DOCSLIB.ORG

Proinsulin Levels in Patients with Pancreatic Diabetes Are Associated

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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). There was a weak inverse association between the total proinsulin/insulin ratio and pancreatic b-cell area (r2Z0.14, PZ0.032), whereas the intact proinsulin/insulin ratio and the intact and total proinsulin levels were unrelated to b-cell area. However, a strong inverse relationship between homeostasis model assessment index of b-cell function and both the total and the intact proinsulin/insulin ratio was found (r2Z0.55 and r2Z0.48 respectively). The association of insulin resistance (IR) with intact proinsulin was much weaker than the correlation with fasting insulin. Conclusions: Hyperproinsulinaemia is associated with defects in insulin secretion rather than a reduction in b-cell area. The weak association between intact proinsulin and IR argues against the usefulness of this parameter in clinical practice. European Journal of Endocrinology 163 551–558 Introduction individuals (6, 7), although this finding has not been confirmed by others (8, 9). Nevertheless, the determina- In health, glucose homoeostasis is primarily controlled tion of intact proinsulin as a marker for the diagnosis of by the secretion of insulin from pancreatic b-cells (1). insulin resistance (IR) has been widely advocated (10). About 80–90% of the total circulating insulin concen- Two major hypotheses have been expounded to trations are derived from mature, biologically fully explain the hyperproinsulinaemia in type 2 diabetes: active, insulin (2). In addition, a small percentage of some investigators have speculated that the increased immature insulin precursors and incomplete proinsulin release of proinsulin in such patients might result from cleavage products, such as intact proinsulin, des an intrinsic defect in proinsulin processing, leading to (31,32)-proinsulin and des (64,65)-proinsulin, are an increased release of immature insulin precursors and being co-secreted along with mature insulin. While in thus contributing to the impairment in b-cell function healthy, non-diabetic subjects, these precursors consti- in type 2 diabetes (5). Alternatively, hyperproinsulinae- tute only a minor fraction of the total amount of mia may be caused by an increased secretory demand secreted insulin, the release of proinsulin is significantly on the b-cells, leading to depletion of the ‘readily increased in patients with type 2 diabetes as well as in releasable’ insulin granule pool and mobilisation of individuals with impaired glucose tolerance (IGT) (2–5). insulin granules from the ‘reserve pool’, which is A couple of recent studies have also reported an thought to contain greater amounts of immature increase in intact proinsulin levels in insulin-resistant insulin precursors (11). The latter explanation would q 2010 European Society of Endocrinology DOI: 10.1530/EJE-10-0330 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 10/01/2021 10:51:11AM via free access 552 T G K Breuer and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010) 163 be supported by the fact that the ratio of proinsulin intact proinsulin levels were carried out, and the over insulin was also increased in humans after a fractional b-cell area of the resected pancreas was hemipancreatectomy (12). measured. The study protocol was approved by the In order to address the aetiology of increased ethics committee of the Ruhr-University Bochum proinsulin release in patients with type 2 diabetes, (registration number 2528). All patients provided two studies have compared the proinsulin/insulin ratios written informed consent prior to study enrolment. after a transient inhibition of insulin secretion aiming to induce b-cell rest (13, 14). Both studies showed clear reductions in relative proinsulin secretion after somato- Patients statin infusion, but only one study could demonstrate a full restoration of the proinsulin/insulin ratio to A total of 33 patients (17 males and 16 females) similar levels as found in non-diabetic individuals (13). undergoing pancreatic resections in the Department of Therefore, the underlying causes for the hyperpro- Surgery, St Josef-Hospital, Ruhr-University Bochum, insulinaemia in type 2 diabetes are still elusive. between the years 2004 and 2007 were included. Furthermore, although some studies have demon- Amongst those, 17 patients had been diagnosed with strated an association of proinsulin/insulin ratio with chronic pancreatitis, 13 underwent surgery for the various measures of insulin secretion, its relationship removal of benign pancreatic adenomas and 3 patients with b-cell mass has not yet been examined. Thus, underwent partial pancreatectomy because of tumours whether this association is due to a reduction in b-cell of the ampulla of Vater. The clinical diagnoses of number or a functional impairment in insulin release chronic pancreatitis, pancreatic carcinoma, pancreatic remains to be elucidated. adenoma or ampullary cancer were confirmed by an An alternative way to address whether the hyper- independent pathologist in all cases. Diabetes was proinsulinaemia in patients with type 2 diabetes is due previously known in six patients (treated with insulin to an intrinsic defect in proinsulin processing or an in four cases, glimepiride in one case and diet in one increased demand on the b-cells is to determine case), whereas the other patients had no history of proinsulin levels in patients with diabetes due to other known diabetes. A detailed description of the patient aetiologies than type 2 diabetes. Furthermore, by characteristics has been previously provided (15). comparing proinsulin concentrations with pancreatic b-cell area and various measures of insulin secretion, it should be possible to ascribe the development of Experimental procedures hyperinsulinaemia to defects in either b-cell mass or The experiments were performed in the morning after the functional regulation of insulin secretion. an overnight fast with subjects in a supine position Therefore, in the present study, total and intact throughout the experiments as described (15). All other proinsulin concentrations as well as various established concomitant medication was withdrawn since the measures of insulin secretion were determined in evening of the preceding day. The experiments were patients with and without diabetes secondary to started by the ingestion of the oral glucose load (75 g pancreatic disorders immediately prior to pancreatic glucose in 300 ml) over 5 min, and capillary and resections, and the fractional b-cell area was venous blood samples were drawn at tZK5, 0, 15, determined in the resected pancreatic tissue. By these 30, 60, 90, 120, 150, 180, 210 and 240 min. Capillary means, we addressed the following questions: i) Do blood samples (w100 ml) were added to NaF (Microvette patients with diabetes due to pancreatic disorders exhibit disproportionate hyperproinsulinaemia CB 300; Sarstedt, Nu¨ mbrecht, Germany) for the compared to non-diabetic individuals? ii) Are increased immediate measurement of glucose. Venous blood was proinsulin levels in these patients associated with drawn into chilled tubes containing EDTA and aprotinin defects in pancreatic b-cell area or b-cell function? iii) (Trasylol; 20 000 KIU/ml, 200 ml per 10 ml blood; Do intact proinsulin levels predict IR in lean patients Bayer AG) and kept on ice. After centrifugation with and without diabetes due to pancreatic disorders? at 4 8C, plasma for hormone analyses was kept frozen at K28 8C. Patients and methods Measurements Glucose was measured as described (15) using a glucose Study design oxidase method with a Glucose Analyser 2 (Beckman Thirty-three patients undergoing pancreatic surgery for Instruments, Munich, Germany). chronic pancreatitis, benign pancreatic adenomas or Insulin was measured as described (15) using an papillary tumours necessitating partial
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]
  • 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]
  • Mutations in the Proinsulin Gene Cause Diabetes with Variable Age Of
    Diabetes Publish Ahead of Print, published online February 11, 2008 Insulin Mutation Screening in 1044 Patients with Diabetes: Mutations in the INS gene are a Common Cause of Neonatal Diabetes but a Rare Cause of Diabetes Diagnosed in Childhood or Adulthood Emma L. Edghill,1 Sarah E. Flanagan,1 Ann-Marie Patch,1 Chris Boustred,1 Andrew Parrish,1 Beverley Shields,1 Maggie H. Shepherd,2 Khalid Hussain,3 Ritika R. Kapoor,3 Maciej Malecki,4 Michael J. MacDonald,5 Julie Støy,6 Donald F. Steiner,6,7 Louis H. Philipson,6 Graeme I. Bell,6,8 the Neonatal Diabetes International Collaborative Group** Andrew T. Hattersley,1 and Sian Ellard1 From the 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, United Kingdom; 2Institute of Health and Social Care, Peninsula Medical School, Exeter EX2 5DW, United Kingdom; 3 Departments of Endocrinology, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, United Kingdom; 4Department of Metabolic Diseases, Jagiellonian University, Krakow, Poland; 5Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin; Departments of 6Medicine, 7Biochemistry and Molecular Biology and 8Human Genetics, The University of Chicago, Chicago, Illinois ** Other members of the Neonatal Diabetes International Collaborative Group are listed in the appendix at the end of the paper. Running title: Insulin Mutations a common cause of neonatal diabetes Correspondence: Dr. Andrew T Hattersley Institute of Biomedical and Clinical Science Peninsula Medical School Barrack Road Exeter EX2 5DW United Kingdom. [email protected] Received for publication 3 October 2007 and accepted in revised form 14 December 2007.
    [Show full text]