Diversity of pathophysiology in type 2 diabetes shown by islet pathology

Abstract

The etiology of type 2 diabetes is multifactorial, in which environmental and genetic factors are involved to varying degrees. This suggests that its pathophysiology might vary depending on the individuals. Knowledge of the differences is critical, because these differences are directly linked to the care and treatment of the patients. Recent studies have attempted to carry out subclassifications of type 2 diabetes based on clinical and genetic differences. However, there is no pathological evidence to support these subclassifications. The pathophysiology of type 2 diabetes is generally divided into insulin resistance in peripheral tissues and pancreatic islet dysfunction. Among them, islet dysfunction causes a deficit in insulin secretion from β-cells. In particular, a deficit in insulin secretion is ascribed to a combination of disruption of the insulin secretory machinery and a decrease in β-cell volume in type 2 diabetes. Recent research has suggested that transdifferentiation and dedifferentiation are involved in the decrease in β-cell volume, and that it might change dynamically depending on the glucose metabolic state. However, it is possible that the numbers of islet cells are decreased in type 2 diabetes. In particular, the loss of endocrine cells due to islet amyloid deposits is an important pathological change in type 2 diabetes in humans. These results show that pathological changes of the islets can be different in each individuals with type 2 diabetes and reflect each pathophysiology, which is useful in establishing further subclassifications and developing tailor-made therapies for type 2 diabetes.

Keywords: Amyloid; Islet pathology; Type 2 diabetes.

Figure 1

Morphological changes in the islets of type 2 diabetes patients. Quadruplicate immunostained sections (red, glucagon; black, insulin; green, somatostatin; blue, PP; brown, Ki67) are shown. (a) Individuals without diabetes. (b) Individuals with diabetes). The occupancy of insulin‐positive cells is decreased and that of glucagon‐positive cells is increased in type 2 diabetes patients compared with individuals without diabetes.

Figure 2

Mechanism of endocrine cell kinetics for the reduction of β‐cells in type 2 diabetes patients. Pancreatic islets have a cell maintenance mechanism, which regulates a proper balance of endocrine cell proliferation, cell death, neogenesis and trans/dedifferentiation. In type 2 diabetes patients, this balance is disturbed by harmful factors, such as oxidative stress, endoplasmic reticulum stress and deficiency of autophagy. Consequently, the proliferative capacity of endocrine cells does not change, whereas cell death and trans/dedifferentiation increase. Islet neogenesis is thought to increase in a compensatory manner.

Figure 3

Promoting factors for amyloid deposition in the islets. Complications involving type 2 diabetes, aging, obesity/insulin resistance, cardiovascular disease, chronic pancreatitis and renal failure can promote amyloid formation in the islets (red arrow). This deposition of amyloid reduces the cell volume of both β‐ and α‐cells in type 2 diabetes patients. Concurrently, inflammatory reactions are evoked in islets.

Figure 4

Pathological changes in islets in type 2 diabetes patients with acute myocardial infarction. Type 2 diabetes complicated with acute myocardial infarction shows amyloid deposition, thickening of the basement membrane and loss of pericyte coverage of microvessels in the islets. These changes are similar to those in microvascular complications of diabetes.

Figure 5

Morphological findings of the pancreas in older‐onset diabetes. (a) Marked amyloid deposits are observed in the islet (arrow). (b) In the same patient as (a), a few examples of intraepithelial neoplasia were observed (arrows). (c) In another patients, stromal fibrosis and atrophy of acinal cells surrounding an intraepithelial neoplasia were observed. (d) Stromal fibrosis in the exocrine pancreas was confirmed by Azan staining (blue).