Dataset Information

Normal glucagon signaling and ?-cell function after near-total ?-cell ablation in adult mice.

ABSTRACT:

Objective

To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic ?-cells and how this sudden massive depletion affects ?-cell function and blood glucose homeostasis.

Research design and methods

We generated a new transgenic model allowing near-total ?-cell removal specifically in adult mice. Massive ?-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 ?-cell loss.

Results

Adult transgenic mice enduring extreme (98%) ?-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal ?-cell mass produced enough glucagon to ensure near-normal glucagonemia. ?-Cell function and blood glucose homeostasis remained unaltered after ?-cell loss, indicating that direct local intraislet signaling between ?- and ?-cells is dispensable. Escaping ?-cells increased their glucagon content during subsequent months, but there was no significant ?-cell regeneration. Near-total ?-cell ablation did not prevent hyperglycemia in mice having also undergone massive ?-cell loss, indicating that a minimal amount of ?-cells can still guarantee normal glucagon signaling in diabetic conditions.

Conclusions

An extremely low amount of ?-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that ?-cells reprogram to insulin production after extreme ?-cell loss and now conjecture that the low ?-cell requirement could be exploited in future diabetic therapies aimed at regenerating ?-cells by reprogramming adult ?-cells.

SUBMITTER: Thorel F

PROVIDER: S-EPMC3198058 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Publications

Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.

Thorel Fabrizio F Damond Nicolas N Chera Simona S Wiederkehr Andreas A Thorens Bernard B Meda Paolo P Wollheim Claes B CB Herrera Pedro L PL

Diabetes 20110916 11

<h4>Objective</h4>To 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.<h4>Research design and methods</h4>We 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 thes ...[more]

PMID: 21926270

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Project description:Glucose homeostasis is determined by a balance between insulin and glucagon, produced by beta and alpha cells of the pancreas respectively. The levels of circulating hormones is partly determined by the mass of these two endocrine cell types. However, in contrast to beta cells, the identity of the signals regulating alpha cell number is not known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) and mice with ablation of prohormone convertase 2 (PC2), the enzyme involved in the conversion of proglucagon into mature glucagon, develop alpha cell hyperplasia. These observations and the fact that Gcgr-/- mice exhibit high levels of circulating glucagon-like peptide-1 (GLP-1) suggested that members of the glucagon family of peptides could be directly involved in the regulation of alpha cell number. In this study we sought to determine whether alpha cells express receptors for Glucagon (Gcgr) and/or the glucagon-like peptide-1 (GLP1r). We examined the expression of these receptors in islets of Gcgr-/-, PC2-/- mice and control littermates, in an alpha (alphaTC1/9) and in a beta (betaTC3) cell line. Gcgr was expressed exclusively by islet beta cells, but not by alpha cells, of the two lines of mice lacking glucagon signaling. Similarly, betaTC but not alphaTC cells, expressed Gcgr. The expression of GLP1r by alpha cells was determined by the genotype and age of the mice. In embryos, GLU+ cells of Gcgr+/+ mice cells express GLP1r during early development, but not in adults. In contrast, alpha cells of Gcgr-/- mice were GLP1r+ throughout life, reflecting the immature state of GLU+ cells when Gcgr is deleted. Unlike alpha cells, beta cells of all mice lines examined initiate GLP1r expression after birth. These results suggest that GLP-1 may affect the maturation of postnatal but not prenatal beta cells. In addition, they also suggest that the incretin could mediate alpha cell proliferation, inducing the development of alpha cell hyperplasia in Gcgr-/- mice.