Dynamic Changes in Pancreatic Endocrine Cell Abundance, Distribution, and Function in Antigen-Induced and Spontaneous Autoimmune Diabetes

Abstract

OBJECTIVE-Insulin deficiency in type 1 diabetes and in rodent autoimmune diabetes models is caused by ␤-cell-specific killing by autoreactive T-cells. Less is known about ␤-cell numbers and phenotype remaining at diabetes onset and the fate of other pancreatic endocrine cellular constituents.RESEARCH DESIGN AND METHODS-We applied multicolor flow cytometry, confocal microscopy, and immunohistochemistry, supported by quantitative RT-PCR, to simultaneously track pancreatic endocrine cell frequencies and phenotypes during a T-cell-mediated ␤-cell-destructive process using two independent autoimmune diabetes models, an inducible autoantigen-specific model and the spontaneously diabetic NOD mouse. RESULTS-The proportion of pancreatic insulin-positive ␤-cellsto glucagon-positive ␣-cells was about 4:1 in nondiabetic mice. Islets isolated from newly diabetic mice exhibited the expected severe ␤-cell depletion accompanied by phenotypic ␤-cell changes (i.e., hypertrophy and degranulation), but they also revealed a substantial loss of ␣-cells, which was further confirmed by quantitative immunohistochemisty. While maintaining normal randomly timed serum glucagon levels, newly diabetic mice displayed an impaired glucagon secretory response to non-insulin-induced hypoglycemia.CONCLUSIONS-Systematically applying multicolor flow cytometry and immunohistochemistry to track declining ␤-cell numbers in recently diabetic mice revealed an altered endocrine cell composition that is consistent with a prominent and unexpected islet ␣-cell loss. These alterations were observed in induced and spontaneous autoimmune diabetes models, became apparent at diabetes onset, and differed markedly within islets compared with sub-islet-sized endocrine cell clusters and among pancreatic lobes. We propose that these changes are adaptive in nature, possibly fueled by worsening glycemia and regenerative processes.

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

“…While a suppressive effect of DPP4 inhibitors on serum glucagon level or glucagon secretion from alpha cells has been reported [10,38], the effect of DPP4 inhibition on alpha cell mass has not been widely studied. Our results showing diminished alpha cell mass in diabetic NOD mice are consistent with a recent paper reporting reduced alpha cell mass in animal models of type 1 diabetes [39]. However, the decrement in alpha cell mass was lower than that in beta cells [39], which is consistent with the suppressed beta/alpha cell mass ratio in this study.…”

“…Our results showing diminished alpha cell mass in diabetic NOD mice are consistent with a recent paper reporting reduced alpha cell mass in animal models of type 1 diabetes [39]. However, the decrement in alpha cell mass was lower than that in beta cells [39], which is consistent with the suppressed beta/alpha cell mass ratio in this study. The decrease in alpha cell mass in NOD mice could be caused by a paucity of local factors from beta cells necessary for alpha cell survival [39].…”

“…However, the decrement in alpha cell mass was lower than that in beta cells [39], which is consistent with the suppressed beta/alpha cell mass ratio in this study. The decrease in alpha cell mass in NOD mice could be caused by a paucity of local factors from beta cells necessary for alpha cell survival [39]. Our results are different from previous reports showing that DPP4 inhibitors attenuated the increase of alpha cell mass in diabetes induced by STZ and a high-fat diet [7,38], and suggest that alpha cell changes associated with DPP4 inhibition vary depending on the experimental models or methods.…”

Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

“…Hence, we also used the light-scattering property of islet endocrine cells to measure total islet volume, which includes all cells and the vascular network of the islet. Light scattering of b-cells reflects the size of their granule stores and its intensity provides insight into the secretory activity of b-cells (27,28). Nevertheless, in the case of backscattered laser light, the functional dependence of signal intensities did not influence total islet volume measurements due to the extremely high signal-to-noise ratio of backscattered laser light in the AC and the applied measurement algorithm.…”

Short‐term changes in pancreatic α‐cell function after the onset of fulminant type 1 diabetes

“…In another study, the areas of α‐ and β‐cells morphologically decreased in patients with fulminant type 1 diabetes compared with those in patients with acute‐onset type 1 diabetes3. Rodent autoimmune diabetes models have revealed a substantial loss of alpha cells and impaired glucagon response to hypoglycemia 4. We have considered that the loss of alpha cells is correlated with the early‐phase attenuation of glucagon response and appears to be delayed in the present case.…”