Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.

BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Adequate connexin-mediated coupling is required for proper insulin production.

To assess whether connexin (Cx) expression contributes to insulin secretion, we have investigated normal and tumoral insulin-producing cells for connexins, gap junctions, and coupling. We have found that the glucose-sensitive cells of pancreatic islets and of a rat insulinoma are functionally coupled by gap junctions made of Cx43. In contrast, cells of several lines secreting insulin abnormally do not express Cx43, gap junctions, and coupling. After correction of these defects by stable transfection of Cx43 cDNA, cells expressing modest levels of Cx43 and coupling, as observed in native beta-cells, showed an expression of the insulin gene and an insulin content that were markedly elevated, compared with those observed in both wild-type (uncoupled) cells and in transfected cells overexpressing Cx43. These findings indicate that adequate levels of Cx-mediated coupling are required for proper insulin production and storage.

Junctional communication of pancreatic beta cells contributes to the control of insulin secretion and glucose tolerance.

Proper insulin secretion requires the coordinated functioning of the numerous beta cells that form pancreatic islets. This coordination depends on a network of communication mechanisms whereby beta cells interact with extracellular signals and adjacent cells via connexin channels. To assess whether connexin-dependent communication plays a role in vivo, we have developed transgenic mice in which connexin 32 (Cx32), one of the vertebrate connexins found in the pancreas, is expressed in beta cells. We show that the altered beta-cell coupling that results from this expression causes reduced insulin secretion in response to physiologically relevant concentrations of glucose and abnormal tolerance to the sugar. These alterations were observed in spite of normal numbers of islets, increased insulin content, and preserved secretory response to glucose by individual beta cells. Moreover, glucose-stimulated islets showed improved electrical synchronization of these cells and increased cytosolic levels of Ca(2+). The results show that connexins contribute to the control of beta cells in vivo and that their excess is detrimental for insulin secretion.

Cx36 preferentially connects beta-cells within pancreatic islets.

Previous studies have provided evidence for the transcripts of Cx43 and Cx45 within pancreatic islets. As of yet, however, it has proven difficult to unambiguously demonstrate the expression of these proteins by islet cells. We have investigated whether Cx36, a new connexin species recently identified in mammalian brain and retina, may also be expressed in pancreatic islets. Using probes that permitted the original identification of Cx36 in the central nervous system, we show that a transcript for Cx36 is clearly detectable in rat pancreatic islets. Using novel and affinity-purified polyclonal antibodies, we have found that Cx36 is actually expressed in pancreatic islets. Both in situ hybridization and immunolabeling indicated that this connexin is abundant in the centrally located insulin-producing beta-cells and is expressed much less, if at all, by the other endocrine cell types. This differential expression was further confirmed on fluorescence-activated cell sorter-purified preparations enriched in either beta- or non-beta-cells. The finding of a differential distribution of Cx36 within distinct regions of pancreatic islets creates the possibility that this connexin may provide the establishment of selective pathways of communication between the different types of endocrine cells comprising the pancreatic islet.

Subcellular distribution and function of Rab3A, B, C, and D isoforms in insulin-secreting cells.

Insulin-secreting cells express four GTPases of the Rab3 family. After separation of extracts of INS-1 cells on a sucrose density gradient, the bulk of the A, B, and C isoforms was recovered in the fractions enriched in insulin-containing secretory granules. Rab3D was also mainly associated with secretory granules, but a fraction of this isoform was localized on lighter organelles. Analyses by confocal microscopy of immunostained HIT-T15 cells transfected with epitope-tagged constructs confirmed the distribution of the Rab3 isoforms. Transfection of HIT-T15 cells with GTPase-deficient mutants of the Rab3 isoforms decreased nutrient-induced insulin release to different degrees (D>B>A>>C), while overexpression of Rab3 wild types had minor or no effects. Expression of the same Rab3 mutants in PC12 cells provoked an inhibition of K+-stimulated secretion of dense core vesicles, indicating that, in beta-cells and neuroendocrine cells, the four Rab3 isoforms play a similar role in exocytosis. A Rab3A/C chimera in which the carboxyterminal domain of A was replaced with the corresponding region of C inhibited insulin secretion as Rab3A. In contrast, a Rab3C/A chimera containing the amino-terminal domain of C was less potent and reduced exocytosis as Rab3C. This suggests that the degree of inhibition obtained after transfection of the Rab3 isoforms is determined by differences in the variable amino-terminal region.

[Course and neurological/behavioral development of preterm children]. / Parcours et développement neurologique et comportemental de l'enfant prématuré

Preterm birth remains a public health priority given that one child out of ten is born before 37 weeks of gestation. Survival without major neonatal morbidity has increased in high-income countries, in particular in France and in cases of extreme preterm birth before 27 weeks of gestation. Rate of severe handicaps, such as cerebral palsy, is probably decreasing, but specific cognitive disabilities in a variety of domains remain frequent, interfering with normal learning abilities at school and explaining the high rate of special education needs. Prevalence of sequelae increases when gestational age at birth decreases. However, because there are more moderate to late preterm children compared to very preterm children, the absolute number of children with specific cognitive or neurological disabilities is equivalent in these two groups. Better characterization of the development in a recent cohort of very preterm children is necessary to improve the early detection of variations in normal neurodevelopment and to propose trials with remediation actions targeting working memory and language for example. These protocols could decrease the rates of learning disabilities at school.

Hyperinsulinemia-induced hypoglycemia is enhanced by overexpression of connexin 43.

To assess whether cell to cell communications via connexins (Cx) participate to insulin secretion in vivo, we studied insulinoma cells (INS1) implanted in rats after stable transfection with connexin 43 (Cx43). We found that compared to wild-type and transfected cells, which in vivo express modest levels of Cx43 and junctional communication, cells overexpressing Cx43 communicated extensively, featured decreased growth, and induced a much higher hyperinsulinemia. As a result, rats with insulinomas made of these cells became more severely hypoglycemic than rats implanted with either wild-type, neomycin-transfected cells or cells transfected with a Cx43 antisense complementary DNA. Rats implanted with transfected cells that expressed modest level of Cx43 showed levels of circulating insulin similar to those in rats implanted with wild-type INS1 cells. The data show that overexpression of Cx43 influences the growth and secretion of the implanted insulinoma cells, providing evidence for a contribution of Cx-mediated cell to cell communication in the functioning of insulin-producing cells in vivo.

Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate.

Prolonged exposure to elevated FFA levels has been shown to induce peripheral insulin resistance and to alter the beta-cell secretory response to glucose. To investigate the effects of FFAs on preproinsulin gene expression, we measured insulin release, cell content, and messenger RNA (mRNA) levels in rat islets after a 24-h exposure to 1 mM palmitate. Insulin release increased at all glucose concentrations studied; in contrast, preproinsulin mRNA levels were specifically reduced by palmitate at high glucose with a decrease in insulin stores, suggesting that palmitate inhibits the glucose-stimulated increase in preproinsulin gene expression. The mechanisms by which palmitate affects preproinsulin gene expression implicate both preproinsulin mRNA stability and transcription, as suggested by an actinomycin D decay assay, quantification of primary preproinsulin transcripts, and transient transfection experiments in Min6 cells. Metabolism of palmitate is not required to obtain these effects, inasmuch as they can be reproduced by 2-bromopalmitate. However, oleate and linoleate did not significantly influence preproinsulin mRNA levels. We conclude that insulin release and preproinsulin gene expression are not coordinately regulated by palmitate and that chronically elevated FFA levels may interfere with beta-cell function and be implicated in the development of noninsulin-dependent diabetes.

Cx36 and the function of endocrine pancreas.

The secretory, duct, connective and vascular cells of pancreas are connected by gap junctions, made of different connexins. The insulin-producing beta-cells, which form the bulk of endocrine pancreatic islets, express predominantly Cx36. To assess the function of this connexin, we have first studied its expression in rats, during sequential changes of pancreatic function which were induced by the implantation of a secreting insulinoma. We observed that changes in beta-cell function were paralleled by changes in Cx36 expression. We have also begun to investigate mutant mice lacking Cx36. The absence of this protein did not affect the development and differentiation of beta-cells but appeared to alter their secretion. We have studied this effect in MIN6 cells which spontaneously express Cx36. After stable transfection of a construct that markedly reduced the expression of this connexin, we observed that MIN6 cells were no more able to secrete insulin, in contrast to wild type controls, and differentially displayed a series of still unknown genes. The data provide evidence that Cx36-dependent signaling contributes to regulate the function of native and tumoral insulin-producing cells.

Expression of connexin36 in the adult and developing rat brain.

The distribution of connexin36 (Cx36) in the adult rat brain and retina has been analysed at the protein (immunofluorescence) and mRNA (in situ hybridization) level. Cx36 immunoreactivity, consisting primarily of round or elongated puncta, is highly enriched in specific brain regions (inferior olive and the olfactory bulb), in the retina, in the anterior pituitary and in the pineal gland, in agreement with the high levels of Cx36 mRNA in the same regions. A lower density of immunoreactive puncta can be observed in several brain regions, where only scattered subpopulations of cells express Cx36 mRNA. By combining in situ hybridization for Cx36 mRNA with immunohistochemistry for a general neuronal marker (NeuN), we found that neuronal cells are responsible for the expression of Cx36 mRNA in inferior olive, cerebellum, striatum, hippocampus and cerebral cortex. Cx36 mRNA was also demonstrated in parvalbumin-containing GABAergic interneurons of cerebral cortex, striatum, hippocampus and cerebellar cortex. Analysis of developing brain further revealed that Cx36 reaches a peak of expression in the first two weeks of postnatal life, and decreases sharply during the third week. Moreover, in these early stages of postnatal development Cx36 is detectable in neuronal populations that are devoid of Cx36 mRNA at the adult stage. The developmental changes of Cx36 expression suggest a participation of this connexin in the extensive interneuronal coupling which takes place in several regions of the early postnatal brain.

[Severe autoimmune immunoglobulin A hemolytic anemia in a 10-month-old infant]. / Anémie hémolytique auto-immune sévère à immunoglobulines A chez un nourrisson de dix mois.

CASE REPORT: A ten-month-old boy presented with a severe auto-immune hemolytic anemia. Direct antiglobin test was positive only for IgA class autoantibodies. He recovered with a high dose corticosteroid treatment. CONCLUSION: IgA class autoantibodies should be searched for in the case of a high suspicion of auto-immune hemolytic anemia with negative direct antiglobin test for IgG and complement. Corticosteroid treatment is most often successful.

[Epilepsy presenting as life-threatening events in infants]. / Les malaises du nourrisson d'origine épileptique.

OBJECTIVE: This study was aimed at assessing the frequency and features of epilepsy presenting as life-threatening events in infancy. PATIENTS AND METHODS: Fifteen cases were collected over eight years. Subtle symptoms suggestive of epilepsy were rare (9/15) in the retrospective analysis; the clinical context and cerebral imaging were occasionally contributive (5/15); interictal EEG was useful but inconstantly contributive, including when the epileptic nature of the episodes had become clinically probable (10/15). Though it had no clear relationships with epileptic episodes but contributed to mislead diagnosis, gastroesophageal reflux was frequently associated. Uncovered epilepsies were not homogeneous, ranging from severe epileptic encephalopathy to benign epilepsy of infancy. CONCLUSION: Epilepsy presenting as life-threatening events is sometimes a diagnostic challenge. When an infant develops recurrent critical episodes during a several-week follow-up, with neurological and general investigations not providing more information, the immediate success of antiepileptic treatment might support diagnosis.

[Indications of electroencephalogram in the newborn]. / Indications de l'électroencéphalogramme en période néonatale. Recommandations du groupe de neurophysiologie clinique de l'enfant.

The electroencephalogram (EEG), an easy-to-use and non invasive cerebral investigation, is a useful tool for diagnosis and early prognosis in newborn babies. In newborn full term babies manifesting abnormal clinical signs, EEG can point focal lesions or specific aetiology. EEG background activity and sleep organization have a high prognostic value. Tracings recorded over long period can detect seizures, with or without clinical manifestations, and differentiate them from paroxysmal non epileptic movements. The EEG should therefore be recorded at the beginning of the first symptoms, and if possible before any seizure treatment. When used as a neonatal prognostic tool, EEG background activity is classified as normal, abnormal (type A and type B discontinuous and hyperactive rapid tracing) or highly abnormal (inactive, paroxysmal, low voltage plus theta tracing). In such cases, the initial recording must be made between 12 and 48 h after birth, and then between 4 and 8 days of life. Severe EEG abnormalities before 12 h of life have no reliable prognostic value but may help in the choice of early neuroprotective treatment of acute cerebral hypoxia-ischemia. During presumed hypoxic-ischemic encephalopathy, unusual EEG patterns may indicate another diagnosis. In premature newborn babies (29-32 w GA) with neurological abnormalities, EEG use is the same as in term newborns. Without any neurological abnormal sign, EEG requirements depend on GA and the mother's or child's risk factors. Before 28 w GA, when looking for positive rolandic sharp waves (PRSW), EEG records are to be acquired systematically at D2-D3, D7-D8, 31-32 and 36 w GA. It is well known that numerous and persistent PRSW are related to periventricular leukomalacia (PVL) and indicate a bad prognosis. In babies born after 32 GA with clinically severe symptoms, an EEG should be performed before D7. Background activity, organization and maturation of the tracing are valuable diagnosis and prognosis indicators. These recommendations are designed (1) to get a maximum of precise informations from a limited number of tracings and (2) to standardize practices and thus facilitate comparisons and multicenter studies.

[Understand the neurodevelopment of language: a necessity to prevent learning disabilities in children]. / Comprendre le neurodéveloppement du langage, une nécessité pour prévenir les troubles des apprentissages de l'enfant ?

Clinical and radiological knowledge of language development in the former premature infant compared to the newborn allows us to argue for exploration of the sensorimotor co-factors required for proper language development. There are early representations of the maternal language in the infant's visual, auditory, and sensorimotor areas, activated or stabilized by orofacial and articulatory movements. The functional architecture of language is different for vulnerable children such as premature infants. We have already mentioned the impact of early dysfunction of the facial praxis fine motor skills in this population presenting comprehension disorders. A recent meta-analysis confirms the increasing difficulty of understanding between 3 and 12 years, questioning the quality of the initial linguistic processes. A precise analysis of language, referenced from 3 years of age, should be completed by sensorimotor tests to assess possible constraints in automating neurolinguistic foundations. The usual assessment at this age can exclude sensory disturbances and communication and offers guidance and socialization. However, a recent study shows the ineffectiveness of "language-reinforced immersion" at 2 and 3 years in a population of vulnerable children. The LAMOPRESCO study of language and motor skills in the premature infant (National PHRC 2010) has assessed language and sensorimotor skills of preterm-born (<33 weeks) 3.5-year-old children without cerebral palsy. Fragile children were randomized into 2 groups, 1 stimulated by a specific individual protocol, the other given guidance. The primary endpoint was phonology, assuming that it is composed of very early good-quality sensorimotor integration stabilized by the child's oral facial motor skills before 5 years of age. This developmental integrative dynamic validates the "motor theory of speech perception." Early and accurate assessment of language and the patient's constraints should differentiate and specify management strategies for all children, whatever their background and pathologies.

[Evaluation of language at 6 years in children born prematurely without cerebral palsy: prospective study of 55 children]. / Évaluation à 6 ans du langage de l'enfant né grand prématuré sans paralysie cérébrale : étude prospective de 55 enfants.

OBJECTIVES: Very premature birth carries a high risk of neurocognitive disabilities and learning disorders. Acquiring sufficient speech skills is crucial to good school performance. METHODS: A prospective study was conducted in 2006 to evaluate speech development in 55 children born very prematurely in 2000 at the Rouen Teaching Hospital (Rouen, France), free of cerebral palsy, compared to 6-year-old born at full term. A computerized speech assessment tool was used (Bilan Informatisé du Langage Oral, BILO II). RESULTS: In the premature-birth group, 49 % of 6-year-old had at least 1 score below the 25th percentile on 1 of the 8 BILO II tests. Significant speech impairments were noted for 2 components of speech, namely, comprehension and phonology. Oral comprehension scores no higher than the 10th percentile were obtained by 23 % of prematurely born children (P<0.02 vs controls). On word repetition tasks used to test phonology, 21 % of prematurely born children obtained scores no higher than the 10th percentile (P<0.01 vs controls). An evaluation of sensorimotor language prerequisites (constraints) in 30 of the 55 prematurely born children showed significant differences with the controls for word memory, visual attention, and buccofacial praxis. CONCLUSION: The speech development impairments found in 6-year-old born very prematurely suggest a distinctive pattern of neurodevelopmental dysfunction that is consistent with the motor theory of speech perception.

[Special outpatient services at 5 and 8 years in very-preterm children in the EPIPAGE study]. / Prises en charge éducatives spécifiques de l'enfant grand prématuré à 5 et 8 ans: résultats de l'étude EPIPAGE.

UNLABELLED: The immature brain is highly susceptible to the consequences of very preterm birth with a high rate of long-term neurodisabilities in survivors and high use of specific outpatient services to limit the functional effects of the disabilities. To assess the economic burden for the social and health care system, it is necessary to inventory the community supports and need for special education or rehabilitation used by preterm children. Such studies are few and were done only in extremely low-birthweight or extremely preterm newborns in the United States. OBJECTIVE: To study the rates of specific outpatient services and special education at 5 years of age and between 5 and 8 years of age in a geographically-defined population of children born very preterm. DESIGN, SETTING AND PATIENTS: 2901 liveborn children before 33 weeks'gestation (WG) and one control group of 666 liveborn children at 39-40WG were included in nine regions of France in 1997 corresponding to more than one third of all births. At five years, these children had a medical examination and were evaluated by a psychologist at local centres organised for the study in every region. Cognitive function was assessed by the mental processing composite scale (PMC) of the Kauffmann Assessement Battery for Children test, which is considered to be equivalent to intelligence quotient and behavioral difficulties using the Strength and Difficulties questionnaire completed by the parents. Data for dependence or compensatory aids, i.e. occupational therapy or physical therapy, speech therapy, psychologist or psychiatrist visits, orthoptic therapy, wearing glasses, wearing hearing aid, specific equipment to walk (walker, wheelchair...), orthopaedic treatment or anti-epileptic treatment were collected from parents. At eight years, a postal questionnaire was sent to the parents to collect data on specific outpatient services and special treatments at home and school. Stata software was used (version 9.0). Main outcome measures. Parent Questionnaire for identifying children with chronic conditions and specific health care needs at 5 and 8 years and categorization of developmental neurodisabilities based on examination of children and psychometric evaluation at 5 years. RESULTS: At 5 years data were obtained for respectively 1817 and 396 children born before 33WG or at 39-40WG, which represent 80% of the very preterm children and 71% of the at term children. At 8 years we obtained data for 63% of the very preterm children and 59% of the at term children. At 5 years, care in a rehabilitation center and/or specific outpatient services were required for 41% of children born between 24 and 28WG, 32% of children born between 24 and 32WG and 15% of those born at 39-40WG. Between 5 and 8 years, these figures were respectively 61%, 50% and 36%. In the very preterm group, rates of specific outpatient services were higher than 80% if the child had a motor and/or a neurosensory deficit. In case of cognitive deficiencies (PMC < 85), rates of specific outpatient services were low at 37% at 5 years and increases at 63% between 5 and 8 years. CONCLUSION: Compared to the children born at term, the very preterm children have considerable educational needs, which are inversely related to gestational age at birth and to age of the children at the time of reporting. Despite economic burden, efforts to improve access to services are necessary, in particular in case of cognitive impairment.

Neurodevelopmental outcome in prenatally diagnosed isolated agenesis of the corpus callosum.

AIM: To evaluate long-term neurodevelopmental outcomes in children with prenatally diagnosed, isolated agenesis of the corpus callosum (ACC). METHODS: We retrospectively reviewed data for 20 children born between January 1991 and November 2003 in the Haute-Normandie region of France with a prenatal diagnosis of isolated ACC. We collected data on pre-and postnatal neuroimaging findings, clinical features at birth and neurodevelopmental outcomes. RESULTS: Follow-up ranged from 3 to 16 years. ACC was complete in 11 patients (55%), partial in 2 (10%), hypoplastic in 3 (15%) and associated with an interhemispheric cyst in 4 (20%). Neurodevelopmental outcome was normal in 11 (55%) patients, including 8 with complete ACC; moderate disability was present in 5 (25%) patients and severe disability in 4 (20%) patients. In 3 of the 4 patients with severe disability, postnatal cerebral magnetic resonance imaging (MRI) showed additional major cerebral abnormalities. CONCLUSION: Neurodevelopmental outcome was good in most of our patients with isolated ACC, with 80% of patients having normal outcomes or moderate disabilities. A prenatal diagnosis of isolated ACC may not warrant termination of pregnancy. A carefully interpreted prenatal cerebral MRI is crucial to detect associated cerebral abnormalities; a longer follow-up is necessary to look for moderate disabilities.

Islet-cell-to-cell communication as basis for normal insulin secretion.

The emergence of pancreatic islets has necessitated the development of a signalling system for the intra- and inter-islet coordination of beta cells. With evolution, this system has evolved into a complex regulatory network of partially cross-talking pathways, whereby individual cells sense the state of activity of their neighbours and, accordingly, regulate their own level of functioning. A consistent feature of this network in vertebrates is the expression of connexin (Cx)-36-made cell-to-cell channels, which cluster at gap junction domains of the cell membrane, and which adjacent beta cells use to share cytoplasmic ions and small metabolites within individual islets. This chapter reviews what is known about Cx36, and the mechanism whereby this beta-cell connexin significantly regulates insulin secretion. It further outlines other less established functions of the protein and evaluates its potential relevance for the development of novel therapeutic approaches to diabetes.

Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.

AIMS/HYPOTHESIS: The IL-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine known to antagonise the actions of IL-1. We have previously shown that IL-1Ra is markedly upregulated in the serum of obese patients, is correlated with BMI and insulin resistance, and is overexpressed in the white adipose tissue (WAT) of obese humans. The aim of this study was to examine the role of IL-1Ra in the regulation of glucose homeostasis in rodents. METHODS: We assessed the expression of genes related to IL-1 signalling in the WAT of mice fed a high-fat diet, as well as the effect of Il1rn (the gene for IL-1Ra) deletion and treatment with IL-1Ra on glucose homeostasis in rodents. RESULTS: We show that the expression of Il1rn and the gene encoding the inhibitory type II IL-1 receptor was upregulated in diet-induced obesity. The blood insulin:glucose ratio was significantly lower in Il1rn ( -/- )animals, which is compatible with an increased sensitivity to insulin, reinforced by the fact that the insulin content and pancreatic islet morphology of Il1rn ( -/- ) animals were normal. In contrast, the administration of IL-1Ra to normal rats for 5 days led to a decrease in the whole-body glucose disposal due to a selective decrease in muscle-specific glucose uptake. CONCLUSIONS/INTERPRETATION: The expression of genes encoding inhibitors of IL-1 signalling is upregulated in the WAT of mice with diet-induced obesity, and IL-1Ra reduces insulin sensitivity in rats through a muscle-specific decrease in glucose uptake. These results suggest that the markedly increased levels of IL-1Ra in human obesity might contribute to the development of insulin resistance.