ライフサイエンスコーパス: proinsulin

1 (cystines 18-61 in IGF-I and 19-85 in human proinsulin).

2 lin receptor more effectively than wild-type proinsulin.

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

4 m a human haplotype expressing low levels of proinsulin.

5 rt from cells co-expressing misfolded mutant proinsulin.

6 ed with improved oxidative folding of mutant proinsulin.

7 y of transcripts, including the one encoding proinsulin.

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

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

10 ccessible to modification in insulin but not proinsulin.

11 endoplasmic reticulum (ER) and retention of proinsulin.

12 omers with impaired secretion of the variant proinsulin.

13 in combination and the in vitro refolding of proinsulin.

14 betes because of the expression of misfolded proinsulin.

15 ombination, and blocks cellular secretion of proinsulin.

16 -I) has significant structural homology with proinsulin.

17 increase the degree of conversion of soluble proinsulin.

18 -migrates with the aberrant isomer 1 band of proinsulin.

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

20 I presentation and proteolytic processing of proinsulin.

21 plasma levels of immunoreactive insulin and proinsulin.

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

23 The binding of a proinsulin epitope, proinsulin-1(47-64) (PI-1[47-64]), to the MHC class II m

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

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

26 Proinsulin/alum monotherapy failed to correct hyperglyce

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

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

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

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

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

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

33 ting peptide (c-peptide) aids the folding of proinsulin and has been considered to have little biolog

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

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

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

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

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

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

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

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

42 ingly, numerous CK19(+) cells costained with proinsulin and PDX-1 antibodies.

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

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

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

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

47 scription factors, appropriate processing of proinsulin and the presence of mature endocrine secretor

48 In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only

49 Both proinsulin and thyroglobulin normally form homodimers; t

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

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

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

53 Adjustment for weight, fasting insulin, proinsulin, and other metabolic factors combined explain

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

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

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

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

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

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

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

61 tant proinsulin or with "hProCpepGFP" (human proinsulin bearing emerald-GFP within the C-peptide), im

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

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

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

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

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

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

68 n between the TCF7L2 risk allele and fasting proinsulin but not insulin levels is notable, as, in thi

69 mean change in weight, fasting insulin, and proinsulin, but not IGR, differed between groups during

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

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

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

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

74 Residue B5, a site of mutation in proinsulin causing neonatal diabetes, is thus of broad b

75 lin expression from a single wild-type human proinsulin cDNA.

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

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

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

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

80 Proinsulin contains a native-like insulin moiety (A- and

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

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

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

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

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

86 oinsulin:insulin ratios, indicating improved proinsulin conversion.

87 Endogenous proinsulin coprecipitates with hPro-CpepSfGFP and even m

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

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

90 roperties of [Val(A16)]insulin and [Val(A16)]proinsulin demonstrate that essential contributions of c

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

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

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

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

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

96 Therapeutic administration of proinsulin DNA was accompanied by a rapid decrease in th

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

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

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

100 T-cell reactivity to the proinsulin epitope was examined in I-A(g7+) and I-A(k+)

101 The binding of a proinsulin epitope, proinsulin-1(47-64) (PI-1[47-64]), t

102 s and T cells reacting with multiple insulin/proinsulin epitopes are present.

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

104 which, in addition to expressing endogenous proinsulin, exhibit beta-cell-specific expression of hPr

105 Proinsulin exhibits a single structure, whereas insulin-

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 nct migrating species are also produced upon proinsulin expression from a single wild-type human proi

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

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

113 However, misfolded proinsulin fails the conversion to active insulin.

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

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

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

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

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

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

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 Although rats and mice have two proinsulin genes, three distinct migrating species are a

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

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

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

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

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

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

129 A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mou

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

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

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

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

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

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

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

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

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

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

140 hat explains the accumulation of denaturated proinsulin in the endoplasmic reticulum (ER) of beta-cel

141 ously been shown that misfolded mutant Akita proinsulin in the endoplasmic reticulum engages directly

142 that misfolded proinsulin perturbs bystander proinsulin in the endoplasmic reticulum, leading to beta

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

144 ulate the trafficking and quality control of proinsulin in the ER relative to the physiological deman

145 n, a much smaller peptide cosynthesized with proinsulin in the ER.

146 ey prevent normal folding and progression of proinsulin in the insulin secretory pathway.

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

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

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

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

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

152 before disease onset and that production of proinsulin increases.

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

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

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

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

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

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

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

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

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

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

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

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

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

166 al structure of insulin is well established, proinsulin is refractory to crystallization.

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

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

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

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

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

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

173 The risk allele increases proinsulin levels and diminishes the 60-min but not 30-m

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

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

176 l assessment of beta-cell function (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio.

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

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

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

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

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

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

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

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

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

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

187 The abnormally folded proinsulin molecule may induce the unfolded protein resp

188 These led to the production of (pre)proinsulin molecules with markedly different trafficking

189 pairing the trafficking of these "bystander" proinsulin molecules.

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 ce of chain topology is demonstrated by mini-proinsulin (MP), a single-chain analogue in which the C-

193 s of both the C-peptide blood levels and the proinsulin mRNA levels in the islets support our conclus

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

195 1alpha deletion was primarily due to reduced proinsulin mRNA translation primarily because of defecti

196 in-diabetic LEW rats and insulin and porcine proinsulin mRNA-expressing cell engraftment in the kidne

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

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

199 The "Akita-type" proinsulin mutation, which causes dominant-negative diab

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

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

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

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

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

205 y in protein complexes either with nonmutant proinsulin or with "hProCpepGFP" (human proinsulin beari

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

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

208 oinsulin (P = 4.55 x 10(-9)) and 32,33 split proinsulin (P = 1.72 x 10(-4)) relative to total insulin

209 ongly and positively associated with fasting proinsulin (P = 4.55 x 10(-9)) and 32,33 split proinsuli

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

211 h anti-CD3epsilon-specific antibody and i.n. proinsulin peptide can reverse recent-onset diabetes in

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

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

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

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

216 The data support that misfolded proinsulin perturbs bystander proinsulin in the endoplas

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

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

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

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

221 As a tool to explore proinsulin (PI) trafficking, a human PI cDNA has been co

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

223 the anthrax protective antigen (PA) or human proinsulin (Pins) fused with the cholera toxin B-subunit

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

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

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

227 Of note, both major genes involved in proinsulin processing (PC1, PC2) contain TCF-binding sit

228 Pc1 (N222D) that leads to obesity, abnormal proinsulin processing and multiple endocrinological defe

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

230 Defective proinsulin processing leads to glucose intolerance, but

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

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

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

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

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

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

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

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

239 major factors influencing the efficiency of proinsulin processing.

240 se to type 2 diabetes by impairing beta-cell proinsulin processing.

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

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

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

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

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

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

247 The structure of proinsulin provides a foundation for studies of insulin

248 creatic islets correlated with expression of proinsulin (r(2) = 0.84-0.90, P < 0.00063).

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

250 We demonstrate that the folding of proinsulin requires a flexible N-terminal hydrophobic re

251 ndings demonstrate that efficient folding of proinsulin requires N-terminal sequences that are dispen

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

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

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

255 clonal beta-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay.

256 TP6ap2 knockdown but paradoxically increased proinsulin secretion.

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

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

259 Smaller-volume misfolded proinsulin species may also win the passage competition

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

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

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

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

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

265 25W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM.

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

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

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

269 fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity f

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

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

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

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

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

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

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

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

278 vel that can inhibit the transport of native proinsulin to the GA influences to a lesser extent the t

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

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

281 man correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly inversely

282 unction (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio.

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

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

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

286 t of both native insulin genes and a mutated proinsulin transgene, alanine at position B16 in preproi

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

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

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

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

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

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

293 ulinogenic index (IGR), fasting insulin, and proinsulin were predictive of diabetes, though to differ

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

295 favorable changes in insulin sensitivity and proinsulin, which contribute to a reduction in the risk

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

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

298 A model is provided by proinsulin, whose misfolding is associated with beta-cel

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

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

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

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