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Diabetes. 2009 May;58(5):1175-84. doi: 10.2337/db08-0616. Epub 2009 Feb 19.

Dynamic changes in pancreatic endocrine cell abundance, distribution, and function in antigen-induced and spontaneous autoimmune diabetes.

Author information

1
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. klausp@intra.niddk.nih.gov

Abstract

OBJECTIVE:

Insulin deficiency in type 1 diabetes and in rodent autoimmune diabetes models is caused by beta-cell-specific killing by autoreactive T-cells. Less is known about beta-cell numbers and phenotype remaining at diabetes onset and the fate of other pancreatic endocrine cellular constituents.

RESEARCH DESIGN AND METHODS:

We applied multicolor flow cytometry, confocal microscopy, and immunohistochemistry, supported by quantitative RT-PCR, to simultaneously track pancreatic endocrine cell frequencies and phenotypes during a T-cell-mediated beta-cell-destructive process using two independent autoimmune diabetes models, an inducible autoantigen-specific model and the spontaneously diabetic NOD mouse.

RESULTS:

The proportion of pancreatic insulin-positive beta-cells to glucagon-positive alpha-cells was about 4:1 in nondiabetic mice. Islets isolated from newly diabetic mice exhibited the expected severe beta-cell depletion accompanied by phenotypic beta-cell changes (i.e., hypertrophy and degranulation), but they also revealed a substantial loss of alpha-cells, which was further confirmed by quantitative immunohistochemisty. While maintaining normal randomly timed serum glucagon levels, newly diabetic mice displayed an impaired glucagon secretory response to non-insulin-induced hypoglycemia.

CONCLUSIONS:

Systematically applying multicolor flow cytometry and immunohistochemistry to track declining beta-cell numbers in recently diabetic mice revealed an altered endocrine cell composition that is consistent with a prominent and unexpected islet alpha-cell loss. These alterations were observed in induced and spontaneous autoimmune diabetes models, became apparent at diabetes onset, and differed markedly within islets compared with sub-islet-sized endocrine cell clusters and among pancreatic lobes. We propose that these changes are adaptive in nature, possibly fueled by worsening glycemia and regenerative processes.

PMID:
19228810
PMCID:
PMC2671059
DOI:
10.2337/db08-0616
[Indexed for MEDLINE]
Free PMC Article
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