DOCSLIB.ORG

Proinsulin and Acute Insulin Response Independently Predict Type 2 Diabetes Mellitus in Men – Report from 27 Years of Follow-Up Study

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Proinsulin and Acute Insulin Response Independently Predict Type 2 Diabetes Mellitus in Men – Report from 27 Years of Follow-Up Study Diabetologia (2003) 46:20–26 DOI 10.1007/s00125-002-0995-2 Articles Proinsulin and acute insulin response independently predict Type 2 diabetes mellitus in men – report from 27 years of follow-up study B. Zethelius1, L. Byberg1, C. N. Hales3, H. Lithell1, C. Berne2 1 Department of Public Health and Caring Sciences / Section of Geriatrics, Uppsala University, Uppsala, Sweden 2 Department of Medical Sciences, Uppsala University, Uppsala, Sweden 3 Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, UK Abstract predictor variables, were analysed with logistic re- gression. Results are shown as odds ratios (ORs) with Aims/hypothesis. Defects in insulin secretion and insu- their 95% confidence intervals (CIs) for a one stan- lin action, resulting in compensatory hyperinsulinae- dard deviation increase in a predictor variable. mia, are the major abnormalities in the development Results. Cumulative incidence of Type 2 diabetes was of Type 2 diabetes mellitus (Type 2 diabetes). The 33% over 27 years of follow-up. Intact proinsulin most frequently used conventional immunoreactive (OR, 1.57, CI, 1.16–2.14), and 32–33 split proinsulin assays for insulin cross-react with proinsulin. In short- (OR, 1.70, CI, 1.20–2.39) were associated with devel- term studies (<5 years), proinsulin predicts the devel- opment of Type 2 diabetes, independent of AIR, ad- opment of Type 2 diabetes. We studied, with a 27-year justed for BMI and fasting glucose, whereas specific follow-up, the longitudinal relationships between in- insulin was not (OR, 1.31, CI, 0.98–1.77), nor was tact proinsulin, 32–33 split proinsulin, specific and IRI (OR, 1.25, CI, 0.96–1.63). Proinsulin and AIR immunoreactive insulin (IRI), acute insulin response interacted in the development of Type 2 diabetes (AIR) after an intravenous glucose load and the devel- (p<0.05). opment of Type 2 diabetes in a population-based co- Conclusion/interpretation. Proinsulin predicts the de- hort of 50-year-old men. velopment of Type 2 diabetes mellitus over a 27-year Methods. Fasting peptide concentrations were mea- period. [Diabetologia (2003) 46:20–26] sured in plasma samples, stored since 1970–73 using specific two-site immunometric assays. IRI was mea- Keywords Proinsulin, insulin, immunoreactive, body sured at baseline using radioimmunoassay. Associa- mass index, epidemiology, risk factors, prospective tions between development of Type 2 diabetes and study. Defects in insulin secretion and insulin action, result- ry dysfunction and insulin resistance, analysed by dif- ing in compensatory hyperinsulinaemia, are the major ferent clamp techniques, were independent predictors abnormalities in the development of Type 2 diabetes of worsening of glucose tolerance [3]. mellitus [1, 2]. It has been shown that insulin secreto- In several prospective studies, impaired insulin se- cretion assessed by a low acute insulin response (AIR) Received: 18 June 2002 / Revised: 20 August 2002 to a glucose load, was shown to be a predictor of the Published online: 8 January 2003 development of Type 2 diabetes [2, 4, 5, 6]. Further- © Springer-Verlag 2003 more, fasting hyperinsulinaemia indicative of insulin resistance is a predictor of Type 2 diabetes [6, 7, 8]. Corresponding author: B. Zethelius MD, Department of Pub- However, this association is less strong in the impaired lic Health and Caring Sciences / Section of Geriatrics, Uppsala University, Box 609, 75125 Uppsala, Sweden, E-mail: bjorn. than in the normal glucose tolerance state [9, 10]. A [email protected] complication in earlier studies is that conventional Abbreviations: AIR acute insulin response; IRI immunoreactive radioimmunoassays for insulin, measuring immunore- insulin. active insulin (IRI), cross-react with proinsulin. B. Zethelius et al.: Proinsulin and acute insulin response independently predict Type 2 diabetes mellitus in men 21 Proinsulin has been shown to predict the onset of and 1984 (1860 subjects participated) [21], at age 70 years Type 2 diabetes in subjects with normal or impaired (U-70) between 1991 and 1995 (1221 out of 1681 eligible men glucose tolerance in studies with follow-up time less participated) [22] and at age 77 years (U-77) between 1998 and 2001 (839 out of 1079 eligible men participated). than 7 years [11, 12, 13, 14, 15, 16]. Both proinsulin Type 2 diabetes was defined according to the World Health and specific insulin are inversely associated with insu- Organisation (WHO) criteria from 1999 [23] (using fasting lin sensitivity and positively associated with the AIR concentrations) and/or use of OHAs. At the first two investiga- in subjects with normal glucose tolerance [17] and in tions (U-50 and U-60), fasting blood glucose concentrations subjects with Type 2 diabetes [18]. The roles of proin- were analysed and Type 2 diabetes was thus defined as a sulin, insulin resistance and impaired insulin secretion fasting blood glucose concentration greater than or equal to in the development of Type 2 diabetes over longer 6.1 mmol/l and/or treatment with OHAs. At the third and fourth investigations (U-70 and U-77), fasting plasma glucose periods of time are not clear. concentrations were analysed and Type 2 diabetes was defined The primary aim of this study was to investigate as a fasting plasma glucose concentration greater than or equal the baseline fasting plasma concentrations of intact to 7.0 mmol/l and/or treatment with OHAs. The cumulative proinsulin, 32–33 split proinsulin, specific insulin and incidence of Type 2 diabetes was calculated, from age 50 years IRI, for the development of Type 2 diabetes and to es- to age 60 years as Type 2 diabetes identified at U-60, from age tablish the role of AIR at an IVGTT in these associa- 50 to age 70 as Type 2 diabetes identified at U-60 or U-70 and from age 50 years to age 77 years as Type 2 diabetes identified tions. Further, possible significant predictors by out- at U-60, U-70 or U-77. come associations were investigated in terms of differ- To avoid potential bias by using only fasting glucose con- ent length of follow-up, i.e. development of Type 2 centrations for the diagnosis of Type 2 diabetes, an additional diabetes 10, 20 and 27 years later. analysis was carried out using data from a 75-gram OGTT, which was carried out in all participants in U-70. Type 2 diabe- tes was defined as a fasting plasma glucose greater than or equal to 7.0 mmol/l or a 2-h glucose glucose greater than or Subjects and methods equal to 11.1 mmol/l, according to WHO criteria from 1999 [23] and/or treatment with OHAs. Study design. The Uppsala Longitudinal Study of Adult Men is a population-based cohort study of diabetes and cardiovascular Baseline characteristics and laboratory methods. The concen- disease in men [6, 19]. In 1970, all men born between 1920 trations of intact and 32–33 split proinsulin were analysed us- and 24 and residing in Uppsala were invited to a health survey ing the two-site immunometric assay technique [24], in plasma at age 50 years (U-50), between 1970 and 1973 (baseline). In samples that had been stored frozen (−70°C) since baseline. all, 2322 of 2841 invited men participated (82%). Plasma sam- Specific insulin concentrations were also analysed in these ples have been stored since that survey, allowing us to study samples using the Access Immunoassay System (Sanofi Pas- proinsulin, using highly specific assays, as a possible predictor teur Diagnostics, Marmes-la-Coquette, France), using a one- for the development of Type 2 diabetes in non-diabetic sub- step chemiluminescent immunoenzymatic assay. These proce- jects at baseline, using the follow-up data over 27 years. dures have been described in detail previously and the long- Due to a freezer failure causing the random loss of some term storage did not interfere with the assessments in plasma 1000 samples, concentrations of intact and 32–33 split proin- that had been stored for 25 years [20]. sulin and true insulin were analysed in baseline plasma sam- At baseline, the serum IRI concentrations were analysed ples from 1306 subjects. There were no differences in baseline with the Phadebas Insulin Test (Pharmacia AB, Uppsala, characteristics other than propeptides, between those with and Sweden) [19, 21]. those without their propeptide concentrations analysed, indi- An IVGTT, using a glucose dose of 0.5 g/kg body weight, cating that no selection bias had occurred due to the loss of was carried out in 1792 men at baseline [19]. The serum IRI samples [20]. concentrations during the IVGTT were measured in duplicate blood samples drawn before and at 4 and 6 minutes after the Subjects. This study was based on those subjects who were start of the glucose injection. The AIR was expressed as non-diabetic at baseline and had complete data from the base- the mean value of the serum insulin concentrations at 4 and line investigation and proinsulin and specific insulin assess- 6 minutes. ments and follow-up data from the 10-year follow-up (n=777), Blood glucose was analysed, at U-50 and U-60 using spec- from the 20-year follow-up (n=436), and from the 27-year fol- trophotometry and the glucose oxidase method [19, 21]. At U-70 low-up (n=348). In order to select non-diabetic men at base- and U-77 plasma glucose was analysed by the glucose dehydro- line, subjects with a fasting blood glucose greater than or equal genase method (Gluc-DH, Merck, Darmstadt, Germany). to 6.1 mmol/l or treatment with oral hypoglycaemic agents Body mass index (BMI) was calculated as weight (in un- (OHAs) were excluded. Subjects with insulin treatment only, derwear) / height squared (kg/m2).
Load more

Recommended publications
  • Type 1 Diabetes Autoantigen Epitope in the Pathogenesis of Junction of Proinsulin Is an Early Evidence That a Peptide Spanning T
    Evidence That a Peptide Spanning the B-C Junction of Proinsulin Is an Early Autoantigen Epitope in the Pathogenesis of Type 1 Diabetes This information is current as of September 24, 2021. Wei Chen, Isabelle Bergerot, John F. Elliott, Leonard C. Harrison, Norio Abiru, George S. Eisenbarth and Terry L. Delovitch J Immunol 2001; 167:4926-4935; ; doi: 10.4049/jimmunol.167.9.4926 Downloaded from http://www.jimmunol.org/content/167/9/4926 References This article cites 50 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/167/9/4926.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Evidence That a Peptide Spanning the B-C Junction of Proinsulin Is an Early Autoantigen Epitope in the Pathogenesis of Type 1 Diabetes1 Wei Chen,2* Isabelle Bergerot,2* John F.
    [Show full text]
  • Sulfatide Preserves Insulin Crystals Not by Being Integrated in the Lattice but by Stabilizing Their Surface
    Hindawi Publishing Corporation Journal of Diabetes Research Volume 2016, Article ID 6179635, 4 pages http://dx.doi.org/10.1155/2016/6179635 Research Article Sulfatide Preserves Insulin Crystals Not by Being Integrated in the Lattice but by Stabilizing Their Surface Karsten Buschard,1 Austin W. Bracey,2 Daniel L. McElroy,2 Andrew T. Magis,2 Thomas Osterbye,1 Mark A. Atkinson,2 Kate M. Bailey,2 Amanda L. Posgai,2 and David A. Ostrov2 1 Bartholin Instituttet, Rigshospitalet, 2100 Copenhagen, Denmark 2Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA Correspondence should be addressed to Karsten Buschard; [email protected] Received 30 October 2015; Revised 14 January 2016; Accepted 14 January 2016 Academic Editor: Fabrizio Barbetti Copyright © 2016 Karsten Buschard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Sulfatide is known to chaperone insulin crystallization within the pancreatic beta cell, but it is not known if this results from sulfatide being integrated inside the crystal structure or by binding the surface of the crystal. With this study, we aimed to characterize the molecular mechanisms underlying the integral role for sulfatide in stabilizing insulin crystals prior to exocytosis. Methods. We cocrystallized human insulin in the presence of sulfatide and solved the structure by molecular replacement. Results. The crystal structure of insulin crystallized in the presence of sulfatide does not reveal ordered occupancy representing sulfatide in the crystal lattice, suggesting that sulfatide does not permeate the crystal lattice but exerts its stabilizing effect by alternative interactions such as on the external surface of insulin crystals.
    [Show full text]
  • Isolation and Proteomics of the Insulin Secretory Granule
    H OH metabolites OH Review Isolation and Proteomics of the Insulin Secretory Granule Nicholas Norris , Belinda Yau * and Melkam Alamerew Kebede Charles Perkins Centre, School of Medical Sciences, University of Sydney, Camperdown, NSW 2006, Australia; [email protected] (N.N.); [email protected] (M.A.K.) * Correspondence: [email protected] Abstract: Insulin, a vital hormone for glucose homeostasis is produced by pancreatic beta-cells and when secreted, stimulates the uptake and storage of glucose from the blood. In the pancreas, insulin is stored in vesicles termed insulin secretory granules (ISGs). In Type 2 diabetes (T2D), defects in insulin action results in peripheral insulin resistance and beta-cell compensation, ultimately leading to dysfunctional ISG production and secretion. ISGs are functionally dynamic and many proteins present either on the membrane or in the lumen of the ISG may modulate and affect different stages of ISG trafficking and secretion. Previously, studies have identified few ISG proteins and more recently, proteomics analyses of purified ISGs have uncovered potential novel ISG proteins. This review summarizes the proteins identified in the current ISG proteomes from rat insulinoma INS-1 and INS-1E cell lines. Here, we also discuss techniques of ISG isolation and purification, its challenges and potential future directions. Keywords: insulin secretory granule; beta-cells; granule protein purification 1. Insulin Granule Biogenesis and Function Citation: Norris, N.; Yau, B.; Kebede, The insulin secretory granule (ISG) is the storage vesicle for insulin in pancreatic M.A. Isolation and Proteomics of the beta-cells. It was long treated as an inert carrier for insulin but is now appreciated as a Insulin Secretory Granule.
    [Show full text]
  • Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes
    258 Diabetes Care Volume 42, February 2019 Proinsulin Secretion Is a Emily K. Sims,1,2 Henry T. Bahnson,3 Julius Nyalwidhe,4 Leena Haataja,5 Persistent Feature of Type 1 Asa K. Davis,3 Cate Speake,3 Linda A. DiMeglio,1,2 Janice Blum,6 Diabetes Margaret A. Morris,7 Raghavendra G. Mirmira,1,2,8,9,10 7 10,11 Diabetes Care 2019;42:258–264 | https://doi.org/10.2337/dc17-2625 Jerry Nadler, Teresa L. Mastracci, Santica Marcovina,12 Wei-Jun Qian,13 Lian Yi,13 Adam C. Swensen,13 Michele Yip-Schneider,14 C. Max Schmidt,14 Robert V. Considine,9 Peter Arvan,5 Carla J. Greenbaum,3 Carmella Evans-Molina,2,8,9,10,15 and the T1D Exchange Residual C-peptide Study Group* OBJECTIVE Abnormally elevated proinsulin secretion has been reported in type 2 and early type 1 diabetes when significant C-peptide is present. We questioned whether individuals with long-standing type 1 diabetes and low or absent C-peptide secretory capacity retained the ability to make proinsulin. RESEARCH DESIGN AND METHODS C-peptide and proinsulin were measured in fasting and stimulated sera from 319 subjects with long-standing type 1 diabetes (‡3 years) and 12 control subjects without diabetes. We considered three categories of stimulated C-peptide: 1) 1Department of Pediatrics, Indiana University ‡ 2 School of Medicine, Indianapolis, IN C-peptide positive, with high stimulated values 0.2 nmol/L; ) C-peptide posi- 2 tive, with low stimulated values ‡0.017 but <0.2 nmol/L; and 3)C-peptide Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indian- <0.017 nmol/L.
    [Show full text]
  • Distinct States of Proinsulin Misfolding in MIDY
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.442447; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Distinct states of proinsulin misfolding in MIDY Leena Haataja1, Anoop Arunagiri1, Anis Hassan1, Kaitlin Regan1, Billy Tsai2, Balamurugan Dhayalan3, Michael A. Weiss3, Ming Liu1,4, and Peter Arvan*1 From: 1The Division of Metabolism, Endocrinology & Diabetes and 2Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor MI 48105; 3Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202; 4Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China *To whom correspondence may be addressed: Peter Arvan MD PhD ORCID ID: http://orcid.org/0000-0002-4007-8799 Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Brehm Tower rm 5112 1000 Wall St. Ann Arbor, MI 48105 email: [email protected] FAX: 734-232-8162 Running Title. Proinsulin Disulfide Mispairing Key Words. endoplasmic reticulum, disulfide bonds, protein trafficking, insulin, diabetes Abbreviations. ER, endoplasmic reticulum; MIDY, Mutant INS-gene induced Diabetes of Youth 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.10.442447; this version posted May 10, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) “interchain” disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge.
    [Show full text]
  • Proinsulin Levels in Patients with Pancreatic Diabetes Are Associated
    European Journal of Endocrinology (2010) 163 551–558 ISSN 0804-4643 CLINICAL STUDY Proinsulin levels in patients with pancreatic diabetes are associated with functional changes in insulin secretion rather than pancreatic b-cell area Thomas G K Breuer1, Bjoern A Menge1, Matthias Banasch1, Waldemar Uhl2, Andrea Tannapfel3, Wolfgang E Schmidt1, Michael A Nauck4 and Juris J Meier1 Departments of 1Medicine I and 2Surgery, St Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany, 3Department of Pathology, Ruhr-University Bochum, 44789 Bochum, Germany and 4Diabeteszentrum Bad Lauterberg, 37431 Bad Lauterberg, Germany (Correspondence should be addressed to J J Meier; Email: [email protected]) Abstract Introduction: Hyperproinsulinaemia has been reported in patients with type 2 diabetes. It is unclear whether this is due to an intrinsic defect in b-cell function or secondary to the increased demand on the b-cells. We investigated whether hyperproinsulinaemia is also present in patients with secondary diabetes, and whether proinsulin levels are associated with impaired b-cell area or function. Patients and methods: Thirty-three patients with and without diabetes secondary to pancreatic diseases were studied prior to pancreatic surgery. Intact and total proinsulin levels were compared with the pancreatic b-cell area and measures of insulin secretion and action. Results: Fasting concentrations of total and intact proinsulin were similar in patients with normal, impaired (including two cases of impaired fasting glucose) and diabetic glucose tolerance (PZ0.58 and PZ0.98 respectively). There were no differences in the total proinsulin/insulin or intact proinsulin/insulin ratio between the groups (PZ0.23 and PZ0.71 respectively).
    [Show full text]
  • Exploring Immune Effects of Oral Insulin in Relatives at Risk for Type 1 Diabetes Mellitus
    Exploring Immune Effects of Oral Insulin in Relatives at Risk for Type 1 Diabetes Mellitus (Protocol TN-20) VERSION: January 15, 2016 IND #: 76,419 Sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Center for Research Resources (NCRR), the Juvenile Diabetes Research Foundation International (JDRF), and the American Diabetes Association (ADA) Page 1 of 37 TrialNet Protocol TN20 Protocol Version: 15Jan2016 PREFACE The Type 1 Diabetes TrialNet Protocol TN20, Exploring Immune Effects of Oral Insulin in Relatives at Risk for Type 1 Diabetes Mellitus, describes the background, design, and organization of the study. The protocol will be maintained by the TrialNet Coordinating Center at the University of South Florida over the course of the study through new releases of the entire protocol, or issuance of updates either in the form of revisions of complete chapters or pages thereof, or in the form of supplemental protocol memoranda. Page 2 of 37 TrialNet Protocol TN20 Protocol Version: 15Jan2016 Glossary of Abbreviations AE Adverse event AICD Activation Induced Cell Death APC Antigen presenting cell CBC Complete Blood Count CFR Code of Federal Regulations cGMP Current Good Manufacturing Practice CHO Carbohydrates CRF Case report form DC Dendritic Cell DPT-1 Diabetes Prevention Trial - Type1Diabetes DSMB Data and Safety Monitoring Board ELISPOT Enzyme-Linked ImmunoSpot Assay FACS Fluorescence activated cell sorting FDA US Food
    [Show full text]
  • Recombinant Human Proinsulin Catalog Number: 1336-PN
    Recombinant Human Proinsulin Catalog Number: 1336-PN DESCRIPTION Source E. coli­derived Phe25­Asn110, with an N­terminal Met, 6­His tag and Lys Accession # NP_000198 N­terminal Sequence Met Analysis Predicted Molecular 10.5 kDa Mass SPECIFICATIONS SDS­PAGE 9 kDa, reducing conditions Activity Measured in a serum­free cell proliferation assay using MCF­7 human breast cancer cells. Karey, K.P. et al. (1988) Cancer Research 48:4083. The ED50 for this effect is 0.15­0.75 μg/mL. Endotoxin Level <0.01 EU per 1 μg of the protein by the LAL method. Purity >95%, by SDS­PAGE under reducing conditions and visualized by silver stain. Formulation Lyophilized from a 0.2 μm filtered solution in PBS. See Certificate of Analysis for details. PREPARATION AND STORAGE Reconstitution Reconstitute at 100 μg/mL in sterile PBS. Shipping The product is shipped at ambient temperature. Upon receipt, store it immediately at the temperature recommended below. Stability & Storage Use a manual defrost freezer and avoid repeated freeze­thaw cycles. l 12 months from date of receipt, ­20 to ­70 °C as supplied. l 1 month, 2 to 8 °C under sterile conditions after reconstitution. l 3 months, ­20 to ­70 °C under sterile conditions after reconstitution. BACKGROUND Proinsulin is synthesized as a single chain, 110 amino acid (aa) preproprecursor that contains a 24 aa signal sequence and an 86 aa proinsulin propeptide. Following removal of the signal peptide, the proinsulin peptide undergoes further proteolysis to generate mature insulin, a 51 aa disulfide­linked dimer that consists of a 30 aa B chain (aa 25 ­ 54) bound to a 21 aa A chain (aa 90 ­ 110).
    [Show full text]
  • Proinsulin, Proamylin and the Beta Cell Endoplasmic Reticulum: the Key for the Pathogenesis of Different Diabetes Phenotypes
    PROINSULIN, PROAMYLIN AND THE BETA CELL ENDOPLASMIC RETICULUM: THE KEY FOR THE PATHOGENESIS OF DIFFERENT DIABETES PHENOTYPES CONSTANTIN IONESCU-TÎRGOVIŞTE and CRISTIAN GUJA National Institute of Diabetes, Nutrition and Metabolic Diseases “N.Paulescu” Ion Movilă str. 5–7, Bucharest, Romania [email protected] Received October 4, 2007 Based on our clinical and epidemiological data, we have sustained for a long time the unitary character of the various phenotypes of the diabetic syndrome. In this paper, we add several arguments sustaining that the unitary character of diabetes is related to a common primary defect in the function of the beta cell endoplasmic reticulum, leading to an inadequate processing of the two main secretory molecules: pre-proinsulin and pre-proamylin. The post-translational changes of these molecules might explain the main proapoptotic and anti-regenerative pathogenic mechanisms leading to a progressive decrease in the β cell mass/function. In our view, the increased proinsulin levels encountered in various diabetes phenotypes could be not only a marker of beta cell dysfunction but also could indicate the main β cell defect, suggesting also its location. Key words: Proinsulin; Proamylin; Beta cell endoplasmic reticulum. INTRODUCTION – THE FOUNDATIONS diabetes”, irrespective of the diabetes phenotype10. FOR A NEW HYPOTHESIS REGARDING By associating obesity (a very concrete element) THE PATHOGENESIS OF DIABETES with insulin-resistance (a construction mostly theoretical and without precise boundaries) and the One hundred years after the description of the last with a supposed hyperinsulinism (frequently beta cell by Lane1, the main cell of pancreatic islets inexistent if from the routine determination of the comes back in the center of diabetes pathogeny.
    [Show full text]
  • Insulin-Like Growth Factor-I Improves Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus
    Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. P D Zenobi, … , M E Røder, E R Froesch J Clin Invest. 1992;90(6):2234-2241. https://doi.org/10.1172/JCI116109. Research Article Hyperglycemia, hyperinsulinemia, and insulin resistance cause vascular disease in type 2 diabetes mellitus. Dietary treatment alone often fails and oral drugs or insulin enhance hyperinsulinemia. In previous studies, an intravenous bolus of recombinant human insulin-like growth factor-I (rhIGF-I) caused normoglycemia in insulin-resistant diabetics whereas rhIGF-I infusions lowered insulin and lipid levels in healthy humans, suggesting that rhIGF-I is effective in insulin-resistant states. Thus, eight type 2 diabetics on a diet received on five treatment days subcutaneous rhIGF-I (2 x 120 micrograms/kg) after five control days. Fasting and postprandial glucose, insulin, C-peptide, proinsulin, glucagon, triglyceride, insulin-like growth factor-I and -II, and growth hormone levels were determined. RhIGF-I administration increased total IGF-I serum levels 5.3-fold above control. During the control period mean (+/- SD) fasting glucose, insulin, C-peptide, and total triglyceride levels were 11.0 +/- 4.3 mmol/liter, 108 +/- 50 pmol/liter, 793 +/- 250 pmol/liter, and 3.1 +/- 2.7 mmol/liter, respectively, and decreased during treatment to a nadir of 6.6 +/- 2.5 mmol/liter, 47 +/- 18 pmol/liter, 311 +/- 165 pmol/liter, and 1.6 +/- 0.8 mmol/liter (P < 0.01), respectively. Postprandial areas under the glucose, insulin, and C-peptide curve decreased to 77 +/- 13 (P < 0.02), 52 +/- 11, and 60 +/- 9% (P < 0.01) of control, respectively.
    [Show full text]
  • Proinsulin: Crystallization and Preliminary X-Ray Diffraction Studies* W
    Proceedings of the National Academy of Sciences Vol. 66, No. 4, pp. 1213-1219, August 1970 Proinsulin: Crystallization and Preliminary X-Ray Diffraction Studies* W. Wardle Fullerton, Reginald Pottert and Barbara W. Lowt COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY, NEW YORK, NEW YORK Communicatcd by Erwin Chargaff, Mlay 15, 1970 Abstract. Bovine proinsulin has been crystallized under a variety of condi- tions at both neutral and acid pH. Microtechniques were employed with sample weights of about 200 jig and volumes of 5-20 1AL The crystalline preparations all differ from each other morphologically. X-ray photographs of one form, tetragonal bipyramids grown at pH 3 with added ammonium sulphate solution, established the space group P41212 (or its enlantiomorph P43212). The cell dimensions are a = 50.8 i 0.2 A, c = 148.0 + 0.4 A. The asymmetric unit in this form is a dimer of proinsulin which is also the dominant species in solution at this pH. Introduction. Following the studies of Steiner arid his co-w%-orkersl2 who estab- lished that insulin is synthesized via a single chain precursor protein, proinsulin has been isolated and characterized from bovine,3-6 porcine,' cod,8 anglerfish,9 and human10"1 tissues. The connecting peptide segment of proinsulin which links the carboxyl-terminal group of the insulin B chain to the amino-terminal group of the insulin A chain is cleaved in vivo by proteolysis. The lengths and sequences of the C-peptide vary markedly between species. In bovine pro- insulin, where the connecting peptide is 30 amino acid residues long," the pro- insulin molecule with a single 81 residue chain has a molecular weight of 868.5.
    [Show full text]
  • Proinsulin Misfolding Is an Early Event in the Progression to Type 2 Diabetes
    RESEARCH ARTICLE Proinsulin misfolding is an early event in the progression to type 2 diabetes Anoop Arunagiri1, Leena Haataja1, Anita Pottekat2, Fawnnie Pamenan1, Soohyun Kim3, Lori M Zeltser4, Adrienne W Paton5, James C Paton5, Billy Tsai6, Pamela Itkin-Ansari7, Randal J Kaufman2*, Ming Liu1,8, Peter Arvan1* 1Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, United States; 2Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States; 3Department of Biomedical Science and Technology, Konkuk University, Gwangjin-gu, Republic of Korea; 4Department of Pathology and Cell Biology, Naomi Berrie Diabetes Center, Columbia University, New York, United States; 5Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; 6Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States; 7Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States; 8Department of Endocrinology and Metabolism, Tianjin Medical University, Tianjin, China Abstract Biosynthesis of insulin – critical to metabolic homeostasis – begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are *For correspondence: more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks [email protected] (RJK); with the onset of islet insulin deficiency and diabetes.
    [Show full text]