Age‐associated changes of islet endocrine cells and the effects of body mass index in Japanese

Abstract

Aims/Introduction: Impaired growth and premature death of b-cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age-related changes of the islet structure in Japanese non-diabetic subjects and explored the underlying mechanism of the changes. Materials and Methods: A total of 115 non-diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, b-and non-b-cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)-1, cell cycle inhibitor P16, and oxidative stress marker cH2AX were also examined.Results: There was a gradual and marginal decline of volume densities of islets, b-and non-b-cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in b-cell mass, but not on the other variables. Ki67 positivity and PDX-1 expressions were high in the young, but low after maturation, whereas expressions of P16 and cH2AX were elevated in the aged. Conclusions: Age-associated decline of b-cell mass is marginal after maturation, and the reduction of b-cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.

Involvement of Oxidative Stress–Induced DNA Damage, Endoplasmic Reticulum Stress, and Autophagy Deficits in the Decline of β-Cell Mass in Japanese Type 2 Diabetic Patients

“…The modest reduction of b-cell mass in this study (;30%) compared with those in Americans (5) (;50-60%) may be ascribed to the lack of influences of increased BMI on Vi and Vb in Japanese nondiabetic subjects (26,27). Mean BMI was 22 in Japanese lean diabetic subjects while it was 35 in Americans (5).…”

“…Mean BMI was 22 in Japanese lean diabetic subjects while it was 35 in Americans (5). In contrast to the marked increase in b-cells in obese European or American nondiabetic subjects (28), compensatory hyperplasia in obese Japanese was not apparent (26,27). Such a modest reduction of b-cells may not itself account for the poor insulin secretion encountered in diabetes, underscoring the importance of b-cell dysfunction in type 2 diabetes rather than b-cell loss (2,6,29).…”

“…In fact, it is shown that life expectancy of b-cells is extremely long (nearly 20 years) (37), and the aged cells are sensitive to cell death (38). Accumulation of gH2AX-positive cells in the aged pancreas underscores this contention (26) since gH2AX was shown to be indicative for preapoptotic state (18,19). The lack of apparent evidence of apoptotic cells may not indicate the real absence of apoptotic cells, which are cleared by macrophages too rapidly to be appreciated on the sections.…”

Obesity, Type 2 Diabetes and Beta Cell Failure: An Asian Perspective

“…As a result, unexpectedly, we were not able to find a significant increase in beta cell mass in Japanese obese individuals compared with lean subjects (Figure 6). Another Japanese study also confirmed our findings [52]. These findings are inconsistent with the findings in the Caucasian population [24,39].…”

Telomere attrition in beta and alpha cells with age

“…More recently, Mizukami et al reported that Ki67-a marker for cell proliferation-positive rate of β and non-β islet cells is prominent in childhood but significantly decreased over 20 years of age (Mizukami et al, 2014). The pattern of telomere shortening in islet cells is compatible with the results of Cnop's and Mizukami's, suggesting that rapid islet cell telomere reduction in childhood and a slow reduction in adulthood.…”