Increased susceptibility to streptozotocin and impeded regeneration capacity of beta-cells in adult offspring of malnourished rats.

BACKGROUND: Epidemiological studies related poor maternal nutrition and subsequent growth retardation in the progeny to the development of diabetes later in life. Low-protein diet during gestation altered the beta-cell development of the rat progeny by decreasing beta-cell proliferation and increasing their sensitivity to nitric oxide and cytokines in the foetus. This disturbed maternal environment had long-lasting consequences because the higher beta-cell vulnerability was maintained at adulthood. AIM: The aim of this study was to determine whether early malnutrition influences the vulnerability and the regeneration capacity of beta-cells after streptozotocin (STZ) damage at adulthood. METHODS: Gestating rats were fed either a control or a low-protein diet until weaning. Adult female offspring received injections of Freund's adjuvant weekly for 5 weeks followed 24 h later by STZ. Half of the cohort was killed at d34, whereas the other half was maintained until d48 to analyse the regeneration capacity of the beta-cells. RESULTS: Although control and low-protein rats had equivalent pancreatic insulin content and beta-cell volume density at d34, hyperglycaemia appeared earlier and was more dramatic in low-protein rats than in control rats. STZ treatment increased beta-cell proliferation similarly in both groups. At d48, apoptotic rate was higher in the low-protein group. Regeneration appeared in control, but not in the low-protein rats, where beta-cell aggregates/surface area and Reg1-positive area were decreased compared to control. CONCLUSION: Maternal malnutrition programmes a more vulnerable endocrine pancreas in the progeny which is unable to regenerate after injury, therefore predisposing it to develop glucose intolerance and diabetes later in life.

Implication of nitric oxide in the increased islet-cells vulnerability of adult progeny from protein-restricted mothers and its prevention by taurine.

An increased vulnerability of adult beta-cells seems to be programmed in early life as adult islets from the progeny of dams fed a low-protein diet exhibited an increased apoptotic rate after cytokine stimulation. This was prevented by maternal taurine supplementation. Here, we investigated the mechanisms implicated in such an increased vulnerability and how taurine exerts its protective role. Throughout gestation and lactation, Wistar rats were fed a 20% (control (C group)) or an isocaloric 8% protein diet (recovery (R group)) supplemented or not with taurine (control+taurine and recovery+taurine groups respectively). Offspring received a 20% protein diet after weaning. Islets from 3-month-old females were isolated and cultured for 48 h before being incubated with or without cytokines for 24 h. In unstimulated islets, apoptotic rate and NO(.) secretion were higher in R than in C. Both GADD153 mRNA and protein were increased, whereas mRNA of mitochondrial gene ATPase6 was downregulated in R group compared with C. In the RT group, taurine prevented apoptosis and restored a normal NO(.) production in GADD153 as well as ATPase6 mRNA expression. After cytokines-induction, apoptosis and NO(.) secretion were still increased in R compared with C but both parameters were normalized in the RT group. In conclusion, a maternal low-protein diet programmes a different pattern of gene expression in islet-cells of adult progeny. Higher NO(.) production by these islets could be an important factor in the subsequent cell death. The prevention of these events by maternal taurine supplementation emphasizes the importance of taurine during endocrine pancreas development.

Intrauterine programming of the endocrine pancreas.

Epidemiological studies have revealed strong relationships between poor foetal growth and subsequent development of the metabolic syndrome. Persisting effects of early malnutrition become translated into pathology, thereby determine chronic risk for developing glucose intolerance and diabetes. These epidemiological observations identify the phenomena of foetal programming without explaining the underlying mechanisms that establish the causal link. Animal models have been established and studies have demonstrated that reduction in the availability of nutrients during foetal development programs the endocrine pancreas and insulin-sensitive tissues. Whatever the type of foetal malnutrition, whether there are not enough calories or protein in food or after placental deficiency, malnourished pups are born with a defect in their beta-cell population that will never completely recover, and insulin-sensitive tissues will be definitively altered. Despite the similar endpoint, different cellular and physiological mechanisms are proposed. Hormones operative during foetal life like insulin itself, insulin-like growth factors and glucocorticoids, as well as specific molecules like taurine, or islet vascularization were implicated as possible factors amplifying the defect. The molecular mechanisms responsible for intrauterine programming of the beta cells are still elusive, but two hypotheses recently emerged: the first one implies programming of mitochondria and the second, epigenetic regulation.

Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines.

AIMS/HYPOTHESIS: A maternal low-protein diet has been shown to induce an increased susceptibility of fetal islets to cytokines, but this effect can be avoided by maternal taurine supplementation. Here, we question whether these effects persist until adulthood in the offspring, despite the animal having a normal diet after weaning. METHODS: Pregnant Wistar rats received a diet of either 20% or 8% protein (control [C group] and recuperated [R group] respectively), which was or was not supplemented with taurine (control treated with taurine [CT group] and recuperated treated with taurine [RT group] respectively) during gestation and lactation. When the female offspring reached adulthood, an OGTT was performed. In a second stage, islets were isolated from these offspring, then pretreated or not with taurine, and subsequently treated with cytokines. RESULTS: Fasting glycaemia was higher (p<0.05) and insulinaemia was lower (p<0.01) in the R group than in the C group. Taurine supplementation decreased insulinaemia in the CT group and tended to increase it in the RT group. After the OGTT, glycaemia in R animals was not different from that in the C group, despite a blunted insulin response (p<0.05) which was restored by taurine. Supplementation in C-group mothers led to a weak glucose intolerance. In vitro, more apoptotic cells were observed in R islets after cytokines treatment (p<0.01). The addition of taurine to the culture medium in the R and C groups protected the islets from the cytokines (p<0.01). Maternal taurine supplementation decreased the sensitivity of islets in the RT group (p<0.01), but increased sensitivity in the CT group (p<0.01). CONCLUSIONS/INTERPRETATION: The increased vulnerability of islets to cytokines due to a restriction of protein during fetal development was still evident when the offspring reached adulthood. The low-protein diet also induced hyperglycaemia in the presence of lower insulinaemia. Taurine supplementation protected adult islets of the R group from cytokine toxicity and restored the insulinaemia. However, unnecessary supplementation of taurine could have detrimental effects.