of streptozotocin into β cells through this system. J. Endocr. (1987) 112, 375–378

scholarly journals The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane

2013 ◽  
Vol 24 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Hao Wang ◽  
Ray Ishizaki ◽  
Jun Xu ◽  
Kazuo Kasai ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Knockout Mice ◽  
Secretory Granules ◽  
Small Gtpase ◽  
Membrane Phospholipids ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Insulin Granules ◽  
Insulin Exocytosis

Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment (docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a- and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function in those cells. We found that one of the putative Rab27a effector family proteins, exophilin7/JFC1/Slp1, is expressed in β cells; however, unlike granuphilin, exophilin7 overexpressed in the β-cell line MIN6 failed to show granule-docking or fusion-inhibitory activity. Furthermore, exophilin7 has no affinities to either Munc18-1 or Munc18-1–interacting syntaxin-1a, in contrast to granuphilin. Although β cells of exophilin7-knockout mice show no apparent abnormalities in intracellular distribution or in ordinary glucose-induced exocytosis of insulin granules, they do show impaired fusion in response to some stronger stimuli, specifically from granules that have not been docked to the plasma membrane. Exophilin7 appears to mediate the fusion of undocked granules through the affinity of its C2A domain toward the plasma membrane phospholipids. These findings indicate that the two Rab27a effectors, granuphilin and exophilin7, differentially regulate the exocytosis of either stably or minimally docked granules, respectively.

Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic β-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement

2010 ◽  
Vol 38 (1) ◽  
pp. 205-208 ◽  
Author(s):  
Angela McDonald ◽  
Sarah Fogarty ◽  
Isabelle Leclerc ◽  
Elaine V. Hill ◽  
D. Grahame Hardie ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glutathione Transferase ◽  
Three Dimensions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Insulin Granules ◽  
Elevated Glucose ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells requires the kinesin-1/Kif5B-mediated transport of insulin granules along microtubules. 5′-AMPK (5′-AMP-activated protein kinase) is a heterotrimeric serine/threonine kinase which is activated in β-cells at low glucose concentrations, but inhibited as glucose levels increase. Active AMPK blocks glucose-stimulated insulin secretion and the recruitment of insulin granules to the cell surface, suggesting motor proteins may be targets for this kinase. While both kinesin-1/Kif5B and KLC1 (kinesin light chain-1) contain consensus AMPK phosphorylation sites (Thr693 and Ser520, respectively) only recombinant GST (glutathione transferase)–KLC1 was phosphorylated by purified AMPK in vitro. To test the hypothesis that phosphorylation at this site may modulate kinesin-1-mediated granule movement, we developed an approach to study the dynamics of all the resolvable granules within a cell in three dimensions. This cell-wide approach revealed that the number of longer excursions (>10 μm) increased significantly in response to elevated glucose concentration (30 versus 3 mM) in control MIN6 β-cells. However, similar changes were seen in cells overexpressing wild-type KLC1, phosphomimetic (S517D/S520D) or non-phosphorylatable (S517A/S520A) mutants of KLC1. Thus, changes in the phosphorylation state of KLC1 at Ser517/Ser520 seem unlikely to affect motor function.

Modeling of Ca2+ flux in pancreatic β-cells: role of the plasma membrane and intracellular stores

2003 ◽  
Vol 285 (1) ◽  
pp. E138-E154 ◽  
Author(s):  
Leonid E. Fridlyand ◽  
Natalia Tamarina ◽  
Louis H. Philipson
Keyword(s):  
Plasma Membrane ◽  
Calcium Oscillations ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Ionic Flux ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca ◽  
Uptake And Release

We have developed a detailed mathematical model of ionic flux in β-cells that includes the most essential channels and pumps in the plasma membrane. This model is coupled to equations describing Ca2+, inositol 1,4,5-trisphosphate (IP3), ATP, and Na+ homeostasis, including the uptake and release of Ca2+ by the endoplasmic reticulum (ER). In our model, metabolically derived ATP activates inward Ca2+ flux by regulation of ATP-sensitive K+ channels and depolarization of the plasma membrane. Results from the simulations support the hypothesis that intracellular Na+ and Ca2+ in the ER can be the main variables driving both fast (2–7 osc/min) and slow intracellular Ca2+ concentration oscillations (0.3–0.9 osc/min) and that the effect of IP3 on Ca2+ leak from the ER contributes to the pattern of slow calcium oscillations. Simulations also show that filling the ER Ca2+ stores leads to faster electrical bursting and Ca2+ oscillations. Specific Ca2+ oscillations in isolated β-cell lines can also be simulated.

scholarly journals Melanophilin accelerates insulin granule fusion without predocking to the plasma membrane

2020 ◽  
Author(s):  
Ada Admin ◽  
Hao Wang ◽  
Kouichi Mizuno ◽  
Noriko Takahashi ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Secretory Granule ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Granule Exocytosis ◽  
Synaptic Vesicle Exocytosis ◽  
Granule Membrane ◽  
Myosin Va ◽  
Vesicle Exocytosis ◽  
Glucose Stimulated Insulin Secretion

Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric GTPase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Both melanophilin-mutated <i>leaden</i> mouse and melanophilin-downregulated human pancreatic β cells exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca<sup>2+</sup>]<sub>i</sub> rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.

Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic β-cells

2009 ◽  
Vol 296 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
Taila Hartley ◽  
John Brumell ◽  
Allen Volchuk
Keyword(s):  
Cell Function ◽  
Ubiquitin Proteasome System ◽  
Contributory Factor ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Pathological Conditions ◽  
Ubiquitin Proteasome

Protein degradation in eukaryotic cells is mediated primarily by the ubiquitin-proteasome system and autophagy. Turnover of protein aggregates and other cytoplasmic components, including organelles, is another function attributed to autophagy. The ubiquitin-proteasome system and autophagy are essential for normal cell function but under certain pathological conditions can be overwhelmed, which can lead to adverse effects in cells. In this review we will focus primarily on the insulin-producing pancreatic β-cell. Pancreatic β-cells respond to glucose levels by both producing and secreting insulin. The inability of β-cells to secrete sufficient insulin is a major contributory factor in the development of type 2 diabetes. The aim of this review is to examine some of the crucial roles of the ubiquitin-proteasome system and autophagy in normal pancreatic β-cell function and how these pathways may become dysfunctional under pathological conditions associated with metabolic syndromes.

scholarly journals Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice

2015 ◽  
Vol 227 (3) ◽  
pp. 153-165 ◽  
Author(s):  
Saeed Alshahrani ◽  
Mohammed Mashari Almutairi ◽  
Shams Kursan ◽  
Eduardo Dias-Junior ◽  
Mohamed Mahmoud Almiahuob ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Chloride Concentration ◽  
Glucose Disposal ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Fasting Glycemia ◽  
Blood Glucose Levels ◽  
Glucose Stimulated Insulin Secretion

The products of theSlc12a1andSlc12a2genes, commonly known as Na+-dependent K+2Cl−co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl−]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl−transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele ofSlc12a2exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15–30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence ofSlc12a2associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl−uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a singleSlc12a2allele may protect β-cells from failure due to increased homeostatic expression ofSlc12a1.

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