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J Duhault

Publications and source records attributed to J Duhault.

At least 37 records · Page 2Linked to original sources
PubMed1997

S 15261, a novel agent for the treatment of insulin resistance. Studies on Psammomys obesus. Effect on pancreatic islets of insulin resistant animals.

A histological study has been conducted on pancreata from insulin resistant sand rats treated with S15261. As previously shown, standard laboratory chow induced dietary hyperinsulinaemia, insulin resistance and hyperlipaemia in sand rats (Psammomys obesus). Degranulation, vacuolization and even necrosis of beta-cells were observed in these animals. These changes were often accompanied by fibrosis and lymphocytic infiltration. Insulin and amylin immuno-reactivity of beta-cells was markedly decreased whilst glucagon secreting cells were localized now in the centre of the islets. Chronic treatment with S15261, a compound able to restore insulin sensitivity in insulin resistant animals, promoted the regranulation of the beta-cells and maintained the usual cytoarchitecture and integrity of the islets.

Animals↗
PubMed1995

S15261 antagonises amylin-induced impaired glucose tolerance.

Amylin has been postulated to antagonise or inhibit the action of insulin in peripheral rat tissues and thus contribute to, or be responsible for, the development of insulin resistance. We have recently reported that S15261 is a compound capable of increasing insulin sensitivity in ageing insulin resistant rats. In order to assess whether S15261 had any effects on amylin induced insulin resistance we used a model where amylin causes an impairement in glucose tolerance in an acute manner, by means of an intraportal infusion of the hormone in normal rats. We report here that S15261 can antagonise this amylin-induced impaired glucose tolerance.

Amyloid↗
PubMed1995

Latent autoimmune diabetes mellitus in adult humans with non-insulin-dependent diabetes: is Psammomys obesus a suitable animal model?

Recent data suggest that in a proportion of NIDDM patients there is a slowly evolving insulitis which results in a latent autoimmune diabetes leading to full insulin-dependence. Many animal models exist of NIDDM but none have reported the spontaneous existence of a similar phenomenon. We have re-examined the histology of pancreata from a few Psammomys obesus who had become insulin-dependent in the late stages of NIDDM. We report here the unexpected finding of the presence of insulitis in these animals and suggest that they could be a model for the clinical observation of latent IDDM in NIDDM patients.

Adult↗
PubMed1995

Synthesis of 1,2-diacyl-3-nicotinoyl glycerol derivatives and evaluation of their acute effects on plasma lipids in the rat.

Nicotinic acid (CAS 59-67-6) is the only hypolipidemic agent whose activity has been shown both on atherosclerotic lesions and on long term mortality. Unfortunately, its use is hindered by the frequent occurrence ( > 70%) of adverse reactions (i.e. cutaneous rash, pruritus and, most significantly, flush). New prodrugs of nicotinic acid have been prepared by the use of diacylglycerol esters. In the rat, after acute oral administration of these products, a significant decrease of the free fatty acid plasma levels was obtained without the dramatic increase in nicotinic acid plasma levels observed after the oral administration of an equimolecular dose of nicotinic acid. The most interesting ester, S 16961 ((d,l)-1,2-dipalmitoyl-3-nicotinoyl glycerol, CAS 160555-46-4) is undergoing clinical trials.

Animals↗
PubMed1995

Euglycaemic and biological activities of novel thiazolidine-2,4-dione derivatives.

A new series of thiazolidine-2,4-dione derivatives was obtained by incorporating one or the other of the two carbons of the central chain into different rings. These compounds lower blood glucose levels in the genetically obese and insulin-resistant ob/ob mouse. Moreover, they decreased insulin and triglyceride levels in the Zucker fa/fa rat. Incorporation of the left hand carbon of the chain afforded compounds among which pyrrolidino derivatives 5, 9 and 13 were the most potent. The same carbon atom was used to elaborate different types of rings (benzocyclobutane, benzodioxane), giving rise to compounds 14 and 19 with moderate to good activity. Finally, cyclization using the right hand carbon of the chain gave rise to highly potent benzofurane 24.

Animals↗
PubMed1994

8-OH-DPAT induces a selective increase in protein intake in ageing overweight animals.

We have examined the effects of a 5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) on food preference in ageing rats that had been given a 'palatable' meal 15 min before administration of the drug. Ageing rats consumed a greater amount of the 'palatable' pre-meal than the young rats. In young rats lipids were the predominant source of calories, but in old animals lipid and protein consumption was similar. Administration of 8-OH-DPAT resulted in an increase in total caloric intake in both groups. Concomitant with this there was a significant increase in protein intake in both groups, which was most important in ageing rats, where proteins became the predominant source of calories.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

S15261, a new compound for the treatment of the insulin resistance syndrome.

A new oral agent, S15261 (the L-isomer of 3-[2-[2-[4-[2-[alpha-fluorenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] trifluoromethyl-benzene), has been developed for the treatment of the so-called "insulin resistance syndrome". In obese, insulin-resistant ageing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg.kg-1.day-1 twice per day, for 14 days) resulted in dose-dependent decreases in plasma insulin (43%), and triglyceride levels (36%), and in an increase of the glucose disposal rate during an intravenous glucose tolerance test (IVGTT) (48.5%). An increase in peripheral insulin sensitivity produced by S15261 was revealed by the glucose clamp technique. Thus, the glucose infusion rate was increased by 20% whilst steady-state insulin levels decreased by 15%. At the higher doses S15261 led to a decrease in body weight (3%), plasma glucose (13%) and blood pressure (8 mm Hg) in mildly hypertensive animals. At the doses used to achieve these results, the compound has no hypoglycaemic activity in normoglycaemic animals. Acute administration of S15261 directly into the portal vein provoked a marked increase in glucose disappearance rate during an intravenous glucose tolerance test (60%) and also in the pancreatic response to the glucose challenge. Thus, acute administration of the compound has a direct effect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome.

Animals↗
PubMed1994

Vascular responsiveness in young, diabetic, and aging hyperinsulinemic rats.

The purpose of this study was to compare vascular responsiveness in young (12 week old), aging hyperinsulinemic-glucose intolerant (52 weeks old) and diabetic (streptozotocin; 14 weeks old) rats. Aortic rings with and without endothelium were maintained in organ chambers for isometric tension recording. The contractile response to KCl was significantly enhanced in aortae from diabetic animals when compared to the responses obtained in young and old ones. The contractile response to norepinephrine or U46619, was significantly shifted to the right in the aortae from aging animals, however the aortae from these hyperinsulinemic rats were hyperresponsive to serotonin. Acetylcholine and ADP provoked an endothelium-dependent relaxation which was markedly depressed in the aortae from diabetic animals. The relaxation to ADP was selectively inhibited in the aging animals. The effect of sodium-nitroprusside was not significantly different in the three groups. Isoproterenol and forskolin induced endothelium-independent relaxation. Isoproterenol responses were inhibited in aging and diabetic animals, however the forskolin-relaxation was inhibited only in the aortae from aging animals. These results suggest that in two models of diabetes (i.e. Type I insulin-dependent and type II non insulin-dependent) vascular responsiveness is differently affected. Aging hyperinsulinemic animals present a selective hyperresponsiveness to serotonin, a selective dysfunction of ADP-induced endothelium-dependent relaxation and smooth muscle adenylate cyclase deficit. In diabetic animals a beta adrenergic hyporesponsiveness, not linked to adenylate-cyclase dysfunction, and non-selective depression of endothelium-dependent responses can be observed.

Age Factors↗
PubMed1994

Magnesium modulates endothelial dysfunction produced by elevated glucose incubation.

In aorta taken from diabetic rabbits studied ex vivo or from normal rabbits exposed to increased glucose for 6 h in vitro the endothelium-dependent relaxation to acetylcholine (ACh) is impaired. Magnesium ion concentration influences vascular smooth muscle (VSM) contractility, endothelium-dependent relaxing factor (EDRF) release and prostaglandin production. We wished to determine the effects of changes in magnesium ion concentration on the abnormality induced by elevated glucose concentration (44 mM) in the endothelium-dependent responses observed in isolated rabbit aorta. In phenylephrine (PE)-precontracted vessels, with physiologic salt solution (PSS) containing 1.2 mM magnesium, endothelium-dependent relaxation and endothelium-independent contraction to ACh was not affected by incubation in elevated glucose (44 mM), indomethacin (10(-5) M) treatment, or both. In solution containing 0.6 mM magnesium, the endothelium-dependent relaxation to ACh was impaired in elevated glucose. Indomethacin treatment did not affect endothelium-dependent relaxation in the control solution but partially restored the response to ACh in elevated glucose. Under basal conditions and in the presence of nitric oxide (NO) synthase inhibition, ACh induced a contraction. In low magnesium-containing medium, this contraction was potentiated by the presence of endothelial cells in control (5.5 mM) and even more in elevated glucose concentration (44 mM). The endothelium-dependent contractions were abolished by pretreatment with indomethacin. However, in control magnesium conditions (1.2 mM), an endothelium-dependent component to the ACh contraction was observed only in elevated glucose concentration. Responses to sodium nitroprusside (SNP), KCI, and serotonin, and the concentration to ACh (in the absence of endothelium) were not influenced by elevated glucose, indomethacin treatment, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Islet amyloid polypeptide in Psammomys obesus: lack of correlation between insulin resistance and plasma IAPP levels.

Sand rats (Psammomys obesus) develop insulin resistance and diabetes when given a standard laboratory diet. We have examined the presence of islet amyloid polypeptide (IAPP), or amylin, in these animals. IAPP is present in the beta-cells of pancreatic islets, its localization and intensity of immuno-reactivity are, thus, similar to that of insulin. In insulin resistant Psammomys obesus, insulin and IAPP immuno-reactivity in pancreas are markedly decreased, plasma insulin levels are 20-fold higher than in controls but IAPP levels are not different from those of normal animals. Therefore, insulin resistance in Psammomys obesus does not appear to result from an elevated plasma IAPP level nor from development of amyloid deposits.

Amyloid↗
PubMed1994

Serotoninergic receptor subtype in coronary artery smooth muscle from young and atherosclerotic rabbit.

In rabbits fed with hypercholesterolemic diet the normal coronary vasodilator response to serotonin is replaced by vasoconstriction sensitive to 5HT2 receptor blockade. These experiments were designed to determine the receptor subtype involved in the contractile response of large isolated coronary arteries (without endothelium) taken from control and atherosclerotic rabbits. In both tissues the agonists' rank potency was 5-carboxamidotryptamine > serotonin (5HT) > sumatriptan > 8-OHDPAT: (+/-)-8-Hydroxydipropylaminotetralin HBr > 2-methylserotonin. In arteries from young rabbits, 5HT and sumatriptan induced contractions which were not influenced by ketanserin up to 3 x 10(-8) M. However, the 5HT2 antagonist at the concentration of 10(-6) M induced a significant rightward shift of the concentration-response curves. The contractions to the two serotoninergic agonists were competitively inhibited by methiothepin. NAN 190, a 5HT1A antagonist, LY 53857, a 5HT1C and 5HT2 antagonist, cyanopindolol, a 5HT1A and 5HT1B antagonist and ICS 205-930, a 5HT3 and 5HT4 antagonist (up to 10(-6) M) did not inhibit the contractile response to 5HT. Rauwolscine (10(-6) M) significantly shifted the concentration-response curves to the two agonists. Very similar results were obtained in coronary arteries from atherosclerotic rabbits. These data demonstrate that in rabbit epicardial coronary artery smooth muscle, the receptor involved in the serotoninergic response is a 5HT1-like subtype, possibly a 5HT1D. In this preparation, under our experimental conditions, there was no evidence for the presence of 5HT2 receptors. The induction of atherosclerosis did not induce significant changes in the serotoninergic response in these large coronary arteries, illustrating the marked heterogeneity between microvasculature and large arteries in the rabbit heart.

Animals↗
PubMed1993

Effect of activation of the serotoninergic system during prolonged starvation on subsequent caloric intake and macronutrient selection in the Zucker rat.

Starvation or dietary restriction are known to modify post-fasting dietary self-selection. We have examined the effects of activation of the serotoninergic system and food deprivation on macronutrient self-selection following a period of starvation. Rats were starved for 4 days and either treated or not with dl-fenfluramine or fluoxetine. Starved untreated animals showed a post-fasting anorexia and an increased preference for carbohydrate intake, even though lipids remained the preferred source of calories. Treatment with fenfluramine or fluoxetine increased post-fasting anorexia, abolished the preference for carbohydrates and decreased lipid intake. Fluoxetine, but not fenfluramine, resulted in decreased protein intake as well. Following a 2-day refeeding period ad libitum, during which the animals were not treated with drugs, the anorectic effect of fenfluramine disappeared but that of fluoxetine remained unchanged. In addition, we noted that at an equimolar dose to dl-fenfluramine (100 mumol/kg/day) fluoxetine treatment resulted in the death of all the animals in the group by the second day of refeeding; no deaths were observed in any of the other groups. In conclusion, we confirm a post-starvation anorexia and increased carbohydrate intake following long-term fasting. In addition we show that activation of the serotoninergic system abolishes the increase in carbohydrate intake and potentiates post-starving anorexia.

Animals↗
PubMed1993

Improvement in glucose tolerance of insulin resistant rats after chronic or acute administration of benfluorex.

The effects of Benfluorex administration on glucose tolerance have been examined in young and old Sprague Dawley rats. The ageing rats were used as a model of insulin resistance. Chronic oral administration of Benfluorex decreased triglycerides levels and normalized glucose tolerance in ageing rats, independently of effects on body weight. Acute intraportal administration of 0.45 mg/kg/h of Benfluorex for 30 min resulted in a 50% increase in glucose tolerance in old rats, but did not modify that in young rats. The improved glucose tolerance brought about by Benfluorex in an animal model of insulin resistance may suggest a wider therapeutic application in man, to include insulin resistant states as type II diabetes or Syndrome X.

Administration, Oral↗
PubMed1993

Effect of aging and drug-induced weight reduction on rat vascular reactivity.

We determined the effects of D-fenfluramine treatment on the changes in vascular reactivity induced by aging. Nine- and 49-week-old Sprague-Dawley rats (a strain known to develop hyperinsulinemia and glucose intolerance during the aging process) were treated for 3 weeks either with D-fenfluramine 2.5 mg/kg twice daily orally or with vehicle. The rats were then exsanguinated and the abdominal aorta was carefully removed, cut into rings, and suspended in organ chambers for isometric tension recording. Control old rats (vehicle) had a significantly lower glucose infusion rate (an index of insulin resistance), and higher blood pressure (BP), glycemia, and insulinemia than young rats. The D-fenfluramine treatment in the aged animals produced a significant decrease in insulinemia and body weight. In aorta from the older treated and nontreated animals, the contraction to alpha-adrenergic stimulation and to the thromboxane analogue U46619 was significantly reduced as compared with that in young animals, but the response to KCl was unaffected. In contrast, in the old nontreated rats, the aorta was hyperresponsive to serotonin. D-Fenfluramine abolished this hyperreactivity. The response to beta-adrenergic stimulation and to forskolin was inhibited in the older animals but was not influenced by the treatment. Endothelium-dependent relaxations to acetylcholine were not statistically different in the various groups, but the endothelium-dependent relaxation to ADP was reduced in the control group of older animals. D-Fenfluramine treatment restored the response to ADP.

Administration, Oral↗
PubMed1992

Immunohistochemical and electron microscope studies of rat islets of Langerhans one month after adult thymectomy.

Ultrastructural and quantitative immunocytochemical studies of rat pancreata were carried out 1 month after adult thymectomy. The proportions of insulin-, glucagon-, and somatostatin-immunoreactive cells in the pancreas were estimated on paraffin sections using the unlabelled peroxidase-antiperoxidase method. Relative islet volume, islet size and number were determined on hematoxylin and eosin stained sections. A moderate increase of the islet volume on account of size was found in the pancreas of the thymectomized rats. The proportion of insulin-immunoreactive cells was also elevated. Ultrastructural studies showed a rich supply of secretory granules in most beta-cells. Mixed beta-endocrine-acinar cells were often observed. Mitotic figures were found in single beta-cells. The blood glucose level was in the normal range. The findings suggest a moderate stimulation of beta-cell secretory activity after thymectomy which is not associated with elevated blood glucose levels.

Animals↗
PubMed1991

Development of macroangiopathy in sand rats (Psammomys obesus), an animal model of non-insulin-dependent diabetes mellitus: effect of gliclazide.

The risk of developing macroangiopathy associated with diabetes led us to study in sand rats the long-term consequences of non-insulin-dependent diabetes on the development of arterial lesions promoted by feeding a high-cholesterol diet. Gliclazide, an agent whose preventive effect has previously been suggested in other experimental models of atheroma, was also investigated in these diabetic and hypercholesterolemic animals. Sand rats were fed a natural diet (ND group), a standard laboratory feed (StD group), or a high-cholesterol feed (HCD group) for 15 months. Biologic parameters were monitored throughout the period of the study, and histologic and histochemical examinations were conducted when the animals were killed (month 15). One StD group and one HCD group were treated with gliclazide from month 3 to month 15. The StD group developed a syndrome of obesity, hyperglycemia, hyperinsulinemia, and triglyceridemia. The high cholesterol feed further increased hypercholesterolemia. These biologic abnormalities were accompanied by arterial lesions (thickening of the intima, deposition of glycosaminoglycans). Foam cells were seen in the intima, and microthrombi were present in the lumen of the arteries of animals in the HCD group. Long-term gliclazide medication at doses that normalized serum glucose levels also reduced the obesity, hyperinsulinemia, lipid disorders, and it prevented or retarded the appearance of arterial lesions.

Animals↗
PubMed1991

History and evolution of the concept of oral therapy in diabetes.

The object of diabetes treatment is to restore adequate carbohydrate, protein and lipid metabolism. The cornerstone of this treatment has been diet since the end of the 18th century, but true antidiabetic therapy started only with the identification and purification of insulin. Pressure for oral therapy then quickly built up. The hypoglycemic effect of guanidines was discovered in 1919, leading to their therapeutic use, but they were withdrawn in 1932 due to their hepatotoxic effects. The related biguanides appeared in the 1950s but have since diminished in importance so that metformin is practically the only representative still used today. Work in the 1940s and 1950s led to the discovery and development of hypoglycemic sulfonylureas (SU), a therapeutic class unique for its specificity and safety. These products were found to stimulate insulin secretion by the endocrine pancreas. In vitro studies have shown that they bind specifically to an ATP-dependent K+ channel of the beta cell membrane. This binding closes the channel so that K+ outflow ceases, the beta cell membrane depolarizes and voltage-dependent Ca2+ channels open to allow an influx of extracellular calcium. The result is migration and extrusion of insulin granules. Although this mechanism of action has been demonstrated in vitro, it cannot account for all the clinical actions of various SU. They thus appear to have extrapancreatic actions, probably potentiating the peripheral effects of insulin at a postreceptor site in target cells. Other effects involve fibrinolytic activity of the blood, platelet behavior and vascular reactivity. The future of oral diabetes therapy thus seems to lie with the sulfonylureas.

Administration, Oral↗