Decreased α-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: An analysis based on the nPOD repository

Abstract

Background and aimsAbnormal glucagon secretion and functional alterations of the exocrine pancreas have been described in patients with type 1 diabetes (T1D), but their respective anatomical substrata have seldom been investigated. Our aim was to develop an automated morphometric analysis process to characterize the anatomy of α-cell and exocrine pancreas in patients with T1D, using the publicly available slides of the Network for Pancreatic Organ Donors (nPOD).Materials and methodsThe ratio of β- and α-cell area to total tissue area were quantified in 75 patients with T1D (thereafter patients) and 66 control subjects (thereafter controls), on 2 insulin-stained and 4 glucagon-stained slides from both the head and the tail of the pancreas. The β- and α-cell masses were calculated in the 66 patients and the 50 controls for which the pancreas weight was available. Non-exocrine-non-endocrine tissue area (i.e. non-acinar, non-insular tissue) to total tissue area ratio was evaluated on both insulin- and glucagon-stained slides. Results were expressed as mean ±SD.ResultsAn automated quantification method was set up using the R software and was validated by quantification of β-cell mass, a well characterized parameter. β-cell mass was 29.6±112 mg in patients and 628 ±717 mg in controls (p<0.0001). α-cell mass was 181±176 mg in patients and 349 ±241mg in controls (p<0.0001). Non-exocrine-non-endocrine area to total tissue area ratio was 39±9% in patients and 29± 10% in controls (p<0.0001) and increased with age in both groups, with no correlation with diabetes duration in patients.ConclusionThe absolute α-cell mass was lower in patients compared to controls, in proportion to the decrease in pancreas weight observed in patients. Non-exocrine-non-endocrine area to total tissue area ratio increased with age in both groups but was higher in patients at all ages.

No acute pancreatitis but reduced exocrine pancreatic function at diagnosis of type 1 diabetes in children

“…The paradigm of T1D as a pure consequence of an autoimmune process has been questioned, both because of the failure to treat the disease with different immune interventions, but also when it has been found that the insulitis is neither common nor pronounced. Similar inflammatory cells are found also in exocrine pancreas, and the whole organ is decreased in size with different structural changes . Furthermore, it is found that the exocrine function decreases gradually in individuals already before they get manifest T1D, and exocrine function is decreased in many children with T1D .…”

“…The insulitis, which should be a cornerstone in the existing paradigm of autoimmunity actually seems to be both mild and rather rare, and similar immune cells to those constituting the insulitis are actually found also in the exocrine pancreas . Several changes are found not only in the beta cells of the islets but also in exocrine tissue, which could be the result of a general pancreas inflammation, a pancreatitis. Autoantibodies have also been found both against exocrine pancreatic enzymes and other antigens of exocrine pancreas…”

Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors

“…Also, a recent study demonstrated that pancreatic alpha cells are more resistant to metabolic stress than beta cells in T2D pancreas, because alpha cells express high levels of anti-apoptotic proteins [72]. On the other hand, in T1D, alpha cell mass seems to be decreased [73]; indicating a complex inter-dependency for alpha and beta cells for development and functioning. Interestingly, the arrangement of endocrine cells within the human islet also hints at the developmental importance of paracrine signaling and coupling for the functional performance of these endocrine cells, as beta cells have multiple contacts with other endocrine cells within the islet [61,65].…”

Exocrine Pancreas Dysfunction in Type 1 Diabetes

“…Neutrophils and products of complement activation have also been found throughout the tissues of some T1D pancreata, suggesting evidence of innate immune system involvement (3,10,14,16,26,27,39). Other histological changes shown in non-endocrine pancreatic tissue in T1D include fibrosis, fatty infiltration, and arteriosclerosis (3,10,14,20,29,33,47). Fibrosis is usually present in an inter-acinar fashion and associated with concomitant arteriosclerosis (3,33).…”