Significant Human β-Cell Turnover Is Limited to the First Three Decades of Life as Determined by in Vivo Thymidine Analog Incorporation and Radiocarbon Dating

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 10; pp. E234 - E239
• Main Authors: Perl, S., Kushner, J. A., Buchholz, B. A., Meeker, A. K., Stein, G. M., Hsieh, M., Kirby, M., Pechhold, S., Liu, E. H., Harlan, D. M., Tisdale, J. F.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2010; The Endocrine Society
• Subjects: Adolescent; Adult; Aged; Aging - metabolism; Aging - physiology; Autopsy; Beta cells; Bromodeoxyuridine; Bromodeoxyuridine - pharmacokinetics; Cadavers; Cell Proliferation; Clinical trials; Deoxyribonucleic acid; Diabetes mellitus; DNA; Female; Humans; Insulin; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - physiology; Longevity; Male; Mass spectroscopy; Middle Aged; Original; Pancreas; Radiocarbon dating; Radiometric Dating - methods; Staining and Labeling - methods; Thymidine; Thymidine - analogs & derivatives; Thymidine - pharmacokinetics; Tissue Donors; Young Adult
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2010-0932

Aims: Diabetes mellitus results from an absolute or relative deficiency of insulin-producing pancreatic β-cells. The turnover rate of adult human β-cells remains unknown. We employed two techniques to examine adult human islet β-cell turnover and longevity in vivo. Methods: Subjects enrolled in National Institutes of Health clinical trials received thymidine analogs [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8 d to 4 yr prior to death. Archival autopsy samples from 10 patients (aged 17–74 yr) were employed to assess β-cell turnover by scoring nuclear analog labeling within insulin-staining cells. Human adult β-cell longevity was determined by estimating the cells’ genomic DNA integration of atmospheric 14C. DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15-yr-old donor, and purified β-cell DNA was obtained from two donors (ages 48 and 80 yr). 14C levels were then determined using accelerator mass spectrometry. Cellular “birth date” was determined by comparing the subject’s DNA 14C content relative to a well-established 14C atmospheric prevalence curve. Results: In the two subjects less than 20 yr of age, 1–2% of the β-cell nuclei costained for BrdU/IdU. No β-cell nuclei costained in the eight patients more than 30 yr old. Consistent with the BrdU/IdU turnover data, β-cell DNA 14C content indicated that the “birth date” of cells occurred within the subject’s first 30 yr of life. Conclusions: Under typical circumstances, human β-cells and their cellular precursors are established by young adulthood. In vivo thymidine analog labeling and carbon-14 dating showed β-cell turnover in humans to be restricted to the first three decades of life.