Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat.
To define the mechanisms involved in the evolution of diabetes in the Zucker diabetic fatty (ZDF) rat, beta-cell mass and replication rates were determined by immunochemistry, point-counting morphometry, and 6-h 5-bromo-2'-deoxyuridine (BrdU) incorporation. The beta-cell mass in 5- to 7-week-old prediabetic ZDF rats (4.3 +/- 0.06 mg) was similar to age-matched insulin-resistant Zucker fatty (ZF) rats (3.7 +/- 0.05 mg) and greater than that in Zucker lean control (ZLC) rats (1.9 +/- 0.3, P < 0.05). At 12 weeks (after diabetes onset), beta-cell mass in the ZDF rats (8.1 +/- 1.7 mg) was significantly lower than the ZF rats (15.7 +/- 1.8 mg). The mass in the ZF rats was significantly greater than in the ZLC rats (4.3 +/- 0.8 mg, P < 0.05). The beta-cell proliferation rate (mean of both time points) was significantly greater in the ZDF rats (0.88 +/- 0.1%) compared with the ZF and ZLC rats (0.53 +/- 0.07%, 0.62 +/- 0.07%, respectively, P < 0.05), yet ZDF rats have a lower beta-cell mass than the ZF rats despite a higher proliferative rate. Morphological evidence of neogenesis and apoptosis is evident in the ZF and ZDF rats. In addition, even at 5-7 weeks a modest defect in insulin secretion per beta-cell unit was found by pancreas perfusion. These studies provide evidence that the expansion of beta-cell mass in response to insulin resistance and insulin secretory defects in diabetic ZDF rats is inadequate. This failure of beta-cell mass expansion in the ZDF rat does not appear to be from a reduction in the rate of beta-cell proliferation or neogenesis, suggesting an increased rate of cell death by apoptosis.
Pick
A
A
Department of Medicine, The University of Chicago and Pritzker School of Medicine, Illinois 60637, USA.
Clark
J
J
Kubstrup
C
C
Levisetti
M
M
Pugh
W
W
Bonner-Weir
S
S
Polonsky
K S
KS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000032:analysis; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000209:etiology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D010191:Pancreatic Polypeptide / Q000032:analysis; D010477:Perfusion; D051381:Rats; D011924:Rats, Zucker; D013004:Somatostatin / Q000032:analysis; D013997:Time Factors
D007328:Insulin; D013004:Somatostatin; D010191:Pancreatic Polypeptide; D005934:Glucagon; D005947:Glucose