The haemochromatotic human pancreas: a quantitative immunohistochemical and ultrastructural study

Abstract

Insulin, glucagon, somatostatin and pancreatic polypeptide cells were quantified after immunoperoxidase staining in sections of pancreases obtained from nine control subjects and seven diabetic patients with primary or secondary iron overload. One was normoglycaemic, two had glucose intolerance and four presented insulin-requiring diabetes. The whole pancreas was studied, taking into account the heterogeneous distribution of the endocrine cells. In the diabetic patients, the weight of the pancreas tended to be lower. Iron overload predominated in the exocrine tissue, whereas in islets iron concentration was quite variable from case to case. At the Haemalun-Eosine staining the histological appearance of the islets was normal, their shape and size being unchanged; amyloid deposits were absent, as were atrophic islets. Immunoperoxidase staining revealed a severe reduction in the number of immunoreactive B cells in the four diabetic patients. The mass of immunoreactive B cells was calculated from their volume density and from the weight of each lobe of the pancreas. It averaged 950 mg in control subjects, 1580 mg in the normoglycaemic patient, 1010 mg in patients with glucose intolerance and 180 mg in insulin-requiring diabetic patients. The electron microscopic examination, performed in four cases, revealed that the iron deposits were restricted to B cells and associated with progressive loss of their endocrine granules. The study shows that the pancreatic islet abnormalities in iron overloaded diabetic patients are completely different from those of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients. This constitutes a further argument for a specific role of iron in the pathogeny of diabetes in haemochromatotic patients.

Cross-Talk Between Iron Metabolism and Diabetes

“…An increase in ␤-cell mass was demonstrated in a small number of nondiabetic or mildly diabetic patients with iron overload (28). In agreement with this increase in ␤-cell mass, raised basal and stimulated C-peptide secretion were observed in type 2 diabetic patients with increased serum ferritin concentration.…”

“…This high amount of ferritin can explain why iron is preferentially retained in the ␤-cell. In fact, iron deposition in islets, albeit variable, is restricted to ␤-cells (28).…”

Abnormal Glucose Tolerance in Transfusion-Dependent β-Thalassemic Patients

“…The mechanism of abnormal glucose homeostasis in patients with ␤-thalassemia major is still unknown but is attributed mainly to insulin deficiency resulting from the toxic effects of iron deposited in the pancreas (5,6,31) and from insulin resistance (12,15,28). Insulin resistance may come from iron deposition in both liver (where iron deposits may interfere with insulin's ability to suppress hepatic glucose production) and muscle (where iron deposits may decrease glucose uptake because of muscle damage) (12).…”

ZIP14 and DMT1 in the liver, pancreas, and heart are differentially regulated by iron deficiency and overload: implications for tissue iron uptake in iron-related disorders

“…8,[30][31][32] Interestingly, ZIP14 in acinar cells was detected diffusely throughout the cytosol and in vesicle-like structures, possibly representing early endosomes, where intracellular ZIP14 has been localized in HepG2 cells. 9 Since early endosomes are formed from invagination of the plasma membrane, the orientation of ZIP14 would be preserved, and thus ZIP14 would be predicted to move iron into the cytosol.…”