Elevated Proinsulin Levels Related to Islet Cell Antibodies in First-Degree Relatives of IDDM Patients

Spinas, Giatgen A.; Snorgaard, Ole; Hartling, Svend G; Oberholzer, M.; Berger, W

doi:10.2337/diacare.15.5.632

Cited by 32 publications

(27 citation statements)

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“…Indeed, our data show a marked increase in the proportion of newly synthesized proinsulin after 48 h IL-1b treatment. These islets have previously been shown to have decreased insulin release in response to glucose and decreased insulin and DNA content (Bendtzen et al 1986, Sandler et al 1987, Spinas et al 1992. Our results are in line with previously published data, indicating decreased conversion rate in rat islets after 24-h IL-1b (Hansen et al 1988) and that exposure of b-cells to IL-1b for 24 h suppresses both proinsulin biosynthesis as well as the expression of PC2 by 46% via an NO-mediated pathway (Zambre et al 2001).…”

Section: Discussionsupporting

confidence: 92%

Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1β

Börjesson¹,

Carlsson²

2007

Journal of Endocrinology

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In order to elucidate a possible relationship between b-cell function and conversion of proinsulin to insulin, isolated rat pancreatic islets were maintained in tissue culture for 1 week at various glucose concentrations (5 . 6-56 mM). Studies were also conducted on islets cultured for 48 h with interleukin-1b (IL-1b). By pulse-chase labelling and immunoprecipitation, the relative contents of newly synthesized proinsulin and insulin were determined. ELISA was used to analyse insulin and proinsulin content in medium and within islets. Using real-time PCR, the mRNA levels of proinsulin converting enzymes (PC1 and PC2) were studied. Islets cultured at 56 mM glucose had an increased proportion of newly synthesized proinsulin when compared with islets cultured at 5 . 6 mM glucose after a 90-min chase periods, however, no difference was observed after culture at 11 and 28 mM glucose. ELISA measurements revealed that culture at increased glucose concentrations as well as islet exposure to IL-1b increased proinsulin accumulation in the culture media. The mRNA expression of PC1 was increased after culture at 11 and 28 mM glucose. Treatment for 48 h with IL-1b increased the proportion of proinsulin both at 45 and 90 min when compared with control islets. These islets also displayed a decreased mRNA level of PC1 as well as PC2. Calculations of the half-time for proinsulin demonstrated a significant prolongation after treatment with IL-1b. We conclude that a sustained functional stimulation by glucose of islets is coupled to a decreased conversion of proinsulin which is also true for islets treated with IL-1b. This may contribute to the elevated levels of proinsulin found both at the onset of type 1 diabetes as well as in type 2 diabetes.

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Section: Discussionsupporting

confidence: 92%

Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1β

Börjesson¹,

Carlsson²

2007

Journal of Endocrinology

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“…Combining these observations with their findings in the study with long-term discordance for IDDM (2), the authors concluded that the changes in B cell function, characterised by increased fasting PIM concentrations, do not necessarily progress to diabetes (19). However, we have previously found greater PIM concentrations in relatives with ICA, even though also the ICA-negative relatives had increased PIM concentrations compared with those in unrelated controls (9). The fact that HLA sharing is not associated with increased PIM concentrations speaks against a dysfunction of the B cells that would progress to IDDM in siblings with increased concentrations of PIM (1, 3).…”

Section: Discussionsupporting

confidence: 52%

“…The increased PIM in healthy siblings of patients with IDDM could be an indicator for risk of progression to IDDM, but this is unlikely, as the twins and siblings (1,2) were discordant for several years, and there was no difference in PIM concentrations between HLA-identical, haploidentical and non-identical siblings (1). Islet cell antibodies (ICA) have been observed to be associated with increased PIM concentrations (9), but most of the first-degree relatives in previous studies tested negative for ICA (1,2,9). However, in some siblings we found increased PIM concentrations or PIM/C-peptide ratios associated with decreased B cell function and later progression to IDDM (10).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Hartling

Knip²,

Röder³

et al. 1997

European Journal of Endocrinology

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Objective: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. Design and methods: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. Results: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. Conclusion: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

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“…Up to a 500-fold excess of C-peptide did not interfere in the proinsulin assay. Because of high crossreactivity with conversion intermediates [74% for split (32)(33) proinsulin, 65% for des (31,32) proinsulin, 78% for split(65-66) proinsulin and 99% for des(64,65) proinsulin], the assay was considered to measure total proinsulin immunoreactive material [27]. It comprises two separate overnight incubations allowing the monoclonal antibodies used in the assay to compete with IAA (if present in the plasma tested) for binding to proinsulin.…”

Section: Methodsmentioning

confidence: 99%

Proinsulin levels and the proinsulin:c-peptide ratio complement autoantibody measurement for predicting type 1 diabetes

et al. 2005

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Aims/hypothesis: We investigated whether random proinsulin levels and proinsulin:C-peptide ratio (PI:C) complement immune and genetic markers for identifying relatives at high risk of type 1 diabetes. Materials and methods: During an initial sampling, random glycaemia, proinsulin, PI:C and HLA DQ genotype were determined in 561 non-diabetic first-degree relatives who had been positive for islet autoantibodies on one or more occasions and in 561 age-and sex-matched persistently antibodynegative relatives. Results: During follow-up (median 62 months), 46 relatives with antibodies at entry developed type 1 diabetes. At baseline, antibody-positive relatives (n=338) had higher PI:C values (p<0.001) than antibodynegative subjects with (n=223) or subjects without (n=561) later seroconversion. Proinsulin and PI:C were graded according to risk of diabetes as expressed by positivity for (multiple) antibodies or IA-2 antibodies, especially in persons carrying the high-risk HLA DQ2/DQ8 genotype and in prediabetic relatives. In the presence of multiple or IA-2 antibodies, a PI:C ratio exceeding percentile 66 of all antibody-negative relatives at entry (n=784) conferred a 5-year diabetes risk of 50% and 68%, respectively (p<0.001 vs 13% for same antibody status with PI:C

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Elevated Proinsulin Levels Related to Islet Cell Antibodies in First-Degree Relatives of IDDM Patients

Abstract: Fasting proinsulin concentrations were raised not only in siblings but also in parents and children of IDDM patients. Because proinsulin is more elevated in ICA+ than in ICA- subjects, increased proinsulin levels could reflect minor beta-cell damage due to previous immunological attack.

Cited by 32 publications

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Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1β

Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1β

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland

Proinsulin levels and the proinsulin:c-peptide ratio complement autoantibody measurement for predicting type 1 diabetes

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