Distinct states of proinsulin misfolding in MIDY

Haataja, Leena; Arunagiri, Anoop; Hassan, Anis; Regan, Kaitlin; Tsai, Billy; Dhayalan, Balamurugan; Weiss, Michael A.; Liu, Ming; Arvan, Peter

doi:10.1007/s00018-021-03871-1

Cited by 23 publications

(17 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 17 , 18 , 20 In humans, monogenic forms of diabetes arising from INS mutations can prevent proper proinsulin disulfide bond formation acting as dominant negative suppressors of wild type proinsulin trafficking. 24 , 60 , 61 While these studies demonstrate that perturbations in ER functions and proinsulin folding can compromise β-cell health and insulin production, direct evidence for ER stress as a causative feature in the development of T2D is less clear. 7 , 39 Increased PERK and Ire1α activity have been described in pre-diabetic β-cells, 37 , 62 , 63 yet diminished, rather than increased, expression of ATF6 and XBP-1(s) occur in β-cells from humans with long-standing T2D 62 .…”

Section: Discussionmentioning

confidence: 99%

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell

et al. 2022

View full text Add to dashboard Cite

Defects in the pancreatic β-cell's secretion system are well-described in Type 2 diabetes (T2D) and include impaired proinsulin processing and a deficit in mature insulin-containing secretory granules; however, the cellular mechanisms underlying these defects remain poorly understood. To address this, we used an in situ fluorescent pulse-chase strategy to study proinsulin trafficking. We show that insulin granule formation and the appearance of nascent granules at the plasma membrane are decreased in rodent and cell culture models of pre-diabetes and hyperglycemia. Moreover, we link the defect in insulin granule formation to an early trafficking delay in ER export of proinsulin, which is independent of overt ER stress. Using a ratiometric redox sensor, we show that the ER becomes hyperoxidized in β-cells from a dietary model of rodent pre-diabetes and that addition of reducing equivalents restores ER export of proinsulin and insulin granule formation and partially restores β-cell function. Together, these data identify a critical role for the regulation of ER redox homeostasis in proinsulin trafficking and suggest that alterations in ER redox poise directly contribute to the decline in insulin granule production in T2D.

show abstract

Section: Discussionmentioning

confidence: 99%

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In the majority of MIDY cases, heterozygous mutations in proinsulin folding function as dominant negative alleles. Dimerization of mutant, misfolded proinsulin with wild type proinsulin prevents the successful exit of the wild type proinsulin from the ER [ 95 ]. The subsequent buildup of proinsulin aggregates becomes proteotoxic to ER function and ultimately leads to β-cell loss from apoptosis [ 96 ].…”

Section: Proinsulin Folding In the Endoplasmic Reticulum (Er)mentioning

confidence: 99%

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

“…2 A – D ) for as long as we followed the animals (up to 6 months of life). Nevertheless, different cell lines may exhibit different degrees of ER quality control of mutant proinsulin ( 34 ); moreover, proinsulin-R(B22)E showed evidence of misfolding in the ER ( Figs. 1 , 7 , and 8 , and Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

et al. 2021

View full text Add to dashboard Cite

and anti-proinsulin immunoblotting is shown below, highlighting the presence of aberrant disulfidelinked proinsulin complexes. B) Quantitation of islet proinsulin and insulin protein levels (each point an independent male animal) by Western blotting as in panel A (mean ± s.d.; * p < 0.05; ** p < 0.01). Supplement Fig. S2. Circulating proinsulin, and proinsulin-to-insulin ratio, from 11.5 week old HFD-fed Ins2-proinsulin-R(B22)E heterozygous males (pink symbols), superimposed onto the data reproduced from Figs 2G and H. Horizontal asterisks represent statistical differences (mean ± s.d.) along the X-axis (blood glucose); vertical asterisks indicate statistical differences along the Y-axis (proinsulin level, or proinsulin-to-insulin ratio). Supplement Fig. S3. Transmission electron micrographs of islets cells from the genotypes (and diet) included in this study. Random blood glucose at the time of euthanasia is indicated on each figure. Scale bars are shown on all figures. A) Typical β-cell from male WT mouse and Ins2proinsulin-R(B22)E heterozygote on normal chow diet (age 4 weeks). B) Another typical β-cell from the animals analyzed in panel A, at higher magnification to highlight ER and secretory granule morphology. C) β-cell from WT mouse fed a HFD for 6 weeks with organelles labeled on the figure. ISG = immature secretory granule. VTCs are a pre-Golgi compartment. D) Upper left image: low-power of islet from HFD-fed male Ins2-proinsulin-R(B22)E heterozygote (age 6 weeks). "Cell A and B" are β-cells; "Cell C" is an α-cell. Note that Cell B is poorly granulated.

show abstract

Distinct states of proinsulin misfolding in MIDY

Cited by 23 publications

References 51 publications

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell

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

Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

Contact Info

Product

Resources

About