Islet Cell Paracrinopathy and the Relevance of Delta-, Alpha- and Beta-Cell Dysfunction in the Development of Hyperglycemia in Non-Human Primates

Background and Aims: The unique composition and architecture of the islet of Langerhans is essential to ensure its normal function (1-3). Morphological and physiological abnormalities are both present in islets of subjects with type 2 diabetes but the relationship between islet cell composition with fasting plasma glucose (FPG) and other metabolic and biochemical parameters is presently unknown. Therefore, we explored the correlation between islet cell abnormalities and FPG and other metabolic markers. Methods:We measured the relative \u3b1-, \u3b2- and \u3b4-cell volumes and amyloid deposition with stereology techniques in the pancreas of 40 baboons stratified according to FPG in 4 groups (G1: FPG<80mg/dl n=10; G2: FPG=80-<95mg/dl n=9, G3: FPG=95-125mg/dl n=9, G4: FPG 65125mg/dl n=12) and examined the correlations between islet composition and various functional and metabolic parameters. We performed double and triple immunofluorescence staining to identify apoptotic islet cells as well as electron microscopy to identify the ultra-structural composition of different islet cells. Results: As compared to G1, G2 showed a significant increase in islet amyloid deposition which increased linearly up to G4. Amyloidosis preceded the decrease in b-cell volume statistically significant only in G4. \u3b1-cell volume increased of ~50% in G3 and G4 (p <0.05), while \u3b4-cell volume decreased in these groups of 39 and 31%, respectively (both p<0.05). In G4, glucagon, cholesterol and free fatty acid levels were higher, while insulin and HOMA-B were lower, than in the other groups. Staining of G4 pancreatic sections with the apoptosis marker CCL3, insulin and somatostatin showed ongoing apoptosis of both b- and d-cells which was confirmed by immuno-electron-microscopy. Ultra-structural analysis confirmed a normal structure in \u3b1-cells while \u3b2- and \u3b4-cells showed multiple signs of cell suffering in baboons with the higher glucose levels. Conclusions/interpretations: In baboons, the changes in islet composition that matches the increase in FPG concentration are in sequence: i. increased amyloid deposition; ii. increased a-cell- and decreased d-cell volumes; iii.decreased b-cell volume. Timing and nature of these changes suggests a so far unrecognized role of d-cells in diabetes pathogenesis. 1) Unger RH, Orci L, Proc Natl Acad Sci U S A 2010;107: 16009-16012. 2)Cabrera, O, et al. Proc Natl Acad Sci U S A. 2006;103(7):2334-9 3) Guardado-Mendoza R, et al. Proc Natl Acad Sci U S A 2009; 106: 13992-1399