Normal Glucagon Signaling and β-Cell Function After Near-Total α-Cell Ablation in Adult Mice

Abstract

OBJECTIVETo evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis.RESEARCH DESIGN AND METHODSWe generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss.RESULTSAdult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions.CONCLUSIONSAn extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes

“…A disadvantage of the GCG.DTR model is that glucagon removal is not complete. Thorel et al reported an even higher degree of glucagon removal and also did not observe any improvement in glucose tolerance and hence concluded that the few preserved alpha cells produced sufficient glucagon for maintaining glucagon action [6]. We had few alpha cells left, and the plasma levels as well as the pancreatic content of glucagon were very low.…”

“…However, total pancreatectomy always renders patients severely diabetic. Thorel et al reported that a 98% alpha cell ablation in mice did not induce changes in fed or fasted blood glucose levels and the animals were not resistant to STZ-induced diabetes [6]. We developed another transgenic mouse model (GCG.DTR) [7] in which the diphtheria toxin (DT) receptor is expressed on all proglucagon producing cells.…”

Partial Duct Ligation: β-Cell Proliferation and Beyond

“…Conversely, in another type of experiment that is not scored by a lack-of-dilution metric, a dramatic interconversion between cell types was detected. The near-total ablation of b-cells (99.6% loss) using targeted diphtheria toxin2based killing led to spontaneous regeneration of up to 17% of the normal b-cell content by an apparently direct transdifferentiation from preexisting a (glucagonproducing) cells into b-cells, with no involvement of proliferation (9). The latter case remains intriguing in that the type of signal inducing such a conversion is still unknown particularly because the interconversion does not occur when there are slightly lower levels of b-cell destruction (9).…”

“…These paradigms are of varying specificity and efficiency, and they use chemical, genetic, or surgical methods (7)(8)(9)(10)(11)(12). Newly emerging b-cells derive mainly from preexisting b-cells in adult mice under normal physiological conditions.…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…While reprogramming of α cells has proven to restore functional β cell mass and cure diabetes in animal models (19,28,29,40), it also results in a severe depletion of α cells and a corresponding decrease in the production of glucagon (28,42). Depletion of α cells in mice does not have overt effects on health or lifespan (42), and even a small number of α cells (2% of total population) is sufficient to maintain glucagon signaling (43). Thus, converting α cells into β cells could be a viable approach to treat diabetes; however, it is currently not known what effect α cell depletion will have in humans.…”