Intervention for childhood obesity based on parents only or parents and child compared with follow-up alone.

OBJECTIVES: The study aims to assess the effects of family-based interventions targeted to parents only or to parents-and-child for the prevention and treatment of childhood obesity. METHOD: An open-label randomized study was conducted in 247 children (166 girls, 5-11 years) with body mass index (BMI) in the 85-98th percentile. Participants were allocated to three groups: parents-only (n = 89), parents-and-child (n = 84) and follow-up alone (n = 74). The intervention consisted of 12 once-weekly meetings with a dietician and psychologist. All children were followed for 2 years. Changes in anthropometric, clinical and lifestyle outcomes were assessed. RESULTS: The 3-month intervention was completed by 58 (65.2%) in the parents-only, 61 (72.6%) in the parents-child and 49 (66.2%) in the control group (P = .554). BMI-standard deviation score (SDS) decreased from baseline to 3 months in both intervention groups (parents-only: from 1.74 ± 0.31 to 1.66 ± 0.36, P < .001; parents-child, 1.83 ± 0.33 to 1.76 ± 0.36, P = .012), with no significant change in the controls (1.73 ± 0.32 to 1.70 ± 0.31, P = .301). The 2-year follow-up was completed by 45 in each of the intervention groups (50.5% and 53.5%, respectively) and 37 controls (50%) (P = .896). Compared with baseline, only the parents-child group showed a significant decrease in BMI-SDS (1.56 ± 0.46, P = .006). The rate of children who met the criteria for metabolic syndrome tended to drop from 6.0% at baseline (14/232) to 1.5% at 3 months (12/137) (P = .109), with no significant between-group differences in the rate of metabolic syndrome at baseline or at completion of the intervention. CONCLUSIONS: An intervention programme that focuses on both parents and children was found to have positive short-term and long-term effects on BMI-SDS.

Congenital malformations in infants conceived following assisted reproductive technology in comparison with spontaneously conceived infants.

OBJECTIVE: To evaluate the risk for congenital malformations diagnosed at birth following assisted reproductive technology (ART) treatments compared with live births conceived spontaneously. METHODS: A retrospective cohort study including 9042 live births following ART and 213 288 spontaneously conceived (SC) live births during the period 1997-2004.The cohort was linked to the national live birth registry to determine the outcome of the pregnancies including congenital malformations. RESULTS: An increased adjusted risk for all congenital malformations was observed in ART compared with SC infants [2.4% versus 1.9%; ORadj = 1.45; 95% CI: 1.26, 1.68]. The increased risk was observed in singleton births [2.4% versus 1.8%; ORadj = 1.41; 95% CI: 1.14, 1.71] but not in the ART conceived multiple births [2.5% versus 2.6%.; ORadj = 1.15; 95% CI: 0.90, 1.46]. Significantly increased adjusted risks for nervous, circulatory, digestive and genital system malformations were evident in the ART singleton group compared to SC infants. In addition, increased risks were also observed in separate comparisons of IVF births versus SC [ORadj = 1.28; 95% CI: 1.00, 1.63] and ICSI births versus SC [ORadj = 1.56; 95% CI: 1.31, 1.84]. Data regarding pregnancy termination or congenital malformation diagnosed later in life were not included. CONCLUSION: Infants born following ART were at significantly increased risk for congenital malformations compared to live birth conceived spontaneously.

Factors associated with radiation exposure in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) patients undergo multiple radiological evaluations. AIM: To estimate total and abdominal radiation exposure from diagnostic X-ray investigations in IBD patients and the associated risk factors. METHODS: Patients with Crohn's disease (CD) or ulcerative colitis (UC) treated in the IBD clinic were recruited. Clinical data were extracted from patient files and radiological data were obtained from the central HMO computer data base. RESULTS: A total of 199 CD and 125 UC patients were included. The mean cumulative estimated doses (CED) for CD and UC were 21.1 19.5 and 15.1 20.4 millisieverts (mSv) respectively (P < 0.001). Twenty-three patients (7.1%) had an estimated CED of > or =50 mSv. In multivariate analyses, predictors of increased CED were: surgery (OR 5.68, 95% CI: 2.73-11.8, P < 0.001), CD (OR 2.56, 95% CI: 1.29-5.07, P = 0.007), prednisone use (OR 2.0, 95% CI: 1.11-3.67, P = 0.02), first year of disease (OR 6.4, 95% CI: 1.3-32, P = 0.02) and age in the upper quartile(OR 3.26, 95% CI: 1.68-6.3, P = 0.001). CONCLUSIONS: Diagnosis of CD, IBD-related surgery, prednisone use, first year of diagnosis and age on the upper quartile are independent predictors of increased exposure in IBD patients. Alternative investigations which do not require radiation exposure should be considered for patients at risk for increased radiation exposure.

Psoriasis and diabetes: a population-based cross-sectional study.

BACKGROUND: Previous reports have shown an association between psoriasis and the metabolic syndrome, but there are only a few studies on the association between psoriasis and diabetes. OBJECTIVES: To study the association between psoriasis and diabetes. METHODS: A cross-sectional study was performed utilizing the database of Clalit Health Services (CHS). Patients who were diagnosed with psoriasis were compared with CHS enrolees without psoriasis regarding the prevalence of diabetes. Patients with diabetes were identified using the CHS chronic diseases registry. Chi-squared tests were used to compare categorical parameters. Logistic regression models were used for multivariate analyses. RESULTS: The study included 16 851 patients with psoriasis and 74 987 subjects without psoriasis (control patients). The proportion of diabetes was significantly higher in patients above 35 years (P < 0.05). The age-adjusted proportion of diabetes was significantly higher in psoriasis patients as compared to the control group [odds ratio (OR), 1.38, P < 0.05] and was similar in men and women (OR, 1.32, 1.45, respectively). A multivariate logistic regression model showed that psoriasis was significantly associated with diabetes, independently of age and gender (OR, 1.58, P < 0.001). CONCLUSIONS: Our study supports previous reports of an association between psoriasis and diabetes. Dermatologists taking care of patients with psoriasis should be aware of this association and advise the patients to reduce additional risk factors such as smoking, hypertension or dyslipidemia.

Association between psoriasis and the metabolic syndrome. A cross-sectional study.

BACKGROUND: Previous reports have shown an association between inflammatory diseases such as systemic lupus erythematosus or rheumatoid arthritis and the metabolic syndrome. Recent data demonstrate that psoriasis is an inflammatory disease, suggesting that psoriasis may be one of the components of the metabolic syndrome. OBJECTIVE: To assess the association between psoriasis and the metabolic syndrome. METHODS: A cross-sectional study was performed utilizing the database of the Clalit Health Services. Case patients were defined as patients with a diagnosis of psoriasis vulgaris. Controls were randomly selected from the list of Clalit Health Services enrollees. The proportions of components of the metabolic syndrome (ischemic heart disease, hypertension, diabetes, obesity and dyslipidemia) were compared between case and control patients by univariate analyses. chi(2) tests were used to compare categorical parameters between the groups. Logistic and linear regression models served to measure the association between psoriasis and the metabolic syndrome. RESULTS: The study included 16,851 patients with psoriasis and 48,681 controls. In the case group, there were 8,449 men (50.1%) and 8,402 women (49.9%), with a mean age of 42.7 years (SD = 20.3, range = 2-111). Diabetes mellitus was present in 13.8% of the patients with psoriasis as compared to 7.3% of the controls (p < 0.001). Hypertension occurred in 27.5% of the patients with psoriasis and in 14.4% of the controls (p < 0.001). Obesity was present in 8.4% of the patients with psoriasis as opposed to 3.6% of the controls (p < 0.001). Ischemic heart disease was observed in 14.2% of the patients with psoriasis as compared to 7.1% of the controls (p < 0.001). Multivariate models adjusting for age, gender and smoking status of the patients demonstrated that psoriasis was associated with the metabolic syndrome (OR = 1.3, 95% CI = 1.1-1.4), ischemic heart disease (OR = 1.1, 95% CI = 1.0-1.2), diabetes mellitus (OR = 1.2, 95% CI = 1.0-1.3), hypertension (OR = 1.3, 95% CI = 1.2-1.5) and obesity (OR = 1.7, 95% CI = 1.5-1.9). LIMITATIONS: The study is designed as a case-control study, thus an association alone was proven and not causality. CONCLUSION: Our findings demonstrate a possible association between psoriasis and the metabolic syndrome. Appropriate treatment of the metabolic syndrome may be an important part of the management of patients with psoriasis.

Physical exercise increases the expression of TNFalpha and GLUT 1 in muscle tissue of diabetes prone Psammomys obesus.

INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) is a major mediator of insulin resistance. On the other hand, it has been suggested that TNFalpha may facilitate glucose uptake through GLUT 1 expression. We recently found that physical exercise prevented the progression to type 2 diabetes mellitus in diabetes prone Psammomys obesus (sand rat). AIM: The aim of the present study was to characterize the influence of physical exercise on the expression of TNFalpha, its receptor R1 and GLUT 1 in muscle tissue of this animal model. METHODS: Animals were assigned for 4 weeks to four groups: high-energy diet (HC), high-energy diet and exercise (HE), low-energy diet (LC), low-energy diet and exercise (LE). TNFalpha, R1 and GLUT 1 expression were analyzed using Western blot technique. RESULTS: None of the animals in the HE group became diabetic while all the animals in the HC group became diabetic. TNFalpha, its receptor (R1) and GLUT 1 expressions were significantly higher in the two exercising groups (LE and HE) and significantly lower in the HC group compared to the control LC group. CONCLUSIONS: Physical exercise augments the expression of TNFalpha, its receptor R1 and the glucose transporter GLUT 1 in muscle tissue. We suggest that this mechanism may improve glucose uptake through pathways parallel and unrelated to insulin signaling that may include MAPK and/or NO. These biochemical processes contribute to the beneficial effects of physical exercise on the prevention of type 2 diabetes mellitus.

Relation of parental history of coronary heart disease to obesity in young adults.

OBJECTIVE: To assess the association between obesity and parental coronary heart disease (CHD) history. DESIGN: Analysis of data from an ongoing, large-scale survey on medical status, health behaviour and attitudes. SUBJECTS: Representative samples of Israeli military personnel upon discharge from compulsory service at age 20-22 y. Overall 14297 men and 11638 women were interviewed and examined upon release from military service between 1989 and 1999. MEASUREMENTS: Data on demographic characteristics, family history of CHD, lifestyle, weight and height were collected. Analysis of variance and logistic regression were used. RESULTS: Higher mean body mass index (BMI) and obesity (BMI>30 kg/m(2)) were associated with paternal CHD history in both sexes, and with maternal CHD history among men. Offspring of a parent with a positive CHD history had a higher mean BMI (23.22 vs 22.86 kg/m(2), P<0.001) and were more likely to be obese (5.4 vs 3.7%, P<0.001) than offspring of parents with no history of CHD. Multivariate adjustment for demographic and behavioural variables associated with obesity attenuated the association (adjusted odds ratio for obesity 1.37, 95% confidence interval: 1.15, 1.64). When stratified by sex, this association remained statistically significant only among males. CONCLUSION: Young adults with a parental history of CHD are more likely to be overweight. This high-risk group should be targeted for early preventive activities.

Hypopituitarism in langerhans cell histiocytosis: seven cases and literature review.

Central nervous system (CNS) involvement and, in particular, hypothalamic-pituitary involvement are well described features of Langerhans cell histiocytosis (LCH). The actual incidence of CNS-LCH disease is unknown and the natural history is poorly understood. Diabetes insipidus (DI) is reported to be the most common and well described manifestation of hypothalamic-pituitary involvement (up to 50%). Anterior pituitary dysfunction has been reported in up to 20% of patients with LCH, and occurs almost exclusively concurrently with DI. In the current paper we describe our experience with 7 patients (6 females and 1 male) in whom hypothalamicpituitary involvement was a major feature of LCH. Diagnosis was made in 4 patients during childhood or adolescence, and 3 patients were over 18 years old at the time of diagnosis. Our series exemplifies the wide spectrum of LCH-induced hypopituitarism, and demonstrates some unique features, including a higher incidence of CRH/ACTH deficiency compared to other reports (4/7 patients), and massive obesity in 2 of our patients. Endocrine function was not improved in any of our patients following medical treatment of LCH with chemotherapy and glucocorticoids. We conclude that pituitary-hypothalamic dysfunction is a common feature of LCH, and therefore all LCH patients should undergo a thorough endocrine evaluation periodically.

The effect of full protective gear on intubation performance by hospital medical personnel.

OBJECTIVE: To assess the influence of protective gear on intubation performance. DESIGN: Prospective, controlled measurement of duration and quality of intubations performed on mannequins by medical personnel with and without protective gear in a crossover design. PARTICIPANTS: Eight teams each comprising an anesthesiologist and a nurse. RESULTS: Intubation duration with and without chemical warfare gear was 69.2 +/- 7 and 47.3 +/- 6 seconds (mean +/- SEM), respectively (p < 0.05). Moreover, rating of intubation quality as "very good" by the anesthesiologists declined significantly from 62.5% without chemical warfare protective gear to 6.25% with the garment and mask. Tube fixation was the rate-limiting step when performed with protective gear (p < 0.05); it was assessed by 81% of the anesthesiologists as the critical step. A learning curve was not observed during the study. CONCLUSION: Protective gear causes a significant prolongation of intubation duration; however, endotracheal intubation can be performed effectively. Technical improvements are warranted for tube fixation because it is the critical step.

Attempt to prevent the development of diabetes in non-obese diabetic mice by oral vanadate administration.

BACKGROUND: Despite current treatment protocols, the long-term complications of insulin-dependent diabetes mellitus have prompted the investigation of strategies for the prevention of IDDM. OBJECTIVES: To investigate the effect of oral vanadate in reducing diabetes type I in non-obese diabetic mice. METHODS: Sodium metavanadate, 3.92 mmol/L, was added to the drinking water of 8-week-old female NOD mice. Blood glucose levels, water consumption and body weight were measured, and the end point of the study was judged by the appearance of hyperglycemia in the mice. RESULTS: Treatment with vanadate did not significantly reduce the incidence of type I diabetes as compared to the control group. However, oral vanadate therapy significantly reduced the blood glucose levels after the fourth week of treatment compared to the control group (3.83 +/- 0.67 vs. 4.44 +/- 0.83 mmol/L, P < 0.03). There was a consistent and significant increase in body weight of the vanadate-treated pre-diabetic NOD mice compared to the controls. Diabetic mice treated with vanadate had significantly lower levels of serum insulin as compared to control diabetic mice (104 +/- 27 vs. 151 +/- 36 mumol/L, P < 0.03). Histologically, no significant differences were found in inflammatory response of the islets of Langerhans between the control and treated groups. CONCLUSIONS: This study suggests that the post-receptor insulin-like effect induced by vanadate is not sufficient to prevent the development of diabetes and insulitis in pre-diabetic NOD mice.

Gluconeogenesis in non-obese diabetic (NOD) mice: in vivo effects of vandadate treatment on hepatic glucose-6-phoshatase and phosphoenolpyruvate carboxykinase.

The contribution of gluconeogenesis to hyperglycemia in non-obese diabetic (NOD) mice has been investigated using oral vanadate administration. Vanadate compounds have been shown to mimic many actions of insulin; however, the exact mechanism is poorly understood. The aims of the present study were (1) to elucidate vanadate's action in vivo, and to assess the possibility that its glucose-reducing effect is dependent on the presence of a minimal concentration of insulin; and (2) to evaluate the effects of vanadate administration on the key hepatic gluconeogenesis enzymes, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), as well as glucose-6-phosphate dehydrogenase (G-6-PDH). Vanadate caused a significant reduction in blood glucose but failed to normalize it, despite effective serum vanadate concentrations (26.2 +/- 1.6 micromol/L). Two weeks after initiation of treatment, blood glucose levels were 26.0 +/- 1.8, 21.7 +/- 3.0, 16.0 +/- 1.6, and 14.3 +/- 2.3 mmol/L in the control (C), insulin (I), vanadate (V), and combined vanadate and insulin (V + I) groups, respectively (P < .001). G-6-Pase activity was significantly reduced by vanadate (622 +/- 134 v365 +/- 83 nmol/min/mg protein in C vV, P < .05). PEPCK activity was also significantly reduced (844 +/- 370, 623 +/- 36, 337 +/- 43, and 317 +/- 75 nmol/min/mg in the C, I, V, and V + I groups, respectively, P < .001). No significant differences in the hepatic glycogen stores and G-6-PDH activity were noted between treatment groups. Our study suggests that the inhibition of hepatic G-6-Pase and PEPCK activity by vanadate plays an important role in reducing blood glucose levels in NOD mice.

Topical iodine-containing antiseptics and subclinical hypothyroidism in preterm infants.

The influence of topical iodine-containing antiseptics on thyroid function test results of premature infants was determined in two separate studies. Thyroxine and thyrotropin levels were measured on blood-spotted filter paper. Samples were obtained from 128 premature infants on their tenth day of life; the infants were treated in two neonatal intensive care units. Both units used similar treatment protocols; however, one routinely used topical iodinated antiseptic agents (n = 73), whereas the other used chlorhexidine-containing antiseptics (n = 55). There was no difference in the mean T4 levels between the two groups. The mean thyrotropin levels were elevated in preterm babies exposed to iodine (15.4 vs 7.8 mIU/L, p < 0.01). Among the iodine-exposed infants, elevated thyrotropin levels (> 30 mIU/L) were found in 13.7% of infants, compared with none in the chlorhexidine-treated group (p < 0.01). We then studied an additional 46 premature infants who were treated in one neonatal intensive care unit. Iodine-containing solutions were used in 24 infants and chlorhexidine was used in 22 infants. T4 and thyrotropin levels were measured weekly during the first 28 days, one every 2 weeks until the age of 60 days, and at the age of 90 days. Among iodine-exposed infants, 20.8% had thyrotropin values > 30 mIU/L, whereas none of the infants in the chlorhexidine group had elevated thyrotropin values (p < 0.05). The elevated thyrotropin levels correlated positively with the area of disinfection. Elevated urine iodine levels were present reflecting an abnormally high iodine absorption. This study suggests that iodine absorption from topical iodine-containing antiseptics may cause disturbances in thyroid function test results in premature infants. We recommend that caution be exercised in the use of iodine-containing antiseptics in premature infants.

Assessment of endocrine functions in children following severe head trauma.

The goal of the present study was to assess endocrine functions in children following severe head trauma. Subjects included 21 children between the ages of 3 years and 18 years 6 months, referred to the Pediatric Rehabilitation Unit at Sheba Medical Center, Israel, between 1984 and 1995. Each was examined 4 months to 11 years following the first admission, undergoing a complete physical examination, including neurologic assessment, biochemical and baseline endocrine profiles, and bone age determination. A GnRH stimulation test was performed in prepubescent children who had advanced bone age. Sixteen children had experienced the head trauma before, or at onset of puberty, according to their chronologic ages. Two children had completed puberty before the head trauma. A 12-year-old male who sustained head trauma at 10 years 6 months of age was found to have Tanner grade 3 pubertal stage and advanced bone age. In addition, 3 prepubescent children also had advanced bone age with no other signs of precocious puberty and a normal GnRH test. For all children studied, the biochemical and hormonal laboratory measurements were in the normal range. Endocrine abnormalities were not found in children examined 4 months or more following severe head trauma. We conclude that clinical monitoring of endocrine status after severe head trauma is sufficient; specific hormonal measurements are not required unless warranted by abnormal physical signs.

Insulin-like actions of vanadate are mediated in an insulin-receptor-independent manner via non-receptor protein tyrosine kinases and protein phosphotyrosine phosphatases.

Most or all mammalian cells contain vanadium at a concentration of 0.1-1.0 microM. The bulk of the vanadium in cells is probably in the reduced vanadyl (IV) form. Although this element is essential and should be present in the diet in minute quantities, no known physiological role for vanadium has been found thus far. In the years 1975-1980 the vanadate ion was shown to act as an efficient inhibitor of Na+,K(+)-ATPase and of other related phosphohydrolyzes as well. In 1980 it was observed that vanadate vanadyl, when added to intact rat adipocytes, mimics the biological actions of insulin in stimulating hexose uptake and glucose oxidation. This initiated a long, currently active, field of research among basic scientists and diabetologists. Several of the aspects studied are reviewed here.

Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway.

Protein-tyrosine phosphatases (PTPases) have been postulated to balance the steady-state phosphorylation and the activation state of the insulin receptor and its substrate proteins. To explore whether PTP1B, a widely expressed, non-receptor-type PTPase, regulates insulin signaling, we used osmotic shock to load rat KRC-7 hepatoma cells with affinity-purified neutralizing antibodies that immunoprecipitate and inactivate the enzymatic activity of recombinant rat PTP1B in vitro. In cells loaded with PTP1B antibody, insulin-stimulated DNA synthesis and phosphatidylinositol 3'-kinase activity were increased by 42% and 38%, respectively, compared with control cells loaded with preimmune IgG (p < 0.005). In order to characterize the potential site(s) of action of PTP1B in insulin signaling, we also determined that insulin-stimulated receptor autophosphorylation and insulin receptor substrate 1 tyrosine phosphorylation were increased 2.2- and 2.0-fold, respectively, and that insulin-stimulated receptor kinase activity toward an exogenous peptide substrate was increased by 57% in the PTP1B antibody-loaded cells. Osmotic loading did not alter the cellular content of PTP1B protein, suggesting that the antibody acts in the cell by sterically blocking catalytic interactions between PTP1B and its physiological substrates. These studies demonstrate that PTP1B has a role in the negative regulation of insulin signaling and acts, at least in part, directly at the level of the insulin receptor. These results also show that insulin signaling can be enhanced by the inhibition of specific PTPases, a maneuver that has potential clinical relevance in the treatment of insulin resistance and Type II diabetes mellitus.

Vanadate normalizes hyperglycemia and phosphoenolpyruvate carboxykinase mRNA levels in ob/ob mice.

Oral vanadate administration has been demonstrated to normalize blood glucose levels in ob/ob and db/db mice and streptozotocin (STZ) diabetic rats. The exact mechanism of this vanadate effect is uncertain, since there are no consistent effects on the insulin receptor tyrosine kinase activity or phosphotyrosine phosphatase activity. We have therefore studied the postreceptor actions of vanadate, focusing our attention on the steady-state levels of mRNA of enzymes involved in carbohydrate metabolism. When compared with their lean (ob/+) controls, the livers of ob/ob mice exhibited an approximately 90% reduction in the levels of phosphoenolpyruvate carboxykinase (PEPCK) mRNA and twofold to fivefold higher levels of the mRNAs for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the "liver beta-cell" glucose transporter (GLUT2), and the proto-oncogene c-myc. Administration of sodium vanadate (0.25 mg/mL) in the drinking water of ob/ob mice over a 45-day period resulted in a near normalization of blood glucose and increased PEPCK mRNA levels more than ninefold. Starvation of the ob/ob mice for 24 to 48 hours also increased PEPCK mRNA levels by fourfold to 15-fold. Vanadate treatment did not alter mRNA levels of any other proteins studied and had no effect on PEPCK mRNA in ob/+ mice. However, 1 to 100 mumol/L vanadate produced a concentration-dependent increase in PEPCK mRNA levels in an H35 hepatoma cell line, an effect opposite to the suppression of PEPCK mRNA produced by insulin. In summary, hyperglycemia in the ob/ob mouse is characterized by decreased expression of PEPCK and increased expression of GAPDH mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin differentially regulates protein phosphotyrosine phosphatase activity in rat hepatoma cells.

We have studied the effect of insulin stimulation on phosphotyrosine phosphatase (PTPase) activity in the well-differentiated rat hepatoma cell line Fao. PTPase activity was measured using a 32P-labeled peptide corresponding to the major site of insulin receptor autophosphorylation. Of the PTPase activity in Fao cells, 14% was in the cytosolic fraction, whereas 86% was in the particulate fraction; this latter fraction also had a 4-fold higher specific activity. Purification of the particulate fraction by lectin chromatography resulted in a 50% increase in specific activity, although this glycoprotein-rich fraction contained only 1.5% of the total activity. Both the cytosolic and particulate PTPase fractions were active toward the tyrosyl-phosphorylated insulin receptor in vitro. The activity of the particulate fraction but not the cytosolic fraction was inhibited by addition of a micromolar concentration of a phosphorylated peptide corresponding to residues 1142-1153 of the human insulin receptor sequence. By contrast, addition of the nonphosphorylated peptide even at millimolar concentration was without effect. Both PTPase fractions were inhibited by Zn+ at similar concentrations, whereas the cytosolic PTPase activity was 10-fold more sensitive to vanadate inhibition. Treatment of cells with 100 nM insulin increased PTPase activity in the particulate fraction by 40% and decreased activity in the cytosolic fraction by 35%. These effects occurred within 15 min and were half-maximal at 3-4 nM insulin. When assessed as total activity, the magnitude of the changes in PTPase activity in the particulate and cytosolic fractions could not be explained on the basis of a translocation of PTPases between the two pools.(ABSTRACT TRUNCATED AT 250 WORDS)

Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus.

We have studied the effects of oral administration of vanadate, an insulinometic agent and a potent inhibitor of phosphotyrosyl protein phosphatase (PTPase) in vitro, on blood glucose and PTPase action, in two hyperinsulinemic rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of vanadate (0.25 mg/ml in the drinking water) to ob/ob mice for 3 wk lowered blood glucose level from 236 +/- 4 to 143 +/- 2 mg/dl without effect on body weight. Administration of vanadate to db/db mice produced a similar effect. Electron microscopic examination revealed no signs of hepatotoxicity after 47 d of treatment. There was a slight reduction in insulin receptor autophosphorylation when tested by immunoblotting with antiphosphotyrosine antibody after in vivo stimulation, and the phosphorylation of the endogenous substrate of the insulin receptor, pp185, was markedly decreased in the ob/ob mice. Both cytosolic and particulate PTPase activities in liver of ob/ob mice measured by dephosphorylation of a 32P-labeled peptide corresponding to the major site of insulin receptor autophosphorylation were decreased by approximately 50% (P less than 0.01). In db/db diabetic mice, PTPase activity in the cytosolic fraction was decreased to 53% of control values (P less than 0.02) with no significant difference in the particulate PTPase activity. Treatment with vanadate did not alter hepatic PTPase activity as assayed in vitro, or receptor and substrate phosphorylation as assayed in vivo, in ob/ob mice despite its substantial effect on blood glucose. These data indicate that vanadate is an effective oral hypoglycemic treatment in NIDDM states and suggest that its major effects occurs distal to the insulin receptor tyrosine kinase.