The KINGS <i>Ins2</i>+/G32S Mouse: A Novel Model of β-Cell Endoplasmic Reticulum Stress and Human Diabetes

Austin, Amazon; Gatward, Lydia F. Daniels; Cnop, Miriam; Andersson, David A.; Gentry, Clive; Bevan, Stuart; Jones, Peter M.; King, Aileen

doi:10.2337/db20-0570

Cited by 17 publications

(37 citation statements)

References 39 publications

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“…Moreover, since UPR activation can lead to cell type‐specific responses, organ‐specific studies (eg in liver, pancreas, kidneys and white adipose tissue) will be informative in developing therapeutic approaches based on modulation of UPR sensors. To that end, new in vivo models such as the recently developed KINGS Ins2 +/G32S mouse model of human diabetes will be invaluable 113 …”

Section: Resultsmentioning

confidence: 99%

“…To that end, new in vivo models such as the recently developed KINGS Ins2 +/G32S mouse model of human diabetes will be invaluable. 113 Taken together, this review highlights a crucial role for UPR in the coordination of lipid metabolism and metabolic reprogramming and suggests this is an important area for further research in relevant diseases.…”

Section: Con Clus Ionmentioning

confidence: 89%

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Regulation of lipid metabolism by the unfolded protein response

Moncan

Mnich

Blomme

et al. 2021

J Cellular Molecular Medi

115

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The endoplasmic reticulum (ER) is the site of protein folding and secretion, Ca 2+ storage and lipid synthesis in eukaryotic cells. Disruption to protein folding or Ca 2+ homeostasis in the ER leads to the accumulation of unfolded proteins, a condition known as ER stress. This leads to activation of the unfolded protein response (UPR) pathway in order to restore protein homeostasis. Three ER membrane proteins, namely inositol‐requiring enzyme 1 (IRE1), protein kinase RNA‐like ER kinase (PERK) and activating transcription factor 6 (ATF6), sense the accumulation of unfolded/misfolded proteins and are activated, initiating an integrated transcriptional programme. Recent literature demonstrates that activation of these sensors can alter lipid enzymes, thus implicating the UPR in the regulation of lipid metabolism. Given the presence of ER stress and UPR activation in several diseases including cancer and neurodegenerative diseases, as well as the growing recognition of altered lipid metabolism in disease, it is timely to consider the role of the UPR in the regulation of lipid metabolism. This review provides an overview of the current knowledge on the impact of the three arms of the UPR on the synthesis, function and regulation of fatty acids, triglycerides, phospholipids and cholesterol.

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Section: Resultsmentioning

confidence: 99%

Section: Con Clus Ionmentioning

confidence: 89%

Regulation of lipid metabolism by the unfolded protein response

Moncan

Mnich

Blomme

et al. 2021

J Cellular Molecular Medi

115

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“…The trafficking defect of the newly described proinsulin-G(B8)V is severe and very similar to that of the G(B8)S mutation (Supplemental Fig. S6), which has been recently described to account for spontaneous diabetes in the KINGS diabetic mouse [38], as well as being one of the first described human MIDY mutants [25]-its folding defect is considered further, below. Additionally, it might be predicted that proinsulin-Y(B26)C and L(A16)P (also discussed further, below) would be catastrophically detrimental to folding as they (in addition to position B8) fall among the more conserved residues within insulin (Fig.…”

Section: Defective Cys(a6)-cys(a11) Pairing Defines Two Subgroups Of Mutationsmentioning

confidence: 77%

“…G(B8), invariant among vertebrate insulins, insulin-like growth factors (IGFs) and relaxins, lacks a side chain but exhibits a critical positive ϕ dihedral angle ordinarily forbidden to L-amino acids [23]. From in vitro folding studies, any L-amino-acid substitution in this position predisposes to impaired disulfide pairing [45] as observed for the G(B8)S MIDY mutant [46], triggering permanent neonatal diabetes [25,38]. We posit that G(B8)V similarly enforces an inappropriate negative B8 ϕ dihedral angle, in turn misorienting the side chain of Cys(B7), which cannot be rescued by the lose-A6/A11 template.…”

Section: Defective Cys(a6)-cys(a11) Pairing Defines Two Subgroups Of Mutationsmentioning

confidence: 99%

Distinct states of proinsulin misfolding in MIDY

Haataja

Arunagiri

Hassan

et al. 2021

Cell. Mol. Life Sci.

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A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)–Cys(A20) “interchain” disulfide bond, facilitating formation of the Cys(B7)–Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)–Cys(A11), is not required for anterograde trafficking, i.e., a “lose-A6/A11” mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here, we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep + 2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic β-cells. Three of these mutants, however, must disrupt the Cys(A6)–Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants.

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“…Several groups have been pursuing the molecular mechanism(s) underlying the β-cell dysfunction and compensatory cellular response(s) in the rare genetic syndrome of Mutant INS-gene induced Diabetes of Youth (MIDY) (1)(2)(3). The fundamental defect in MIDY is observed in humans (4), large animal models (5), small animal models (6), and has been replicated in cell culture (7), in vitro (8) and modeled in silico (9). The clinical problem originates from the fact that misfolded proinsulin within the endoplasmic reticulum (ER) can propagate its misfolding and ER retention onto wild-type (WT) bystander proinsulin molecules, thereby impairing insulin production (10; 11).…”

Section: Introductionmentioning

confidence: 99%

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

Alam

Arunagiri

Haataja

et al. 2021

Preprint

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Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic β-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of Mutant INS gene induced Diabetes of Youth (MIDY). Here we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation develop diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance and within a few week exposure to a high-fat diet, they develop frank diabetes. Diabetes is more severe in homozygotes, and the development of disease parallels a progressive heterogeneity of β cells with increasing fractions of proinsulin rich/insulin-poor cells, as well as glucagon-positive cells. Evidently, sub-threshold predisposition to proinsulin misfolding can go undetected, but provides genetic susceptibility to diet-induced β-cell failure.

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The KINGS Ins2+/G32S Mouse: A Novel Model of β-Cell Endoplasmic Reticulum Stress and Human Diabetes

Cited by 17 publications

References 39 publications

Regulation of lipid metabolism by the unfolded protein response

Regulation of lipid metabolism by the unfolded protein response

Distinct states of proinsulin misfolding in MIDY

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

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