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 ...

We have previously shown that fetuses from undernourished (U) pregnant rats exhibited an increased β-cell mass probably related to an enhanced IGF-I replicative response. Because IGF-I signaling pathways have been implicated in regulating β-cell growth, we investigated in this study the IGF-I transduction system in U fetuses. To this end, an in vitro model of primary fetal islets was developed to characterize glucose/IGF-I-mediated signaling that specially influences β-cell proliferation. We found that U fetal islets showed a greater replicative response to glucose and IGF-I than controls. Furthermore, insulin receptor substrate (IRS)-2 protein and its association with p85 were also increased. In the complete absence of IGF-I or stimulatory glucose, U islets presented an increased basal phosphorylation of downstream signals of the phosphatidylinositol 3-kinase (PI3K) pathway such as PKB, glycogen synthase kinase (GSK)3α/β, PKCζ, and mammalian target of rapamycin (mTOR). Similarly, phosphorylation of these proteins (except GSK3α/β) by glucose and IGF-I was augmented even though total protein content remained unchanged. Downstream of PKB, direct glucose activation of mTOR was increased as well. In contrast, ERK1/2 phosphorylation was unaffected by undernutrition, but ERK activation seemed to be required to induce a higher proliferative response in U islets. In conclusion, we have demonstrated that fetal U islets show increased IRS-2 content and an enhancement in both basal and glucose/IGF-I activations of the IRS-2/PI3K/PKB pathway. These molecular changes may be responsible for the greater glucose/IGF-I islet replication and contribute to the increased β-cell mass found in these fetuses.

1 The contribution of the relaxant mechanisms of nicorandil (NIC) were analysed by comparing its eects with those of sodium nitroprusside (SNP), levcromakalim (LEM) and mixtures (1:10, 1:30 and 1:100) of SNP:LEM in isolated endothelium-denuded rat aorta. 2 In rings precontracted with KCl (25 mM), the relative inhibitory potency of the soluble guanylate cyclase inhibitor ODQ and the K ATP channel inhibitor glibenclamide (GLI) on SNP:LEM mixtures showed a good correlation with the relative proportion of SNP and LEM in the mixtures. Furthermore, the degree of the inhibition by ODQ and GLI of the eects of the 1:30 SNP:LEM mixture varied as a function of the relative potency of SNP and LEM in KCl-, noradrenaline-(NA) or NA plus nifedipine-treated arteries. 3 The inhibitory eects of ODQ, GLI and ODQ plus GLI on NIC-induced relaxation was similar to that for the 1:30 SNP:LEM mixture in NA plus nifedipine-contracted arteries, but the inhibition of GLI or ODQ plus GLI was smaller in KCl-contracted arteries. 4 In conclusion, the relative importance of activation of the cyclic GMP pathway and K ATP channel opening in mixtures of SNP and LEM could be predicted by the proportion of the drugs in the mixtures and by the relative potency of SNP vs LEM in dierent experimental conditions. Furthermore, the present results suggest that besides these two mechanisms, a third ODQ-and GLIinsensitive mechanism, possibly involving Ca 2+ channel blockade, also participates in the relaxant eects of NIC in KCl-induced contractions.

1 The endothelial modulation of the relaxant responses to the nitric oxide (NO) donor sodium nitroprusside (SNP) and the K ATP channel opener levcromakalim (LEM) and the interactions between these agents were analysed in isolated rat aorta. 2 LEM-induced relaxation was unchanged by endothelium removal or by the presence of L-NAME (10 74 M) or ODQ (10 76 M). In contrast, in KCl-(25 mM), but not in noradrenaline-(NA, 10 76 M) contracted arteries, SNP-induced relaxation was augmented by endothelium removal but not by L-NAME, indomethacin, glibenclamide nor charybdotoxin plus apamin. 3 The isobolographic analysis of the interactions between exogenously activated K ATP channels and cyclic GMP using mixtures of SNP and LEM revealed that there were no interactions between both drugs at the proportions at which both drugs were active. However, the points for the SNP : LEM mixtures in proportions 10 : 1 and 1 : 10,000 (i.e. at concentrations at which LEM and SNP were inactive, respectively) fell signi®cantly above the line of additivity indicating that there were negative interactions between both drugs at these selected proportions (about 5-and 2 fold inhibition, respectively). The former interaction was sensitive to glibenclamide, whereas the latter was insensitive ODQ. The magnitude of the 10 : 1 SNP : LEM interaction was smaller in endotheliumintact arteries and was absent in arteries stimulated by NA. 4 In conclusion, the relaxations induced by LEM and SNP were additive. However, the presence of endothelium and low concentrations of LEM inhibited SNP-induced relaxation. Both inhibitory eects were not additive and were only observed in KCl-and not in NA-contracted aortae.

As oral oncology agents continue to be approved by FDA, oncology treatment teams must establish a comprehensive plan for their management. Because of their pharmacologic expertise, access to patients' medical records, and unique position within ambulatory care oncology teams, pharmacists can play an important role in patient education, laboratory monitoring, medication adherence, and cost saving.