Characterisation of the endocrine pancreas in type 1 diabetes: islet size is maintained but islet number is markedly reduced

Abstract

Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of~65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

Targeted pharmacological therapy restores β-cell function for diabetes remission

“…Recently, the Kushner laboratory has provided evidence that some of the remaining insulin in the blood stream of patients with long-term T1D 57 originates from dedifferentiated β cells and/or from polyhormonal non-β cells that function as 'insulin microsecretors' 58 . Similarly, the Korsgren laboratory found histological evidence for β-cell dedifferentiation at T1D onset 59 . Therefore, triggering the redifferentiation of dedifferentiated β cells seems to be an intuitive approach for the treatment of diabetes that does not involve β-cell proliferation or neogenesis per se 60 .…”

β-Cell Maturation and Identity in Health and Disease

“…In accordance with the abovementioned work, another study showed the existence of PDX1-expressing α-cells (glucagon positive cells) in biopsies from patients with T1D. The authors speculated that these are exhausted β-cells, transdifferentiated towards the α-cell fate under extreme conditions [151]. These changes in identity might hide the cells from the immune system and prevent the onset or progression of the disease, as shown in another study in which by inducing proliferation and thus maintaining the immature features of β-cells, it was possible to prevent the progression of T1D in NOD mice [152].…”

Natural Protection From Type 1 Diabetes in NOD Mice Is Characterized by a Unique Pancreatic Islet Phenotype

“…However, surprisingly, the CD3 + immune infiltrate was not localized to the smaller islets or within a particular islet region (16). In humans, individuals with recent-onset type 1 diabetes have larger islets compared with people with long standing type 1 diabetes (17).…”