Sonia Brichard

Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome.

Obesity plays a causative role in the pathogenesis of the metabolic syndrome. Adipokines may link obesity to its co-morbidities. Most adipokines with pro-inflammatory properties are overproduced with increasing adiposity, while some adipokines with anti-inflammatory or insulin-sensitizing properties, like adiponectin are decreased. This dysregulation of adipokine production may promote obesity-linked metabolic disorders and cardiovascular disease. Besides considering adipokines, this review will also highlight the cellular key players and molecular mechanisms involved in adipose inflammation. Targeting the changes in the cellular composition of adipose tissue, the underlying molecular mechanisms, and the altered production of adipokines may have therapeutic potential in the management of the metabolic syndrome.

The role of vanadium in the management of diabetes.

Diabetes mellitus results from an absolute or relative deficiency in insulin secretion and a resistance of target tissues to the action of insulin, in proportions that vary with the type of the disease. The shortage of insulin can be corrected by administration of exogenous insulin or stimulation of pancreatic beta-cells with sulphonylureas. However, insulin resistance remains a major therapeutic problem. Here, Sonia Brichard and Jean-Claude Henquin review the recent discoveries that indicate a possible role for vanadium in management of the disease. In vitro, vanadium salts mimic most effects of insulin on the main target tissues of the hormone, and in vivo they induce a sustained fall in blood glucose levels in insulin-deficient diabetic rats, and improve glucose homeostasis in obese, insulin-resistant diabetic rodents. Recent short-term clinical trials with vanadium salts also seem promising in type II (non-insulin-dependent) diabetic patients in whom liver and peripheral insulin resistance was attenuated, indicating the therapeutic potential of vanadium salts, pending demonstration of their long-term innocuity.

Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats.

Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non‐ketotic, streptozotocin‐diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3‐ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied. Oral administration of the three organic vanadium compounds (125 mg vanadium element l−1 in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly. Activities and mRNA levels of key glycolytic enzymes (glucokinase and L‐type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc. VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin‐like properties. There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds. In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin‐like properties.

Pre- and post-translational negative effect of beta-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies.

The adipose-derived hormone, adiponectin (ApN), has a role in fuel homoeostasis, insulin action and atherosclerosis. Regulation of ApN by catecholamines has scarcely been investigated. We examined the effects of beta-adrenergic agonists (and their second messenger, cAMP) on ApN gene expression, production and secretion in mouse in vitro and in vivo; their effects in human fat were also briefly studied in vitro. beta-Adrenergic agonists and cAMP inhibited ApN gene expression in human visceral adipose tissue. Likewise, cAMP down-regulated ApN mRNAs in cultured mouse explants from visceral and subcutaneous regions. The amount of ApN released into the medium decreased concomitantly. cAMP also caused qualitative changes in ApN secretion. Under basal conditions, ApN was secreted as a single 32 kDa species. In the presence of cAMP, an additional and probably immature (not modified post-translationally) 30 kDa species was also sorted. This altered secretion resulted from cAMP-induced quantitative and qualitative changes of ApN within the adipocyte. Under basal conditions, the 32 kDa form of ApN was mainly associated with high-density microsomes (HDMs), while the 30 kDa species was confined to a pool recovered with the cytosol fraction. cAMP depleted intracellular ApN at the expense of both HDM and cytosol fractions, and abnormally targeted ApN species to the different subcellular compartments as a result of impaired maturation. beta-Adrenergic agonists mimicked the inhibitory effects of cAMP on ApN mRNA and secretion, the beta(3)-agonist BRL37344 being the most potent. Administration of BRL37344 to mice reduced ApN mRNAs in both adipose regions, and ApN levels in plasma. In conclusion, beta-agonists inhibited ApN production and maturation, and thus exerted a dual (pre- and post-translational) negative effect on ApN secretion by cultured mouse adipose explants. ApN inhibition by beta-agonists was reproduced in mouse in vivo and in humans in vitro. ApN down-regulation may have an important role in fuel homoeostasis, insulin resistance and stress-induced atherosclerosis.

Diet- and diabetes-induced changes of ob gene expression in rat adipose tissue

ob gene regulation is as yet unknown. We first examined whether the ob gene is under physiological control by the nutritional state. Fasting produced a sharp (95%) decrease of ob mRNA in epididymal and inguinal fat pads from 24 h onward. Refeeding rapidly (3–6 h) re‐induced ob gene expression and corrected it within 24 h. Similar changes in fatty acid synthase (FAS) and GLUT4 mRNAs were observed, whereas phosphoenolpyruvate car☐ykinase (PEPCK) mRNA showed an opposite evolution. We next examined the potential role of insulin. In adipose tissue of streptozotocin‐diabetic rats, ob mRNA levels were decreased by 80%. Insulin treatment (4 days) only marginally increased ob mRNA, but restored euglycemia and overcorrected FAS, GLUT4 and PEPCK expression. In conclusion, we provide evidence for a physiological regulation of ob gene by variations in the nutritional state. We also show that ob expression is impaired in streptozotocin‐diabetic rats and only slightly restored by insulin treatment, which suggests that ob gene is not or only minimally regulated by the hormone.

Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats.

SummarySelenium is a trace element that exerts certain insulin-like actions in vitro. In this study, we evaluated its in vivo effects on the glucose homeostasis of rats made diabetic and insulin-deficient by streptozotocin. Na2SeO4 was administered ad libitum in drinking water and/or food for 10 weeks. The elevated plasma glucose levels (~ 25 mmol/l) and glucosuria (~ 85 mmol/day) of untreated rats were decreased by 50 and 80%, respectively, by selenate treatment. The beneficial effect of selenate was also evident during oral and intravenous glucose tolerance tests: the integrated glucose responses were decreased by 40–50% as compared to those in untreated rats. These effects were not due to an increase in plasma insulin levels. Compared to non-diabetic rats, pancreatic insulin reserves were reduced by more than 90% in treated and untreated diabetic rats. The hepatic activities and mRNA levels of two key glycolytic enzymes, glucokinase and l-type pyruvate kinase were blunted in diabetic rats. They increased ~ two- to threefold after selenate treatment, to reach 40–75% of the values in non-diabetic rats. In contrast, elevated activity and mRNA levels of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, were reduced by 40–65% after selenate administration. Since selenate induced a moderate decrease in body weight due to an anorexigenic effect, we checked that there was no improvement of glucose homeostasis or hepatic glucose metabolism in an additional group of calorie-restricted diabetic rats, which was weight-matched with the selenate group. In addition, no obvious toxic side-effects on the kidney or liver were observed in the rats receiving selenate. In conclusion, selenate induces a sustained improvement of glucose homeostasis in streptozotocin-diabetic rats by an insulin-like action, which involves partial correction of altered pretranslational regulatory mechanisms in liver metabolism.

Hyperadiponectinaemia in anorexia nervosa.

objective Adiponectin (ApN) is a fat‐derived hormone that enhances insulin sensitivity, controls body weight, prevents atherosclerosis and negatively regulates haematopoiesis and immune functions. In contrast to many proteins secreted by adipose tissue, the circulating level of ApN falls in obesity and insulin resistance states. The influence of starvation‐induced depletion of fat stores on ApN concentrations is yet unknown. We therefore investigated plasma ApN in anorexia nervosa (AN).

Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate.

The trace element vanadium exerts insulinlike effects in vitro and decreases hyperglycemia in insulindeficient animals. This study examined whether vanadate can improve glucose homeostasis in genetically obese hyperglycemic insulin-resistant ob/ob mice, which present metabolic abnormalities similar to those of human non-insulin-dependent diabetes. Sodium orthovanadate (0.3 mg/ml) was administered for 7 wk in H2O. Vanadate treatment induced a fall in fed and fasted plasma glucose and insulin levels and improved tolerance to oral glucose; the stimulated glucose area was decreased by 65%, and an early peak of insulin secretion was restored. During an intravenous glucose tolerance test, the glucose disappearance rate was twofold higher in vanadate-treated mice, and the reappearance of a significant insulin response was also observed. Moreover, vanadate produced a twofold increase in hepatic glycogen content and prevented the exhaustion of pancreatic insulin stores. The hypoglycemic response to exogenous insulin was similar in control and treated mice. In vitro experiments showed that basal glucose oxidation by hemidiaphragms was 32% higher in vanadate-treated mice than in controls, although stimulation by insulin was similar in both groups. In conclusion, oral vanadate caused a marked and sustained improvement of glucose homeostasis in diabetic insulin-resistant mice by exerting an insulinlike effect on peripheral tissues and apparently preventing the exhaustion of pancreatic insulin stores.

In-vivo Effects of Hyperinsulinemia On Lipogenic Enzymes and Glucose-transporter Expression in Rat-liver and Adipose Tissues

Chronic hyperinsulinemia with maintenance of euglycemia was imposed on normal rats for 4 days. In white adipose tissue, hyperinsulinemia resulted in a twofold increase in GLUT4 protein and mRNA and a sixfold to 15-fold increase in fatty acid synthase (FAS) and acetyl coenzyme A (CoA) carboxylase (ACC) activity, respectively. Lipogenic enzyme mRNA was also markedly increased (20- to 30-fold). This was specific for white adipose tissue and was not observed in brown adipose tissue. In the liver, hyperinsulinemia was accompanied by a threefold increase in glucokinase (GK) activity and mRNA and by a threefold to fivefold increase in lipogenic enzyme activities and mRNA. In agreement with the changes in lipogenic activities, lipogenesis was markedly increased in white adipose tissue and liver of hyperinsulinemic rats. The data strongly suggest that in the rat, insulin is a driving force leading to increased lipid synthesis in liver and white adipose tissue.

Repercussions of chronic protein-calorie malnutrition on glucose homeostasis in the rat

SummaryThe characteristics, progressivity and reversibility of the changes in glucose homeostasis brought about by chronic protein-calorie malnutrition were studied in the rat. Four-week-old male rats received a control diet (15% protein) or a low-protein diet (5% protein) until the age of 28 weeks. Other rats received the low-protein diet until 12–15 weeks, and then the control diet. In malnourished rats, fasting plasma glucose levels and both fasting and fed plasma insulin levels were lower than in control rats. At the age of 15 weeks, tolerance to oral glucose was slightly poorer, whereas tolerance to intravenous glucose was slightly better in rats receiving the low-protein diet than in control rats. During both tests the insulin response of malnourished rats was severely blunted. This inhibition largely exceeded the small decrease in their pancreatic insulin reserves. Similar results were obtained when the same test was repeated 9 weeks later. If the rats were transferred from a low-protein to a control diet for these 9 weeks, the changes in glucose tolerance were partially corrected, but the insulin response remained inhibited. Though hepatic glycogen stores were increased in malnourished rats, i. v. glucagon or arginine caused a smaller rise in plasma glucose levels than in control rats. The insulin response was also impaired and, unlike the glucose response, was not restored by 6 weeks on a control diet. The hypoglycaemia induced by intravenous insulin was more sustained in malnourished than in control rats, but this abnormality was corrected by refeeding a control diet for 6 weeks. The results thus show that chronic protein-calorie malnutrition in the rat severely impairs insulin secretion, but only mildly alters glucose tolerance, likely because of an associated high sensitivity to insulin. These changes do not aggravate with time and are only partially reversed by several weeks on a control diet.