Variation in characteristics of islets of Langerhans in insulin-resistant, diabetic and non-diabetic-rat strains.
Assessment of the histopathological and plasma biochemical characteristics of diabetic and non-diabetic rat strains [Han and AP Wistar, lean and obese Zucker Fatty (ZF), and lean and obese Zucker Diabetic Fatty (ZDF) rats] was performed at 6 or 14 weeks of age. Wistar and lean ZF and ZDF rats showed no or minimal islet pathology or plasma biochemical alterations at both timepoints. Obese ZFs were euglycaemic at both timepoints and mildly and severely hyperinsulinaemic at 6 and 14 weeks respectively. Islet morphology was normal at 6 weeks but at 14 weeks, islet hyperplasia was present with a minority showing degenerative changes namely, beta-cell vacuolation, vascular congestion and haemorrhage with minimal mononuclear cell and T lymphocytic infiltration. Obese ZDFs were euglycaemic and moderately hyperinsulinaemic at 6 weeks and severely hyperglycaemic with minor hypoinsulinaemia at 14 weeks. Obese ZDFs at 6 weeks showed mainly normal islets with some displaying degeneration (ranging from beta-cell vacuolation alone to the features described above). At 14 weeks, islet degeneration was more severe and widespread: beta-cell death was present in numerous islets at low level. Islet beta-cell numbers were reduced or absent (with associated reduction in insulin immunostaining) within the islets that now consisted predominantly of fibroblasts, collagen and mononuclear cells. Fibroproliferation consisting of smooth muscle actin-alpha-positive tissue was associated with mononuclear cell infiltration. Some fibrous scars were visible indicative of lost islets. Islet degeneration in obese ZF and ZDF rats was not accompanied by a reduction in beta-cell proliferation or in compensatory proliferation of beta-cell neogenic clusters. In the light of recent reports of adaptive and inflammation-mediated degenerative changes in human non-insulin dependent diabetes mellitus (NIDDM) islets, the hypertrophy/hyperplasia of beta-cells and islet degeneration involving infiltration by monocyte/macrophages in obese ZF and obese ZDF rats respectively offers substantial potential for elucidation of the processes involved.
Jones
Huw Bowen
HB
Pathology Department, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK. huw.jones@astrazeneca.com
Nugent
David
D
Jenkins
Richard
R
D000818:Animals; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005230:Fatty Acids, Nonesterified / Q000097:blood; D019270:Fructosamine / Q000097:blood; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology*; D019344:Lactic Acid / Q000097:blood; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D019344:Lactic Acid; D019270:Fructosamine; D002784:Cholesterol
Annu Rev Med. 2002;53:319-36
11818477
Diabetes. 2001 Feb;50 Suppl 1:S20-4
11272192
Diabetologia. 1983 May;24(5):366-71
6347784
J Clin Invest. 1998 May 1;101(9):1905-15
9576755
Diabetes. 2002 Aug;51(8):2530-5
12145167
Annu Rev Med. 1995;46:223-34
7598459
Metabolism. 1999 Apr;48(4):477-83
10206441
Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E848-56
11350766
Horm Metab Res. 1999 Nov;31(11):610-5
10598829
Diabetes. 1995 Dec;44(12):1447-57
7589853
Biochem Biophys Res Commun. 2004 Feb 13;314(3):870-7
14741717
Cytokine. 2008 Oct;44(1):141-8
18723371
Cell Transplant. 1995 Jul-Aug;4(4):371-83
7582568
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3077-82
12629214
Diabetes. 1998 Mar;47(3):358-64
9519740
Diabetes Metab. 2001 Nov;27(5 Pt 1):535-42
11694852
Diabetes Care. 2008 Feb;31 Suppl 2:S161-4
18227479
Proc Soc Exp Biol Med. 1983 May;173(1):68-75
6344096
Endocrinology. 2003 Jun;144(6):2717-27
12746336
Diabetologia. 1995 Feb;38(2):173-9
7713311
Arch Physiol Biochem. 2009 Oct;115(4):240-7
19645635
Endocr Rev. 2008 May;29(3):351-66
18048763
Physiology (Bethesda). 2009 Dec;24:325-31
19996363
Am J Pathol. 2007 Jun;170(6):1807-16
17525249
Endocrinology. 1994 Sep;135(3):849-53
7520863
J Clin Invest. 1987 Feb;79(2):319-26
3543052
Trends Immunol. 2004 May;25(5):222-9
15099561
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1784-9
10677535
Am J Physiol. 1986 Dec;251(6 Pt 1):E644-7
3538897
Diabetologia. 2009 Aug;52(8):1686-8
19504085
N Engl J Med. 2007 Apr 12;356(15):1517-26
17429083
J Endocrinol Invest. 2003 Jun;26(6):508-15
12952363
Diabetes. 1982 Aug;31(8 Pt 1):694-700
6131002
Biochem Biophys Res Commun. 2003 May 23;305(1):122-8
12732205
Diabetes. 2003 May;52(5):1256-64
12716761
Diabetes. 1997 Jun;46(6):947-52
9166664
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498-502
9482914
Diabetes Res. 1988 Dec;9(4):151-9
3073901
Diabetes. 2006 Jun;55(6):1625-33
16731824
J Clin Invest. 1997 Jul 15;100(2):290-5
9218505
Am J Physiol. 1992 May;262(5 Pt 1):E736-40
1590384
Diabetes. 2005 Jan;54(1):85-91
15616014
Diabetes. 2007 Sep;56(9):2356-70
17579207
Diabetologia. 1994 Jul;37(7):677-80
7958538
Exp Clin Endocrinol Diabetes. 2001;109(5):273-82
11507651
J Pathol. 2003 Jul;200(4):500-3
12845617
Ilar News. 1990 Jan;32(3):13-15
34191867
Surv Synth Pathol Res. 1985;4(2):110-25
3901180