Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia

Cierra K Boyer; Casey J Bauchle; Jianchao Zhang; Yanzhuang Wang; Samuel B Stephens

doi:10.1038/s41598-023-32322-z

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Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia

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Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia

Cierra K Boyer, Casey J Bauchle, Jianchao Zhang, Yanzhuang Wang and Samuel B Stephens

Scientific reports, Vol.13(1), 5218

03/30/2023

DOI: 10.1038/s41598-023-32322-z

PMCID: PMC10063606

PMID: 36997560

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Abstract

The pancreatic islet β-cell's preference for release of newly synthesized insulin requires careful coordination of insulin exocytosis with sufficient insulin granule production to ensure that insulin stores exceed peripheral demands for glucose homeostasis. Thus, the cellular mechanisms regulating insulin granule production are critical to maintaining β-cell function. In this report, we utilized the synchronous protein trafficking system, RUSH, in primary β-cells to evaluate proinsulin transit through the secretory pathway leading to insulin granule formation. We demonstrate that the trafficking, processing, and secretion of the proinsulin RUSH reporter, proCpepRUSH, are consistent with current models of insulin maturation and release. Using both a rodent dietary and genetic model of hyperglycemia and β-cell dysfunction, we show that proinsulin trafficking is impeded at the Golgi and coincides with the decreased appearance of nascent insulin granules at the plasma membrane. Ultrastructural analysis of β-cells from diabetic leptin receptor deficient mice revealed gross morphological changes in Golgi structure, including shortened and swollen cisternae, and partial Golgi vesiculation, which are consistent with defects in secretory protein export. Collectively, this work highlights the utility of the proCpepRUSH reporter in studying proinsulin trafficking dynamics and suggests that altered Golgi export function contributes to β-cell secretory defects in the pathogenesis of Type 2 diabetes.

Details

Title: Subtitle: Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia
Creators: Cierra K Boyer - University of Iowa
Casey J Bauchle - Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA
Jianchao Zhang - University of Michigan
Yanzhuang Wang - University of Michigan
Samuel B Stephens - Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA. samuel-b-stephens@uiowa.edu
Resource Type: Journal article
Publication Details: Scientific reports, Vol.13(1), 5218
DOI: 10.1038/s41598-023-32322-z
PMID: 36997560
PMCID: PMC10063606
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: W81XWH-20-1-0200 / Congressionally Directed Medical Research Programs R35GM130331 / NIH HHS
Language: English
Date published: 03/30/2023
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984381027502771

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