scholarly journals Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

2020 ◽  
Author(s):  
Ada Admin ◽  
Christian H. Burns ◽  
Belinda Yau ◽  
Anjelica Rodriguez ◽  
Jenna Triplett ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Transmembrane Protein ◽  
Secretory Granules ◽  
Protein Composition ◽  
Regulated Exocytosis ◽  
Specific Proteins ◽  
Pancreatic B Cells ◽  
Cytosolic Factor ◽  
Hops Complex

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

2020 ◽  
Author(s):  
Ada Admin ◽  
Christian H. Burns ◽  
Belinda Yau ◽  
Anjelica Rodriguez ◽  
Jenna Triplett ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Transmembrane Protein ◽  
Secretory Granules ◽  
Protein Composition ◽  
Regulated Exocytosis ◽  
Specific Proteins ◽  
Pancreatic B Cells ◽  
Cytosolic Factor ◽  
Hops Complex

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

scholarly journals Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

2020 ◽  
Author(s):  
Ada Admin ◽  
Christian H. Burns ◽  
Belinda Yau ◽  
Anjelica Rodriguez ◽  
Jenna Triplett ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Transmembrane Protein ◽  
Secretory Granules ◽  
Protein Composition ◽  
Regulated Exocytosis ◽  
Specific Proteins ◽  
Pancreatic B Cells ◽  
Cytosolic Factor ◽  
Hops Complex

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

scholarly journals Pancreatic β-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

2020 ◽  
Author(s):  
Ada Admin ◽  
Christian H. Burns ◽  
Belinda Yau ◽  
Anjelica Rodriguez ◽  
Jenna Triplett ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Transmembrane Protein ◽  
Secretory Granules ◽  
Protein Composition ◽  
Regulated Exocytosis ◽  
Specific Proteins ◽  
Pancreatic B Cells ◽  
Cytosolic Factor ◽  
Hops Complex

Insulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic b-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

scholarly journals Pancreatic beta-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion

2020 ◽  
Author(s):  
Christian H. Burns ◽  
Belinda Yau ◽  
Anjelica Rodriguez ◽  
Jenna Triplett ◽  
Drew Maslar ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Transmembrane Protein ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Protein Composition ◽  
Β Cells ◽  
Regulated Exocytosis ◽  
Specific Proteins ◽  
Hops Complex

AbstractInsulin secretory granules (SGs) mediate the regulated secretion of insulin, which is essential for glucose homeostasis. The basic machinery responsible for this regulated exocytosis consists of specific proteins present both at the plasma membrane and on insulin SGs. The protein composition of insulin SGs thus dictates their release properties, yet the mechanisms controlling insulin SG formation, which determines this molecular composition, remain poorly understood. VPS41, a component of the endo-lysosomal tethering HOPS complex, was recently identified as a cytosolic factor involved in the formation of neuroendocrine and neuronal granules. We now find that VPS41 is required for insulin SG biogenesis and regulated insulin secretion. Loss of VPS41 in pancreatic β-cells leads to a reduction in insulin SG number, changes in their transmembrane protein composition, and defects in granule regulated exocytosis. Exploring a human point mutation, identified in patients with neurological but no endocrine defects, we show that the effect on SG formation is independent of HOPS complex formation. Finally, we report that mice with a deletion of VPS41 specifically in β-cells develop diabetes due to severe depletion of insulin SG content and a defect in insulin secretion. In sum, our data demonstrate that VPS41 contributes to glucose homeostasis and metabolism.

scholarly journals Activation of alpha-2-adrenoceptors results in an increase in F-actin formation in HIT-T15 pancreatic B-cells

1995 ◽  
Vol 307 (1) ◽  
pp. 169-174 ◽  
Author(s):  
H C Cable ◽  
A el-Mansoury ◽  
N G Morgan
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
B Cells ◽  
Fluorescence Microscopy ◽  
Pertussis Toxin ◽  
Actin Polymerization ◽  
Secretory Granules ◽  
Rhodamine Phalloidin ◽  
Late Step ◽  
Pancreatic B Cells

1. Alpha-2-adrenoceptor agonists, such as noradrenaline, are potent inhibitors of insulin secretion, and it has been suggested that they control a late step in the pathway of exocytosis. We have investigated whether this could be related to a change in the extent of actin polymerization in the pancreatic B-cell, since actin microfilaments are implicated in regulating the access of secretory granules to the plasma membrane prior to exocytosis. 2. Cultured HIT-T15 pancreatic B-cells responded to noradrenaline with an increase in F-actin content, as judged by a rise in the fluorescence output after probing of the cells with phalloidin (a toxin which binds specifically to F-actin) conjugated to rhodamine. The response to noradrenaline was rapid, dose-dependent and sustained and could be reproduced by the highly selective alpha-2-agonist UK14,304. Examination of HIT-T15 cells by fluorescence microscopy after treatment with rhodamine-phalloidin, revealed a significant localization of F-actin immediately adjacent to the plasma membrane. The pattern of F-actin distribution in the cells was not altered dramatically by noradrenaline, although the intensity of staining close to the plasma membrane appeared to be slightly reduced. 3. The increase in F-actin content induced by noradrenaline and UK14,304 was inhibited significantly by the alpha-2-antagonist idazoxan but not by the alpha-1-selective antagonist prazosin. Pretreatment of HIT-T15 cells with pertussis toxin did not lead to any direct alteration in F-actin content, although the toxin significantly modified the responses induced by noradrenaline and UK14,304. In each case, cells incubated for 24 h with pertussis toxin responded to the alpha-2-agonist with an enhanced fluorescence output, indicating that F-actin levels had increased still further. This did not correlate with any gross change in the distribution of F-actin as judged by fluorescence microscopy. 4. The results demonstrate that alpha-2-adrenoceptors are coupled to control of actin polymerization in HIT-T15 cells. They suggest that regulation of F-actin formation could be a component of the mechanism by which alpha-2-agonists mediate inhibition of insulin secretion.

scholarly journals Aged insulin granules display reduced microtubule-dependent mobility and are disposed within actin-positive multigranular bodies

2015 ◽  
Vol 112 (7) ◽  
pp. E667-E676 ◽  
Author(s):  
Peter Hoboth ◽  
Andreas Müller ◽  
Anna Ivanova ◽  
Hassan Mziaut ◽  
Jaber Dehghany ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Secretory Granules ◽  
Glucose Stimulation ◽  
Actin Depolymerization ◽  
Insulin Granules ◽  
Dependent Transport ◽  
Over Time ◽  
Dynamic Microtubule ◽  
Three Components

Insulin secretion is key for glucose homeostasis. Insulin secretory granules (SGs) exist in different functional pools, with young SGs being more mobile and preferentially secreted. However, the principles governing the mobility of age-distinct SGs remain undefined. Using the time-reporter insulin-SNAP to track age-distinct SGs we now show that their dynamics can be classified into three components: highly dynamic, restricted, and nearly immobile. Young SGs display all three components, whereas old SGs are either restricted or nearly immobile. Both glucose stimulation and F-actin depolymerization recruit a fraction of nearly immobile young, but not old, SGs for highly dynamic, microtubule-dependent transport. Moreover, F-actin marks multigranular bodies/lysosomes containing aged SGs. These data demonstrate that SGs lose their responsiveness to glucose stimulation and competence for microtubule-mediated transport over time while changing their relationship with F-actin.

Relative importance of first- and second-phase insulin secretion in glucose homeostasis in conscious dog. II. Effects on gluconeogenesis

Diabetes ◽  
1986 ◽  
Vol 35 (7) ◽  
pp. 776-784 ◽  
Author(s):  
K. E. Steiner ◽  
S. M. Mouton ◽  
P. E. Williams ◽  
W. W. Lacy ◽  
A. D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Second Phase ◽  
Relative Importance ◽  
Conscious Dog
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