[Oculo-cerebro-renal Lowe syndrome: clinical, biochemical and molecular studies in a Moroccan patient]. / Syndrome oculo-cérébro-rénal de Lowe: étude clinique, biochimique et moléculaire chez un patient marocain.

The oculo-cerebro-renal syndrome of Lowe is a rare X-linked disorder, caused by the inositol biphosphate 5-phosphatase deficiency, localized to the Golgi complex. Several mutations were reported in patient's OCRL gene leading to enzyme deficiency. We report a Moroccan case of OCRL syndrome of Lowe with a neo mutation in exon 10. The patient aged of 19 months was referred to our medical centre because of a psychomotor retardation. He had a medical history of eye abnormalities including cataract and bilateral glaucoma, diagnosed when he was 5 weeks old. Cataract has been treated after chirurgical therapy but ocular hypertonia persisted. Physical examination revealed an axial hypotonia and walking difficulties. Laboratory tests revealed a moderate acidosis (20 mmol/L), a slight decrease of serum phosphate level (24 mg/L) and an increased serum phosphatase activity. Further studies showed mild proteinuria, urinary bicarbonates loosing and generalised hyperaminoaciduria. Based on both clinical and biological data, Lowe syndrome has been suggested. In this context, molecular investigation has been performed using dHPLC/sequencing techniques which allow identifying an original mutation c.776T>C (p.Phe259Ser), localized on the exon 10 of the OCRL gene. The mutation was not found in the probant's mother suggesting a neo mutation. Lowe syndrome is a rare hereditary X-linked disorder resulting from a variety of heterogeneous mutations of OCRL gene. Indeed, numerous mutations have been reported, variations were noted concerning their localization as well as their type. To our knowledge, this is the first report of the neo mutation c.776T>C of OCRL gene and the first published case report of the Lowe syndrome in a Moroccan patient.

A protein-restricted diet during pregnancy alters in vitro insulin secretion from islets of fetal Wistar rats.

Previous studies indicate that insulin secretion from the fetuses of dams fed a low protein (LP) diet is reduced in response to leucine or arginine. The aim of this study was to locate the defect in the insulin secretion pathway induced by a LP diet during gestation. The effects of various secretagogues acting at different levels of the insulin secretion cascade were investigated in vitro in fetal islets from dams fed either a normal or a LP diet during pregnancy. Insulin content, insulin secretion and the cAMP content were then measured. Although insulin content of LP islets did not differ from that of control islets, insulin secretion from LP fetal islets was reduced when challenged by amino acids or cAMP enhancers. This reduction did not appear to be related solely to an altered islet cAMP content. An impairment of insulin secretion remained after stimulation of fetal LP islets with either metabolic or nonmetabolic secretagogues. The insulin secretion by LP islets was restored to normal, however, with barium or cytochalasin-B. These findings demonstrate that an in utero isocaloric LP diet impairs insulin secretion of the fetus. This alteration is located at the exocytosis step in the insulin secretion cascade and not in the insulin pool of the beta cell.

Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro.

Islets of rat fetuses born to mothers fed a low protein diet (LP) have a depressed insulin secretion in vitro in response to secretagogues. These fetuses have lower plasma levels of taurine than controls. The aim of this study was to analyze the effect of taurine on fetal islets insulin secretion. After 5 days of culture in serum containing standard RPMI medium, islets were cultured for 2 days in serum-free DME/F12 medium with 8.2 or 16.7 mM glucose alone or with taurine at 0.3 or 3 mM. They were then incubated for 120 min in Krebs Ringer solution with glucose alone (5.6 or 16.7 mM) or glucose (5.6 mM) added to leucine or arginine (both at 10 mM). In both concentrations of glucose, taurine increased the fractional insulin release by islets stimulated with secretagogues tested during the incubation. The effect did not seem to be mediated by changes in cAMP content. In a second set of experiments, islets cultured in RPMI medium for 7 days were incubated in the presence of Krebs Ringer solution with leucine (10 mM) or with sulfur amino acids (taurine at 10 mM, methionine or cysteine at 5 mM) for 120 min. Taurine and methionine stimulated insulin release at the same magnitude as leucine, whereas cysteine had no effect. In conclusion, taurine enhances insulin secretion by fetal islets, at least in vitro. Low taurine levels in fetuses from LP mothers might be implicated in their depressed insulin secretion.

Pre- and postnatal low protein diet affect pancreatic islet blood flow and insulin release in adult rats.

The pancreatic islet blood flow and insulin secretion of adult rats submitted to an isocaloric low protein diet (8% vs. 20%) during pre- and postnatal life were investigated by the nonradioactive microsphere technique. In the basal state, female rats chronically exposed to a low protein diet (LP) displayed a specific marked decrease in islet blood flow (10 +/- 2 vs. 29 +/- 5 microliters/min.g pancreas; P < 0.01) and overall pancreatic blood flow (P < 0.01). The plasma insulin level, however, was not affected. During a glucose challenge, the control animals enhanced their islet blood flow 2.3-fold, whereas the LP group reached control values with a 6-fold increase. Plasma insulin levels rose similarly in the control and LP animals. A third group of animals designated the recuperation group, exposed to a low protein diet only in utero, displayed islet blood flow comparable to control values, but increased basal plasma insulin (2.0 +/- 0.3 vs. 1.2 +/- 0.1 ng/ml; P < 0.05). These data are consistent with the possibility of dissociation of islet blood flow and insulin release under basal conditions, which may not be the case after a glucose challenge. Furthermore, the low blood flow values in the LP group may reflect an adaptive physiological response, an impaired pancreatic vasculogenesis, or a dysfunction of endothelial cells.

Impaired activity of rat pancreatic islet mitochondrial glycerophosphate dehydrogenase in protein malnutrition.

In rats that received a low protein isocaloric diet (protein content of the diet: 8 instead of 20%) during fetal life and thereafter up to the time of sacrifice at 12-13 weeks of age, a low plasma insulin concentration, a decreased insulin content of isolated pancreatic islets, and an impaired secretory response of the islets to either D-glucose or the association of L-leucine and L-glutamine coincided, in islet homogenates, with a low activity of the mitochondrial glycerophosphate dehydrogenase and an abnormally high ratio between glutamate-alanine and glutamate-aspartate transaminase activities. Opposite enzymatic changes were found in liver extracts of the same rats. No obvious change in these hormonal, secretory, and enzymatic variables were observed when the period of protein deficiency was restricted to fetal life. These findings support the view that, in protein malnutrition, an impaired activity of pancreatic B-cell mitochondrial glycerophosphate dehydrogenase contributes, possibly in association with other enzymatic anomalies, to the perturbation of islet function.

[Importance of diets and their effect on fetal development: function and structure of the endocrine pancreas following protein deficiency during intrauterine life]. / Importance des régimes et leur influence sur le développement foetal: fonction et structure du pancréas endocrine suite à une carence en protéines au cours de la vie intra-utérine.

When an isocaloric low protein diet (8% versus 20%) is administrated to rats during gestation, the fetus or the neonate has a lower body weight and the structure and function of the endocrine pancreas is altered: islet cell proliferation, islet size and islet vascularisation are reduced when compared with a control group. If these fetal islets are cultured during 7 days in vitro, they secrete less insulin than normal islets in response to an AA challenge. When these newborns are fed with a low protein diet until adult age and analyzed at 70 days, the same alterations of the endocrine pancreas persist: the in vitro insulin secretion of the isolated islets in response to AA is dramatically depressed although their response to glucose is normal. However in vivo glucose and insulin levels in response to oral glucose challenge are abnormal. In addition, permanent functional alterations seem to persist when induced in utero. A normal diet (20% protein) given from birth to adulthood does not restore a normal insulin response in vivo to an oral glucose challenge.

Islet function in offspring of mothers on low-protein diet during gestation.

A low-protein diet (8 vs. 20%) administered during pregnancy affects the structure and function of the endocrine pancreas of the offspring. At 21.5 days of gestation, we reported a reduction of cell proliferation, islet size, islet vascularization, and pancreatic insulin content. In this study, we demonstrated an impairment of insulin secretion of these fetal islets when stimulated in vitro with amino acids such as arginine and leucine. If the offspring is kept on the same low-protein diet during suckling, weaning, and adulthood, fasting insulin levels remain low in the presence of normal blood glucose levels. Glucose tolerance at 70 days is impaired, with lower insulin response. In addition, permanent functional damage seems to be induced in utero by a low-protein diet, because a normal diet given from birth to adulthood does not restore normal insulin response after a glucose challenge. Our experimental results stress the impact of a balanced diet with qualitative and quantitative amino acid composition for the fetal endocrine pancreas to develop normally, without lasting functional and structural consequences in adulthood.