Pancreatic β cell–selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis

Xu, Jie; Wijesekara, Nadeeja; Regeenes, Romario; Rijjal, Dana Al; Piro, Anthony L.; Song, Youchen; Wu, Aibin; Bhattacharjee, Ananya; Liu, Ying; Marzban, Lucy; Rocheleau, Jonathan V.; Fraser, Paul E.; Dai, Feihan F.; Hu, Cheng; Wheeler, Michael B.

doi:10.1172/jci.insight.143037

Cited by 16 publications

(14 citation statements)

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“…A broad consensus on the specific nature of the signaling compound(s) and on its (their) mechanism(s) of action has so far failed to emerge. For a review dealing specifically with the shortcomings of current models of stimulus-secretion coupling, the reader is referred to [126]. Here, we have placed an emphasis on the alternative experimental protocol and on the use of amino acids and keto acids as experimental tools to delineate the mechanisms operative during the metabolic amplification (for an encompassing overview, see [127]).…”

Section: Discussionmentioning

confidence: 99%

“…If one considers that ISGs released during β-cell failure are a source of hIAPP processing intermediates (Figure 2C), we could look to luminal factors that might explain the propensity of these molecules to become pathogenic. Indeed, insulin, Zn 2+ , H + , Ca 2+ , C-peptide, and proinsulin have been assessed individually or in combination, in vitro, along with hIAPP, in various studies to reason that a delicate balance of cofactors is required to inhibit hIAPP oligomerization [109][110][111][112][113][114]126]. In healthy cells, regulated exocytosis of MSGs could maintain this balance as components are released in an appropriate molar ratio.…”

Section: Figurementioning

confidence: 99%

“…Many beta-cell pathologies are intimately linked to ISG formation, despite the most common diabetes therapies targeting defective ISG secretion. Dysregulated ISG biogenesis leads to glucose intolerance in vivo [30,33,41,126], while increased proinsulin / insulin ratios are archetypical of diabetic patients and indicative of impaired processing within immature ISG [126,127].…”

Section: Moving Forwardmentioning

confidence: 99%

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Islet Biology and Metabolism

2022

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Moving Forwardmentioning

confidence: 99%

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Islet Biology and Metabolism

2022

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“…Mice were fasted overnight (14-16 hours), and a 2 g/kg bolus of glucose was administered by oral gavage as previously described ( 23 , 24 ). Briefly, blood glucose was measured using a Contour glucometer (Ascensia Diabetes Care, Mississauga, ON, Canada) at 0, 10, 30, 60, 90 and 120 mins.…”

Section: Methodsmentioning

confidence: 99%

Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice

et al. 2022

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ObjectivePregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established.MethodsA timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy.ResultsFasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation.ConclusionBeta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.

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Section: Cargo Moleculesmentioning

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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Pancreatic β cell–selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis

Cited by 16 publications

References 57 publications

Islet Biology and Metabolism

Islet Biology and Metabolism

Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice

Inside the Insulin Secretory Granule

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