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Annual Review of Medicine 1971
Review
Topics: Animals; Antigen-Antibody Reactions; Cattle; Chemical Phenomena; Chemistry, Physical; Chromatography, Gel; Electrophoresis; Half-Life; Humans; Immune Sera; Insulin; Iodine Isotopes; Pancreas; Peptides; Proinsulin; Swine
PubMed: 4944416
DOI: 10.1146/annurev.me.22.020171.000245 -
Annals of the New York Academy of... Apr 2018The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta... (Review)
Review
The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7-A7, B19-A20, and A6-A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide-linked protein complexes, is a natural by-product of proinsulin biosynthesis, as is the case for many proteins. The steady-state level of misfolded proinsulin-a potential ER stressor-is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene-induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.
Topics: Animals; Diabetes Mellitus; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Insulin-Secreting Cells; Mutation; Proinsulin; Protein Folding; Protein Transport
PubMed: 29377149
DOI: 10.1111/nyas.13531 -
Metabolism: Clinical and Experimental May 1977The recent work on proinsulin and C-peptide has been reviewed with major emphasis on the most significant findings since 1972. Proinsulin has now been established as the... (Review)
Review
The recent work on proinsulin and C-peptide has been reviewed with major emphasis on the most significant findings since 1972. Proinsulin has now been established as the biosynthetic precursor of insulin in all species examined, including man, with a preproinsulin as a possible precursor of the prohormone. The conversion of proinsulin which appears to occur exclusively in the pancreas leads to equimolar production of insulin and C-peptide. Although proinsulin has a direct biologic effect which is one-tenth as much as that of insulin, C-peptide has no biologic activity on homologous or heterologous tissue and no ability to modify the action of insulin and/or proinsulin. Previous work on proinsulin immunoassay suggested that this prohormone, but not C-peptide, cross-reacts with insulin antiserum. On the other hand, in the C-peptide immunoassay, proinsulin but not insulin cross-reacts with the antiserum. Up to this time, therefore, it has not been possible to immunoassay human proinsulin or C-peptide specifically. The very recent work from the laboratory of Heding, however, has brought about major advances in this area in which human C-peptide and proinsulin can be separated in the plasma by the use of Sepharose particles. With this recent major advancement, it is now possible to measure human C-peptide specifically. This measurement has been shown to be a useful tool for the assessment of beta-cell function in diabetic patients treated with insulin and in insulinoma patients in whom endogenous C-peptide secretion is not suppressed with exogenous insulin-induced hypoglycemia. With the use of a specific enzyme which degrades insulin but not proinsulin, postprandial plasma proinsulin values have been measured in a large number of subjects under a variety of physiologic and pathologic conditions. These results, which are comparable to those obtained by the more laborious column chromatography, could be summarized as follows: (1) proinsulin values in lean, young normal subjects do not vary greatly in response to insulin secretagogues; (2) proinsulin secretion in response to glucose results in a greater percentage of proinsulin in the older age group than in the younger group; (3) in lean adult and juvenile diabetic patients, the percentage of proinsulin is not excessive, whereas obese diabetics and pregnant diabetics appear to secrete relatively greater proinsulin than their diabetic controls; and (4) whereas most hyperinsulinemic states (Cusing's syndrome, adult-onset diabetics, acromegaly, and glucocorticoid therapy) are not associated with an increase in percentage of proinsulin, hyperinsulinemia of insulinoma, selected cases of functional hypoglycemia, and genetic hyperproinsulinemia are associated with a greater percentage of proinsulin. Identification of a possible new proinsulin intermediate(s) in these conditions deserves further investigation...
Topics: Amino Acid Sequence; Animals; Antibodies; C-Peptide; Cattle; Cross Reactions; Diabetes Mellitus; Dogs; Endoplasmic Reticulum; Female; Guinea Pigs; Haplorhini; Horses; Humans; Hyperinsulinism; Insulin; Male; Mice; Molecular Conformation; Pancreas; Pancreatic Neoplasms; Peptides; Proinsulin; Rats; Structure-Activity Relationship; Swine; Terminology as Topic
PubMed: 403392
DOI: 10.1016/0026-0495(77)90099-3 -
Journal of Diabetes and Its... 1993An improved understanding of the characteristics of proinsulin and its intermediate conversion products has resulted from the use of novel assays for distinguishing... (Review)
Review
An improved understanding of the characteristics of proinsulin and its intermediate conversion products has resulted from the use of novel assays for distinguishing these molecules from insulin. Use of such assays may help clarify the role of insulin deficiency in non-insulin-dependent diabetes mellitus (NIDDM). Levels of proinsulin-like molecules are elevated in subjects who have NIDDM or impaired glucose tolerance. However, the observation that hyperproinsulinemia may occur in individuals without hyperglycemia suggests that elevated proinsulin levels may be a manifestation of beta-cell dysfunction rather than of increased demand on the beta cell. Although the metabolic effects of proinsulin-like molecules have yet to be elucidated, some studies indicate that the effect of these molecules on hepatocytes is greater than that on other insulin-sensitive cells. A potential therapeutic role of proinsulin in NIDDM thus has been envisioned, in that suppression of hepatic glucose output might reduce the risk of hypoglycemia caused by increased peripheral glucose uptake. Clinical study of proinsulin has been discontinued, however, owing to the finding of an association between use of human proinsulin and cardiovascular adverse events in one study. In NIDDM subjects, associations have been reported between elevated des 31,32 proinsulin concentrations and such cardiovascular risk factors as elevated blood pressure, increased serum triglyceride and total cholesterol values, and elevated plasminogen-activator inhibitor levels, suggesting a role of proinsulin in cardiovascular risk. Epidemiologic data, however, indicate that elevated levels of proinsulin-like molecules are related to low birth weight and that low birth weight is associated with increased risk of cardiovascular events, suggesting that inadequate intrauterine nutrition may be the common antecedent of augmented proinsulin levels and cardiovascular risk.
Topics: Amino Acid Sequence; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Proinsulin
PubMed: 8518453
DOI: 10.1016/1056-8727(93)90036-x -
Diabetologia Jun 2006In postnatal organisms, insulin is well known as an essential anabolic hormone responsible for maintaining glucose homeostasis. Its biosynthesis by the pancreatic beta... (Review)
Review
In postnatal organisms, insulin is well known as an essential anabolic hormone responsible for maintaining glucose homeostasis. Its biosynthesis by the pancreatic beta cell has been considered a model of tissue-specific gene expression. However, proinsulin mRNA and protein have been found in embryonic stages before the formation of the pancreatic primordium, and later, in extrapancreatic tissues including the nervous system. Phylogenetic studies have also confirmed that production of insulin-like peptides antecedes the morphogenesis of a pancreas, and that these peptides contribute to normal development. In recent years, other roles for insulin distinct from its metabolic function have emerged also in vertebrates. During embryonic development, insulin acts as a survival factor and is involved in early morphogenesis. These findings are consistent with the observation that, at these stages, the proinsulin gene product remains as the precursor form, proinsulin. Independent of its low metabolic activity, proinsulin stimulates proliferation in developing neuroretina, as well as cell survival and cardiogenesis in early embryos. Insulin/proinsulin levels are finely regulated during development, since an excess of the protein interferes with correct morphogenesis and is deleterious for the embryo. This fine-tuned regulation is achieved by the expression of alternative embryonic proinsulin transcripts that have diminished translational activity.
Topics: Aging; Animals; Embryonic Development; Gene Expression Regulation, Developmental; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Phylogeny; Proinsulin
PubMed: 16596360
DOI: 10.1007/s00125-006-0232-5 -
The Journal of Biological Chemistry Jul 2009Insulin 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... (Review)
Review
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.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin; Models, Biological; Mutation; Proinsulin; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 19395706
DOI: 10.1074/jbc.R109.009936 -
Experimental Diabesity Research 2004The C-peptide links the insulin A and B chains in proinsulin, providing thereby a means to promote their efficient folding and assembly in the endoplasmic reticulum... (Review)
Review
The C-peptide links the insulin A and B chains in proinsulin, providing thereby a means to promote their efficient folding and assembly in the endoplasmic reticulum during insulin biosynthesis. It then facilitates the intracellular transport, sorting, and proteolytic processing of proinsulin into biologically active insulin in the maturing secretory granules of the beta cells. These manifold functions impose significant constraints on the C-peptide structure that are conserved in evolution. After cleavage of proinsulin, the intact C-peptide is stored with insulin in the soluble phase of the secretory granules and is subsequently released in equimolar amounts with insulin, providing a useful independent indicator of insulin secretion. This brief review highlights many aspects of its roles in biosynthesis, as a prelude to consideration of its possible additional role(s) as a physiologically active peptide after its release with insulin into the circulation in vivo.
Topics: Amino Acid Sequence; Animals; C-Peptide; Evolution, Molecular; Humans; Insulin; Molecular Conformation; Molecular Sequence Data; Proinsulin; Protein Processing, Post-Translational
PubMed: 15198367
DOI: 10.1080/15438600490424389 -
Frontiers in Immunology 2021T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop...
T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice.
Topics: Animals; Autoantibodies; Diabetes Mellitus, Type 1; Glucose-6-Phosphatase; Immune Tolerance; Insulin; Mice; Mice, Inbred NOD; Proinsulin
PubMed: 33841427
DOI: 10.3389/fimmu.2021.645817 -
Indian Journal of Medical Sciences Sep 1972
Review
Topics: Adenoma, Islet Cell; Adipose Tissue; Amino Acid Sequence; Animals; Binding Sites, Antibody; Cattle; Epitopes; Humans; Immunoassay; In Vitro Techniques; Insulin; Islets of Langerhans; Muscles; Proinsulin; Protein Conformation; Ribosomes; Species Specificity; Swine; Trypsin
PubMed: 4118865
DOI: No ID Found -
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