β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats

Abstract

Téllez N, Vilaseca M, Martí Y, Pla A, Montanya E. ␤-Cell dedifferentiation, reduced duct cell plasticity, and impaired ␤-cell mass regeneration in middle-aged rats. Am J Physiol Endocrinol Metab 311: E554 -E563, 2016. First published July 12, 2016 doi:10.1152/ajpendo.00502.2015.-Limitations in ␤-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated ␤-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px ϩ V) and gastrin administration (Px ϩ G). Pancreatic remnants were analyzed 3 and 14 days after surgery. ␤-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, ␤-cell mass did not change after Px or after gastrin treatment in middle-aged rats. ␤-Cell replication and individual ␤-cell size were similarly increased after Px in young and middle-aged animals, and ␤-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet ␤-cells of middle-aged rats and further increased after Px. The percentage of chromogranin Aϩ/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory ␤-cell hyperplasia and hypertrophy was retained in middle-aged rats, but ␤-cell dedifferentiation and impaired duct cell plasticity limited ␤-cell regeneration.aging; regeneration; ␤-cell replication; duct cell plasticity; ␤-cell dedifferentiation; gastrin THE INCIDENCE OF TYPE 2 DIABETES (T2D) increases with aging (8), but the factors contributing to this higher risk are not well established. Although age-related impairments of ␤-cell function and insulin action have been associated largely with the development of T2D (11), limitations in ␤-cell regenerative capacity could also contribute to increase the risk of diabetes in aged individuals. ␤-Cell mass expands throughout life in rodents and humans (14,31,38), and in young adults it increases in response to the metabolic challenges imposed by obesity, insulin resistance, or pregnancy (7, 38). However, the decline in ␤-cell replication in middle-aged individuals (28, 31, 34) may limit the capacity of ␤-cell mass to expand (51). The ␤-cell replicative response has been reported as completely blunted in middle-aged mice (35, 51), but increased ␤-cell replication has been identified in middle-aged humans and rodents in particular physiological and experimental contexts (27,29,44). Thus, it is unclear whether limitations in ␤-cell replication may reduce the capacity of ␤-cell mass to expand in middle-aged individuals. Moreover, little is known about aging and ␤-cell neogenesis and ␤-cell hypertrophy, the two main additional mechanisms of ␤-cell mass expansion.Partial pancreate...

Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans

“…Interestingly, gastrin treatment was only found effective in combination with other proliferative stimuli, such as GLP-1, DPP-4 inhibitors, epidermal growth factor, previous duct ligation or partial pancreatectomy (25,27,28,29,34). The proposed molecular mechanism of gastrin's action on beta-cell regeneration includes an induction of differentiation of ductal cells into endocrine cells, as suggested by an increased expression of endocrine markers, such as neurogenin 3 or nkx6.1 (35,36). Furthermore, a recovery of insulin expression, as well as increased beta-cell replication, has been described in alloxan-induced diabetic mice (37).…”

Pancreatic β Cell Regeneration as a Possible Therapy for Diabetes

“…We showed that after partial pancreatectomy in adult rats, pancreatic-duct cells undergo a reproducible dedifferentiation and expansion forming transient areas composed of proliferating ductules; these foci of regeneration subsequently recapitulate aspects of embryonic pancreatic differentiation to form new pancreatic lobes with new islets (Bonner-Weir et al, 1993; Li et al, 2010). Recent data has shown that by 1 year of age there was a loss of this plasticity of the pancreatic ducts resulting in less neogenesis (Tellez et al, 2016). In these older rats, without the neogenesis, the β cell mass did not increase after Px even though β cell replication and apoptosis frequency did not differ with that of 1 month old and individual cell size had similar increases.…”

Endogenous Pancreatic β Cell Regeneration: A Potential Strategy for the Recovery of β Cell Deficiency in Diabetes

“…Px : Removal of 60~90% of the adult rat pancreas through Px administration induces extensive pancreatic regeneration with formation of new lobes and islets, and proliferation of acinar cells. The Px model has been used to study β cell neogenesis and replication (86, 127, 128). PDL : PDL is defined as surgical ligation of the pancreatic duct at the level of the pylorus.…”