Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation.

Polyoma virus middle T antigen (PyVmT) is a powerful viral oncogene; however, the mechanisms of PyVmT activation are poorly understood. The insulin-like growth factor I receptor (IGF-IR) and the insulin receptor (IR) are known to be implicated in the development of many cancers. Furthermore, PyVmT-overexpressing mouse mammary carcinoma Met-1 cells are highly responsive to IGF-I and insulin. Herein, we demonstrate that PyVmT physically interacts with IGF-IR and IR in Met-1 cells. Insulin and IGF-I increase association of the IR and IGF-IR with PyVmT, enhance tyrosine phosphorylation of PyVmT and augment the recruitment of Src and PLCgamma(1) to PyVmT. This is accompanied by robust and sustained phosphorylation of Akt and ERK1/2, which are implicated in both PyVmT and IGF-IR/IR signalling. Both ligands significantly increase proliferation, survival, migration and invasion of Met-1 cells. Furthermore, orthotopic inoculation of Met-1 cells with shRNAmir-mediated knockdown of IR or IGF-IR fails to initiate tumour growth in recipient mice. In conclusion, our data indicate that the physical and functional interaction between PyVmT and cellular receptor tyrosine kinases, including IR and IGF-IR, is critical for PyVmT activation and tumour initiation. These results also provide a novel mechanism for oncogene activation in the host cell.

Apolipoprotein E deficiency abrogates insulin resistance in a mouse model of type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Although it is known that lipid metabolism plays a role in insulin resistance in type 2 diabetes and in obesity, the mechanism is still largely unknown. Apolipoprotein E (ApoE) regulates plasma lipid levels and also plays a role in the uptake of lipids into various tissues. To investigate whether the suppression of whole-particle lipoprotein uptake into tissues affects insulin responsiveness and the diabetic condition, we examined the effect of an ApoE (also known as Apoe) gene deletion in MKR mice, a mouse model of type 2 diabetes. METHODS: ApoE ( -/- ), MKR, ApoE ( -/- )/MKR and control mice were placed on a high-fat, high-cholesterol diet for 16 weeks. Glucose tolerance, serum insulin, blood glucose, insulin tolerance, tissue triacylglycerol content and atherosclerotic lesions were assessed. RESULTS: ApoE ( -/- )/MKR and ApoE ( -/- ) mice showed significantly improved blood glucose, glucose tolerance and insulin sensitivity. Reduced triacylglycerol content in liver and reduced fat accumulation in liver and adipose tissue were found in ApoE ( -/- )/MKR and ApoE ( -/- ) mice compared with control and MKR mice. ApoE ( -/- ) and ApoE ( -/- )/MKR mice demonstrated similarly large atherosclerotic lesions, whereas MKR and control mice had small atherosclerotic lesions. CONCLUSIONS/INTERPRETATION: We demonstrated that ApoE deficiency abrogates insulin resistance in a mouse model of type 2 diabetes, suggesting that lipid accumulation in tissue is a major cause of insulin resistance in this mouse model.

Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence.

Both obesity and Type 2 diabetes are independently associated with an increased risk of developing cancer and an increased mortality. The etiology is yet to be determined but insulin resistance and hyperinsulinemia maybe important factors. Hyperglycemia, hyperlipidemia and inflammatory cytokines in addition to the insulin-like growth factors are also possible factors involved in the process.

Insulin resistance and the metabolic syndrome.

The metabolic syndrome is a constellation of risk factors including glucose dysregulation, central obesity, dyslipidemia, and hypertension. There are multiple definitions that have been described by various health organizations. However, we do know that insulin resistance plays a major role as the underlying cause for the development and potentiation of the metabolic syndrome. At present, it is unclear if the diagnosis of metabolic syndrome is greater than the sum of its parts. However, the presence of more than one of the associated risk factors should indicate that a patient is at increased risk for developing diabetes, cardiovascular disease and death. Thus, the primary care physician should aggressively treat the metabolic risk factors in their patients to prevent the onset and progression to more severe disease.

Insulin-like growth factor-I protects cells from ER stress-induced apoptosis via enhancement of the adaptive capacity of endoplasmic reticulum.

Disruption of endoplasmic reticulum (ER) homeostasis causes accumulation of unfolded and misfolded proteins in the ER, triggering the ER stress response, which can eventually lead to apoptosis when ER dysfunction is severe or prolonged. Here we demonstrate that human MCF-7 breast cancer cells, as well as murine NIH/3T3 fibroblasts, are rescued from ER stress-initiated apoptosis by insulin-like growth factor-I (IGF-I). IGF-I significantly augments the adaptive capacity of the ER by enhancing compensatory mechanisms such as the IRE1 alpha-, PERK- and ATF6-mediated arms of ER stress signalling. During ER stress, IGF-I stimulates translational recovery and induces expression of the key molecular chaperone protein Grp78/BiP, thereby enhancing the folding capacity of the ER and promoting recovery from ER stress. We also demonstrate that the antiapoptotic activity of IGF-I during ER stress may be mediated by a novel, as yet unidentified, signalling pathway(s). Application of signal transduction inhibitors of MEK (U1026), PI3K (LY294002 and wortmannin), JNK (SP600125), p38 (SB203580), protein kinases A and C (H-89 and staurosporine) and STAT3 (Stattic) does not prevent IGF-I-mediated protection from ER stress-induced apoptosis. Taken together, these data demonstrate that IGF-I protects against ER stress-induced apoptosis by increasing adaptive mechanisms through enhancement of ER stress-signalling pathways, thereby restoring ER homeostasis and preventing apoptosis.

[The role of umbilical Doppler in the monitoring of pregnancy]. / Intérêts du Döppler ombilical dans la surveillance de grossesse.

Doppler recordings from the umbilical cord in utero explores the placental reserves and fetal well being. Compliance with the technical conditions of performance ensures reliability of the determination. This examination predicts the state of the child at birth, particularly in cases of delayed intra-uterine growth, maternal hypertension or gestosis, and in cases of twin pregnancies. The change is maximum when the umbilical diastolic flow disappears. In the absence of any pathological context, a congenital or chromosomal abnormality should be considered and the fetal karyotype should be determined. Follow-up is carried out during hospitalization, and the decision on whether to extract the fetus is based on cerebral Doppler recordings and a detailed analysis of the fetal heartbeat.

Secular trend in the rate of small-for-gestational-age infants: Haguenau Study 1971-1985.

Between 1971 and 1985, at the Haguenau Maternity Hospital, a 20% decrease was observed in the rate of small-for-gestational-age infants (birthweight less than 10th centile using figures from all the study births) among 20,101 births between 28 and 42 weeks. This decrease could not be explained by simultaneous changes in socio-demographic and anthropometric characteristics of the pregnant women, nor a recruitment bias. The earliness of prenatal care at the Maternity Hospital may have played a role in the downward trend. Further research is needed to confirm the influence of prenatal care on the rate of small-for-gestational-age babies.

[Induced prematurity]. / La prématurité provoquée.

Voluntary induction of a premature delivery, which goes against our constant battle to reduce prematurity, represents, at this time, a paradoxical situation which is not exceptional in vasculorenal syndromes and premature rupture of the membranes. Advances in ressuscitation and the care of premature newborn babies, on the one hand, and techniques of artificial induction of labor, on the other hand, account for this obvious paradox. Even advances in artificial induction of labor explain also the decrease in the cesarean sections indications, under such circumstances.

[Antenatal diagnosis of the sex of the fetus by diagnostic ultrasound (echography) (author's transl)]. / Diagnostic échographique anténatal du sexe.

The authors present the results they obtained in diagnosing fetal sex in utero by the use of real-time echography. They also have reviewed the other different techniques for the diagnosis and their fallibility. The prediction of fetal sex is possible in 90 p. 100 of echographies carried out routinely. When a very careful well codified technique is used the method becomes highly reliable. In a successive series of 103 pregnancies fetal sex was diagnosed correctly in every case. The authors point out that they diagnose female sex through positive echographic finding and not by a process of exclusion of the male organs.