ライフサイエンスコーパス: proinsulin

1 but overlapping epitopes in the C-peptide of proinsulin.

2 I presentation and proteolytic processing of proinsulin.

3 eatic beta-cells as the precursor prohormone proinsulin.

4 plasma levels of immunoreactive insulin and proinsulin.

5 ted, it reduced the abundance of ER-targeted proinsulin.

6 lin receptor more effectively than wild-type proinsulin.

7 oinsulin, and the clinical mutant [L-Ser(B8)]proinsulin.

8 m a human haplotype expressing low levels of proinsulin.

9 rt from cells co-expressing misfolded mutant proinsulin.

10 ed with improved oxidative folding of mutant proinsulin.

11 y of transcripts, including the one encoding proinsulin.

12 cleavage is linked to the oxidation of (pre)proinsulin.

13 ant as well as that of coexpressed wild-type proinsulin.

14 ccessible to modification in insulin but not proinsulin.

15 s at the initiation of diabetes derived from proinsulin.

16 n to be naturally processed from whole human proinsulin.

17 the C-peptide (C25-35) or A-chain (A1-15) of proinsulin.

18 esulted in the accumulation of intracellular proinsulin.

19 hain transgenic NOD mouse on a TCRCalpha and proinsulin 2 (PI2)-deficient background, designated as A

20 d type 1 diabetes development in a subset of proinsulin 2-deficient NOD mice, the activation of iNKT

21 ree component coating formulation containing proinsulin, a diluent and a surfactant, facilitated unif

22 an intradermal MN delivery system to target proinsulin, a large multi-epitope protein capable of ind

23 also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavio

24 ellular pathways needed to prevent misfolded proinsulin accumulation remain incompletely understood.

25 brane damage during ER escape of a misfolded proinsulin aggregate destined for lysosomal degradation

26 ed Diabetes of Youth (MIDY) syndrome, mutant proinsulin aggregates interfere with the folding of wild

27 lt: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogeni

28 Proinsulin/alum monotherapy failed to correct hyperglyce

29 Proinsulin/alum monotherapy induced interleukin (IL)-4-

30 ed the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic N

31 perturbs insulin production from endogenous proinsulin and activates ER stress response.

32 Surrogate beta-cell lines secreting proinsulin and expressing HLA-A24 were generated and the

33 We used transplastomic plants expressing proinsulin and GAD to protect the autoantigens from degr

34 sion triggered intracellular accumulation of proinsulin and Glut2, massive endoplasmic reticulum (ER)

35 raits, including levels of glucose, insulin, proinsulin and hemoglobin A1c (HbA1c).

36 enic line had lower pancreatic [Zn(2+)]i and proinsulin and higher insulin and glucose tolerance comp

37 speptin potently decreases the intracellular proinsulin and insulin ((pro)insulin) content and insuli

38 insulin half-life, and lowered intracellular proinsulin and insulin levels.

39 educed cord blood CD4(+) T-cell responses to proinsulin and insulin, a reduction in the inflammatory

40 is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is ineffi

41 ut also processing and possibly clearance of proinsulin and insulin.

42 n A and proICA512/ICA512-TMF, in addition to proinsulin and insulin.

43 riate for human application, secreting human proinsulin and interleukin-10, cured 66% of mice with ne

44 cific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9

45 gle major association signal between fasting proinsulin and noncoding variants (p = 7.4 x 10(-50)).

46 Elevated levels of proinsulin and proinsulin intermediates are markers of b

47 selectively compromises oxidative folding of proinsulin and promotes glucose intolerance in mutant mi

48 e high-MW complexes, enhancing ERAD of Akita proinsulin and restoring WT insulin secretion.

49 opes formed by the covalent cross-linking of proinsulin and secretory granule peptides.

50 e found that GRP94 coimmunoprecipitated with proinsulin and that inhibition of GRP94 function and/or

51 at all pH values compared with the wild-type proinsulin and the other two analogs, but showed only ve

52 Both proinsulin and thyroglobulin normally form homodimers; t

53 rative studies of diabetes-associated mutant proinsulins and their aberrant modes of aggregation.

54 ypeptide chain folded much more rapidly than proinsulin, and at physiological pH.

55 biochemical research and then on to insulin, proinsulin, and many relevant related areas that continu

56 e analogs: [D-Ala(B8)]proinsulin, [L-Ala(B8)]proinsulin, and the clinical mutant [L-Ser(B8)]proinsuli

57 We found naive proinsulin- and GAD65-responsive T cells in cord blood (

58 ce of targeted delivery of the multi-epitope proinsulin antigen to skin-resident APCs, in vivo, in a

59 Efficient PDI engagement of Akita proinsulin appears linked to the availability of Hrd1, s

60 As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impa

61 ed degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-

62 At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identifi

63 ved regulation of CD4(+) T cell responses to proinsulin at 9 months of age, as compared with offsprin

64 is genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory c

65 we have exploited "hPro-CpepSfGFP," a human proinsulin bearing "superfolder" green fluorescent C-pep

66 P = 5 x 10(-3); n = 13,118) but not fasting proinsulin (beta = 0.01 log10; P = 0.5; n = 6,985).

67 etaPFOA=15.93; 95% CI: 6.78, 25.08), fasting proinsulin (betaPFOS=1.37 pM; 95% CI: 0.50, 2.25; betaPF

68 and in this way affects pancreatic beta-cell proinsulin biogenesis.

69 endent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content.

70 Although glucose uniquely stimulates proinsulin biosynthesis in beta cells, surprisingly litt

71 directly in obese diabetic mouse models, and proinsulin biosynthesis was found to be contrastingly in

72 Regulated proinsulin biosynthesis, disulfide bond formation and ER

73 , suppression of PC1/3 blocked processing of proinsulin but not proglucagon.

74 vated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in

75 rating that healthy human beta-cells process proinsulin by PC1/3 but not PC2, we suggest that there i

76 However, coexpression of ER-entrapped mutant proinsulin-C(A7)Y shifts the steady-state distribution o

77 egulation of proinsulin synthesis, misfolded proinsulin can accumulate in the endoplasmic reticulum (

78 pepGFP mice, misfolding of transgenic mutant proinsulin causes its retention in the ER.

79 s, blocking glucagon formation and enhancing proinsulin cleavage with a single compound could represe

80 ecular basis of the aberrant properties of a proinsulin clinical mutant in which residue Gly(B8) is r

81 When applied to a murine model these proinsulin-coated MNs efficiently punctured the skin and

82 on of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidativ

83 ency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loc

84 The study had a retrospective design, no proinsulin concentrations were available, and a nonspeci

85 demonstrate that in its monomeric form, (i) proinsulin contains a native-like insulin moiety and (ii

86 biosynthesis, and PERK-dependent increase in proinsulin content.

87 The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD

88 cells had no impact on insulin secretion or proinsulin conversion in mice.

89 ells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature ves

90 n due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with i

91 oinsulin:insulin ratios, indicating improved proinsulin conversion.

92 Endogenous proinsulin coprecipitates with hPro-CpepSfGFP and even m

93 for rs11603334 showed that the T2D-risk and proinsulin-decreasing allele (C) is associated with incr

94 rences between the footprints of insulin and proinsulin, defining a "shadow" of the connecting (C) do

95 xed to an MHC class II molecule presenting a proinsulin-derived peptide.

96 The proinsulin-derived peptides followed a trajectory from t

97 Surprisingly, although [L-Ser(B8)]proinsulin did not fold well under the physiological con

98 The data demonstrate that wild-type proinsulin dimerizes within the ER but accumulates at a

99 es Akita proinsulin in a novel way, reducing proinsulin disulfide bonds and priming the Akita protein

100 kly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a tren

101 Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal

102 py with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but

103 e that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding.

104 However, proinsulin epitopes recognized by human CD4(+) T cells h

105 proinsulin for degradation while enabling WT proinsulin escape from the ER.

106 This is accompanied by improved proinsulin exit from the ER and increased total insulin

107 nesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production t

108 pression is effective in promoting wild-type proinsulin export from cells co-expressing misfolded mut

109 -CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine.

110 have been reports of hyperglycemia inducing proinsulin expression in extrapancreatic tissues, we did

111 e is decreased insulin secretion when mutant proinsulin expression prevents wild-type (WT) proinsulin

112 Mutations in the insulin gene can impair proinsulin folding and cause diabetes mellitus.

113 that Grp170 participates in preparing mutant proinsulin for degradation while enabling WT proinsulin

114 roducts are of potential value, namely human proinsulin, foreign luciferase, and exogenous hydrogenas

115 Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that ent

116 roinsulin expression prevents wild-type (WT) proinsulin from exiting the endoplasmic reticulum (ER),

117 in the degradation process by shifting Akita proinsulin from high-molecular weight (MW) complexes tow

118 Sel1L membrane complex, which conducts Akita proinsulin from the ER lumen to the cytosol, and the p97

119 te a reference using INS-1E cells expressing proinsulin fused to a fluorescent protein (FP) under bas

120 Secretory rescue of proinsulin-G(B23)V is correlated with improved oxidative

121 king regulatory disulfides can rescue mutant proinsulin-G(B23)V, in parallel with its ability to prov

122 chemokines), clinical parameters (C-peptide, proinsulin, glucose), and cortisol, as an indicator of s

123 ey features of IR, including higher insulin, proinsulin, glucose, glucagon, and triglyceride (TG) lev

124 ucose-dependent insulin secretion, shortened proinsulin half-life, and lowered intracellular proinsul

125 nclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.

126 nown to fold insulin-like growth factors, in proinsulin handling within beta-cells.

127 c reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaper

128 RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin,

129 and proinsulin hexamers, suggesting that the proinsulin hexamer retains an A/B structure similar to t

130 i region, reflecting either slow kinetics of proinsulin hexamerization, steps in formation of nascent

131 within core insulin moieties of insulin and proinsulin hexamers, suggesting that the proinsulin hexa

132 Here, we engineered a variant of human proinsulin (hProinsulin-B10) into an Ad vector and demon

133 The clinical mutant [L-Ser(B8)]proinsulin impaired folding at pH 7.5 even in the presen

134 d Diabetes of Youth (MIDY), misfolded mutant proinsulin impairs ER exit of co-expressed wild-type pro

135 s blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and incr

136 otein oxidase of the ER lumen, engages Akita proinsulin in a novel way, reducing proinsulin disulfide

137 of ongoing misfolding of a subpopulation of proinsulin in beta cells, the rate-limiting step in tran

138 d a high accumulation of vesicles containing proinsulin in beta-cells from Ab+ donors, suggesting a d

139 autoantigens in human T1D, GAD65, IA-2, and proinsulin in exosomes, which are taken up by and activa

140 The expression level of human proinsulin in milk was as high as 8.1 g/L.

141 Localized delivery of proinsulin in non-obese diabetic (NOD) mice using the co

142 pressing equally small amounts of transgenic proinsulin in pancreatic beta-cells.

143 Accumulation of misfolded proinsulin in the beta-cell leads to dysfunction induced

144 oluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby bl

145 ates interfere with the folding of wild-type proinsulin in the endoplasmic reticulum, ultimately decr

146 direct physical interaction between PDI and proinsulin in the ER of pancreatic beta-cells, in a mann

147 PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and B

148 plore the production of high levels of human proinsulin in the milk of dairy animals.

149 s to test the feasibility of producing human proinsulin in the milk of transgenic animals.

150 merase (PDI) has long been assumed to assist proinsulin in this process.

151 Central tolerance to proinsulin in transgenic NOD mice was broken on a granzy

152 mbers of Tregs, including those specific for proinsulin, in the thymus and peripheral lymphoid tissue

153 before disease onset and that production of proinsulin increases.

154 ize that PDI exhibits unfoldase activity for proinsulin, increasing retention of proinsulin within th

155 nts bind and block ER exit of wild-type (WT) proinsulin, inhibiting insulin production.

156 ith inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compar

157 ferences were found in fasting or stimulated proinsulin/insulin ratio, and (2) higher rates of T2DM r

158 -sectional studies comparing (1) glucose and proinsulin/insulin response to a standardized liquid mix

159 d proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated ins

160 ad defective insulin secretion with elevated proinsulin:insulin ratios compared with control strains.

161 cteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsuli

162 T-cell responses to beta-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 pep

163 Elevated levels of proinsulin and proinsulin intermediates are markers of beta-cell dysfun

164 Several studies suggest that proinsulin is an early and integral target autoantigen i

165 the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its ce

166 The Golgi regional distribution of proinsulin is dynamic, influenced by fasting/refeeding,

167 ccumulation of hPro-CpepSfGFP and endogenous proinsulin is in the Golgi region, as if final stages of

168 in dimers and hexamers are well established, proinsulin is refractory to crystallization.

169 sults demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing an

170 the function of the 35 residue C-peptide of proinsulin is replaced by a single covalent bond--as a k

171 previous results revealed that mutant Akita proinsulin is triaged by ER-associated degradation (ERAD

172 tein chaperones in the handling of wild-type proinsulin is underinvestigated.

173 ut was finally clarified by the discovery of proinsulin, its single-chain precursor.

174 sulin molecule and three analogs: [D-Ala(B8)]proinsulin, [L-Ala(B8)]proinsulin, and the clinical muta

175 ion in Akita mice, which carry a mutation in proinsulin, leading to its severe misfolding.

176 transplantation because serum C-peptide and proinsulin levels are difficult to interpret due to the

177 hese data suggest that pancreatic Zn(2+) and proinsulin levels covary but are inversely variant with

178 rg) associated with T2D risk and glucose and proinsulin levels.

179 in impairs ER exit of co-expressed wild-type proinsulin, limiting insulin production and leading to e

180 Iron normalizes ms(2)t(6)A37 and proinsulin lysine incorporation, restoring insulin conte

181 rowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tol

182 ting that enhancing the oxidative folding of proinsulin may be a viable therapeutic strategy in the t

183 Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin

184 might nevertheless be beneficial in limiting proinsulin misfolding and its adverse downstream consequ

185 es common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of

186 We studied the effects of proinsulin misfolding on autophagy and the impact of sti

187 before the development of diabetes caused by proinsulin misfolding with ER stress, i.e., the existenc

188 This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged

189 s was used to prepare the wild-type [Gly(B8)]proinsulin molecule and three analogs: [D-Ala(B8)]proins

190 Although an NMR structure of an engineered proinsulin monomer has been reported, structures of the

191 xidation between the respective C-domains of proinsulin monomers and hexamers suggest that this loop

192 etion, which was accompanied by the enhanced proinsulin mRNA transcription and insulin content.

193 1alpha deletion was primarily due to reduced proinsulin mRNA translation primarily because of defecti

194 achinery components used to triage the Akita proinsulin mutant, including the Hrd1-Sel1L membrane com

195 ), characterized by insulin deficiency, MIDY proinsulin mutants misfold and fail to exit the endoplas

196 expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by q

197 n principle, selective destruction of mutant proinsulin offers a rational approach to rectify the ins

198 rglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, po

199 the beta-cell ER fails to process sufficient proinsulin once it becomes overloaded.

200 administration of T1D-related autoantigens [proinsulin or glutamic acid decarboxylase 65 (GAD)] dela

201 w-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PA

202 ter PDI-KD, enhanced export is selective for proinsulin over other secretory proteins, but the same e

203 In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as

204 group showed increases in both C-peptide and proinsulin (P <= 0.01).

205 ulins, we find that both WT-WT and WT-mutant proinsulin pairs exhibit FRET.

206 sulin peptide, but cross-reacted with native proinsulin peptide upon restimulation.

207 could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proins

208 Here we show that proinsulin peptides are targeted by islet-infiltrating T

209 epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in beta ce

210 ot develop frank diabetes, yet the misfolded proinsulin perturbs insulin production from endogenous p

211 enicity to BMDCs, which are characterized by proinsulin (PI) and TNF-alpha coexpression; coincubation

212 We report the role of proinsulin (PI) expression on the development and activa

213 el strain for human type 1 diabetes, express proinsulin (PI) in the thymus.

214 that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (B

215 sing only approximately 0.04% of total islet proinsulin plus insulin, exerting no metabolic impact.

216 For insulin synthesis, the proinsulin precursor is translated at the endoplasmic re

217 nctional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in

218 ed expression of the major genes involved in proinsulin processing and the pancreatic beta cell stimu

219 Defective proinsulin processing has been implicated in the pathoge

220 nt PC2 expression may contribute to impaired proinsulin processing in beta-cells of patients with dia

221 F4G1) and carboxypeptidase E (CPE)-dependent proinsulin processing in betaOGTKO mice.

222 lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin cont

223 Proinsulin processing is quite sensitive to nutrient flu

224 on and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal.

225 d plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for

226 roliferation, altered insulin production and proinsulin processing, and increased islet ER stress and

227 sulin signaling, translation initiation, and proinsulin processing, and provide previously unidentifi

228 of insulin granules in beta-cells, impaired proinsulin processing, increased the serum proinsulin:in

229 ucose-stimulated insulin secretion, impaired proinsulin processing, inflammation, formation of islet

230 ablished susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin se

231 -binding protein 1, together leading to poor proinsulin processing.

232 a need to revise the long-standing theory of proinsulin processing.

233 on were higher in PI-CF, suggesting impaired proinsulin processing.

234 ich could degrade a subset of mRNAs encoding proinsulin-processing enzymes.

235 The protein diastereomer [D-Ala(B8)]proinsulin produced higher folding yields at all pH valu

236 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX

237 relatively limited accumulation of misfolded proinsulin protein and maintenance of endogenous insulin

238 ons investigated, once folded the [L-Ser(B8)]proinsulin protein molecule bound to the insulin recepto

239 mature alpha cells and although they produce proinsulin protein, they do not secrete significant amou

240 (2) = 0.57, P = 0.05), nor did mean baseline proinsulin (R (2) = 0.45, P = 0.10).

241 n of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4(+) T cells grown from islets of

242 e pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic i

243 T C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively co

244 duction in the inflammatory profile of their proinsulin-responsive CD4(+) T cells, and improved regul

245 In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in panc

246 The mature insulin derived from the milk proinsulin retained its biological activity.

247 in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and be

248 TP6ap2 knockdown but paradoxically increased proinsulin secretion.

249 Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation

250 -limiting step in transport of the remaining proinsulin shifts to the ER.

251 od, we generated and characterized 24 unique proinsulin-specific CD4(+) T cell clones from the periph

252 ancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4.

253 In type 1 diabetes, proinsulin-specific CD8(+) T cells, escaping central and

254 D prevention, potentially by augmentation of proinsulin-specific IL-4 production.

255 sequences matching the TCR sequences of the proinsulin-specific T cell clones in pancreatic lymph no

256 lood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironmen

257 sed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors.

258 Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-res

259 25W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM.

260 We measured Zn(2+), insulin, and proinsulin stainings and performed intraperitoneal gluco

261 omplexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activitie

262 tory capacity of the beta cell for increased proinsulin synthesis and to limit oxidative stress that

263 We attenuated the beta-cell ER proinsulin synthesis with a treat-to-target insulin ther

264 Upon chronic up-regulation of proinsulin synthesis, misfolded proinsulin can accumulat

265 In hProCpepGFP mice, human proinsulin (tagged with green fluorescent protein [GFP]

266 The folding of proinsulin, the single-chain precursor of insulin, ensur

267 stress induced by accumulation of misfolded proinsulin, thereby improving diabetes and preventing be

268 s and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a p

269 of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile.

270 ata establish that upon PDI-KD, oxidation of proinsulin to form native disulfide bonds is unimpaired

271 uctase of over 17 members, can interact with proinsulin to influence disulfide maturation.

272 highly targeted and reproducible delivery of proinsulin to local immune cells warrants further evalua

273 s the steady-state distribution of wild-type proinsulin to the ER.

274 Fasting proinsulin-to-C-peptide and proinsulin secretory ratios

275 Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in t

276 hallmark of type 2 diabetes is a failure of proinsulin-to-insulin processing in pancreatic beta-cell

277 n betaOGTKO islets rescued the dysfunctional proinsulin-to-insulin ratio.

278 pecific staining for insulin, C-peptide, and proinsulin together with insulin secretory granules by e

279 the same effect is observed for recombinant proinsulin trafficking upon PDI-KD in heterologous cells

280 n protein design through the introduction of proinsulin-transferrin (ProINS-Tf) fusion protein as a l

281 Proinsulin-transferrin (ProINS-Tf) fusion protein was ev

282 ntial evidence that mouse beta-cells process proinsulin using prohormone convertase 1/3 (PC1/3) and t

283 Misfolding of proinsulin variants in the pancreatic beta-cell, a monog

284 insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy

285 detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals.

286 Importantly, ER stress induced by misfolded proinsulin was limited by increased expression of Ero1al

287 Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blo

288 ific insulin immunoassay (crossreactive with proinsulin) was used.

289 ing G9Calpha(-/-)CD8(+) T cells specific for proinsulin, we studied the mechanisms by which LNSC regu

290 Using Cerulean and Venus-tagged proinsulins, we find that both WT-WT and WT-mutant proin

291 ulating large quantities of misfolded mutant proinsulin, whereas another subset of beta-cells has muc

292 shows larger beta-cell vesicles enriched for proinsulin, whereas smaller vesicles predominantly conta

293 ied novel (to our knowledge) epitopes within proinsulin, which are presented by HLA class II molecule

294 proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, pot

295 gly, overexpressing Grp170 also liberates WT proinsulin, which is no longer trapped in these high-MW

296 Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune dia

297 Human proinsulin with C-peptide-bearing Superfolder Green Fluo

298 Pase, which couples the cytosolic arrival of proinsulin with its proteasomal degradation.

299 s has much less accumulated misfolded mutant proinsulin, with some of these cells containing abundant

300 vity for proinsulin, increasing retention of proinsulin within the ER of pancreatic beta-cells.