Altered Islet Composition and Disproportionate Loss of Large Islets in Patients with Type 2 Diabetes

The University of Hong Kong, Hong Kong
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e27445. DOI: 10.1371/journal.pone.0027445
Source: PubMed


Human islets exhibit distinct islet architecture with intermingled alpha- and beta-cells particularly in large islets. In this study, we quantitatively examined pathological changes of the pancreas in patients with type 2 diabetes (T2D). Specifically, we tested a hypothesis that changes in endocrine cell mass and composition are islet-size dependent. A large-scale analysis of cadaveric pancreatic sections from T2D patients (n = 12) and non-diabetic subjects (n = 14) was carried out combined with semi-automated analysis to quantify changes in islet architecture. The method provided the representative islet distribution in the whole pancreas section that allowed us to examine details of endocrine cell composition in individual islets. We observed a preferential loss of large islets (>60 µm in diameter) in T2D patients compared to non-diabetic subjects. Analysis of islet cell composition revealed that the beta-cell fraction in large islets was decreased in T2D patients. This change was accompanied by a reciprocal increase in alpha-cell fraction, however total alpha-cell area was decreased along with beta-cells in T2D. Delta-cell fraction and area remained unchanged. The computer-assisted quantification of morphological changes in islet structure minimizes sampling bias. Significant beta-cell loss was observed in large islets in T2D, in which alpha-cell ratio reciprocally increased. However, there was no alpha-cell expansion and the total alpha-cell area was also decreased. Changes in islet architecture were marked in large islets. Our method is widely applicable to various specimens using standard immunohistochemical analysis that may be particularly useful to study large animals including humans where large organ size precludes manual quantitation of organ morphology.

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    • "In type 2 diabetes patients, there are changes in endocrine cell mass (including β-cells) occurring in large islets of (cadaveric) pancreatic sections (Kilimnik et al., 2011), especially in the head regions of the pancreas (Wang et al., 2013). In fact, large islets (>60 mm in diameter) are preferentially lost in type 2 patients when compared to non-diabetic subjects. "
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    ABSTRACT: Pancreatic β-cells in the islets of Langerhans play a crucial role in regulating glucose homeostasis in the circulation. Loss of β-cell mass or function due to environmental, genetic and immunological factors leads to the manifestation of diabetes mellitus. The mechanisms of pancreatic β-cell mass development during normal development and diabetes progression are complex. To fully unravel such complexity, experimental and clinical approaches need to be combined with mathematical and computational models. In the natural sciences, mathematical and computational models have aided the identification of key mechanisms underlying the behavior of systems comprising multiple interacting components. A number of mathematical and computational models have been proposed to explain the development, growth and death of pancreatic β-cells. In this review, we discuss some of these models and how their predictions provide novel insight into the mechanisms controlling β-cell mass during normal development and diabetes progression. Lastly, we discuss a handful of the major open questions in the field. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "We examined regional heterogeneity in the human pancreas comparing head, body and tail regions from each individual to understand species differences, whereas past studies characterized the pancreatic regions to a limited extent using point-count morphometry [30]–[34]. In the present study, we have particularly applied large-scale image capture and computer-assisted quantification of islet size distribution and architecture that provides an unbiased representative view of an entire tissue section [5], [6], [26]. We report that largely similar to rodents, the tail region contains >2-fold higher islet distribution compared to the head and body region. "
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    ABSTRACT: While regional heterogeneity in islet distribution has been well studied in rodents, less is known about human pancreatic histology. To fill gaps in our understanding, regional differences in the adult human pancreas were quantitatively analyzed including the pathogenesis of type 2 diabetes (T2D). Cadaveric pancreas specimens were collected from the head, body and tail regions of each donor, including subjects with no history of diabetes or pancreatic diseases (n = 23) as well as patients with T2D (n = 12). The study further included individuals from whom islets were isolated (n = 7) to study islet yield and function in a clinical setting of islet transplantation. The whole pancreatic sections were examined using an innovative large-scale image capture and unbiased detailed quantitative analyses of the characteristics of islets from each individual (architecture, size, shape and distribution). Islet distribution/density is similar between the head and body regions, but is >2-fold higher in the tail region. In contrast to rodents, islet cellular composition and architecture were similar throughout the pancreas and there was no difference in glucose-stimulated insulin secretion in islets isolated from different regions of the pancreas. Further studies revealed preferential loss of large islets in the head region in patients with T2D. The present study has demonstrated distinct characteristics of the human pancreas, which should provide a baseline for the future studies integrating existing research in the field and helping to advance bi-directional research between humans and preclinical models.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "In order to minimize a sampling bias with a practical stereological approach, we have developed a computer-assisted large-scale image analysis of the entire section that provides information on every endocrine cell mass (from singlets to large islets) such as area, shape, cellular composition, and islet architecture (i.e. coordinates of each endocrine cell within a given islet) [16], [20], [21]. The whole pancreas analysis in this report provides an example of how endocrine cell mass changes regionally in an individual pancreas. "
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