title: Impaired insulin turnover in islets from type 2 diabetic patients.
abstract: Failure of pancreatic β-cells contributes to the development of type 2 diabetes. Besides evidence of reduced glucose-stimulated insulin secretion and β-cell mass, little information is available about the molecular deficits of human diabetic islets. Islets were isolated from macroscopically normal pancreatic tissue from 8 patients with type 2 diabetes and 17 matched non-diabetic patients who underwent pancreatic surgery. Insulin content and insulin secretion were measured before and after islet stimulation with 25 mM glucose for 2 hours. In parallel, we also investigated the subcellular localization of polypyrimidine tract-binding protein 1 (PTBP1), whose nucleocytoplasmic translocation is involved in the rapid posttranscriptional up-regulation of insulin biosynthesis following islet stimulation with glucose and GLP-1. Glucose stimulated insulin secretion was decreased, albeit not significantly, in type 2 diabetic islets compared to non-diabetic islets. Stimulation increased the total amount of insulin (islet insulin content + secreted insulin) in islet preparation from non-diabetic patients, but not from type 2 diabetic subjects. Furthermore, the nuclear levels of PTBP1 were decreased in stimulated non-diabetic islets, but not in type 2 diabetic islets. These results suggest that impairment of rapid insulin increase in response to glucose is a specific trait of type 2 diabetic islets. Nuclear retention of PTBP1 is likely to play a role in this deficit, which in turn can contribute to impaired insulin secretion in type 2 diabetes. Overall, these data highlight the importance of investigating mechanisms of insulin biosynthesis and degradation to gain insight into the pathogenesis of type 2 diabetes.
authors.affiliation: Department of GI, Thoracic and Vascular Surgery, Dresden University of Technology, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Ehehalt
authors.forename: Klaus
authors.initials: K
authors.lastname: Knoch
authors.forename: Katja
authors.initials: K
authors.lastname: Erdmann
authors.forename: Christian
authors.initials: C
authors.lastname: Krautz
authors.forename: Melanie
authors.initials: M
authors.lastname: Jäger
authors.forename: Anja
authors.initials: A
authors.lastname: Steffen
authors.forename: Carolin
authors.initials: C
authors.lastname: Wegbrod
authors.forename: Ronny
authors.initials: R
authors.lastname: Meisterfeld
authors.forename: Stephan
authors.initials: S
authors.lastname: Kersting
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bergert
authors.forename: E
authors.initials: E
authors.lastname: Kuhlisch
authors.forename: Stefan
authors.initials: S
authors.lastname: Bornstein
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Hans-Detlev
authors.initials: HD
authors.lastname: Saeger
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002469:Cell Separation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D005260:Female; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D014018:Tissue Distribution
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007328:Insulin; C450006:PTBP1 protein, human; D038941:Polypyrimidine Tract-Binding Protein