Decreased pancreatic acinar cell number in type 1 diabetes (original) (raw)
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Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of specific beta-cell loss. Since healthy pancreatic islets consist of ~65% beta cells, this would lead to reduced islet size if the beta cells are not replaced by other cells or tissue. The number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. Results show that subjects with T1D, regardless of disease duration, had a dramatically reduced islet number per mm2, while the islet size was similar in all groups. Insulin- negative islets in T1D subjects were dominated by glucagon-positive cells that frequently had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally expressed in beta cells. Based on our findings, we propose that failure during childhood to establish a sufficient islet num...
The Journal of Pathology: Clinical Research
Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of~65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.
Journal of Anatomy, 2010
The present study was initiated to improve our understanding of pancreatic beta-cell dynamics in male Zucker Diabetic Fatty (ZDF) rats and hence provide a framework for future diabetes studies in this animal model. Male ZDF rats from 6, 8, 10, 12, 14, 16, 20 and 26 weeks of age were subjected to an oral glucose tolerance test (OGTT). The animals were then euthanized and pancreases were removed for morphometric analyses of pancreatic beta-cell mass. As evident by a marked fourfold increase in insulin secretion, insulin resistance developed rapidly from 6 to 8 weeks of age. Simultaneously, the pancreatic beta-cell mass expanded from 6.17 ± 0.41 mg at 6 weeks of age, reaching a maximum of 16.5 ± 2.5 mg at 16 weeks of age, at which time pancreatic beta-cell mass gradually declined. The corresponding changes in glucose ⁄ insulin homeostasis were analysed using a standard insulin sensitivity index (ISI), an area under the curve (AUC) glucose-insulin index, or simple semi-fasted glucose levels. The study demonstrated that male ZDF rats underwent rapid changes in pancreatic beta-cell mass from the onset of insulin resistance to frank diabetes coupled directly to marked alterations in glucose ⁄ insulin homeostasis. The study underscores the need for a critical co-examination of glucose homeostatic parameters in studies investigating the effects of novel anti-diabetic compounds on pancreatic beta-cell mass in the male ZDF rat. A simple assessment of fasting glucose levels coupled with information about age can provide a correct indication of the actual pancreatic beta-cell mass and the physiological state of the animal.
Variations in Rodent Models of Type 1 Diabetes: Islet Morphology
Journal of Diabetes Research, 2013
Type 1 diabetes (T1D) is characterized by hyperglycemia due to lost or damaged islet insulin-producing -cells. Rodent models of T1D result in hyperglycemia, but with different forms of islet deterioration. This study focused on 1 toxin-induced and 2 autoimmune rodent models of T1D: BioBreeding Diabetes Resistant rats, nonobese diabetic mice, and Dark Agouti rats treated with streptozotocin. Immunochemistry was used to evaluate the insulin levels in the -cells, cell composition, and insulitis. T1D caused complete or significant loss of -cells in all animal models, while increasing numbers of -cells. Lymphocytic infiltration was noted in and around islets early in the progression of autoimmune diabetes. The loss of lymphocytic infiltration coincided with the absence of -cells. In all models, the remaining -and -cells regrouped by relocating to the islet center. The resulting islets were smaller in size and irregularly shaped. Insulin injections subsequent to induction of toxin-induced diabetes significantly preserved -cells and islet morphology. Diabetes in animal models is anatomically heterogeneous and involves important changes in numbers and location of the remaining -and -cells. Comparisons with human pancreatic sections from healthy and diabetic donors showed similar morphological changes to the diabetic BBDR rat model.
Human pancreatic islet function at the onset of Type 1 (insulin-dependent) diabetes mellitus
Diabetologia, 1993
Viable human pancreatic islets isolated from a recent-onset Type 1 (insulin-dependent) diabetic patient were used to perform in vitro studies. Pre-proinsulin mRNA and insulin content, as well as insulin response were analyse d . Insulin response to glucose and forskolin was completely absent in diabetic islets, as compared to control islets. Insulin content was reduced to only one-third of control values (395.0 + 3.5 vs 989.0 _+ 46.3 gU/islet) and 20.7 + 3.9 % of islets from the diabetic pancreas contained insulin-positive cells in immunofluorescence studies. Northern blot analysis re-vealed a severe reduction in the content of pre-proinsulin mRNA in diabetic pancreatic tissue. Our results indicate that although markedly decreased, beta cells in human pancreatic islets at the onset of Type 1 diabetes are still present. Nevertheless, pancreatic islet function is disproportionately impaired with a complete absence of an insulin response.
Functional pancreatic beta-cell mass: Involvement in type 2 diabetes and therapeutic intervention
Diabetes & Metabolism, 2009
In the adult, the pancreatic -cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulinresistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of  cells to compensate for insulinresistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional -cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the -cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional -cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional -cell mass. The latter is governed by a constant balance between -cell growth (replication from pre-existing  cells and neogenesis from precursor cells) and -cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in -cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances -cell survival (by activating -cell proliferation and differentiation, and inhibiting -cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional -cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.
Increased hormone-negative endocrine cells in the pancreas in type 1 diabetes
Context and objective: Type 1 diabetes (T1D) is characterized by a beta-cell deficit due to auto-immune inflammatory mediated beta-cell destruction. It has been proposed the deficit in beta-cell mass in T1D may be in part due to beta-cell degranulation to chromogranin positive hormone negative (CPHN) cells. Design, setting and participants: We investigated the frequency and distribution of CPHN cells in pancreas of 15 individuals with T1D, 17 autoantibody positive non diabetics and 17 non-diabetic controls. Results: CPHN cells were present at a low frequency in pancreas from non-diabetic and autoan-tibody positive brain dead organ donors, but are more frequently found in pancreas from donors with type 1 diabetes. (Islets: 1.110.20 vs 0.260.06 vs 0.270.10% of islet endocrine cells, T1D vs AA vs ND; T1D vs AA and ND p0.001). CPHN cells are most commonly found in the single cells and small clusters of endocrine cells rather than within established islets, (Clusters: 18.99 2.09 vs 9.671.49 vs 7.421.26% of clustered endocrine cells, T1D vs AA vs ND; T1D vs AA and ND p0.0001) mimicking the distribution present in neonatal pancreas. Conclusions: From these observations, we conclude that CPHN cells are more frequent in T1D and, as in (type 2 diabetes) T2D, are distributed in a pattern comparable to neonatal pancreas, implying possible attempted regeneration. In contrast to rodents, CPHN cells are insufficient to account for loss of beta-cell mass in T1D.
PLoS ONE, 2011
The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPR dn transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPR dn transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitativestereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated betacells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPR dn transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPR dn transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPR dn transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPR dn transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis.
The pancreatic beta-cell in human Type 2 diabetes
Nutrition, Metabolism and Cardiovascular Diseases, 2006
Aim: There is growing evidence that the beta-cell is central to the development of Type 2 diabetes. In this brief review we discuss the factors predisposing to beta-cell dysfunction and some characteristics of islet cells in Type 2 diabetes. Data synthesis: Several genes have been associated with islet cell dysfunction in Type 2 diabetes, including those encoding for transcription factors, glucose metabolism proteins, molecules of the insulin signaling pathways, and several others. On the other hand, many environmental factors can directly or indirectly affect pancreatic islet cells, and possibly contribute to the development and/or progression of Type 2 diabetes. In this regard, the role of prolonged exposure to high glucose (glucotoxicity) and high fatty acid (lipotoxicity) concentrations seems to be of particular relevance. More recently, it has been possible to directly evaluate some properties of pancreatic islets prepared from Type 2 diabetic donors. Consistently, a marked decrease in insulin secretion during glucose stimulation has been found, although the secretory response to amino acids or sulphonylurea is usually less severely affected. In addition, increased beta-cell apoptosis in Type 2 diabetes islets has been reported. Interestingly, experimental data show that in vitro manipulation of human Type 2 diabetes islets by agents that are able to reduce oxidative stress can improve beta-cell function and survival. Conclusion: Available data are consistent with the concept that the defect of the beta-cell is of primary importance in Type 2 diabetes; the evidence that some alterations in Type 2 diabetes beta-cells can be reverted, at least in vitro, may open new perspectives in the treatment of this disease. ª