Human type 2 diabetes: morphological evidence for abnormal beta-cell function

The exact nature of the beta-cell defect in type 2 diabetic patients is still unclear. beta-Cell mass reduction has been reported but remains controversial. A preliminary study of a large series of patients has demonstrated that in most, the beta-cell defect is not related to a decreased beta-cell mass. Amyloid deposits are observed in the islets of some type 2 diabetic patients but also in normoglycemic subjects. Because it has been claimed that these deposits interfere with beta-cell function, we evaluated in situ the effect of insular amyloid deposits on beta-cell transcription and translation. Pancreases were obtained at autopsy from 28 normoglycemic patients and 41 type 2 diabetic patients. Staining with hemaluneosin and Congo red was used to analyze the general features of the islets and the presence of amyloid deposits, respectively. Immunohistochemistry for proinsulin was performed with an antibody recognizing the junction between B-chain and C-peptide, thus specifically labeling the Golgi area where proinsulin is produced. In seven patients, we evaluated insulin gene transcription by in situ hybridization of proinsulin mRNA combined with Congo red staining, and we evaluated insulin storage by double immunostaining for insulin and amylin. In many type 2 diabetic patients, the islets appeared entirely normal. Amyloid deposits were found in 57% of diabetic subjects and 33% of normoglycemic age-matched control subjects. The percentage of amyloid-infiltrated islets varied from 0.4 to 74%. beta-Cells from amyloid-containing islets still had specific Golgi proinsulin labeling. In obese type 2 diabetic patients, the number of beta-cells with abnormal expression of proinsulin in the whole cytoplasm was significantly higher than in normoglycemic control subjects. Proinsulin mRNA was significantly reduced in islets with amyloid deposits when compared with amyloid-free islets, but the mean reduction did not exceed 16%. Insulin was still present in the beta-cells of amyloid-containing islets, and its amount, estimated by measurement of the insulin-labeling optical density, was not statistically different from that in amyloid-free islets. In conclusion, even in amyloid-containing islets, beta-cells maintain active insulin transcription and translation and normal insulin storage. Taking into account that in most cases only a small proportion of islets are infiltrated by amyloid, the limited reduction in proinsulin mRNA is unlikely to play a major role in the pathogenesis of diabetes.