Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation

MacDonald, Michael J.; Ade, Lacmbouh; Ntambi, James M.; Ansari, Israrul H.; Stoker, Scott W.

doi:10.1074/jbc.m114.628420

Cited by 55 publications

(69 citation statements)

References 87 publications

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“…Our recent study that characterized the phospholipid composition of insulin secretory granules (ISG) 2 of pancreatic beta cells suggested that ISG phosphatidylserine (PS) facilitates docking and fusion of the ISG with the plasma membrane during insulin exocytosis (1). We found that the concentration of PS in ISG is 5-fold that of the whole cell, and with glucose stimulation its concentration in ISG increases even more (1).…”

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confidence: 87%

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confidence: 88%

“…We found that the concentration of PS in ISG is 5-fold that of the whole cell, and with glucose stimulation its concentration in ISG increases even more (1). PS is the most abundant negatively charged phospholipid in most cells, including in the beta cell (1), and the concentration of PS in the plasma membrane of most cells is known to be high. The movement of PS from the inner (luminal) to the outer (cytosolic) leaflet of the ISG and from the outer to the cytosolic leaflet of the plasma membrane should facilitate docking of the ISG with the plasma membrane.…”

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confidence: 88%

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Characterization of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells

Ansari

Longacre

Paulusma

et al. 2015

Journal of Biological Chemistry

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Background: Flippases translocate phosphatidylserine (PS) across lipid bilayers in secretory granules (SG) and plasma membranes (PM). Results: Flippases were characterized in pancreatic beta cells, including in SG. Flippase knockdown inhibited insulin secretion. Conclusion: Flippases play key roles in insulin secretion by rapidly moving PS across lipid bilayers. Significance: PS couples fusion of SG with the PM to promote insulin exocytosis.

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confidence: 87%

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confidence: 88%

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confidence: 88%

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Characterization of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells

Ansari

Longacre

Paulusma

et al. 2015

Journal of Biological Chemistry

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“…The intracellular trafficking process exposes ZnT8 to a dynamic lipid composition as subcellular membrane compartments undergo enormous lipid remodeling, resulting in enrichments of anionic phosphatidylinositol (PI), phosphatidylserine (PS), non-bilayer lysophosphatidylcholine (LPC), and cholesterol in insulin granules (16) (Fig. 4a).…”

Section: Functional Modulation Of Human Znt8mentioning

confidence: 99%

“…4b and Table 1). LPC is highly enriched in insulin granules, accounting for 20% of total granule lipids (16). When inserted into the lipid bilayer, the cone-shaped LPC introduces positive curvature.…”

Section: Functional Modulation Of Human Znt8mentioning

confidence: 99%

Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes

Merriman¹,

Huang²,

Rutter

et al. 2016

Journal of Biological Chemistry

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Edited by F. Peter GuengerichZinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-offunction mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.Zinc forms stable complexes with insulin hexamers, enabling crystalline insulin packing in secretory granules of pancreatic beta cells. Defective insulin secretion in the face of insulin resistance is a characteristic feature of T2D, 4 a complex multifactorial polygenetic disease with more than 80 T2D susceptibility loci/genes identified so far by genome-wide association studies (GWASs). A nonsynonymous single nucleotide polymorphism in SLC30A8 (rs13266634 C3 T), which causes an arginine to tryptophan change at position 325, is associated with increased risk of developing T2D (1). The risk allele is widespread in more than 50% of the population according to HapMap data (build 35). SLC30A8 encodes a granular zinc transporter known as ZnT8. In pancreatic beta cells, ZnT8 is highly expressed and responsible for transporting cytosolic zinc into insulin granules (2). However, the molecular mechanism underlying the genetic susceptibility of ZnT8 polymorphisms remains controversial. ZnT8 inactivation in various mouse models revealed large phenotypic variations ranging from decreased, unchanged to even enhanced insulin secretion (3). Functional characterization of overexpressed polymorphic alleles in pancreatic beta cells suggested an attenuated zinc transport activity associated with an increased T2D susceptibility (4, 5), whereas genotyping rare nonsense and frameshift mutations of ZnT8 in humans indicated an opposite causal relationship, suggesting that a reduction of ZnT8 expression actually decreased T2D risk (6). The conflicting results conce...

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Insulin granule biogenesis and exocytosis

Omar‐Hmeadi

Idevall‐Hagren

2020

Cell. Mol. Life Sci.

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Insulin is produced by pancreatic β-cells, and once released to the blood, the hormone stimulates glucose uptake and suppresses glucose production. Defects in both the availability and action of insulin lead to elevated plasma glucose levels and are major hallmarks of type-2 diabetes. Insulin is stored in secretory granules that form at the trans-Golgi network. The granules undergo extensive modifications en route to their release sites at the plasma membrane, including changes in both protein and lipid composition of the granule membrane and lumen. In parallel, the insulin molecules also undergo extensive modifications that render the hormone biologically active. In this review, we summarize current understanding of insulin secretory granule biogenesis, maturation, transport, docking, priming and eventual fusion with the plasma membrane. We discuss how different pools of granules form and how these pools contribute to insulin secretion under different conditions. We also highlight the role of the β-cell in the development of type-2 diabetes and discuss how dysregulation of one or several steps in the insulin granule life cycle may contribute to disease development or progression.

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Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation

Cited by 55 publications

References 87 publications

Characterization of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells

Characterization of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells

Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes

Insulin granule biogenesis and exocytosis

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