Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2

Kreutzberger, Alex J. B.; Kiessling, Volker; Doyle, Catherine A.; Schenk, Noah; Upchurch, Clint; Elmer-Dixon, Margaret M.; Ward, Amanda E.; Preobraschenski, Julia; Hussein, Syed S; Tomaka, Weronika; Seelheim, Patrick; Kattan, Iman; Harris, M; Liang, Binyong; Kenworthy, Anne K.; Desai, Bimal N.; Leitinger, Norbert; Anantharam, Arun; Castle, J. David; Tamm, Lukas K.

doi:10.7554/elife.62506

Cited by 33 publications

(27 citation statements)

References 73 publications

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“…The increase in the resting plasma membrane potential from roughly −70 mV to −15 mV stimulates the opening of the voltage-gated L-type Ca 2+ -channels [ 39 , 40 , 41 , 42 , 43 ], and Ca 2+ influx triggers the exocytotic release of plasma membrane-docked insulin granules [ 44 ] via interactions of Ca 2+ -regulated synaptotagmins and the SNARE complex [ 45 , 46 ]. Recent data has identified specific subpopulations of insulin granules that show compositional differences defined by the presence of either synaptotagmin 7 or 9 on the granule membrane [ 47 ]. Granules containing synaptotagmin 9, which shows high-affinity Ca 2+ binding, exhibit fast release kinetics and may be initially utilized during first-phase insulin release (3–5 min following glucose stimulation).…”

Section: Nutrient-regulated Insulin Secretionmentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

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Section: Nutrient-regulated Insulin Secretionmentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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“…Nevertheless, we also observed a significant downregulation of the soluble N-ethyl maleimide sensitive factor associated receptor (SNARE) protein Vamp3 (also known as cellubrevin) and an upregulation of Syt1 (synaptotagmin 1), as well as Syt17 and Syt12 . Interplay between these, and potentially other, components of the docking/fusion machinery could contribute to the defective docking and secretion observed in these animals 49 .…”

Section: Discussionmentioning

confidence: 99%

Glucose-dependent miR-125b is a negative regulator of β-cell function

Cheung

Pizza

Chabosseau

et al. 2021

Preprint

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Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of endocrine cells. MiR-125b is a highly conserved miRNA abundant in β-cells, though its role in these cells remains unclear. Here, we show that miR-125b expression in human islets correlates with body mass index (BMI) of the donors and is regulated by glucose in an AMP-activated protein kinase-dependent manner in both mice and humans. Using and unbiased high-throughput approach, we identify dozens of direct gene targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Whereas inactivation of miR-125b in human β-cells led to shorter mitochondria and improved glucose stimulated insulin secretion, mice over-expressing mir-125b selectively in β-cells displayed defective insulin secretion and marked glucose intolerance. Moreover, the β-cells of these transgenic animals showed strongly reduced insulin content and secretion and contained enlarged lysosomal structures. Thus, miR125b provides a glucose-controlled regulator of organelle dynamics that negatively regulates insulin secretion in β-cells.

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“…Sphingolipid–cholesterol lipid rafts accumulate in microdomains of the TGN [ 136 , 137 ], and these rafts can alter the distribution of transmembrane components to create sorting stations that are essential for granule biogenesis [ 138 , 139 ]. These rafts are also enriched in vesicles of the regulated secretory pathway [ 140 , 141 , 142 , 143 ], indicating that SG membranes originate from the sorting domains where granins and other SG constituents aggregate and bind. Importantly, saturated fatty acid and cholesterol intake can change the composition of lipid species distributed among cell membranes to influence trafficking and SG morphology [ 144 , 145 ].…”

Section: Luminal Components Of the Insulin Secretory Granulementioning

confidence: 99%

Inside the Insulin Secretory Granule

et al. 2021

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The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

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Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2

Cited by 33 publications

References 73 publications

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

Glucose-dependent miR-125b is a negative regulator of β-cell function

Inside the Insulin Secretory Granule

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