GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice.

OBJECTIVE: In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism. EXPERIMENTAL APPROACH: The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined. RESULTS: CNTO3649 and exendin-4 reduced fasting plasma glucose (up to -30% and -28% respectively) and insulin (-43% and -65% respectively). In addition, these agents reduced VLDL-TG production (-36% and -54% respectively) and VLDL-apoB production (-36% and -43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (-39% and -55% respectively), cholesterol (-30% and -55% respectively), and phospholipids (-23% and -36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob). CONCLUSION: GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Delayed onset of the diurnal melatonin rise in patients with Huntington's disease.

Sleep disturbances are very prevalent in Huntington's disease (HD) patients and can substantially impair their quality of life. Accumulating evidence suggests considerable dysfunction of the hypothalamic suprachiasmatic nucleus (SCN), the biological clock, in both HD patients and transgenic mouse models of the disease. As melatonin has a major role in the regulation of sleep and other cyclical bodily activities and its synthesis is directly regulated by the SCN, we postulated that disturbed SCN function is likely to give rise to abnormal melatonin secretion in HD. Therefore, we compared 24 h melatonin secretion profiles between early stage HD patients and age-, sex- and body mass index-matched controls. Although mean diurnal melatonin levels were not different between the two groups (p = 0.691), the timing of the evening rise in melatonin levels was significantly delayed by more than 01:30 h in HD patients (p = 0.048). Moreover, diurnal melatonin levels strongly correlated with both motor (r = -0.70, p = 0.036) and functional impairment (r = +0.78, p = 0.013). These findings suggest a delayed sleep phase syndrome-like circadian rhythm disorder in early stage HD patients and suggest that melatonin levels may progressively decline with advancing disease.

CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice.

CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimetibody platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet-induced insulin-resistant C57BL/6 mice received a single intraperitoneal injection of CNTO736 or vehicle. Chronic effects were studied after 4 weeks of daily intraperitoneal administration. A hyperinsulinemic-euglycemic clamp monitored insulin sensitivity. A single dose of CNTO736 reduced fasting plasma glucose levels (CNTO736, 4.4 +/- 1.0; control, 6.3 +/- 2.4 mM) and endogenous glucose production (EGP) (CNTO736, 39 +/- 11; control, 53 +/- 13 micromol/min/kg) and increased insulin-mediated glucose uptake (CNTO736, 76 +/- 25; control, 54 +/- 13 micromol/min/kg). Chronic administration of CNTO736 reduced fasting glucose levels (CNTO736, 4.1 +/- 0.8; control 6.0 +/- 1.0 mM), improved insulin-dependent glucose uptake (CNTO736, 84 +/- 19; control, 61 +/- 15 micromol/min/kg), and enhanced inhibition of EGP (CNTO736, 91 +/- 18; control, 80 +/- 10% inhibition). In addition, chronic dosing with CNTO736 reduced fasting EGP (CNTO736, 39 +/- 9; control, 50 +/- 8 micromol/min/kg) and VLDL production (CNTO736, 157 +/- 23; control, 216 +/- 36 micromol/h/kg). These results indicate that CNTO736 reinforces insulin's action on glucose disposal and production in diet-induced insulin-resistant mice. In addition, CNTO736 reduces basal hepatic glucose and VLDL output in these animals. The data suggest that CNTO736 may be a useful tool in the treatment of type 2 diabetes.

Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation.

OBJECTIVE: We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The downstream mechanisms responsible for these effects of NPY remain to be elucidated. Therefore, the aim of this study was to establish whether intracerebroventricular NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation. RESEARCH DESIGN AND METHODS: The effects of a continuous intracerebroventricular infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemic-euglycemic clamp. Either rats were sham operated, or the liver was sympathetically (hepatic sympathectomy) or parasympathetically (hepatic parasympathectomy) denervated. RESULTS: Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroventricular vehicle-infused animals (50 +/- 8 vs. 49 +/- 6 vs. 55 +/- 6%, in hepatic sympathectomy vs. hepatic parasympathectomy vs. sham, respectively). Intracerebroventricular infusion of NPY significantly hampered the suppression of EGP by insulin in sham-denervated animals (29 +/- 9 vs. 55 +/- 6% for NPY/sham vs. vehicle/sham, respectively, P = 0.038). Selective sympathetic denervation of the liver completely blocked the effect of intracerebroventricular NPY administration on insulin action to suppress EGP (NPY/hepatic sympathectomy, 57 +/- 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 +/- 7%). CONCLUSIONS: Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.

Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet.

We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 +/- 460, P < 0.01; 2.5 nmol, 1,828 +/- 684, P < 0.01; 0.75 nmol, 2,322 +/- 303, P < 0.05; control: 2,790 +/- 222 mmol.l(-1).120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 +/- 14.7 vs. 39.9 +/- 5.7 micromol.min(-1).kg(-1), P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 +/- 2.8 vs. 4.4 +/- 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 +/- 30.8 vs. 38.8 +/- 26.4 microl/h, P < 0.001) and glucose disposal (88.1 +/- 13.0 vs. 45.2 +/- 6.9 micromol.min(-1).kg(-1), P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 +/- 15.5 vs. 15.8 +/- 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action.

Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high-fat feeding in mice.

Several studies have demonstrated an association in humans between plasma levels or production capacity of the antiinflammatory cytokine IL-10 and insulin sensitivity. The aim of our study was to investigate the protective role of endogenous IL-10 availability in the development of diet-induced insulin resistance. We compared parameters of glucose and lipid metabolism between IL-10(-/-) mice and wild-type (wt) mice fed a high-fat diet for 6 wk. This diet has previously been shown to induce steatosis and insulin resistance. After 6 wk on the high-fat diet, no differences in body weight, basal metabolism (measured by indirect calorimetry), or plasma levels of glucose, triglycerides, or cholesterol were observed between IL-10(-/-) and wt mice. Nonetheless, in IL-10(-/-) mice, plasma free fatty acid levels were 75% increased compared with wt mice after overnight fasting (P < 0.05). In addition, hepatic triglyceride content was 54% increased in IL-10(-/-) mice (P < 0.05). During a hyperinsulinemic euglycemic clamp, no differences were observed in whole-body or hepatic insulin sensitivity between both groups. We conclude that basal IL-10 production protects against hepatic steatosis but does not improve hepatic or whole-body insulin sensitivity, during high-fat feeding.

Differential effects of natural flavonoids on growth and iodide content in a human Na*/I- symporter-transfected follicular thyroid carcinoma cell line.

OBJECTIVE: Natural flavonoids (plant pigments) have been shown to inhibit thyroid peroxidase (TPO) in vitro and the growth of thyroid cancer cell lines. We have studied the role of flavonoids on the iodide transport and the growth of the human follicular thyroid cancer cell line (FTC133) which was stably transfected with the human Na(+)/I(-) symporter (hNIS). DESIGN AND METHODS: Cells were treated with flavonoids (0.5-50 microM) for 0, 2, 4 and 6 days; (125)I content and (125)I efflux of the cells and DNA content were measured. RESULTS: Cell growth was inhibited significantly at day 6 by most flavonoids. Eight out of ten flavonoids decreased the (125)I content of the cells at day 4. Morin did not influence the (125)I content of the cells and, surprisingly, myricetin increased the (125)I content of the cells. Kaempferol, apigenin, luteolin and F21388 decreased NIS mRNA expression after 15, 29 and 48 h; after 96 h NIS mRNA returned to normal. CONCLUSION: As TPO is not present in this cell line, the effects of the flavonoids on the iodide uptake are not related to organification. Myricetin was the only flavonoid studied that increased the influx and decreased the efflux of iodide. The effect of myricetin (decreased growth and increased retention of iodide) can be of therapeutic value in the radioiodide treatment of thyroid carcinoma.

Flavonoids and thyroid disease.

UNLABELLED: The most potent natural plant-derived compounds that can affect thyroid function, thyroid hormone secretion and availability to tissues is the group of flavonoids, i.e. plant pigments. They are present in our daily food, such as vegetables, fruits, grains, nuts, wine, and tea. Epidemiological studies suggest beneficial effects on health of flavonoids, which are commonly attributed to their activity as antioxidants. Experimental studies in vitro, however, showed inhibition of organification in thyroid cells and follicles by several flavonoids. Studies in vivo and vitro with synthetic and natural flavonoids showed displacement of T4 from transthyretin leading to disturbances in thyroid hormone availability in tissues. Radioactive labeled flavonoids appeared to be eliminated rapidly from the body mainly through excretion in the feces. In pregnant rats synthetic flavonoids cross the placenta and accumulate in the fetal compartment, including the fetal brain. Therefore, a high intake of flavonoids is contraindicated. IN CONCLUSION: flavonoids show strong interference with many aspects of thyroid hormone synthesis and availability.

Dietary flavonoids and iodine metabolism.

Flavonoids have inhibiting effects on the proliferation of cancer cells, including thyroidal ones. In the treatment of thyroid cancer the uptake of iodide is essential. Flavonoids are known to interfere with iodide organification in vitro, and to cause goiter. The influence of flavonoids on iodine metabolism was studied in a human thyroid cancer cell line (FTC-133) transfected with the human sodium/iodide transporter (NIS). All flavonoids inhibited growth, and iodide uptake was decreased in most cells. NIS mRNA expression was affected during the early hours after treatment, indicating that these flavonoids can act on NIS. Pendrin mRNA expression did not change after treatment. Only myricetin increased iodide uptake. Apeginin, luteolin, kaempferol and F21388 increased the efflux of iodide, leading to a decreased retention of iodide. Instead myricetin increased the retention of iodide; this could be of use in the radioiodide treatment of thyroid cancer.

Iodide kinetics and experimental (131)I therapy in a xenotransplanted human sodium-iodide symporter-transfected human follicular thyroid carcinoma cell line.

Uptake of iodide is a prerequisite for radioiodide therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium-iodide symporter (hNIS). We studied whether transfection of hNIS into the hNIS-deficient follicular thyroid carcinoma cell line FTC133 restores the in vivo iodide accumulation in xenografted tumors and their susceptibility to radioiodide therapy. In addition, the effects of low-iodide diets and thyroid ablation on iodide kinetics were investigated. Tumors were established in nude mice injected with the hNIS-transfected cell line FTC133-NIS30 and the empty vector transfected cell line FTC133-V4 as a control. Tumors derived from FTC133-NIS30 in mice on a normal diet revealed a high peak iodide accumulation (17.4% of administered activity, measured with an external probe) as compared with FTC133-V4 (4.6%). Half-life in FTC133-NIS30 tumors was 3.8 h. In mice kept on a low-iodide diet, peak activity in FTC133-NIS30 tumors was diminished (8.1%), whereas thyroid iodide accumulation was increased. In thyroid-ablated mice kept on a low-iodide diet, half-life of radioiodide was increased considerably (26.3 h), leading to a much higher area under the time-radioactivity curve than in FTC133-NIS30 tumors in mice on a normal diet without thyroid ablation. Experimental radioiodide therapy with 2 mCi (74 MBq) in thyroid-ablated nude mice, kept on a low-iodide diet, postponed tumor development (4 wk after therapy, one of seven animals revealed tumor vs. five of six animals without therapy). However, 9 wk after therapy, tumors had developed in four of the seven animals. The calculated tumor dose was 32.2 Gy. We conclude that hNIS transfection into a hNIS-defective thyroid carcinoma cell line restores the in vivo iodide accumulation. The unfavorable iodide kinetic characteristics (short half-life) can be partially improved by conventional conditioning with thyroid ablation and low-iodide diet, leading to postponed tumor development after radioiodide therapy. However, to achieve sufficient radioiodide tumor doses for therapy, further strategies are necessary, aiming at the mechanisms of iodide efflux in particular.

Low grade supratentorial astrocytomas. Management and prognostic factors.

BACKGROUND: The authors examined the principal prognostic factors for supratentorial low grade astrocytomas and the effects of treatment on survival time. METHODS: Fifty-eight patients, 32 males and 26 females, treated from January 1970 through December 1990 are reported. Thirty-five patients underwent surgery, of whom three died. Among the survivors there were 7 gross total resections, 13 subtotal resections, and 12 partial resections. Of the 23 remaining patients, diagnosis was obtained by stereotactic biopsy. Twenty-five patients were irradiated and eight received chemotherapy. The histologic material, originally graded 1 or 2 according to Kernohan's system, was reviewed using the St. Anne-Mayo Clinic system, with which there were 18 Grade 3 tumors. RESULTS: Six patients had pilocytic astrocytomas (mean age, 18 years), of which three astrocytomas could be removed, and the patients were well 128, 152, and 254 months, respectively, after diagnosis. Among the other three patients, one with a hypothalamic localization refused any form of treatment and died rapidly. The remaining two patients also had deep-seated tumors and were irradiated: one died 17 months later, and the other remained relapse free 56 months after diagnosis. The 49 patients with ordinary astrocytomas who survived surgery (mean age, 37 years) had a median survival time of 64 months and 5- and 10-year survival rates of 54.6% and 34.1%, respectively. Patients with Grade 1 or 2 tumors had a median survival time of 108.6 months, compared with 39.4 months for patients with Grade 3 tumors. Gross total and subtotal resections were significantly associated with longer survival time only in patients with Grade 1 and 2 tumors: in this group, the 5- and 10-year survival rates were 87.5% and 68.2%, respectively, when tumor was completely resected, instead of 57% and 31.2% in patients with incomplete or no surgical resection. There was a trend suggesting that antimitotic drugs and X-ray therapy could benefit patients with Grade 3 tumors. CONCLUSION: The importance of an accurate histologic grading system and a gross total resection of Grade 1 and 2 astrocytomas is emphasized.

[Chronic hydrocephalus in adults]. / L'hydrocéphalie chronique de l'adulte.

The aim of this study is to sum up our current knowledge on the so-called "normal pressure hydrocephalus" syndrome, revisited by the authors as the "adult chronic hydrocephalus" syndrome (A.C.H.). It is based upon 1) a review of the literature dealing with the subject (518 references) and 2) an original series of 243 cases summarizing a 10 year experience of 2 french neurosurgical teams (Lyon: 123 cases, Clermont-Ferrand: 120 cases). Part I is devoted to the review of pathologic and pathophysiologic data. Both autopsy and microscopic findings clearly show 2 categories of anomalies in the brains of patients showing this condition: "non specific" lesions may be either causative (leptomeningeal thickening, villositar sclerosis) or secondary to hydrocephalus (ependymal wall disruption, sub-ependymal "edema"). Conversely, "specific lesions" are either degenerative (Alzheimer-type) or ischemic in origin. They seem unrelated to hydrocephalus, but may play a role in the ventricular enlargement by favoring changes in brain elastic properties. Data available from brain biopsies (13 cases) have confirmed the high incidence of such "specific lesions" of the parenchyma. Following the Hakim's initial hypothesis, several mechanisms have been proposed to explain the progressive ventricular dilation despite a fall in C.S.F. pressure. Experimental and clinical data (namely those referring to the pathogenesis of secondary A.C.H.) are reviewed. The sequence of events following acute ventricular obstruction is analysed. The ultimate state of chronic uncompensated hydrocephalus involve multiple factors among which a trans-cerebral mantle pressure gradient may play a major role. The intervention of compensatory mechanisms (reduction of C.S.F. production, establishment of alternative pathways of C.S.F. absorption) is also discussed. Part II is devoted to the presentation of the clinical material. Series of the literature including more than 20 surgical cases are briefly reviewed together with the authors' material and methods. Criteria of selection of patients, methods of clinical evaluation and of statistical analysis of results are exposed. Of the 243 patients of the present series, 225 were managed by C.S.F. shunt (V.A.: 137, V.P.:60, L.P.:28). Results were as follows (mean follow-up:31 mths +/- 28): good results (including excellent results): 128 (52.6%), fair: 52 (21.3%), poor and aggravated: 49 (20%), early deaths: 14 (5.7%), 12 of those post-operatively. The rate of surgical complications was 35% (S.D.H.: 16.8%, sepsis: 4%, seizures: 4%, shunt malfunction: 10.6%) leading to reoperation in 25.7%. Long-term survival rate was 75% (172 alive patients and 57 late deaths).(ABSTRACT TRUNCATED AT 400 WORDS)

[Ventricular subarachnoidal hydrocephalus of arachnoid villi origin]. / Hydrocéphalie ventriculo sous-arachnoidienne d'origine villositaire.

In 102 infants (0.5 to 22 months), the C.T. scan performed for various neurological symptoms, was systematically reviewed with analysis of ventricular size, pericerebral space and interhemispheric fissure. In 70% of the cases, an increase of the intracranial volume of C.S.F. was noted, with a good correlation between the ventricular and pericerebral volume. The authors discuss the pathophysiological mechanism of this condition an evoke the possibility of an idiopathic disturbance of the C.S.F. reabsorption. In two cases, suffering from severe axial hypotonus, this fact was explored by four methods: continuous monitoring of intracranial pressure, intraventricular infusion test, isotopic cisternography through ventricular injection and venous phase of angiography. From these investigations showing no venous anomaly, and because of the lack of any pathological event able to induce a C.S.F. obstruction, we suggest a delay in the maturation of arachnoïd villi (normally ended at 18 months) to explain this condition.

[Treatment of vasospasm in aneurysmal meningeal hemorrhage using intravenous nimodipine. Multicenter cooperative study]. / Traitement curatif du vasospasme des hémorragies méningées d'origine anévrysmale par la nimodipine intraveineuse. Etude coopérative multicentrique.

We present a multicentric randomized double-blind study of the curative effect of intravenous Nimodipine on the post hemorrhagic vasospasm after aneurysmal rupture. On 122 validated cases out of 188 analyzed patients, the study demonstrates a significative effect on the mortality and severe morbidity related to vasospasm: the reduction of the risk is appreciated to 72%. The major effect is obtained on the mortality risk. A selective effect can be demonstrate on the isolated vasospasm.

Transfer kinetics of pefloxacin into cerebro-spinal fluid after one hour i.v. infusion of 400 mg in man.

Nine subjects (5 women) aged between 17-66 years, with hydrocephalus were studied. An external ventricular drain was introduced for diagnostic purposes. Cerebro-spinal fluid (CSF) and plasma samples were obtained at suitable intervals after 1 h infusion of 400 mg pefloxacin. In plasma, pefloxacin Cmax was 8.54 +/- 1.53 (mean +/- S.E.M.) mg/l, at the end of infusion, whereas N-desmethyl pefloxacin concentration was 0.17 +/- 0.03 mg/l. The metabolite accounted for only 2% of plasma levels of pefloxacin. In CSF, pefloxacin Cmax was 2.97 +/- 0.32 mg/l, 5-6 h after the start of infusion, whereas N-desmethyl pefloxacin Cmax varied between 0.1-0.2 mg/l. Apart from the 1 h sample, the CSF/plasma ratio of pefloxacin was 60% which is similar to the unbound fraction of pefloxacin in plasma. The apparent half-life (T1/2) of transfer of pefloxacin from plasma to CSF was 1.26 +/- 0.18 h, assuming a first order process, while the apparent elimination T1/2 in CSF was 13.40 +/- 1.76 h, which is similar to the elimination T1/2 found previously in plasma, thus accumulation of pefloxacin in CSF is unlikely. With the present dosage regimen, CSF quickly attains therapeutic levels of pefloxacin.

[Prospective trial of treating aneurysmal meningeal hemorrhage by delayed operation under cover of antifibrinolytic therapy]. / Essai prospectif de traitement des hémorragies méningées anévrysmales par intervention différée sous couvert d'un traitement antifibrinolytique.

Seventy patients with subarachnoid haemorrhage due to ruptured intracranial aneurysms were managed by delayed intervention (third week) along with the prescription of antifibrinolytic drugs (tranexamic acid 6 g/daily). During the pre-operative period, 41 patients stayed in the same clinical status as on admission or improved, whereas 29 deteriorated due to rebleeding (4 cases), vasospasm (18 cases), large hematoma (4 cases), hydrocephalus (2 cases) and postarteriographic accident (1 case). Clipping the aneurysm was finally achieved in 42 patients only; with 3 deaths, 3 severe sequellae, 8 light handicaps, and 28 patients considered as cured with returning to previous occupations. As far as the whole series is concerned, these results yield a 38.5% rate of mortality, 20% morbidity, and 41.5% recovery. It is concluded that 1) Tranexamic acid was effective in reducing the risk or rebleeding, 2) Third week delayed intervention associated with this drug significantly reduced the operative mortality, but probably favoured vasospasm, and finally had no beneficial effect on the overall results concerning the entire series of patients.