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Journal of Medicine and Life 2013The objective of this study was to assess the relationship between fasting proinsulin (PI) and age in general population and to determine whether there are differences...
OBJECTIVE
The objective of this study was to assess the relationship between fasting proinsulin (PI) and age in general population and to determine whether there are differences regarding this association in obese and non-obese persons.
METHODS
A random population-based sample (n=656) of Romanians (26-80 years) living in Bucharest, Romania was studied; 432 persons had diabetes and they were not analyzed in this paper. Circulating levels of fasting plasma glucose (FPG), fasting plasma insulin (FPI), fasting plasma proinsulin (FPP), fasting plasma C-peptide, HbA1c, lipid profile, creatinine, urea were measured. The homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-B, and Quicki index were also calculated.
RESULTS
For all participants proinsulin was the highest in the third quartile of the age group (59-67 years), with a median proinsulin of 5.8 pmol/L. Subsequently, proinsulin increased with age, from 2.6 pmol/L for participants aged 20-51 years, to 4.7 pmol/L for participants aged 51-59 years; proinsulin levels decreased in the upper quartile 4.8 pmol/L for those aged over 67 years. In sex-specific analyses, proinsulin increased with age for both men and women, except for those in the upper quartile. The prevalence of the obesity was 30.4% (n=68); obesity prevalence did not increase with age (p=0.26). Fasting proinsulin levels significantly increased with body mass index (BMI) category from lean (n=67, 2.9 pmol/L) to overweight (n=89, 4.5 pmol/L) and obese (n=69, 6.63 pmol/L) (p<0.0001).
CONCLUSIONS
Our study has demonstrated a close association between age and elevated proinsulin and proinsulin/insulin ratio in general population.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; C-Peptide; Female; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Proinsulin
PubMed: 24868254
DOI: No ID Found -
Diabetes Sep 2022Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a...
Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.
Topics: Animals; Autoantigens; Autoimmunity; Diabetes Mellitus, Type 1; Humans; Insulin; Islets of Langerhans; Mice; Mice, Inbred NOD; Proinsulin; Protein Processing, Post-Translational; Proteins
PubMed: 35730902
DOI: 10.2337/db21-0989 -
Frontiers in Endocrinology 2022The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin's biosynthetic precursor. Also designated (MIDY), this...
The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin's biosynthetic precursor. Also designated (MIDY), this syndrome defines molecular determinants of foldability in the endoplasmic reticulum (ER) of β-cells. Here, we describe a peptide model of a key proinsulin folding intermediate and variants containing representative clinical mutations; the latter perturb invariant core sites in native proinsulin (Leu→Pro, Leu→Pro, and Phe→Ser). The studies exploited a 49-residue single-chain synthetic precursor (designated DesDi), previously shown to optimize efficiency of disulfide pairing. Parent and variant peptides contain a single disulfide bridge (cystine B19-A20) to provide a model of proinsulin's first oxidative folding intermediate. The peptides were characterized by circular dichroism and redox stability in relation to effects of the mutations on (a) foldability of the corresponding insulin analogs and (b) ER stress induced in cell culture on expression of the corresponding variant proinsulins. Striking correlations were observed between peptide biophysical properties, degree of ER stress and age of diabetes onset (neonatal or adolescent). Our findings suggest that age of onset reflects the extent to which nascent structure is destabilized in proinsulin's putative folding nucleus. We envisage that such peptide models will enable high-resolution structural studies of key folding determinants and in turn permit molecular dissection of phenotype-genotype relationships in this monogenic diabetes syndrome. Our companion study (next article in this issue) employs two-dimensional heteronuclear NMR spectroscopy to define site-specific perturbations in the variant peptides.
Topics: Adolescent; Diabetes Mellitus; Disulfides; Humans; Insulin; Peptides; Proinsulin; Protein Folding
PubMed: 35299972
DOI: 10.3389/fendo.2022.821069 -
Frontiers in Endocrinology 2022An end-of-fast insulin level ≥ 3 µIU/ml, C-peptide level ≥ 0.6 ng/ml, and proinsulin level ≥ 5 pmol/l with end-of-fast glucose level ≤ 3.0 mmol/l...
PURPOSE
An end-of-fast insulin level ≥ 3 µIU/ml, C-peptide level ≥ 0.6 ng/ml, and proinsulin level ≥ 5 pmol/l with end-of-fast glucose level ≤ 3.0 mmol/l have been established as the criteria for endogenous hyperinsulinemic hypoglycemia. However, all these criteria have been proposed based on patients in Western populations. This study aimed to determine the optimal criteria using a large series of Chinese patients.
METHODS
This retrospective study comprised 144 patients with surgically proven insulinoma and 40 controls who underwent a 72-h fasting test at the Peking Union Medical College Hospital(PUMCH) from 2000 to 2020. Receiver operating characteristic curves were used for analysis.
RESULTS
In this series of patients, the optimal diagnostic criteria for endogenous hyperinsulinemic hypoglycemia were insulin ≥ 5.5 μIU/ml, C-peptide ≥ 0.7 ng/ml, and proinsulin ≥ 12 pmol/l with end-of-fast glucose ≤ 2.8 mmol/l; the sensitivity and specificity were 99% and 100% for insulin, 100% and 100% for C-peptide, and 93% and 100% for proinsulin, respectively. The diagnostic efficacy of the criteria based on Western populations was then tested. The sensitivity and specificity of end-of-fast insulin ≥ 3 μIU/ml, C-peptide ≥ 0.6 ng/ml, and proinsulin ≥ 5 pmol/l with end-of-fast glucose ≤ 3.0 mmol/l were 100% and 83%, 100% and 80%, and 97% and 78%, respectively.
CONCLUSIONS
New and optimized diagnostic criteria for endogenous hyperinsulinemic hypoglycemia in Chinese populations have been proposed, and these criteria yield satisfactory accuracy.
Topics: Humans; Proinsulin; C-Peptide; Retrospective Studies; Fasting; Pancreatic Neoplasms; Insulin; Congenital Hyperinsulinism; Glucose; China
PubMed: 36339408
DOI: 10.3389/fendo.2022.994707 -
Atherosclerosis Nov 2017Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are... (Meta-Analysis)
Meta-Analysis
Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation.
BACKGROUND AND AIMS
Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.
METHODS
We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.
RESULTS
We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMT and IMT (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.
CONCLUSIONS
We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
Topics: Asymptomatic Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Chromosomes, Human, Pair 15; Europe; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Linear Models; Male; Mendelian Randomization Analysis; Phenotype; Polymorphism, Single Nucleotide; Proinsulin; Quantitative Trait Loci; Risk Factors; Vascular Remodeling
PubMed: 29040868
DOI: 10.1016/j.atherosclerosis.2017.09.031 -
Protein Expression and Purification Oct 2020Assessing the specificity of protein binders is an essential first step in protein biomarker assay development. Affimers are novel protein binders and can potentially...
INTRODUCTION
Assessing the specificity of protein binders is an essential first step in protein biomarker assay development. Affimers are novel protein binders and can potentially replace antibodies in multiple protein capture-based assays. Affimers are selected for their high specificity against the target protein and have benefits over antibodies like batch-to-batch reproducibility and are stable across a wide range of chemical conditions. Here we mimicked a typical initial screening of affimers and commercially available monoclonal antibodies against two non-related proteins, IL-37b and proinsulin, to assess the potential of affimers as alternative to antibodies.
METHODS
Binding specificity of anti-IL-37b and anti-proinsulin affimers and antibodies was investigated via magnetic bead-based capture of their recombinant protein targets in human plasma. Captured proteins were analyzed using SDS-PAGE, Coomassie blue staining, Western blotting and LC-MS/MS-based proteomics.
RESULTS
All affimers and antibodies were able to bind their target protein in human plasma. Gel and LC-MS/MS analysis showed that both affimer and antibody-based captures resulted in co-purified background proteins. However, affimer-based captures showed the highest relative enrichment of IL-37b and proinsulin.
CONCLUSIONS
For both proteins tested, affimers show higher specificity in purifying their target proteins from human plasma compared to monoclonal antibodies. These results indicate that affimers are promising antibody-replacement tools for protein biomarker assay development.
Topics: Biomarkers; Biomimetic Materials; Humans; Interleukin-1; Proinsulin; Recombinant Proteins
PubMed: 32461183
DOI: 10.1016/j.pep.2020.105677 -
Current Diabetes Reports Oct 2016The hallmark of type 1 diabetes (T1D) is a decline in functional β-cell mass arising as a result of autoimmunity. Immunomodulatory interventions at disease onset have... (Review)
Review
The hallmark of type 1 diabetes (T1D) is a decline in functional β-cell mass arising as a result of autoimmunity. Immunomodulatory interventions at disease onset have resulted in partial stabilization of β-cell function, but full recovery of insulin secretion has remained elusive. Revised efforts have focused on disease prevention through interventions administered at earlier disease stages. To support this paradigm, there is a parallel effort ongoing to identify circulating biomarkers that have the potential to identify stress and death of the islet β-cells. Whereas no definitive biomarker(s) have been fully validated, several approaches hold promise that T1D can be reliably identified in the pre-symptomatic phase, such that either β-cell preservation or immunomodulatory agents might be employed in at-risk populations. This review summarizes the most promising protein- and nucleic acid-based biomarkers discovered to date and reviews the context in which they have been studied.
Topics: Biomarkers; C-Peptide; DNA Methylation; Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Proinsulin; RNA, Untranslated
PubMed: 27541297
DOI: 10.1007/s11892-016-0783-x -
BMC Endocrine Disorders Jan 2021Currently, there is a lack of data relating to glycemic parameters and their relationship with C-peptide (CP) and proinsulin (PI) during the partial remission period... (Comparative Study)
Comparative Study
A comparison of glycemic parameters and their relationship with C-peptide and Proinsulin levels during partial remission and non-remission periods in children with type 1 diabetes mellitus - a cross-sectional study.
BACKGROUND
Currently, there is a lack of data relating to glycemic parameters and their relationship with C-peptide (CP) and proinsulin (PI) during the partial remission period (PRP) in type 1 diabetes mellitus (T1D). The aim of this study was to evaluate glycemic parameters in children with T1D who are in the PRP using intermittently scanned continuous glucose monitoring systems (isCGMS) and to investigate any relationships between CP and PI levels.
METHODS
The study included 21 children who were in the PRP and 31 children who were not. A cross-sectional, non-randomized study was performed. Demographic, clinical data were collected and 2 week- isCGMS data were retrieved.
RESULTS
The Serum CP showed a positive correlation with time-in-range in the PRP (p:0.03), however PI showed no correlations with glycemic parameters in both periods. The Serum CP and PI levels and the PI:CP ratio were significantly higher in the PRP group than in the non-PRP group. In the non-PRP group, the PI level was below 0.1 pmol/L (which is the detectable limit) in only 2 of the 17 cases as compared with none in the PRP group. Similarly, only 2 of the 17 children in the non-PRP group had CP levels of less than 0.2 nmol / L, although both had detectable PI levels. Overall time-in-range (3. 9-1.0 mmol/L) was significantly high in the PRP group. In contrast, the mean sensor glucose levels, time spent in hyperglycemia, and coefficient of variation levels (32.2vs 40.5%) were significantly lower in the PRP group.
CONCLUSIONS
Although the mean glucose and time in range during the PRP was better than that in the non-PRP group, the glycemic variability during this period was not as low as expected. While the CP levels showed an association with TIR during the PRP, there was no correlation between PI levels and glycemic parameters. Further studies are needed to determine if PI might prove to be a useful parameter in clinical follow-up.
Topics: Adolescent; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Proinsulin; Remission, Spontaneous
PubMed: 33485357
DOI: 10.1186/s12902-021-00681-1 -
Biomolecular Concepts May 2014Many biological roles have been assigned to proinsulin C-peptide over the years. Some appear surprisingly disparate and sometimes even contradictory, like chaperone-like... (Review)
Review
Many biological roles have been assigned to proinsulin C-peptide over the years. Some appear surprisingly disparate and sometimes even contradictory, like chaperone-like actions and depository tendencies. This review summarizes recently reported biomolecular interactions of the peptide and presents how they correlate with structural and functional aspects into a partitioned molecular architecture. At the structural level, the C-peptide sequence and fold can be subdivided into three distinct parts ('tripartite'). At the functional level, its chaperone-like abilities, self-assembly, and membrane interactions, as well as interactions with relevant proteins can be separately ascribed to these three segments. At the biological level, the assignments are compatible with the suggested roles of C-peptide in granular insulin storage, chaperone-like activities on insulin oligomers, possible depository tendencies, and proposed receptor interactions. Finally, the assignments give interesting parallels to further bioactive peptides, including glucagon and neurotensin. Provided pharmaceutical and clinical trials are successfully completed, the present interpretations should supply mechanistic explanations on C-peptide as a bioactive compound of importance in health and diabetes.
Topics: Amino Acid Sequence; Animals; Binding Sites; C-Peptide; Conserved Sequence; Diabetes Mellitus; Humans; Insulin; Molecular Sequence Data; Proinsulin; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, G-Protein-Coupled
PubMed: 25372746
DOI: 10.1515/bmc-2014-0005 -
Physiological Research Dec 2023In order to understand the pathological changes associated with glucose homeostasis in old age, it is necessary to know the natural changes in the processing of...
In order to understand the pathological changes associated with glucose homeostasis in old age, it is necessary to know the natural changes in the processing of proinsulin to mature insulin. While there is abundant information about insulin production and function in diabetics, the situation in healthy adults and the elderly has surprisingly rarely been investigated. The aim of the study was to determine how proinsulin secretion changes in individuals with normal glucose tolerance during the process of natural aging. A total of 761 individuals (539 women, 222 men) aged 18-90 years with normal fasting glycemia (less than 5.6 mmol/l) were divided into five groups according to age. Body composition and levels of fasting blood glucose, proinsulin, insulin, and C-peptide were determined, and the ratios of proinsulin to both insulin and C-peptide were calculated. The homeostasis model of ?-cell function (HOMA F) and peripheral insulin resistance (HOMA R) were calculated. The effect of age was assessed using an ANOVA model consisting of the factors sex, age, and sex × age interaction. Statgraphics Centurion v. XVIII statistical software was used. Glycemia, insulin, C-peptide and HOMA R increased in both sexes up to 75 years. On the contrary, proinsulin levels as well as proinsulin/insulin and proinsulin/C-peptide ratios decreased with age up to 75 years. In normoglycemic and normotolerant people, both women and men, the aging process is associated with decreased insulin sensitivity compensated by potentiation of insulin production. In older age, there is also a gradual decrease in circulating proinsulin, which can be explained by its more efficient processing into active insulin by matured healthy beta cells.
Topics: Adult; Aged; Female; Humans; Male; Blood Glucose; C-Peptide; Insulin Resistance; Proinsulin; Aging; Adolescent; Young Adult; Middle Aged; Aged, 80 and over
PubMed: 38116775
DOI: 10.33549/physiolres.935181