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Proinsulin and the genetics of diabetes mellitus.

ABSTRACT: Insulin plays a central role in the regulation of vertebrate metabolism. The hormone, the post-translational product of a single-chain precursor, is a globular protein containing two chains, A (21 residues) and B (30 residues). Recent advances in human genetics have identified dominant mutations in the insulin gene causing permanent neonatal-onset DM(2) (1-4). The mutations are predicted to block folding of the precursor in the ER of pancreatic beta-cells. Although expression of the wild-type allele would in other circumstances be sufficient to maintain homeostasis, studies of a corresponding mouse model (5-7) suggest that the misfolded variant perturbs wild-type biosynthesis (8, 9). Impaired beta-cell secretion is associated with ER stress, distorted organelle architecture, and cell death (10). These findings have renewed interest in insulin biosynthesis (11-13) and the structural basis of disulfide pairing (14-19). Protein evolution is constrained not only by structure and function but also by susceptibility to toxic misfolding.

SUBMITTER: Weiss MA

PROVIDER: S-EPMC2740536 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Proinsulin and the genetics of diabetes mellitus.

Weiss Michael A MA

The Journal of biological chemistry 20090424 29

Insulin plays a central role in the regulation of vertebrate metabolism. The hormone, the post-translational product of a single-chain precursor, is a globular protein containing two chains, A (21 residues) and B (30 residues). Recent advances in human genetics have identified dominant mutations in the insulin gene causing permanent neonatal-onset DM(2) (1-4). The mutations are predicted to block folding of the precursor in the ER of pancreatic beta-cells. Although expression of the wild-type al ...[more]

PMID: 19395706

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Project description:INTRODUCTION:Gestational diabetes mellitus (GDM) is a common metabolic disorder occurring in up to 10% of pregnancies in the western world. Most women with GDM are asymptomatic; therefore, it is important to screen, diagnose and manage the condition as it is associated with an increased risk of maternal and perinatal complications. Diagnosis of GDM is made in the late second trimester or early third trimester because accurate diagnosis or risk stratification in the first trimester is still lacking. An increase in serum proinsulin may be seen earlier in pregnancy and before a change in glycaemic control can be identified. This study will aim to establish if fasting proinsulin concentrations at 16-18 weeks gestation will help to identify or risk stratify high-risk pregnant women with GDM. METHODS AND ANALYSIS:This is a prospective, longitudinal cohort study. Two oral glucose tolerance tests will be carried out at 16-18 and 24-28 weeks gestation in 200 pregnant women with at least one risk factor for GDM (body mass index>30?kg/m2, previous macrosomic baby (>4.5?kg), previous gestational diabetes, first degree relative with type 2 diabetes mellitus) recruited from antenatal clinics. Blood samples will be taken fasting and at 30?min, 1 and 2?hours following the 75?g glucose load. In addition, a fasting blood sample will be taken 6-weeks post delivery. All samples will be analysed for glucose, insulin, C peptide and proinsulin. Recruitment began in November 2017. Optimal cut-off points for proinsulin to diagnose gestational diabetes according to National Institute for Health and Care Excellence (2015) criteria will be established by the receiver operating characteristic plot and sensitivity and specificity will be calculated to assess the diagnostic accuracy of proinsulin at 16-18 weeks gestation. ETHICS AND DISSEMINATION:This study received ethical approval from the Wales Research Ethics Committee (Panel 6) (Ref. 17/WA/0194). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:ISRCTN16416602; Pre-results.

Dataset Information

Proinsulin and the genetics of diabetes mellitus.

Publications

Proinsulin and the genetics of diabetes mellitus.

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