RESUMEN
The presence of remaining insulin-positive cells in type 1 diabetes (T1D) is well-known. These cells are part of islets or appear as extra-islet insulin-positive cells scattered in the exocrine parenchyma. The latter are poorly described, and the presence of scattered endocrine cells expressing other islet hormones than insulin has not been explored. This study aimed to compare the extra-islet insulin- or glucagon-positive cells concerning their frequency, transcription-factor expression, and mitotic activity in subjects with and without T1D. Multispectral imaging was used to examine extra-islet cells by staining for insulin, glucagon, ARX, PDX1, and Ki67. This was done in well-preserved pancreatic tissue obtained from heart-beating organ donors with or without T1D. In three T1D donors, lobes with insulin-containing islets (ICI) were found. Within these, a higher frequency of extra-islet insulin-positive cells was observed compared to lobes with insulin-deficient islets (IDI). Increased frequency of glucagon-positive extra-islet cells was observed in donors with T1D (median 53 cells/mm2) when compared with non-diabetic donors (11 cells/mm2, p = 0.004). Proliferating endocrine cells were present in donors with, and without T1D, as demonstrated by Ki67-positive staining (0-3% of the cells expressing insulin or glucagon). The reduced frequency of extra-islet insulin-positive cells in lobes with IDI in donors with T1D suggests that the pathological mechanism causing beta cell demise in T1D affects entire lobes. The presence of an increased frequency of glucagon-positive extra-islet cells supports the notion of a preserved capacity to regenerate the endocrine pancreas in donors with T1D.
RESUMEN
AIMS: The existence of insulin- or glucagon-expressing extra-islet endocrine cells scattered in the pancreas is well-known, but they have been sparsely characterized. The aim of this study was to examine their density, distribution, transcription-factor expression, and mitotic activity in young non-diabetic subjects. METHODS: Multispectral imaging was used to examine PDX1, ARX, Ki67, insulin and glucagon in extra-islet endocrine cells in pancreatic tissue from organ donors aged 1-25 years. RESULTS: Extra-islet insulin- or glucagon-positive cells were frequent in all donors (median 17.3 and 22.9 cells/mm2 respectively), with an insulin:glucagon cell ratio of 0.9. The density was similar regardless of age. PDX1 localized mainly to insulin-, and ARX mainly to glucagon-positive cells but, interestingly, many of the cells were negative for both transcription factors. Double-hormone-positive cells were rare but found in all age groups, as were insulin-positive cells expressing ARX and glucagon-positive cells expressing PDX1. Extra-islet endocrine cells with Ki67 expression were present but rare (0-2%) in all age groups. CONCLUSIONS: Extra-islet endocrine cells are more frequent than islets. The preserved extra-islet cell density during pancreas volume-expansion from childhood- to adulthood indicates that new cells are formed, possibly from replication as cells with mitotic activity were discovered. The lack of transcription-factor expression in many cells indicates that they are immature, newly formed or plastic. This, together with the mitotic activity, suggests that these cells could play an important role in the expansion of beta-cell mass in situations of increasing demand, or in the turnover of the endocrine cell population.