期刊
DIABETES
卷 58, 期 6, 页码 1365-1372出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-1198
关键词
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资金
- Juvenile Diabetes Research Foundation International
- National Institutes of Health [K08-DK064101, R03-DK078546, R01-DK081469]
- March of Dimes Basil O'Connor Starter Scholar Research Award
- Lawson Wilkins Pediatric Endocrine Society Clinical Scholar Award
- Charles H. Hood Foundation Child Health Research
- The Children's Hospital of Philadelphia
- University of Pennsylvania Diabetes and Endocrinology Research Center [DK19525]
OBJECTIVE-Regeneration of the insulin-secreting beta-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. beta-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive beta-cell regeneration capacity is retained into old age. RESEARCH DESIGN AND METHODS-We assessed adaptive beta-cell proliferation capacity in adult mice across a wide range of ages with a variety Of stimuli: partial pancreatectomy, low-dose administration of the beta-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. beta-Cell proliferation was measured by administration of 5-bromo-2'-deoxyuridine (BrdU) in the drinking water. RESULTS-Basal beta-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly Stimulated beta-cell proliferation in young mice but failed to increase beta-cell replication in old mice. Streptozotocin stimulated beta-cell replication in Young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated beta-cell proliferation in Young but not in old mice. Surprisingly, adaptive beta-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span. CONCLUSIONS-Adaptive beta-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-. Thus, beta-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of beta-cells in mature adult mice. Diabetes 58:1365-1372, 2009
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