Ghrelin mitigates β-cell mass loss during insulitis in an animal model of autoimmune diabetes mellitus, the BioBreeding/Worcester rat.
Ghrelin is a peptide hormone with pleiotropic effects. It stimulates cell proliferation and inhibits apoptosis-mediated cell death. It prevents diabetes mellitus in several models of chemical, surgical and biological toxic insults to pancreas in both in vivo and in vitro models and promotes glucose-stimulated insulin secretion under cytotoxic conditions. It has not yet been tested in vivo in an autoimmune model of diabetes with a persistent insult to the β-cell. Given the immunomodulating effects of ghrelin and its trophic effects on β-cells, we hypothesized that ghrelin treatment during the early stages of insulitis would delay diabetes onset.



BioBreeding/Worcester male rats received ghrelin (10 ng/kg/day) before insulitis development. Glucose metabolism was characterized by glucose and insulin tolerance tests. β-cell mass, islet area, islet number, β-cell clusters, proliferation and apoptosis and degree of insulitis were analysed by histomorphometry. A Kaplan-Meier survival curve was plotted and analysed applying the log-rank (Mantel-Cox) test.



Ghrelin treatment significantly reduced the probability of developing diabetes in our model (p < 0.0001). It decreased islet infiltration and partially prevented β-cell mass loss, enabling the maintenance of β-cell neogenesis and proliferation rates. Furthermore, ghrelin treatment did not induce any metabolic perturbations.



These findings support the hypothesis that ghrelin delays the development of autoimmune diabetes by attenuating insulitis and supporting β-cell mass.



Ghrelin promotes β-cell viability and function through diverse mechanisms that may have significant implications for diabetes prevention, therapy and also transplant success of both islets and complete pancreas. Copyright © 2016 John Wiley & Sons, Ltd.
Department of Endocrinology and Nutrition, Puerta del Mar University Hospital, Cadiz, Spain.|Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.
Gloria
G
Baena-Nieto
Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.|Andalusian Cellular Reprogramming Laboratory, Sevilla, Spain.
Isabel M
IM
Lomas-Romero
Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.|Department of Biotechnology, Biomedicine and Public Health, Cadiz University Medical School, Cadiz, Spain.
Rosa M
RM
Mateos
Department of Child and Mother Health and Radiology, Cadiz University Medical School, Cadiz, Spain.
Noelia
N
Leal-Cosme
Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.
Gonzalo
G
Perez-Arana
Department of Endocrinology and Nutrition, Puerta del Mar University Hospital, Cadiz, Spain.
Manuel
M
Aguilar-Diosdado
"Salus Infirmorum" Faculty of Nursing, Cadiz University, Cadiz, Spain.
Carmen
C
Segundo
Research Unit, Puerta del Mar University Hospital, Cadiz, Spain.|Department of Child and Mother Health and Radiology, Cadiz University Medical School, Cadiz, Spain.
Alfonso M
0000-0001-5861-6041
AM
Lechuga-Sancho
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D054439:Ghrelin / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011913:Rats, Inbred BB
D054439:Ghrelin; D007004:Hypoglycemic Agents; D007328:Insulin
autoimmne; cytokines; ghrelin; prevention; type 1 diabetes; β-cell viability