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Journal of Diabetes Science and... May 2011Insulin resistance (IR) and deterioration of beta-cell secretion are main features in the development of type 2 diabetes, which is reflected in increasing serum intact... (Review)
Review
BACKGROUND
Insulin resistance (IR) and deterioration of beta-cell secretion are main features in the development of type 2 diabetes, which is reflected in increasing serum intact proinsulin levels in later disease stage. Introduction of stable assays that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products has resulted in the finding that serum intact proinsulin values can serve as a direct marker for beta-cell dysfunction, are a highly specific indicator of IR, and can predict cardiovascular risk.
METHOD
Determination of fasting intact proinsulin may be used to monitor and optimize antidiabetic therapeutic approaches. Our study group has been involved in a variety of clinical studies investigating drug effects on beta-cell secretory capacity, IR, and intact proinsulin levels. One focus was on the impact of insulin-sensitizing therapy with pioglitazone on the pancreatic beta-cell load.
RESULTS
Treatment with pioglitazone resulted in significant decreases in elevated proinsulin levels in type 2 diabetes patients. This effect was independent from glycemic control.
CONCLUSIONS
Measurement of fasting intact proinsulin values allows a staging of beta-cell dysfunction and evaluation of IR, thus providing an interesting diagnostic tool for both selection of appropriate therapy and monitoring of treatment success.
Topics: Biomarkers; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Progression; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Pioglitazone; Proinsulin; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Thiazolidinediones
PubMed: 21722594
DOI: 10.1177/193229681100500333 -
Trends in Endocrinology and Metabolism:... Nov 2010Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene.... (Review)
Review
Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene. Not all mutations in the INS gene cause the autosomal dominant Mutant INS-gene Induced Diabetes of Youth (MIDY) syndrome, but most missense mutations affecting proinsulin folding produce MIDY. MIDY patients are heterozygotes, with the expressed mutant proinsulins exerting dominant-negative (toxic gain of function) behavior in pancreatic beta cells. Here we focus primarily on proinsulin folding in the endoplasmic reticulum, providing insight into perturbations of this folding pathway in MIDY. Accumulated evidence indicates that, in the molecular pathogenesis of the disease, misfolded proinsulin exerts dominant effects that initially inhibit insulin production, progressing to beta cell demise with diabetes.
Topics: Amino Acid Sequence; Animals; Diabetes Mellitus, Type 1; Endoplasmic Reticulum; Humans; Insulin-Secreting Cells; Models, Biological; Molecular Sequence Data; Mutation; Proinsulin; Protein Folding; Proteostasis Deficiencies
PubMed: 20724178
DOI: 10.1016/j.tem.2010.07.001 -
Diabetologia Jun 2020It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease...
AIMS/HYPOTHESIS
It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue.
METHODS
Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7-12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges.
RESULTS
Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7-12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3-151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10-0.31) vs 0.01, IQR 0.009-0.10 pmol/l; p < 0.0001).
CONCLUSIONS/INTERPRETATION
Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression.
Topics: Adolescent; Age Factors; Child; Diabetes Mellitus, Type 1; Humans; Insulin; Male; Pancreas; Proinsulin
PubMed: 32172310
DOI: 10.1007/s00125-020-05115-6 -
Clinical Immunology (Orlando, Fla.) Dec 2013Some clinical trials in humans have aimed at modulation of type 1 diabetes (T1D) via alteration of the immune response to putative islet cell antigens, particularly... (Review)
Review
Some clinical trials in humans have aimed at modulation of type 1 diabetes (T1D) via alteration of the immune response to putative islet cell antigens, particularly proinsulin and insulin, glutamic acid decarboxylase and the peptide, DiaPep 277, derived from heat shock protein 60. The focus here is on development of a specially engineered DNA plasmid encoding proinsulin to treat T1D. The plasmid is engineered to turn off adaptive immunity to proinsulin. This approach yielded exciting results in a randomized placebo controlled trial in 80 adult patients with T1D. The implications of this trial are explored in regards to the potential for sparing inflammation in islets and thus allowing the functioning beta cells to recover and produce more insulin. Strategies to further strengthen the effects seen thus far with the tolerizing DNA plasmid to proinsulin will be elucidated. The DNA platform affords an opportunity for easy modifications. In addition standard exploration of dose levels, route of administration and frequency of dose are practical. Optimization of the effects seen to date on C-peptide and on depletion of proinsulin specific CD8 T cells are feasible, with expected concomitant improvement in other parameters like hemoglobin A1c and reduction in insulin usage. T1D is one of the few autoimmune conditions where antigen specific therapy can be achieved, provided the approach is tested intelligently. Tolerizing DNA vaccines to proinsulin and other islet cell autoantigens is a worthy pursuit to potentially treat, prevent and to perhaps even 'cure' or 'prevent' type 1 diabetes.
Topics: Adaptive Immunity; Autoantigens; C-Peptide; CD8-Positive T-Lymphocytes; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Immunomodulation; Islets of Langerhans; Plasmids; Proinsulin; Vaccines, DNA
PubMed: 24094739
DOI: 10.1016/j.clim.2013.08.010 -
The Journal of Clinical Investigation Jun 1975Concentrations of insulin, proinsulin, and C-peptide were measured in portal and peripheral venous blood in six nondiabetic, nonobese subjects. Portal vein samples were...
Concentrations of insulin, proinsulin, and C-peptide were measured in portal and peripheral venous blood in six nondiabetic, nonobese subjects. Portal vein samples were obtained by umbilical vein catheterization. Three subjects were studied with intravenous infusion of 25 g glucose, and three with 30 g arginine. Insulin and proinsulin were determined in the insulin immunoassay after separation by gel filtration, and C-peptide was measured by direct immunoassay. With both glucose and arginine stimulation, portal vein levels of all three peptides peaked at 90-120 s after the onset of the stimulus. Relative increases in insulin concentration were greater than those of proinsulin or C-peptide. In peripheral venous blood, maximal levels of the three peptides were observed later (2-5 min), and the increase in insulin relative toproinsulin and C-peptide was not as great. At the time of peak secretion, portal vein insulin and C-peptide approached equimolar concentrations, and proinsulin, as measured against an insulin standard, comprised approximately 2.5% of the total immunoreactive insulin. After stimulation by glucose or arginine, portal insulin, proinsulin and C-peptide levels were not correlated with the concentrations measured in simultaneously drawn peripheral samples. At all sampling times, however, significant correlation was found between insulin and C-peptide in both peripheral and portal blood. The results indicate that under the conditions studied, insulin and C-peptide are secreted in equimolar concentrations in man, and that proinsulin is secreted in the same proportion to insulin as found in the pancreas. Consideration of the relative secretory and metabolic rates of the three beta cell peptides explains their peripheral concentrations. The data further support the use of plasma C-peptide as an indicator of beta cell secretory function.
Topics: Antigens; Arginine; Blood Glucose; Glucose; Humans; Insulin; Peptides; Portal Vein; Proinsulin; Veins
PubMed: 1133173
DOI: 10.1172/JCI108047 -
Molecular Aspects of Medicine Apr 2015A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been... (Review)
Review
A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved.
Topics: Diabetes Mellitus; Endoplasmic Reticulum; Humans; Insulin; Insulin-Secreting Cells; Mutation; Proinsulin; Protein Folding; Protein Precursors; Protein Transport; Receptor, Insulin; Transcription, Genetic
PubMed: 25542748
DOI: 10.1016/j.mam.2014.12.001 -
Journal of Diabetes Investigation Jan 2020We investigated associations between glucose tolerance and β-cell function using a series of estimation methods in a population-based study.
AIMS/INTRODUCTION
We investigated associations between glucose tolerance and β-cell function using a series of estimation methods in a population-based study.
MATERIALS AND METHODS
Data from the Dynamics of Lifestyle and Neighborhood Community on Health Study were analyzed. A total of 489 participants (263 women) were divided into three groups: normal glucose tolerance (NGT), prediabetes (PDM) and diabetes group. We estimated β-cell function by the homeostasis model assessment of β-cell function, proinsulin level (PI), C-peptide index, proinsulin-to-C-peptide ratio (PI/CPR) and proinsulin-to-insulin ratio. Because data on all five parameters of β-cell function showed skewed distributions, the values of these parameters were normalized by natural logarithmic (ln) transformation. Next, the association between glucose tolerance and β-cell function among participants without diabetes was examined. In this analysis, glucose tolerance was assessed based on glycated hemoglobin levels.
RESULTS
In the crude analysis, ln(PI) and ln(PI/CPR) were significantly higher in the diabetes group than those in the PDM and NGT groups, and these parameters were significantly higher in the PDM group than in the NGT group. Only ln(PI) in the PDM group was significantly higher compared with that in the NGT group after adjustment for age, sex and body mass index (ln[PI]: PDM group 2.38 pmol/L, 95% confidence interval 2.29-2.47 pmol/L; NGT group 2.17 pmol/L, 95% confidence interval 2.12-2.22 pmol/L; P < 0.05). In addition, ln(PI) levels were significantly and positively correlated with glycated hemoglobin quartile in participants without diabetes.
CONCLUSIONS
Our results showed that PI was the most sensitive to reflect glucose intolerance.
Topics: Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; Cross-Sectional Studies; Female; Follow-Up Studies; Glucose Intolerance; Humans; Insulin; Male; Middle Aged; Prognosis; Proinsulin
PubMed: 31222973
DOI: 10.1111/jdi.13106 -
PloS One 2020The environment within the Endoplasmic Reticulum (ER) influences Insulin biogenesis. In particular, ER stress may contribute to the development of Type 2 Diabetes (T2D)...
The environment within the Endoplasmic Reticulum (ER) influences Insulin biogenesis. In particular, ER stress may contribute to the development of Type 2 Diabetes (T2D) and Cystic Fibrosis Related Diabetes (CFRD), where evidence of impaired Insulin processing, including elevated secreted Proinsulin/Insulin ratios, are observed. Our group has established the role of a novel ER chaperone ERp29 (ER protein of 29 kDa) in the biogenesis of the Epithelial Sodium Channel, ENaC. The biogenesis of Insulin and ENaC share may key features, including their potential association with COP II machinery, their cleavage into a more active form in the Golgi or later compartments, and their ability to bypass such cleavage and remain in a less active form. Given these similarities we hypothesized that ERp29 is a critical factor in promoting the efficient conversion of Proinsulin to Insulin. Here, we confirmed that Proinsulin associates with the COP II vesicle cargo recognition component, Sec24D. When Sec24D expression was decreased, we observed a corresponding decrease in whole cell Proinsulin levels. In addition, we found that Sec24D associates with ERp29 in co-precipitation experiments and that ERp29 associates with Proinsulin in co-precipitation experiments. When ERp29 was overexpressed, a corresponding increase in whole cell Proinsulin levels was observed, while depletion of ERp29 decreased whole cell Proinsulin levels. Together, these data suggest a potential role for ERp29 in regulating Insulin biosynthesis, perhaps in promoting the exit of Proinsulin from the ER via Sec24D/COPII vesicles.
Topics: COP-Coated Vesicles; Cystic Fibrosis; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Humans; Insulin; Proinsulin; Protein Transport; Vesicular Transport Proteins
PubMed: 32433667
DOI: 10.1371/journal.pone.0233502 -
Lifestyle Genomics 2022"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution.
BACKGROUND
"Quantile-dependent expressivity" is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution.
METHODS
Quantile-specific offspring-parent regression slopes (βOP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study.
RESULTS
Quantile-specific heritability (h2), estimated by 2βOP/(1 + rspouse), increased 0.0045 ± 0.0007 (p = 8.8 × 10-14) for each 1% increment in the fasting glucose distribution, that is, h2 ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (p = 1.2 × 10-6), homeostatic model assessment of insulin resistance (HOMA-IR, p = 5.3 × 10-5), insulin/glucose ratio (p = 3.9 × 10-5), proinsulin (p = 1.4 × 10-6), proinsulin/insulin ratio (p = 2.7 × 10-5), and glucose concentrations during a glucose tolerance test (p = 0.001), and their logarithmically transformed values.
DISCUSSION/CONCLUSION
These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between ACE, ADRB3, PPAR-γ2, and TNF-α polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2), gene-exercise (INS), gene-diet (ACSL1, ELOVL6, IRS-1, PLIN, S100A9), and gene-socioeconomic interactions.
Topics: Cell Cycle Proteins; DNA-Binding Proteins; Glucose; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Oncogene Proteins; Proinsulin; Receptors, Adrenergic, beta-3
PubMed: 34872092
DOI: 10.1159/000519382 -
Communications Biology May 2022Insulin is an essential peptide hormone that maintains blood glucose levels. Although the mechanisms underlying insulin exocytosis have been investigated, the mechanism...
Insulin is an essential peptide hormone that maintains blood glucose levels. Although the mechanisms underlying insulin exocytosis have been investigated, the mechanism of proinsulin export from the endoplasmic reticulum (ER) remains unclear. Here, we demonstrated that Surf4, a cargo receptor homolog, regulates the ER export of proinsulin via its recruitment to ER exit sites (ERES). Under high-glucose conditions, Surf4 expression was upregulated, and Surf4 proteins mainly localized to the ER at a steady state and accumulated in the ERES, along with proinsulin in rat insulinoma INS-1 cells. Surf4-knockdown resulted in proinsulin retention in the ER and decreased the levels of mature insulin in secretory granules, thereby significantly reducing insulin secretion. Surf4 forms an oligomer and can physically interact with proinsulin and Sec12, essential for COPII vesicle formation. Our findings suggest that Surf4 interacts with proinsulin and delivers it into COPII vesicles for ER export in co-operation with Sec12 and COPII.
Topics: Animals; Endoplasmic Reticulum; Insulin; Insulin Secretion; Insulin-Secreting Cells; Proinsulin; Protein Transport; Rats
PubMed: 35562580
DOI: 10.1038/s42003-022-03417-6