Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #23: Pancreatic Morphology in Normal and Diabetic States Part 3 of 4

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #23: Pancreatic Morphology in Normal and Diabetic States Part 3 of 4

May 10, 2016

DeFronzoCoverDisturbances in pancreas/islet morphology in diabetes

Type 1 diabetes


Type 1 diabetes (T1DM) is classically associated with autoimmune destruction of β cells [68] (Figure 5.2). However, the pancreas is more broadly affected, with overall pancreas size being decreased in individuals with this form of diabetes [68,69], and loss of exocrine tissue occurring close to areas of immune infiltration [70]. β-Cell destruction is largely a T-cell-mediated process, involving mainly CD8+ cells, but also including CD4+ cells and other immune cells such as macrophages and B cells [71,72]. Lymphocytic infiltration of islets is well documented in animal models [73,74]. However, the degree of infiltration can vary widely even among islets from the same animal in various stages of diabetes development [73,74]. Further, the extent of leukocyte infiltration in humans appears to be less than that seen in animal models, while the variability in affected islets is similar [70,72,75]. In human T1DM, insulitis is primarily reported in individuals with recent onset disease [70,76], although it has been detected in patients 8 years following diagnosis [72,76]. That insulitis occurs predominantly around the time of disease onset is consistent with the clinical observation that the largest decline in C-peptide responses occurs between 6 months prior to and 12 months following disease diagnosis [77,78]. Despite the variability in detectable insulitis, autoimmune destruction appears to result in eventual elimination of the majority of β cells [70,79]. However, β cells can persist for many years into the course of the disease [79,80] and low levels of β-cell replication have been documented in some [81], but not all studies [82]. Further, there is evidence for residual insulin release many years after the development of hyperglycemia [83]. This raises the possibility that β-cell destruction may not be complete and that regeneration may be possible. A recent study documenting the efficacy of stem cell therapy in rapidly reversing T1DM, in many cases up to 36 months of follow-up, provides support for this concept [84].

While β-cell destruction is widespread in T1DM, non-β-cell islet populations, particularly α cells, appear to be spared the autoimmune destruction [70]. However, despite the persistence of α cells in T1DM, their function is undoubtedly dysregulated. Specifically, meal-stimulated glucagon responses are exaggerated [85], while glucagon release in response to hypoglycemia is markedly impaired [86]. These abnormalities may be due to the lack of oscillating insulin levels, which would normally act to regulate glucagon release [87]. However, the lack of glucagon response to hypoglycemia is likely also impacted by the early loss of sympathetic nerve terminals in islets, which has been demonstrated in rodent models of T1DM [88,89] and in human T1DM [90]. This islet neuropathy is selective, with islet parasympathetic innervation appearing to be normal, at least in rodent models of T1DM [90].

Whether islet capillary density is altered in T1DM is currently unknown. Recently however, significant alterations in the extracellular matrix closely apposed to the islet vasculature have been described in human T1DM and animal models thereof [36,42]. Degradation of peri-islet extracellular matrix has been shown to correlate with leukocyte infiltration and β-cell loss in human T1DM and NOD diabetic mice [36,42]. Interestingly, however, once insulitis is resolved, peri-islet extracellular matrix is regenerated, even in the absence of insulin-positive cells, providing further support for a role of leukocytic infiltration in the degradation of this extracellular matrix. Altered localization of the extracellular matrix component hyaluronan [91,92] and increased production of extracellular matrix degrading enzyme heparanase [93] have also been described in association with lymphocytic infiltration of islets in NOD diabetic mice, in common with other autoimmune diseases [94]. The contribution of these changes in extracellular matrix to diabetes onset and progression are not fully understood at present, but they may be important in allowing leukocytes to gain access to the islet, and are an active area of investigation.

Type 2 diabetes

Macroscopically, the pancreas appears largely unchanged in T2DM. Fibrosis in the exocrine pancreas has been described [95], suggesting some abnormality in the exocrine pancreas, but this has not been widely studied. In contrast, the presence of morphologic abnormalities in islets from subjects with T2DM has long been established. More than a century ago, Opie described decreased cell number and accumulation of what was later identified as islet amyloid [96]. Subsequently, it was confirmed that islet β-cell volume is decreased in T2DM [59,97], an observation has been reproduced in numerous studies, across several ethnic groups [15–17] (Figure 5.2). Butler et al. additionally showed that β-cell volume is also decreased in subjects with impaired fasting glucose, with the extent of reduction being intermediate between that of subjects with T2DM and nondiabetic controls [15]. Overall, the extent of β-cell loss reported varies widely among studies (0–63% reduction), most likely due to the variability of β-cell volume among subjects [16,17] and also to the site of sampling [16]. Similar to the situation in T1DM, islet α-cell mass has been shown to be maintained in T2DM, resulting in a relative increase in the α:β cell ratio [2,95,98]. In animal models, islet glucagon and pancreatic polypeptide immunoreactivity have been reported to be similar or increased relative to nondiabetic animals [99,100], while somatostatin immunoreactivity is more variable, being reportedly increased, similar or decreased in comparison to nondiabetic animals [99–101].

Alterations in density and/or morphology of islet capillaries have been described in a variety of rodent models of diabetes. Early in the course of hyperglycemia, distorted islet capillary morphology is present and with more advanced diabetes, loss of capillary density occurs and is frequently associated with islet fibrosis [102–108]. No published studies have been performed on human pancreas specimens, but our unpublished data suggest that while islet capillary morphology is distorted, islet capillary density is not decreased in T2DM relative to nondiabetic controls (Brissova, Powers, Hull, unpublished observation).Decreased islet innervation has also been reported in animal models of T2DM [109], but has not been determined in humans with the disease. Abnormalities in islet extracellular matrix have also been documented in human T2DM and animal models thereof. These include accumulation of islet amyloid, which comprises the aggregated form of the β-cell peptide IAPP [17,95,110], and islet fibrosis occurring due to fibrillar collagen deposition [111,112].

Influence of exocrine pancreas abnormalities on islet morphology and function

Diseases affecting the exocrine pancreas are associated with diabetes. Acute pancreatitis has been associated with glucose intolerance and impaired insulin release, but this disturbance seems to be temporary [113], suggesting that exocrine pancreas abnormalities can impact islet function. In cases of chronic pancreatitis whose primary disease etiology is exocrine in nature, diabetes is present in the majority of cases [114]. However, pancreatitis is also more common in individuals with T2DM[95,115], making the link between exocrine disease and the subsequent onset of diabetes less clear.

Cystic fibrosis is an autosomal recessive disorder, arising due to one of several mutations in the cystic fibrosis transmembrane receptor (CFTR), a chloride channel, with disease onset usually occurring in childhood [116]. Lung disease is the primary manifestation of CFTR mutation. However, with improved treatment including lung transplantation, survival has significantly improved in recent years; as a result, other complications of cystic fibrosis are now more common. Pancreatic involvement, namely significant exocrine pancreas fibrosis is the second most common feature of cystic fibrosis, after lung pathology. Accordingly, cystic fibrosis-related diabetes complicates a large proportion of cystic fibrosis cases [117]. This form of diabetes does not seem to include underlying autoimmunity, suggesting its etiology differs from that of T1DM[118]. Unlike T2DM, insulin resistance does not appear to be a major underlying cause [119,120]. However, defective insulin release has been clearly demonstrated [119,120]. This is accompanied by decreased islet β-cell volume, which has been documented in several studies [121,122]. The mechanisms of β-cell loss in cystic fibrosis-related diabetes remain unclear, although islet amyloid deposition is also present in this population [123], suggesting that at least certain aspects of islet pathology share features with T2DM.Thus, some mechanisms that may explain β-cell loss in T2DM, and which are discussed later, are likely also pertinent to cystic fibrosis-related diabetes.

Mechanisms of beta-cell loss in type 2 diabetes

While alterations in several islet cell types have been reported in T2DM or animal models thereof, only β cells have reproducibly been shown to be reduced [15–17,59,96,97]. Decreased β-cell volume in T2DM is associated with an increase in β-cell apoptosis [15,17], which occurs without a compensatory increase in β-cell replication due at least in part to the limited regenerative capacity of adult human islets [57,58]. Thus, mechanisms that result in β-cell apoptosis or other forms of β-cell death appear to be critical for loss of β cells in T2DM. This process has been widely studied, and numerous mechanisms have been implicated.

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