title: Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes.
abstract: Human islets exhibit distinct islet architecture with intermingled alpha- and beta-cells particularly in large islets. In this study, we quantitatively examined pathological changes of the pancreas in patients with type 2 diabetes (T2D). Specifically, we tested a hypothesis that changes in endocrine cell mass and composition are islet-size dependent. A large-scale analysis of cadaveric pancreatic sections from T2D patients (n = 12) and non-diabetic subjects (n = 14) was carried out combined with semi-automated analysis to quantify changes in islet architecture. The method provided the representative islet distribution in the whole pancreas section that allowed us to examine details of endocrine cell composition in individual islets. We observed a preferential loss of large islets (>60 µm in diameter) in T2D patients compared to non-diabetic subjects. Analysis of islet cell composition revealed that the beta-cell fraction in large islets was decreased in T2D patients. This change was accompanied by a reciprocal increase in alpha-cell fraction, however total alpha-cell area was decreased along with beta-cells in T2D. Delta-cell fraction and area remained unchanged. The computer-assisted quantification of morphological changes in islet structure minimizes sampling bias. Significant beta-cell loss was observed in large islets in T2D, in which alpha-cell ratio reciprocally increased. However, there was no alpha-cell expansion and the total alpha-cell area was also decreased. Changes in islet architecture were marked in large islets. Our method is widely applicable to various specimens using standard immunohistochemical analysis that may be particularly useful to study large animals including humans where large organ size precludes manual quantitation of organ morphology.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: German
authors.initials: G
authors.lastname: Kilimnik
authors.forename: Billy
authors.initials: B
authors.lastname: Zhao
authors.forename: Junghyo
authors.initials: J
authors.lastname: Jo
authors.forename: Vipul
authors.initials: V
authors.lastname: Periwal
authors.forename: Piotr
authors.initials: P
authors.lastname: Witkowski
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Misawa
authors.forename: Manami
authors.initials: M
authors.lastname: Hara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D007515:Islets of Langerhans / Q000033:anatomy & histology* / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D010179:Pancreas / Q000473:pathology; D055815:Young Adult
references.citation: Am J Physiol Endocrinol Metab. 2009 Dec;297(6):E1331-8
references.pmid: 19808908
references.citation: Recent Prog Horm Res. 1994;49:91-104
references.pmid: 8146438
references.citation: Diabetes Res Clin Pract. 2009 Sep;85(3):252-7
references.pmid: 19595468
references.citation: Regul Pept. 2008 Feb 7;146(1-3):4-11
references.pmid: 17889380
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2334-9
references.pmid: 16461897
references.citation: Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E177-83
references.pmid: 12388130
references.citation: J Clin Endocrinol Metab. 2003 May;88(5):2300-8
references.pmid: 12727989
references.citation: Horm Metab Res. 2004 Nov-Dec;36(11-12):775-81
references.pmid: 15655708
references.citation: J Histochem Cytochem. 2005 Sep;53(9):1087-97
references.pmid: 15923354
references.citation: PLoS One. 2009 Nov 06;4(11):e7739
references.pmid: 19893748
references.citation: Diabetes Care. 1998 Feb;21(2):246-9
references.pmid: 9539990
references.citation: Biophys J. 1993 Jun;64(6):1668-80
references.pmid: 8369400
references.citation: Diabetologia. 2011 Jul;54(7):1720-5
references.pmid: 21465328
references.citation: Biophys J. 2005 Sep;89(3):1534-42
references.pmid: 15994889
references.citation: Islets. 2009 Sep-Oct;1(2):129-36
references.pmid: 20606719
references.citation: Diabetes. 2000 Aug;49(8):1341-6
references.pmid: 10923635
references.citation: Diabetologia. 1983 May;24(5):366-71
references.pmid: 6347784
references.citation: Diabetes. 2004 Mar;53(3):624-32
references.pmid: 14988246
references.citation: Diabetes Metab Res Rev. 2000 Jul-Aug;16(4):230-6
references.pmid: 10934451
references.citation: Islets. 2010 May-Jun;2(3):135-45
references.pmid: 20657742
references.citation: Diabetes. 2010 May;59(5):1202-10
references.pmid: 20185817
references.citation: Diabetes Res. 1988 Dec;9(4):151-9
references.pmid: 3073901
references.citation: Adv Exp Med Biol. 2010;654:501-14
references.pmid: 20217512
references.citation: J Clin Invest. 2006 Jul;116(7):1802-12
references.pmid: 16823478
references.citation: Diabetes. 2003 Jan;52(1):102-10
references.pmid: 12502499
references.citation: J Vis Exp. 2011 Mar 04;(49):
references.pmid: 21403638
references.citation: Diabetes Obes Metab. 2008 Nov;10 Suppl 4:23-31
references.pmid: 18834430