PubMed Health⌕ Search

Biomedical subjects

B Portha

Publications and source records attributed to B Portha.

At least 91 records · Page 5Linked to original sources
PubMed1990

Insulin resistance in rats with non-insulin-dependent diabetes induced by neonatal (5 days) streptozotocin: evidence for reversal following phlorizin treatment.

We have examined the effect of chronic (4 weeks) phlorizin treatment (osmotic minipumps) on tissue sensitivity to insulin in adult female rats with non-insulin-dependent diabetes (NIDD) induced by streptozotocin (STZ) (80 mg/kg) administered 5 days after birth. Insulin sensitivity was assessed with the euglycemic-hyperinsulinemic clamp technique in anesthetized animals. In the untreated diabetic rats, the basal glucose production (GP) and glucose utilization (GU) were increased (P less than .001), and both the liver and peripheral tissues showed insulin resistance. In the phlorizin-treated diabetic rats, postabsorptive plasma glucose levels were decreased and remained stable during the last 3 weeks of the treatment (142 +/- 3 mg/dL as compared with 308 +/- 19 in the untreated diabetic rats and 119 +/- 3 in the phlorizin-control rats); their percent glycosylated hemoglobin values returned to normal (3.2 +/- 0.2 as compared with 5.8 +/- 0.4 in the untreated diabetic rats); their basal plasma insulin levels (55 +/- 5 microU/mL as compared with 52 +/- 3 in the untreated diabetic rats and 130 +/- 10 in the phlorizin-control rats), their in vivo glucose-induced insulin secretion, and their pancreatic insulin content were kept unchanged. In the phlorizin-treated diabetic rats, the basal GP and GU were normalized. Following a submaximal or maximal hyperinsulinemia, GP was normally suppressed and GU normally enhanced. Phlorizin treatment in the control rats did not affect any of the above parameters. These data demonstrate that correction of hyperglycemia with phlorizin normalizes insulin action on glucose metabolism by the liver and peripheral tissues in this diabetic model. This is in line with the proposal that hyperglycemia per se can lead to the development of insulin resistance.

Animals↗
PubMed1990

Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate.

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity.

Animals↗
PubMed1989

In vivo insulin resistance in streptozotocin-diabetic rats--evidence for reversal following oral vanadate treatment.

Hepatic glucose production and peripheral glucose utilisation were measured in vivo with the euglycaemic-hyper-insulinaemic clamp technique in rats rendered severely diabetic with streptozotocin (45 mg/kg) and in control rats. The rats were studied in the post-absorptive state while anaesthetised. The basal glucose production and glucose utilisation were significantly higher (p less than 0.001) in diabetic rats 9 days after streptozotocin administration. During the clamp studies, suppression of glucose production by the liver induced by submaximal or maximal insulin levels was significantly less (p less than 0.01 and p less than 0.001 respectively) effective in diabetic rats as compared to control rats. Glucose utilisation was significantly lower following both submaximal (p less than 0.01) or maximal (p less than 0.001) hyperinsulinaemia as compared to control rats. Oral administration of vanadate (0.2 mg/ml in drinking water) for a 20-day period in diabetic rats lowered their plasma glucose levels to normal near values within 4 days, normalised plasma insulin levels, and increased pancreatic insulin stores. The rate of glucose disappearance (K value) and in vivo glucose-induced insulin secretion as estimated during an i.v. glucose tolerance test were not significantly improved. In control rats, vanadate treatment did not significantly affect any of the above parameters. In vanadate treated diabetic rats, basal glucose production was normalised. Following submaximal or maximal hyperinsulinaemia, glucose production was suppressed normally. Basal glucose utilisation was restored and returned to normal values during submaximal hyperinsulinaemia. However, during maximal hyperinsulinaemia, glucose utilisation still remained significantly lower (p less than 0.05) as compared to vanadate-treated control rats. (ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin.

Neonatal rats treated with streptozotocin on the day of birth (n0-STZ) or on day 5 (n5-STZ) exhibited when fully grown a very mild or frank basal hyperglycaemia respectively and a specific failure of insulin release in response to glucose. To determine whether short (1 day) or long-term (30 days) gliclazide treatment modifies the pancreatic insulin content and the B-cell response to secretagogues, diabetic rats were given oral gliclazide (10 mg/kg per day) and compared to control diabetic and non-diabetic rats. Insulin secretion in the isolated perfused pancreas was studied the day after the last gliclazide administration. In severely hyperglycaemic n5-STZ rats (plasma glucose levels greater than 16 mmol/l) long-term gliclazide treatment did not lower the plasma glucose values, did not affect the pancreatic insulin stores, nor did it significantly modify the insulin release in vitro in response to glucose or arginine. In moderately hyperglycaemic n5-STZ rats (plasma glucose levels less than 16 mmol/l) the plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of the gliclazide therapy. In the n5-STZ rats responsive to gliclazide the pancreatic insulin stores were increased twofold as compared to values in untreated n5-STZ rats, however, this difference did not reached significance and the pancreatic insulin stores in the responsive gliclazide treated rats remained depleted by 76% compared to normal insulin stores. In the n0-STZ rats (very mild hyperglycaemia) the long-term gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Ultrastructural analysis of VIP internalization in rat beta- and acinar cells in situ.

We perfused the pancreas with 125I-labeled vasoactive intestinal peptide (VIP) to follow the concomitant distribution of radioactivity in beta- and acinar cells as a function of time. This distribution was quantitated by computer-assisted analysis of high-resolution video autoradiographs. Density labeling was expressed as normalized specific activity (disintegration density per volume density). Immediately after a 4-min perfusion of 125I-VIP, labeling in beta-cells was mainly concentrated on the cell surface and peripheral tubules and vesicles. After three 30-s pulses of 125I-VIP, separated by intervals of 3.5 min of buffer perfusion, lysosome-like structures were heavily labeled. When VIP internalization was prolonged, labeling was similar to that observed with the 4-min perfusion, indicating a high VIP disposal rate in the lysosome-like structures. In acinar cells, labeling persisted on the surface and the early vacuolar system. We conclude the following: 1) an active endocytotic system, linked to the transport and sorting of a neuromediator, is present in beta-cells; and 2) the differences between the distribution of labeling in acinar and beta-cells suggest that the regulation of VIP internalization is tissue specific.

Animals↗
PubMed1989

The desensitization of normal B-cells to glucose in vitro is transient and not related to high glucose levels.

To examine the postulated phenomenon of glucotoxicity toward the B-cell, islets isolated from normal adult rats were cultured for 1-6 days in RPMI medium at various glucose concentrations. Insulin release and (pro)insulin biosynthesis by these islets were then measured in short term incubations. The 1-day cultured islets (at 9.7 mM glucose) displayed a deficient glucose-stimulated insulin release which was partially restored in the presence of forskolin (5 microM). By contrast they exhibited a consistent insulin release in response to ketoisocaproate (10 mM), 12-O-tetradecanoylphorbol-13-acetate (2 microM), or the combination of Ba2+ (2 mM) and theophylline (1.4 mM) in the absence of extracellular Ca2+. Desensitization of their B-cells was not specific for glucose, since glyceraldehyde (10 mM) or leucine (10 mM) also failed to stimulate insulin release. Desensitization was not related to glucose concentration (5.6, 9.7, or 16.7 mM) in the medium during the 1-day culture period and was restricted to the secretory function, with no impairment of the biosynthesis process. The desensitization to glucose was transient, and high glucose levels (9.7 and 16.7 mM) in the culture medium favored restoration of the subsequent secretory response to the hexose. Under conditions of recovery of B-cell sensitivity to glucose in vitro (5 days at 9.7 mM glucose), the secretory response to acute glucose was in fact significantly enhanced after an additional exposure (1 day) to very high glucose levels (22 or 55 mM). The present results argue against 1) the possibility that islets suffer from some unspecific decreased viability after a 1-day culture period; and 2) the hypothesis that glucose insensitivity in the 1-day cultured islets is primarily caused by a direct deleterious effect of high glucose concentrations on the B-cells. They, rather, reinforce the view that high glucose levels are actually crucial in the preservation of the insulin secretory response to glucose of islets maintained in tissue culture.

Animals↗
PubMed1989

Relation of insulin deficiency to impaired insulin action in NIDDM adult rats given streptozocin as neonates.

We assessed the impact of chronic insulin deficiency on basal and insulin-stimulated glucose utilization by the whole-body mass in vivo in female albino Wistar rats. This assessment was based on a comparison of results in rats given streptozocin (STZ) on day of birth (n0-STZ), when 2 days old (n2-STZ), or when 5 days old (n5-STZ). At 10 wk of age, the n2-STZ rats exhibited characteristics similar to those obtained in the n0-STZ rats: normal growth, modest elevation of basal plasma glucose (8.23 +/- 0.24 mM), glucose intolerance, depleted pancreatic insulin stores (approximately 50% of normal value), and lack of insulin release in response to glucose in vivo. In contrast, the n5-STZ rats exhibited frank basal hyperglycemia (glucose 11.9 +/- 1.1 mM) and glucose intolerance, increased glycosylated hemoglobins, strong reduction of the pancreatic insulin stores (10% of normal value), decreased basal plasma insulin levels (50% of normal value), and lack of insulin release in response to glucose in vivo. Changes in the sensitivity of the neonatal beta-cell to STZ and the regeneration capacity of the beta-cells during the 1st postnatal wk were liable factors for the contrast. In vivo insulin action was assessed with the euglycemic-hyperinsulinemic clamp technique in 10-wk-old anesthetized animals. In the n2-STZ rats compared with controls 1) endogenous glucose production was significantly higher despite a normal plasma insulin level in the basal state, 2) endogenous glucose production rate was similarly suppressed by hyperinsulinemia, and 3) glucose utilization by the whole-body mass was similarly increased by hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Insulin binding and insulin receptor tyrosine kinase activity are not altered in the liver of rats with non-insulin-dependent diabetes.

Using the insulin-glucose clamp technique, we have previously shown that an increased sensitivity to insulin in vivo is a characteristic of the liver in rats with non-insulin-dependent diabetes induced by neonatal streptozotocin administration. We have thus studied the properties of liver insulin receptor in that model. 125I-porcine insulin binding was found normal both in isolated plasma membranes and in solubilized, wheat germ agglutinin purified receptors prepared from livers of rats with non-insulin-dependent diabetes, when compared to controls. Basal and insulin-stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1. Thus, in that model of chronic insulin deficiency and mild hyperglycemia: 1) liver insulin receptors are not up-regulated; 2) tyrosine kinase activity remains unaffected. This last observation supports the hypothesis that the increased insulin effect in the liver of rats with non-insulin-dependent diabetes is probably distal to the insulin receptor kinase.

Animals↗
PubMed1988

Insulin production and glucose metabolism in isolated pancreatic islets of rats with NIDDM.

Rats with non-insulin-dependent diabetes mellitus (NIDDM) induced by neonatal injection of streptozocin are known to have a deficient insulin response to glucose. To evaluate to what extent this glucose insensitivity can be attributed to a perturbation of the islet glucose metabolism, we estimated the rates of glucose phosphorylation, glucose utilization, oxygen consumption, and glucose oxidation in islets isolated from normal and NIDDM rats and compared these values with rates of islet insulin biosynthesis and release in vitro. The data confirm that islets from rats with NIDDM display a deficient response to glucose of both insulin biosynthesis and release that is still present after an overnight culture of the islets at 5.5 mM glucose. Furthermore, they show that islets of these rats have 1) normal low- and high-Km glucose-phosphorylating activities and no major alteration of the glucose utilization rate, 2) decreased insulin release in response to glyceraldehyde, 3) decreased rates of basal respiration and glucose oxidation and a markedly reduced stimulation by glucose of both islet oxygen consumption and glucose oxidation, and 4) decreased glucose-stimulated net 45Ca uptake. We conclude that the relative unresponsiveness to glucose of islets from NIDDM rats is associated with, and perhaps due to, a deficient islet glucose metabolism. This defect is not due to gross alterations in the glycolytic pathway but probably reflects alteration in the islet mitochondria function.

Animals↗
PubMed1987

Effect of high sucrose diet on insulin secretion and insulin action: a study in the normal rat.

The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in normal male rats. As compared to the standard chow diet, the high sucrose diet induced excess in vivo insulin response to an intravenous glucose load; the high sucrose diet also slightly improved glucose tolerance, as demonstrated by significantly higher rate of glucose disappearance (p less than 0.02). The increased insulin secretion in response to glucose in vivo seems to be related to an hyper-reactivity of the pancreatic B cell to glucose, since it was still observed in vitro with the isolated perfused pancrease preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a normal response to arginine and a significantly lowered (p less than 0.05) response to acetylcholine. The insulin action in the sucrose-fed rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilization were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilization was found significantly higher (p less than 0.001) in sucrose-fed rats. During the clamp studies the glucose utilization induced by submaximal (400 microU/ml) or maximal (7500 microU/ml) insulin levels was significantly more important (p less than 0.02) in the sucrose-fed rats than in the chow-fed rats. This suggests that insulin-mediated glucose uptake is enhanced over a large range of plasma insulin levels in the sucrose-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of high sucrose diet on insulin secretion and insulin action. A study in rats with non-insulin-dependent diabetes induced by streptozotocin.

The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in rats with non-insulin-dependent diabetes. As compared to the standard diet, the high sucrose diet induced an increase of the in vivo insulin response to an intravenous load and deteriorated the glucose tolerance as attested by significantly lower rates of glucose disappearance (K values, p less than 0.001). The increased insulin secretion in response to glucose in vivo seems to be related to a slight increase of the pancreatic B-cell reactivity to glucose, since it was still observed in vitro with the isolated perfused pancreas preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a significantly lowered (p less than 0.01) response to acetylcholine and arginine. The insulin action in the sucrose-fed diabetic rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilisation were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilisation was found significantly higher (p less than 0.001) in sucrose-fed rats. During the clamp studies the glucose utilisation induced by submaximal (450 mU/l) insulin level was significantly less important (p less than 0.01) in the sucrose-fed rats than in the chow-fed rats. Following a maximal hyperinsulinaemia (5000 mU/l) the glucose utilisation was similar in both groups. This suggests that insulin-mediated glucose uptake is decreased over the range of submaximal plasma insulin levels in the sucrose-fed diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Insulin treatment improves glucose-induced insulin release in rats with NIDDM induced by streptozocin.

Insulin-deficient diabetes in humans, as well as in the neonatal streptozocin-induced rat model of non-insulin-dependent diabetes mellitus (NIDDM), are associated with islet beta-cell insensitivity to glucose. We hypothesized that the chronic hyperglycemia-hypoinsulinemia pattern causes this impairment of the glucose influence on insulin secretion. This study was designed to determine whether the glucose defect could be counteracted by normalizing the diabetic state in rats with NIDDM after insulin therapy. Mixte lente insulin (5 U X kg-1 X day-1) was given daily at 1700 h over 24 h or 5 consecutive days. Insulin secretion was studied the morning after the last insulin injection with the isolated perfused pancreas preparation. Fed basal plasma glucose levels decreased in diabetic rats from 183 +/- 8 to 136 +/- 10 mg/dl after the 1-day insulin treatment and to 135 +/- 5 mg/dl after the 5-day insulin treatment (vs. 116 +/- 3 mg/dl in control rats). Pancreatic insulin stores were not affected by insulin therapy. Although the 1-day insulin treatment did not modify the lack of glucose response in the diabetic rats, the 5-day insulin treatment improved their glucose-induced insulin secretion. Moreover, insulin therapy improved the priming effect of glucose on a second stimulation with glucose. The return of this glucose effect was hardly detectable after the 1-day insulin therapy but was clearly present after the 5-day treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Structural requirements for gastric inhibitory polypeptide (GIP) receptor binding and stimulation of insulin release.

The effect of bovine GIP 1-42 and several of its fragments in competing with the binding of 125I-GIP to beta-cell plasma membranes from transplantable hamster insulinoma, and in stimulating insulin release from the isolated perfused rat pancreas, was investigated. Our results, in association with the results of previous studies, indicate that the sequence 17-38 is necessary for receptor binding and biological activity of GIP. By contrast, the N-terminal portion of GIP can be removed without seriously impairing the activity of the molecule.

Animals↗
PubMed1986

Evidence for normal in vitro Ca2+-stimulated insulin release in rats with non-insulin-dependent diabetes.

Non-insulin-dependent diabetes (NIDD) was induced in adult rats following a neonatal injection of streptozotocin. Rats with NIDD exhibited moderate basal hyperglycemia (less than 2g/l) with defective glucose-induced insulin secretion and preserved or enhanced responsiveness to various non-glucose secretagogues. The possible sites of defects in the B cells of these diabetic rats are at present unknown. Extracellular Ca2+ at concentrations exceeding 10 mmol/l causes a dose-related stimulation of insulin release by the perfused normal rat pancreas. This technique provokes an increase of cytosolic Ca2+ accumulation in the B cell sufficient to trigger activation of the microtubular-microfilamentous effector system responsible for the exocytosis of insulin granules. It is therefore possible to compare functional efficiency of this process in the B cells of diabetic rats to that in the normal B cells. Results obtained in response to Ca2+ stimulation over the range 10-13.5 mmol/l provide evidence that the insulin release is stimulated in the pancreas of diabetic rats to the same extent as that in the controls, in both the kinetic and the quantitative aspect of the response. These data are compatible with the idea that in the B cells of rats with NIDD : 1) the effector system of insulin secretion is not grossly altered and 2) the lesion responsible for the loss of glucose-induced insulin secretion occurs before the effector system, involving either the mechanism by which glucose is metabolized as previously proposed by us, or another step yet to be identified.

Animals↗
PubMed1985

Effect of exogenous insulin on glucose kinetics in rats with noninsulin-dependent diabetes.

Noninsulin-dependent diabetes (NIDD) was induced in adult female rats by neonatal administration of streptozotocin. Despite elevated basal plasma glucose values in the postabsorptive state (196 +/- 16 mg/100 mL as compared to 118 +/- 7 in the controls), the glucose disappearance rate measured after the intravenous glucose load was not significantly lower in the diabetic than in control rats. In contrast, in vivo glucose-induced insulin release was drastically reduced, thus suggesting that endogenous insulin was more effective on the target tissues of the diabetic rats. Glucose kinetics (glucose production, utilization, and clearance) in response to intravenous insulin injection were studied in anesthetized postabsorptive diabetic and control female rats using [6-3H] glucose. With a maximal dose of insulin (0.5 U/kg body weight) no difference in blood glucose-lowering effect of insulin was found between the 2 groups. With 2 submaximal insulin doses (0.15 and 0.3 U/kg body weight), glucose production was inhibited more rapidly and more efficiently in diabetic rats than in control rats: 2 minutes after the 0.15 U/kg insulin injection, endogenous glucose production fell by 79 +/- 5% in the diabetics while being unchanged in the controls and the maximal decrease of glucose production after the same insulin injection was significantly greater in the diabetic rats (79 +/- 5% at 2 minutes) compared to the controls (33 +/- 4% at 6 min). The rise of glucose clearance in response to insulin was not significantly different in the 2 groups. These findings are discussed in view of the increased insulin clearance rate in these diabetic females.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Decreased glucose-induced insulin release and biosynthesis by islets of rats with non-insulin-dependent diabetes: effect of tissue culture.

Non-insulin dependent diabetes (NIDD) was obtained in adult rats after a neonatal streptozotocin injection. In the fed state 3- to 5-month-old rats with NIDD exhibited modestly elevated plasma glucose levels (controls, 131 +/- 7 mg/dl; diabetics, 159 +/- 4 mg/dl; P less than 0.01), impaired glucose tolerance, and a very low insulin response after glucose injection. In the present study the secretion and biosynthesis of insulin were measured using isolated islets from these rats. The insulin and DNA content of islets freshly isolated from rats with NIDD were significantly lower (60% and 80%, respectively, P less than 0.001) than in the controls. The insulin content per islet cell from diabetic rats was also significantly reduced (75%) (P less than 0.01) as compared to controls. At a low glucose concentration (2.8 mM) the insulin release from islets of diabetic rats was 60% (P less than 0.05) of that the controls. At a glucose concentration of 16.5 mM it was stimulated 5-fold from the islets of NIDD rats and 7-fold from the islets of control rats. (Pro)insulin biosynthesis, assessed in the same islets by measuring the incorporation of [3H]phenylalanine into immunoprecipitable material, was significantly higher (50%) (P less than 0.01) in islets from NIDD rats when measured at 2.8 mM glucose. Although (pro)insulin biosynthesis in these islets was significantly stimulated by 16.5 mM glucose (5-fold), it was less (P less than 0.05) than in the control islet (9-fold). To determine whether the derangements described above in the islets of the rats with NIDD could be modified by changing the environmental conditions of the B cells, corresponding experiments were performed after a 5-day culture of the islets at 5.5 mM glucose or at 11 mM glucose. The insulin release and the (pro)insulin biosynthesis, either measured in basal or stimulated states, were then found to be similar in the islets of diabetic and control islets after the 5.5 mM glucose culture period. By contrast, after the 11 mM glucose culture period the insulin release and the proinsulin biosynthesis in the islets of diabetic rats were found significantly less stimulated by 16.5 mM glucose than in the control islets. This suggests that islets of rats with NIDD, once removed from the chronic in vivo exposure to diabetic metabolic disorders, can behave as isolated islets of normal rats, at least as far as insulin handling is concerned.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗