Undernutrition does not alter the activation of β-cell neogenesis and replication in adult rats after partial pancreatectomy

Abstract

In previous work, we demonstrated that a 65% protein calorie food restriction started during the third trimester of gestation in rats caused a reduced ␤-cell mass at 4 days of life that persisted until adult age. In this study with adult undernourished (U) rats, we investigated 1) whether undernutrition affects the ␤-cell growth potential and both ␤-cell proliferation and differentiation and 2) the implication of the IGFs, highly responsive to nutritional status, in these processes. To this end, we used the 90% pancreatectomy (Px) procedure in U and control (C) adult rats. The results show that, on day 2 after Px, ␤-cell replication was significantly higher in C rats, whereas the ␤-cell neogenesis was markedly increased in U/Px rats. Both the serum levels of IGF-I and the liver IGF-I mRNA expression were reduced in adult U rats before and after Px compared with C rats. Pancreatic IGF-I mRNA expression was reduced in U animals on day 0. However, on day 2 after Px, the increase of pancreatic IGF-I mRNA expression was significantly higher in U rats than in C rats. These data suggest that ␤-cells still have the capacity to regenerate in the adult U rats, with a higher efficiency than C rats on day 2, and that both ␤-cell neogenesis and ␤-cell replication are stimulated. The increased pancreatic IGF-I mRNA may be instrumental in these processes.␤-cell regeneration; proliferation; insulin-like growth factors DIETARY INFLUENCES DURING EARLY STAGES of development present a risk factor for the onset of both perinatal and later life diseases. As indicated by the "thrifty phenotype hypothesis" (23), the endocrine pancreas may be particularly susceptible to the effects of poor maternal nutrition, since fetal and postnatal periods are critical for ␤-cell development and maturation of pancreatic function. In concert, several studies in experimental models with rats subjected to different patterns of malnutrition have reported that maternal food restriction significantly affects the ␤-cell mass in the fetuses (2, 4, 49) and in the offspring neonates at day 1 (19) and day 4 of postnatal life (37). This effect persists until adulthood (37) and can provoke long-lasting consequences related to the plasticity of the endocrine pancreas under situations of increased insulin demand, such as aging (19) and pregnancy (5). However, to our knowledge, the effect of prolonged global malnutrition starting in the fetal period on the potential for regeneration of the pancreatic islets in adulthood has not been investigated.The adult pancreas has the capacity to respond to changing physiological needs such as the requirement for increased ␤-cell mass/function during pregnancy, obesity, or insulin resistance and an ability to regenerate cells (both replication and neogenesis), including ␤-cells, which has been convincingly demonstrated in animal models of pancreatic injury and diabetes (46,47). One of these models is the partial pancreatectomy in rats (7,11). In this model, the pancreatic regeneration involves, first, replication of preexisting ...

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

“…So, although new islets can form by neogenesis in the undernourished animals it appears that they cannot get larger as reflected by the high number of very small islets in restricted pups at the end of the suckling period. This agrees with previous results obtained by our group after partial pancreatectomy of undernourished adult rats (Fernández et al 2006) and with those observed in diabetic models induced by selective perfusion of alloxan (Waguri et al 1997) or by the administration of low dose of streptozotocin (Bernard et al 1999). In contrast, studies performed in rats submitted to a low-protein diet reported impaired islet cell proliferation and increased islet cell apoptosis (Petrik et al 1999, Dumortier et al 2007) but b-cell neogenesis when submitted to a low-energy diet (Garofano et al 2000, Dumortier et al 2007.…”

“…Immunohistochemistry was performed as previously described (Fernández et al 2006). Pancreas sections (5 mm) at fixed intervals throughout the paraffin block were immunostained for insulin using guinea pig anti-porcine insulin (ICN, Biolink, Barcelona, Spain) and a peroxidase-conjugated rabbit anti-guinea pig IgG (Dako Diagnostics, Barcelona, Spain).…”

“…Other pancreas sections were used to measure b-cell replication rate as previously described (Fernández et al 2006). In each group, neonates were injected with 5 0 -bromo-2 0 deoxyuridine (BrdU), 50 mg/kg body weight i.p.…”

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation

“…In 9-month-old undernourished rats, insulinemia has been normalized, which could be explained by a regenerative capacity of ␤-cells previously reported in undernourished adult rats (50). After rehabilitation, these rats became hypoinsulinemic, regardless of dietary regime.…”

Review : Animal Models Of Diabetes Mellitus : Pathology And Mechanism Of Some Diabetogenics

“…Meskipun demikian, dengan tujuan penelitian tertentu beberapa peneliti sampai sekarang masih menggunakan metode tersebut (Fernandez et al, 2006;Ani et al, 2006).…”