Biomedical subjects

B Portha

Publications and source records attributed to B Portha.

At least 73 records · Page 4Linked to original sources

PubMed1993

Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver.

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of 125I-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.

Spontaneously diabetic nonobese GK rats exhibit high basal plasma glucose and insulin levels and a poor insulin secretory response to glucose. We studied insulin biosynthesis, insulin release, and glucose metabolism in freshly isolated islets from GK rats and control Wistar rats. In GK rats, islet insulin content was decreased when expressed per islet but normal when related to DNA content. In the presence of a low concentration (2.8 mM) of glucose both (pro)insulin and total protein biosynthesis was doubled in islets from GK rats. As judged from the (pro)insulin/total protein synthesis ratio, (pro)insulin biosynthesis was normally stimulated by 16.7 mM glucose. In islets from diabetic rats both basal and glucose-stimulated insulin release were dramatically decreased. A reduced secretory response to 10 mM leucine or 10 mM leucine plus 10 mM glutamine and a lack of response to 10 mM monomethylsuccinate were observed. By contrast the insulinotropic capacity of nonnutrient secretagogues such as 62 microM gliclazide or the combination of 2 mM Ba2+ and 1.4 mM theophylline in the absence of extracellular Ca2+ remained normal. Glucose oxidation (estimated as the production of 14CO2 from D-[6-14C]glucose) was severely impaired, whereas no major alteration of glycolytic flux (as judged from the conversion of D-[5-3H]glucose to 3H2O) could be detected. Accordingly, the D-[6-14C]glucose oxidation/D-[5-3H]glucose use ratio was less markedly increased in response to a rise in glucose concentration in islets from GK rats than in islets from control rats. Thus, in islets from diabetic GK rats, glucose-induced insulin release but not insulin biosynthesis was impaired. This defect is associated with, and probably at least in part due to, a deficient oxidative metabolism of glucose in islet mitochondria.

Animals↗

PubMed1993

Benfluorex normalizes hyperglycemia and reverses hepatic insulin resistance in STZ-induced diabetic rats.

We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of NIDDM, induced by injection of STZ 5 days after birth and characterized by frank hyperglycemia, hypoinsulinemia, and hepatic and peripheral insulin resistance. We assessed the following: 1) basal blood glucose and insulin levels, 2) glucose tolerance and glucose-induced insulin release in vivo and in vitro, and 3) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. The in vivo insulin response of several individual tissues also was evaluated under the steady-state conditions of the clamp, using the uptake of the glucose analogue 2-deoxy-D-glucose as a relative index of glucose metabolism. In the benfluorex-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (8.1 +/- 0.2 mM compared with 10.5 +/- 0.5 mM in the pair-fed untreated diabetic rats and 6.1 +/- 0.2 mM in the benfluorex-treated nondiabetic rats), whereas the basal and glucose-stimulated intravenous glucose tolerance test plasma insulin levels were not improved. Such a lack of improvement in the glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the pair-fed untreated diabetic rats, the basal glucose production and overall glucose utilization were significantly increased, and during hyperinsulinemia both liver and peripheral tissues revealed insulin resistance. In the benfluorex-treated diabetic rats, the basal glucose production and basal overall glucose utilization were normalized. After hyperinsulinemia, glucose production was normally suppressed, whereas overall glucose utilization was not significantly improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Evaluation of in vivo insulin action and glucose metabolism in milk-fed rats.

Milk diet has long been recommended in the management of gastrointestinal pathologies. Since milk feeding represents a high fat-low carbohydrate diet and it is acknowledged that insulin resistance is one of the consequences of high fat feeding, it is important to know whether or not chronic milk feeding leads to an impairment of the insulin-mediated glucose metabolism. To examine this question, adult female rats were given raw cow's milk (50% of total calories as lipids) for 18 days. They were compared to rats raised in parallel and fed the standard laboratory diet (15% of total calories as lipids). At the end of the 18 day period, body weight, daily caloric intake, basal plasma glucose and insulin levels in the milk-fed rats were similar to those in the control rats. In vivo insulin action was assessed with the euglycemichyperinsulinemic clamp technique in anesthetized animals. These studies were coupled with the 2-deoxyglucose technique allowing a measurement of glucose utilization by individual tissues. In the milk fed rats: 1) the basal rate of endogenous glucose production was significantly (p < 0.01) reduced (by 20%); 2) their hepatic glucose production was however normally suppressed by hyperinsulinemia; 3) their basal glucose utilization rate was significantly (p < 0.01) reduced (by 20%); 4) their glucose utilization rate by the whole-body mass or by individual tissues was normally increased by hyperinsulinemia. These results indicate that insulin action in adult rats is not grossly altered after chronic milk-feeding, at least under the present experimental conditions.

Animals↗

PubMed1992

Study of hexose transport, glycerol phosphate shuttle and Krebs cycle in islets of adult rats injected with streptozotocin during the neonatal period.

At 3-4 degrees C, the transport of 3-O-methyl-D-glucose (30 mM) was severely impaired in islets prepared from adult rats injected with streptozotocin during the neonatal period. However, at 37 degrees C, the first and second phase of glucose-stimulated insulin release were decreased to the same relative extent in perifused islets of diabetic, as compared to control, animals. Moreover, the time-related increase in the oxidative response of the islets to 16.7 mM D-glucose was less pronounced in diabetic than control rats. The activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase in islet homogenates of diabetic rats only represented one-fifth of that found in control rats, whereas the activity of the cytosolic NAD-glycerophosphate dehydrogenase was comparable in both types of rats. This coincided with the fact that a rise in D-glucose concentration from 2.8 to 16.7 mM failed to increase significantly L-[2-3H]glycerol conversion to 3HOH in islets from diabetic rats, in contrast to the situation found in control animals. The activity of 2-ketoglutarate dehydrogenase in islet homogenates when expressed per microgram protein was not different in control and diabetic rats. Likewise, the ratio between D-[6-14C]glucose oxidation and D-[3,4-14C]glucose oxidation and the capacity of either a non-metabolized analog of L-leucine or 3-phenylpyruvate to preferentially stimulated D-[6-14C]glucose oxidation relative to D-[5-3H]glucose utilization were both unaffected in islets from diabetic rats. These findings argue against the existence of a primary defect in the Krebs cycle of diabetic rats. It is proposed that, despite an obvious alteration of the hexose transport system in the islet cells of diabetic rats, the preferential impairment of the B-cell secretory response to D-glucose, as distinct from other secretagogues, in this model of non-insulin-dependent diabetes is mainly attributable to the low activity of FAD-linked glycerophosphate dehydrogenase, resulting in a decreased metabolic flow through the glycerol phosphate shuttle and a reduced rate of aerobic glycolysis.

3-O-Methylglucose↗

PubMed1992

Glucose utilization and insulin action in adult rats submitted to prolonged food restriction.

Glucose tolerance and insulin effects on glucose production and utilization by various tissues were studied in 70-day-old anesthetized rats submitted to food restriction from the fetal stage. Basal and glucose-induced plasma insulin levels were reduced in food-restricted rats without alterations in glucose tolerance. Insulin action was quantified by using the euglycemic-hyperinsulinemic clamp technique. Glucose turnover rates were measured by using D-[6-3H]glucose. Exogenous insulin failed to decrease glucose production in food-restricted rats. Weight-related whole body glucose utilization was higher in restricted rats than in controls both in the basal (21.9 +/- 0.7 vs. 9.4 +/- 0.6 mg.min-1.kg-1) and hyperinsulinemic states (37.5 +/- 1.1 vs. 14.0 +/- 1.2 mg.min-1.kg-1). Local glucose utilization by peripheral tissues was estimated by a 2-deoxy-D-[1-3H]glucose technique. In both basal and hyperinsulinemic conditions glucose utilization was increased in various adipose and muscle tissues of the food-restricted rats as compared with the controls. Thus we conclude that food restriction leads to an increase in the insulin-mediated glucose uptake by various peripheral tissues and to insulin resistance in the liver.

Adipose Tissue↗

PubMed1992

Enzymic and metabolic anomalies in islets of diabetic rats: relationship to B cell mass.

A preferential impairment of the pancreatic B cell secretory response to D-glucose occurs in adult rats injected with streptozotocin during the neonatal period. Three possible explanations for such a preferential defect were investigated in the present study. First, the time course for 3-O-methyl-D-glucose uptake by islets suggested that the anomaly in hexose transport was mainly attributable to a decrease in the space accessible to the D-glucose analog commensurate with the decrease in B cell mass, rather than to a delayed equilibration of hexose concentration across the B cell plasma membrane. Second, the activity of glucose-6-phosphatase was found to be equally low in islets from diabetic and control rats, ruling out the futile cycling between D-glucose and D-glucose 6-phosphate as a cause for the preferential alteration of the secretory response to the hexose. Third, the activity of flavine adenine dinucleotide-linked glycerophosphate dehydrogenase was found to be decreased to a greater relative extent than the B cell mass. This coincided with an impaired generation of 3HOH from L-[2-3H] glycerol in intact islets. It is proposed, therefore, that an altered circulation in the glycerol phosphate shuttle may play a major role in the impaired process of glucose-stimulated insulin release in this model of noninsulin-dependent diabetes.

3-O-Methylglucose↗

PubMed1992

Effect of prolonged in vivo glucose infusion on insulin secretion in rats with previous glucose intolerance.

This work was designed to investigate the effect of an additional hyperglycemia on the subsequent in vivo insulin secretion in rats with various degrees of glucose intolerance. Four groups of rats received a unique injection of a low concentration of streptozotocin (STZ): 20, 27, 30, or 35 mg/kg corresponding, respectively, to STZ 20, STZ 27, STZ 30, or STZ 35 rats. Control rats were injected with citrate buffer. In all STZ groups, impaired glucose tolerance and insulin secretion were observed. These defects were roughly proportional to STZ concentration. Three weeks after STZ administration, hyperglycemia (17 mM) was produced by a 48-h glucose infusion via an indwelling catheter. Insulin secretion in response to glucose was investigated 3 h after stopping glucose infusion, by performing iv glucose tolerance tests. Insulin secretion in response to glucose doubled in control rats previously submitted to glucose infusion, and still more in rats with mild glucose intolerance (three and four times higher in STZ 20 and STZ 27 rats, respectively). By contrast, glucose infusion increased insulin secretion only slightly in STZ 30 rats and it was unchanged in STZ 35 rats. These data show that prolonged hyperglycemia has an improving effect on insulin secretion in rats with mild glucose intolerance, whereas the potentiating effect of previous hyperglycemia is lost in rats with more severe glucose intolerance.

Animals↗

PubMed1991

Improvement in glucose-induced insulin secretion in diabetic rats after long-term gliclazide treatment: a comparative study using different models of non-insulin-dependent diabetes mellitus induced by neonatal streptozotocin.

Understanding of the long-term action of sulfonylureas in humans with non-insulin-dependent diabetes mellitus (NIDDM) may be facilitated by studying the effect of long-term sulfonylurea administration to animal models of the disease. In this study two different versions of the neonatal streptozotocin-induced diabetes (STZ) rat model of NIDDM were used. The n5-STZ model (STZ on day 5 after birth), which is characterized by basal hyperglycemia, a marked reduction of pancreatic insulin stores, and insulin resistance, and the n0-STZ model (STZ on day of birth), which develops mild hyperglycemia, have an approximately 50% reduction in pancreatic insulin content, and no insulin resistance. The diabetic rats were given oral gliclazide (10 mg/kg/day) and compared with untreated diabetic rats and nondiabetic rats. Insulin secretion was studied the day after the last gliclazide dose using the isolated perfused pancreas preparation. In severely hyperglycemic n5-STZ rats (plasma glucose levels greater than 16 mmol/L) the long-term gliclazide treatment did not lower the plasma glucose values, did not affect pancreatic insulin stores, and did not significantly modify in vitro insulin release in response to glucose or arginine. In moderately hyperglycemic n5-STZ rats (plasma glucose levels less than 16 mmol/L) the plasma glucose levels declined progressively and reached a mean of 8 mmol/L at the end of gliclazide therapy. The increase in pancreatic insulin stores in n5-STZ rats remained marginal. In the n0-STZ rats gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores. After gliclazide therapy in both the n5-STZ gliclazide responder group and the n0-STZ group: (a) in vitro glucose-induced insulin secretion was increased three- to fivefold; (b) the response to arginine, which is increased in diabetic rats, was amplified by two- to threefold; (c) insulin release in response to gliclazide was unchanged. In conclusion, long-term gliclazide therapy augments stimulated insulin secretion in these two rat models of NIDDM and does not induce any refractoriness to short-term sulfonylurea administration. The improvement of beta-cell function observed here was not related to the concomitant variations of hyperglycemia and/or pancreatic insulin content.

Animals↗

PubMed1991

Increased insulin action in the rat after protein malnutrition early in life.

The effect of a limited period of low protein feeding in young rats on insulin secretion and insulin action during adult-age has been studied. Four-week-old rats were maintained for 4 weeks on isocaloric diets containing 5% protein (low protein) or 15% protein (control). The low protein rats gained weight at a considerably lower rate than the control rats. This was obtained in the absence of any decrease of spontaneous food intake. Basal plasma insulin levels were decreased (p less than 0.01) by 40% in low protein rats. However, the glucose-stimulated insulin secretion obtained in vivo after an i.v. glucose load remained normal. The basal plasma glucose level in the low protein rats was only marginally decreased (by 20%). The tolerance to i.v. glucose was found to be slightly enhanced in the low protein rats as compared to the control rats as shown by a significantly increased K value (p less than 0.01). In vivo insulin action in the low protein rats was investigated using the euglycaemic-hyperinsulinaemic clamp technique in conjunction with isotopic measurements of glucose turnover. The overall glucose utilization rate was normal in the basal state but significantly increased (p less than 0.05) when measured at a submaximal plasma insulin level. The basal hepatic glucose production in the low protein rats was similar to that in the control rats. During the clamp studies, the suppression of endogenous glucose production was found to be similar in the low protein rats and the control rats but this was obtained at significantly lower (p less than 0.01) steady-state insulin levels in the low protein group than in the control group. In conclusion, the current results indicate that the modest improvement of glucose tolerance which is revealed in the low protein rats results from changes in the insulin action upon the target tissues: both the insulin-mediated glucose uptake by peripheral tissues and the ability of insulin to suppress hepatic glucose output are enhanced.

Aging↗

PubMed1991

Neonatal streptozotocin injection: a model of glucotoxicity?

Adult rats injected with streptozotocin during the neonatal period displayed in the fed state moderate hyperglycemia. However, the percentages of glycated hemoglobin in erythrocytes and glycated lactate dehydrogenase in liver and pancreatic islets, as well as the sorbitol and glycogen content of the islets, were not significantly increased. Likewise, in intact islets, the ouabain-sensitive inflow of 86Rb+, and the ratio between 3H2O production from D-[2-3H]glucose and D-[5-3H]glucose were not different in control and streptozotocin-injected rats. These findings suggest that the alteration in both the mitochondrial catabolism of D-glucose and secretory response to the hexose previously documented in the islets of the latter animals are not attributable to factors such as the excessive nonenzymatic glycation of cytosolic proteins, sorbitol or glycogen accumulation, or impaired Na+, K(+)-adenosine triphosphatase (ATPase) activity. Although a contributive role of glucotoxicity in the impaired function of beta cell in this model of non-insulin-dependent diabetes should not be ruled out, it is speculated that streptozotocin might also cause a long-term damage of key mitochondrial dehydrogenases in the pancreatic beta cells and, possibly, their precursor cells.

Animals↗

PubMed1991

Abnormal B-cell function in rats with non-insulin-dependent diabetes induced by neonatal streptozotocin: effect of in vivo insulin, phlorizin, or vanadate treatments.

Neonatal rats treated with streptozotocin on day 5 after birth (n5-STZ model) exhibited, when fully grown, a frank basal hyperglycemia (17.4 +/- 0.7 vs. 6.6 +/- 0.2 mmol/L in nondiabetic rats), a specific failure of glucose-induced insulin release, and hyperresponse to arginine. To investigate whether or not chronic correction of the hyperglycemia can improve the defects on insulin secretion, we tested diverse maneuvers, all of which aimed to lower chronically the hyperglycemia. Insulin secretion was studied with the isolated perfused pancreas preparation. A 16-day subcutaneous insulin therapy (approximately 10 U/kg/day) unevenly correcting the plasma glucose levels (10.8 +/- 1.6 mmol/L) did not improve the lack of insulin response to glucose while the arginine-induced insulin release returned to values close to normal. A 28-day intraperitoneal phlorizin infusion (50 mg/kg/day0 or a 20-day oral vanadate administration (40 mg/kg/day) caused near normalization of the basal plasma glucose level in the treated n5-STZ rats (7.8 +/- 0.5 and 8.2 +/- 0.5 mmol/L, respectively). Nevertheless, these treatments did not correct the insulin secretion in response to glucose nor the hyperresponsiveness to arginine. Furthermore, we investigated whether or not glucopenia in vitro could restore the glucose-induced insulin release in this diabetic model. After a 50 min glucose-free period, the insulin response to a subsequent glucose stimulation still did not materialize. These observations suggest that in the present n5-STZ diabetic model, (a) hyperresponsiveness to arginine cannot be solely regarded as a residual effect of hyperglycemia; (b) the return to normal values of insulin release in response to arginine after insulin therapy, despite a still prevailing mild hyperglycemia, suggests that exogenous insulin per se may regulate to some extent the diabetic B cells; and (c) near normalization of the basal glucose levels is not a sufficient condition to obtain improvement of the B-cell response to glucose, such a finding being consistent with the concept that stringent normalization of glycemia is a prerequisite.

Animals↗

PubMed1991

Increased insulin action in rats with mild insulin deficiency induced by neonatal streptozotocin.

The effect of chronic moderate insulin deficiency on in vivo insulin action was studied in young rats after neonatal (day of birth) streptozotocin (n0-STZ model) at a time (4 wk) when basal hyperglycemia is not yet established. The insulin action was quantified in vivo during insulin-glucose clamps performed on anesthetized rats while in the postabsorptive state; under basal or hyperinsulinemic conditions, total glucose production and utilization were assessed with a [3- 3H]-glucose perfusion, and local glucose utilization was estimated by measuring 2-deoxy-D-[1-3H]glucose 6-phosphate accumulation in various tissues. Compared with controls, the 4-wk-old n0-STZ rats were normoglycemic and hypoinsulinemic (P less than 0.05). The basal glucose production rate in the diabetics was significantly greater (P less than 0.05). During the clamp studies, suppression of endogenous glucose production by submaximal (1 nmol/l) or maximal (30 nmol/l) hyperinsulinemia was similar in both groups. Overall glucose utilization in the diabetics was significantly higher in the basal state and, after submaximal or maximal hyperinsulinemia, it remained significantly greater (P less than 0.001) than the corresponding utilization in the controls. This was correlated with an increased stimulation of glucose utilization in soleus muscle, diaphragm, white adipose tissue, and brown adipose tissue. In vitro studies using inguinal adipocytes showed that the glucose oxidative pathway retained normal sensitivity to insulin in the n0-STZ rats while the glucose conversion into lipids was significantly higher at sub-maximal insulin concentration compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1991

Increased insulin action in cultured hepatocytes from rats with diabetes induced by neonatal streptozotocin.

Previous studies have shown that Wistar rats injected at birth (n0) with STZ (n0-STZ) develop as adults a noninsulin-dependent diabetic state characterized by a lack of insulin response to glucose in vivo, a mild basal hyperglycemia, and an impaired glucose tolerance. Our former in vivo studies using the insulin-glucose clamp technique revealed an increased insulin action upon hepatic glucose production in these animals. We have now cultured hepatocytes from these mildly diabetic rats in parallel with hepatocytes from control rats, to examine more closely basal and insulin-regulated glucose production and glucose incorporation into glycogen. In addition, we extended our investigation to other hepatic functions such as lipid synthesis and amino acid transport, which could not be studied in vivo. Although glucose production from glycogenolysis or gluconeogenesis in absence or presence of glucagon was identical in the two cell populations, glucagon-stimulated glycogenolysis was more sensitive to insulin action in diabetic hepatocytes. Similarly, insulin action on glucose incorporation into glycogen, lipogenesis, and amino acid transport were enhanced in diabetic hepatocytes. The hormone effect was manifested by an increase in the sensitivity and/or in the responsiveness, reflecting the multiplicity of the pathways whereby the insulin signal is transduced through the insulin receptor to multiple postreceptor sites. To gain insight into the possible mechanism of these disturbances, we evaluated the initial insulin receptor interaction and the kinase activity of the receptor beta-subunit. In accordance with our previous study on intact livers, we found no alteration in either of these parameters in n0-STZ rat hepatocytes. Thus, the present study clearly demonstrates that these diabetic rats exhibit a postreceptor hyperresponsiveness to insulin at the cellular level. It strengthens the notion that a beta-cell deficiency with glucose intolerance does not necessarily lead to a hepatic insulin resistance.

Aminoisobutyric Acids↗

PubMed1991

Differential effects of prolonged hyperglycemia on in vivo and in vitro insulin secretion in rats.

The purpose of this study was to investigate the effects of a 48-h glucose (30% wt/vol) infusion in unrestrained catheterized healthy rats (HG) on subsequent in vivo and in vitro insulin response to glucose. High hyperglycemia (400-450 mg/dl) and resulting hyperinsulinemia (1.2 +/- 0.1 mU/ml vs. 0.15 +/- 0.03 mU/ml in controls) were maintained throughout the infusion period. Glucose-induced insulin secretion was examined in vivo 3 h after the end of infusion by performing either a glucose tolerance test or a hyperglycemic clamp (225 mg/dl for 60 min). In addition, in vivo insulin secretion was studied on day 1, 3, 5, and 7 after the end of glucose infusion by performing glucose tolerance tests. Insulin secretion was also investigated in vitro, using the isolated perfused pancreas technique, 3 h and 1 day post glucose infusion. During glucose tolerance tests and hyperglycemic clamps performed at 3 h, insulin secretion was much greater in HG rats than in controls, and remained increased until day 5. By contrast, when studied in vitro 3 h after the end of the infusion, glucose-induced insulin release from isolated perfused pancreases was impaired in HG rats as compared with controls, and the insulin response to arginine was dramatically increased. However, insulin secretion in vitro returned partially to normal after day 1. These data indicate that prolonged hyperglycemia has quite different effects on the subsequent insulin secretion in vivo or in vitro. It impairs, but reversibly, glucose-induced insulin secretion in vitro, whereas it increases it durably in vivo. This suggests that humoral and/or nervous interferences can counterbalance the possible perturbing effects of prolonged hyperglycemia on the normal B cell responsiveness to glucose.

Animals↗

PubMed1991

Impairment of glycerol phosphate shuttle in islets from rats with diabetes induced by neonatal streptozocin.

In islets from adult rats injected with streptozocin during the neonatal period, the oxidative and secretory responses to D-glucose are more severely affected than those evoked by L-leucine. A possible explanation for such a preferential defect was sought by comparing the rate of aerobic glycolysis, taken as the sum of D-[3,4-14C]glucose conversion to labeled CO2, pyruvate, and amino acid, with the total glycolytic flux, as judged from the conversion of D-[5-3H]glucose to 3H2O. A preferential impairment of aerobic relative to total glycolysis was found in islets from diabetic rats incubated at either low or high D-glucose concentration. This coincided in islet mitochondria of diabetic rats with a severe decrease in both the basal (no-Ca2+) generation of 3H2O from L-[2-3H]glycerol-3-phosphate and the Ca2(+)-induced increment in [3H]glycerophosphate detritiation. The mitochondria of diabetic rats were also less efficient than those of control animals in generating 14CO2 from [1-14C]-2-ketoglutarate. The diabetes-induced alteration of 2-ketoglutarate dehydrogenase in islet mitochondria was less marked, however, than that of the FAD-linked glycerophosphate dehydrogenase and was not associated with any change in responsiveness to Ca2+. Sonicated islet mitochondria of diabetic rats displayed normal to slightly elevated glutamate dehydrogenase activity. We propose, therefore, that the preferential impairment of the oxidative and secretory responses of islet cells to D-glucose in this experimental model of diabetes may be at least partly attributable to an altered transfer of reducing equivalents into the mitochondria as mediated by the glycerol phosphate shuttle.

Animals↗

PubMed1991

Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes.

In early 1988, a colony of GK rats was started in Paris with progenitors issued from F35 of the original colony reported by Goto and Kakisaki. When studied longitudinally up to 8 mo, GK rats showed as early as 1 mo (weaning) significantly higher basal plasma glucose (9 mM) and insulin levels (doubled), altered glucose tolerance (intravenous glucose), and a very poor insulin secretory response to glucose in vivo compared with Wistar controls. Males and females were similarly affected. Studies of in vitro pancreatic function were carried out with the isolated perfused pancreas preparation. Compared with nondiabetic Wistar rats, GK rats at 2 mo showed a significantly increased basal insulin release, no insulin response to 16 mM glucose, and hyperresponse to 19 mM arginine. Pancreatic insulin stores were only 50% of that in Wistar rats. Perfusion of GK pancreases for 50 or 90 min with buffer containing no glucose partially improved the insulin response to 16 mM glucose and markedly diminished the response to 19 mM arginine, whereas the responses by Wistar pancreases were unchanged. These findings are similar to those reported in rats with non-insulin-dependent diabetes induced by neonatal streptozocin administration and support the concept that chronic elevation in plasma glucose may be responsible, at least in part, for the beta-cell desensitization to glucose in this model. The GK rat seems to be a valuable model for identifying the etiology of beta-cell desensitization to glucose.

Aging↗

PubMed1990

Impairment of the mitochondrial oxidative response to D-glucose in pancreatic islets from adult rats injected with streptozotocin during the neonatal period.

Pancreatic islets removed from adult rats injected with streptozotocin during the neonatal period display an impaired secretory response to D-glucose and, to a lesser extent, to L-leucine. Despite normal to elevated hexokinase and glucokinase activities in the islets of these glucose-intolerant animals and despite normal mitochondrial binding of the hexokinase isoenzymes, the metabolic response to a high concentration of D-glucose is severely affected, especially in terms of D-[6-14C]glucose oxidation. Thus, the ratio in D-[6-14C]glucose oxidation/D-[5-3H]glucose utilization is much less markedly increased in response to a rise in hexose concentration and, at a high concentration of D-glucose (16.7 mmol/l), less markedly decreased by the absence of Ca2+ and presence of cycloheximide in diabetic than control rats. This metabolic defect contrasts with (1) a close-to-normal or even increased capacity of the islets of diabetic rats to oxidize D-[6-14C]glucose, [2-14C]pyruvate, L-[U-14C]glutamine and L-[U-14C]leucine at low, non-insulinotropic, concentrations of these substrates; (2) a lesser impairment of the oxidation of L-[U-14C]leucine tested in high concentration (20 mmol/l), the effect of Ca2+ deprivation upon the latter variable being comparable in diabetic and control rats; (3) an unaltered transamination of either [2-14C]pyruvate or L-[U-14C]leucine; and (4) a modest perturbation of glycolysis. The most obvious alteration in glycolysis consists in a lesser increase of the glycolytic flux in response to a rise of D-glucose concentration in diabetic than control rats, this coinciding with an apparent decrease in affinity of glucokinase for the hexose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗