Streptozocin Administration Research Articles

Fetal vascular responses to maternal glucose administration in streptozocin-induced ovine diabetes mellitus.

To assess the impact of administration of a glucose load to the pregnant diabetic ewe on fetal biochemistry and umbilical-placental perfusion. Six pregnant ewes were rendered glucose intolerant by the administration of streptozocin at 85-90 days gestation. An intravenous glucose load was administered to the 6 diabetic ewes and 4 control animals at 125-130 days gestation. Assessment of the fetal responses to this glucose load was made by cardiovascular monitoring, biochemical evaluation and measurement of fetal blood flows by the radioactive microsphere technique. In the fetus of the diabetic ewe the arterial pH progressively decreased from 7.36 +/- 0.04 to 7.10 +/- 0.09 (p < 0.05) 180 minutes after the maternal glucose load. These fetuses displayed a consistent and significant reduction in arterial oxygen tension compared to controls, with a decrease in pO2 from 14.9 +/- 3.3 mmHg at baseline to 11.3 + 3.7 mmHg after 180 minutes. Umbilical-placental blood flow did not alter significantly in the fetus of the diabetic ewe following glucose administration, although in the control fetuses there was a significant reduction from baseline after 60 minutes. Blood flow to the fetal brain and kidney were significantly elevated in the fetus of the diabetic ewe compared to control at all times, suggesting a metabolic adaptation to preserve oxygen delivery may be present. Maternal hyperglycemia produces profound metabolic alterations in the ovine fetus which are unaccompanied by significant alterations in umbilical-placental blood flow. In the chronically hyperglycemic pregnant ewe, a glucose load produces a major disturbance of fetal homeostasis.

Streptozotocin-induced diabetes increases (Ca2+-Mg2+)-ATPase activity in hepatic plasma membranes of rats: involvement of protein kinase C.

The alteration in calcium transport in the liver of rats with streptozocin(STZ)-diabetic state was investigated. STZ (6 mg/100 g body weight) was subcutaneously administered in rats, and 1 or 2 weeks later they were sacrificed by bleeding. STZ administration caused a remarkable elevation of serum glucose concentration. Liver calcium content was significantly increased by STZ administration. Hepatic plasma membrane (Ca2+-Mg2+)-ATPase activity was markedly elevated by STZ administration. This increase was completely abolished by the presence of staurosporine (10(-7)-10(-5) M), an inhibitor of protein kinase C, in the enzyme reaction mixture, suggesting an involvement of protein kinase C signalling. Moreover, the STZ-induced increase in liver plasma membrane (Ca2+-Mg2+)-ATPase activity was significantly raised by the presence of okadaic acid (10(-5) and 10(-4) M). Meanwhile, the STZ-increased (Ca2+-Mg2+)-ATPase activity was not appreciably altered by the presence of anti-regucalcin IgG in the reaction mixture, indicating that the activatory protein regucalcin does not participate in the elevation of the enzyme activity. The present study demonstrates that STZ-induced diabetes causes the increase in hepatic plasma membrane (Ca2+-Mg2+)-ATPase activity of rats.

Attenuation by nicotinamide of the streptozocin induced early hyperglycaemia in fasting rats.

The effect of nicotinamide on the streptozocin induced early hyperglycaemia in 48-hour fasted rats was investigated. It was shown that 240 or 400 mg/kg nicotinamide significantly attenuated the streptozocin induced early hyperglycaemia. Nicotinamide should be administered no later than 1 hour after the streptozocin administration. Lower level doses of nicotinamide such as 80 mg/kg were unable to attenuate the streptozocin induced early hyperglycaemia. The possibility of nicotinamide offsetting the streptozocin effect was discussed.

Reduction by streptozocin of blood glucose utilization during the appearance of the streptozocin induced early hyperglycaemia in fasting rats.

During the fasting state, in which the hepatic glycogen storage is almost depleted, streptozocin administration (60 mg/kg, iv) also induces an early hyperglycaemia. It was found that the blood glucose concentration in the hepatic vein was significantly higher than that in the tail vein before and at 4 hours after the injection of the vehicle without streptozocin. However, the blood glucose concentration in the hepatic vein was insignificantly different from that in the tail vein 4 hours after streptozocin administration. The data are interpreted as showing that streptozocin may reduce blood glucose utilization during the period of early hyperglycaemia induced by streptozocin.

Decreased Adrenal Medullary Catecholamine Release in Spontaneously Diabetic BB-Wistar Rats: Role of Hypoglycemia

We have demonstrated previously that spontaneously diabetic BB-Wistar rats exhibit decreased adrenal medullary catecholamine secretion in response to splanchnic nerve terminal stimulation. We hypothesized that this abnormality is caused by changes in the sensitivity of the adrenomedullary chromaffin cells to acetylcholine (ACh). To study this hypothesis, we isolated adrenal glands from control and spontaneously diabetic BB-Wistar rats, perfused them with ACh, and measured catecholamine secretion. Adrenal catecholamine release in response to ACh was significantly decreased at 2, 8, and 16 weeks after the onset of diabetes compared with age-matched, nondiabetic control rats. Catecholamine release in response to perfusion with 20 mM K+ was the same in adrenals from diabetic and control rats. The decreased responsiveness of diabetic rat adrenals to perfusion with ACh was significantly correlated with a decrease in the release of catecholamines in response to splanchnic nerve stimulation. A similar defect in catecholamine secretion was also seen in adrenals harvested from nondiabetic BB-Wistar rats following a 3-h period of acute hypoglycemia; however, the adrenal response to potassium was also decreased as was the catecholamine content of the adrenal. Conversely, nondiabetic BB-Wistar rats made diabetic with streptozocin (STZ) and maintained in a hyperglycemic state did not exhibit catecholamine hyposecretion 2 weeks after STZ administration. Collectively, the data describe decreased adrenomedullary response to cholinergic stimulation in spontaneously diabetic rats as early as 2 weeks after the onset of diabetes and that a similar, although more severe, hyposecretion occurs after acute, severe hypoglycemia.

Multiple low-dose streptozocin-induced diabetes in NOD-scid/scid mice in the absence of functional lymphocytes.

The murine severe combined immunodeficiency (scid) mutation was used to assess whether the diabetogenic effects of multiple low-dose streptozocin (MD-STZ) administration required the presence of functional T-cells. An STZ dose as low as 30 mg/kg body wt for 5 days induced hyperglycemia in young NOD/Lt-+/+ male mice, whereas a dose of 50 mg/kg for 5 days was required to elicit comparable hyperglycemia in C.B.-17-+/+ male mice. The greater NOD strain sensitivity was not a function of preexisting insulitis, because insulitis- and diabetes-free NOD male mice congenic for a diabetes-resistant major histocompatibility complex haplotype were equally susceptible to MD-STZ. This was confirmed in NOD-scid/scid and C.B.-17-scid/scid males. Both were completely insulitis-free, and despite the absence of functional T- cells and B-cells, both congenic stocks were as sensitive to MD-STZ as congenic +/+ controls. Indeed, MD-STZ-induced hyperglycemia in NOD-scid/scid male mice was significantly higher than in NOD/Lt-+/+ male mice. The NOD-scid/scid mouse as a recipient of adoptively transferred splenocytes clearly delineated a distinct pathogenesis of spontaneous insulin-dependent diabetes mellitus (IDDM) versus MD-STZ-induced hyperglycemia. Splenocytes from spontaneously diabetic NOD/Lt males, but not those from donors given MD-STZ, readily transferred IDDM, even when host beta-cells were sensitized by a single injection of STZ before adoptive transfer. We conclude that IDDM induced by MD-STZ is not mediated by T-cell- or B-cell-dependent autoimmune mechanisms in a fashion analogous to the spontaneous IDDM characteristic of NOD mice.

ACTH4-9 analogue ORG 2766 can improve existing neuropathy in streptozocin-induced diabetic rats.

The effect of treatment of an existing neuropathy in streptozocin-induced diabetic rats with the ACTH4-9 analogue ORG 2766 was examined. Four groups of rats were studied: group 1 consisted of age-matched, non-diabetic controls and groups 2, 3 and 4 of diabetic rats. Sensory and motor nerve conduction velocity (SNCV and MNCV) were measured at weeks 0, 4, 6, 8 and 10. Four weeks after the administration of streptozocin (STZ) all diabetic rats showed a significant slowing of SNCV and MNCV. Treatment was then started: group 2 was treated with placebo, group 3 with a low dos (1 microgram) of ACTH4-9 subcutaneously every 48 h, and group 4 with a high dos (10 micrograms) of ACTH4-9 subcutaneously every 48 h. The animals treated with the high peptide dosage showed a significant improvement in both SNCV and MNCV from week 6 onwards, whereas this beneficial effect was not demonstrated for the rats treated with the low dosage. This study demonstrates that the ACTH4-9 analogue ORG 2766 can ameliorate existing diabetic neuropathy in STZ-induced diabetic rats.

Ganglioside Treatment Modifies Abnormal Elemental Composition in Peripheral Nerve Myelinated Axons of Experimentally Diabetic Rats

Effects of ganglioside administration on elemental composition of peripheral nerve myelinated axons and Schwann cells were determined in streptozotocin-induced diabetic rats and nondiabetic controls. Diabetic rats (50 days after administration of streptozocin) exhibited a loss of axoplasmic K and Cl concentrations in sciatic nerve relative to control, whereas intraaxonal levels of these elements increased in tibial nerve. These regional changes in diabetic rat constitute a reversal of the decreasing proximodistal gradients for K and Cl concentrations that characterize normal peripheral nerve. Treatment of diabetic rats with a ganglioside mixture for 30 days (initiated 20 days after the administration of streptozocin) returned proximal sciatic nerve axoplasmic K and Cl concentrations to control levels, whereas in tibial axons, concentrations of these elements increased further relative to diabetic levels. Also in the ganglioside/diabetic group, mean axoplasmic Na concentrations were reduced and Ca levels were elevated. Mixed ganglioside treatment of nondiabetic rats significantly increased axoplasmic dry weight concentrations of K and Cl in proximal sciatic and tibial axons. Schwann cells did not exhibit consistent alterations in elemental content regardless of treatment group. Changes in elemental composition evoked by ganglioside treatment of diabetic rats might reflect the ability of these substances to stimulate Na+,K(+)-ATPase activity and might be related to the mechanism by which gangliosides improve functional deficits in experimental diabetic neuropathy.

Time-dependent regulation of rat adipose tissue glucose transporter (GLUT4) mRNA and protein by insulin in streptozocin-diabetic and normal rats

Streptozocin (STZ) administration (125 mg/kg) to normal rats resulted in a rapid (24-hour) decrease in circulating insulin levels, marked hyperglycemia, and weight loss. Adipose tissue glucose transporter 4 (GLUT4) mRNA levels decreased approximately eightfold, whereas GLUT4 protein levels were unchanged. However, GLUT4 protein levels decreased approximately 30% by 48 hours and fivefold by 72 hours of insulin deficiency. Although GLUT4 mRNA levels were rapidly restored by insulin therapy (twofold above control levels within 12 hours), GLUT4 protein levels increased only gradually, reaching peak values of 1.5-fold control levels following 7 to 10 days of insulin treatment. Insulin treatment in normal rats increased adipose GLUT4 mRNA levels nearly 100% by 24 hours, while GLUT4 protein levels increased in a more gradual fashion. The delay in GLUT4 protein induction relative to its mRNA was shorter in normal rats treated with insulin than in insulin-treated diabetic rats. These data demonstrate that insulin-induced changes in adipose GLUT4 protein are considerably delayed relative to its mRNA, and that the diabetic state enhances this difference. The known in vivo time-dependent effects of insulin treatment on adipocyte glucose transport activity can be at least partly explained by altered specific expression of GLUT4 protein.

Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus.

An elevated plasma proinsulin (PI) to immunoreactive insulin (IRI) ratio occurs in relatives of patients with insulin-dependent diabetes mellitus and in subjects with non-insulin-dependent diabetes mellitus. To determine whether this alteration is the result of B-cell dysfunction and/or insulin resistance, we infused nicotinic acid for 3 weeks to produce insulin resistance in five adolescent male baboons before and after the administration of streptozocin (200 mg/kg). We measured basal PI and IRI levels and the acute incremental PI (APIR) and IRI (AIRIR) responses to iv arginine. The quantity of IRI comprised of PI was calculated in the basal state (PI/IRI) and following arginine injection (APIR/AIRIR). Streptozocin administration did not change the fasting plasma glucose (FPG) compared to that in the normal animals (4.7 +/- 0.3 vs. 4.3 +/- 0.2 mM) but raised the PI/IRI (16.4 +/- 3.4 vs. 5.9 +/- 1.7%) and APIR/AIRIR (7.1 +/- 1.0 vs. 2.8 +/- 1.0%) due to a concurrent reduction in IRI and increase in PI concentrations. The induction of experimental insulin resistance with nicotinic acid in the normal animals had no effect on the FPG (4.4 +/- 0.2 mM) but in the streptozocin treated animals, fasting hyperglycemia (8.3 +/- 1.7 mM) developed. Neither the basal PI/IRI (10.2 +/- 2.2%) or the APIR/AIRIR (2.3 +/- 0.6%) increased in the insulin-resistant streptozocin animals thus being no different to that of normal control animals before or during experimental insulin resistance. We conclude that disproportionate proinsulinemia is a manifestation of B-cell damage from streptozocin which is not exacerbated by insulin resistance or hyperglycemia.

The metabolic clearance rate of epinephrine in the fetus of the diabetic ewe

Delayed organ maturation is a characteristic of the fetus of the diabetic mother with poor glucose control. We hypothesized that the ovine fetal catecholamine maturation sequence would be delayed in the fetus of the diabetic ewe. Twelve pregnant ewes were rendered glucose intolerant by the administration of streptozocin at 85 to 95 days' gestation. Maternal diabetic status was verified with fasting blood glucose assessments. The fetal metabolic clearance rate of epinephrine was determined at 126 to 140 days' gestation by the constant infusion of 0.1 μg epinephrine per kilogram estimated fetal weight per minute. Fetal arterial blood gas values, lactate, glucose, and insulin levels were measured before infusion; after 20, 30, and 40 minutes of epinephrine infusion; and 15, 30, and 60 minutes after cessation of infusion. Fetal plasma glucose rose significantly from a control level of 42.1 ± 8.2 to 64.6 ± 5.9 mg/dl during the epinephrine infusion (p < 0.05). Fetal insulin levels increased from a baseline of 9.2 ± 2.6 μIU/ml to 32.4 ± 18.0 in the recovery period (p < 0.05), and lactate levels similarly rose from 36.4 ± 4.8 to 52.2 ± 8.2 mg/dl (p < 0.05). The plasma epinephrine production rates did not vary significantly between fetuses <135 and τ135 days' gestation (15.4 ± 1.5 vs 13.9 ± 2.0 ng/min, p τ 0.5). The fetal metabolic clearance rate of epinephrine at early gestations (< 135 days) was similar to that of the fetus of the nondiabetic ewe (35.3 ± 3.4 vs 28.0 ± 4.3 ml/min/kg, p τ 0.2). However, at later gestations (τ135 days) the fetus of the diabetic ewe did not have the increase in the metabolic clearance rate previously published for the control fetus (32.0 ± 4.6 vs 133.7 ± 41.7 ml/min/kg, p < 0.05). These data appear to indicate an absence in the maturation of the metabolic clearance rate of epinephrine in the fetus of the diabetic ewe. The observed alteration in the metabolic clearance rate of epinephrine of the fetus of the diabetic ewe could potentially impair the response to stress. (AM J OBSTET GYNECOL 1991;165:1655-60.)

Effects of Insulin and myo-Inositol on Embryo Growth and Development During Early Organogenesis in Streptozocin-Induced Diabetic Rats

We have previously shown that myo-inositol depletion in the embryonic tissue at a critical stage of organogenesis has a crucial role in hyperglycemia-induced embryopathy. This study tested whether myo-inositol depletion in early organogenesis contributes to the pathogenesis of streptozocin-induced diabetic embryopathy. Rats were made diabetic by streptozocin administration before conception, and the diabetic rats were treated with diet supplemented by 2% myo-inositol or insulin from 6 to 11 gestational days during the period of maximum teratological susceptibility. In each group on the 11th gestational day, growth retardation and incidence of malformations were recorded, and myo-inositol and sorbitol content in the embryonic and extraembryonic tissues were examined. In diabetic rats, the myo-inositol content of the embryos was decreased by 36% (P less than 0.01) compared with control rats, and there was growth retardation (crown-rump length 3.37 +/- 0.04 vs. 3.87 +/- 0.03 mm, P less than 0.01; somite no. 27.5 +/- 0.2 vs. 29.1 +/- 0.2, P less than 0.01) and a significantly increased incidence of the neural lesions (17.6 vs. 1.9%, P less than 0.01). Insulin treatment resulted in near normalization of maternal serum glucose and complete restoration of myo-inositol content in the embryos with significant improvement of the growth retardation (crown-rump length 3.55 +/- 0.06 vs. 3.37 +/- 0.04 mm, P less than 0.05; somite no. 28.2 +/- 0.13 vs. 27.5 +/- 0.2, P less than 0.05) and a significantly lowered incidence of neural lesions (2.5 vs. 17.6%, P less than 0.01) compared with those of the untreated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Superoxide dismutase in low-dose-streptozocin-treated mice

Superoxide dismutase (SOD) is a free-radical scavenger present in B cells. It is thought to be responsible for protection against the autoimmune processes that characterize type I diabetes mellitus. Streptozocin (STZ) has been used as a low-dose treatment (LDS) to induce diabetes in animal models. The aim of this study was to follow the islet SOD levels in a day-to-day study after an LDS treatment with STZ, 40 mg/kg body wt/d in C57BL6/J mice. Results reveal a progressive SOD decrease in pancreatic islets with increasing periods from the LDS treatment. This SOD decrease starts from the end of the STZ administration (d 5). In addition, it was noticed that glycemia starts to rise when SOD values have already reached their lowest levels. This indicates that a reduction of free-radical defense is a prerequisite for further cellular injuries. Furthermore, a difference was noticed between males and females: only 40% of female mice underwent a SOD decrement and an increase in glycemia, indicating an androgen-dependent mechanism.

Low-Dose Streptozocin-Induced Autoimmune Diabetes in Islet Transplantation Model

An islet transplant model was used to gain further insight into the immunologic mechanisms involved in low-dose streptozocin (STZ)-induced diabetes. As shown by others, male C57BL/KsJ mice developed diabetes and insulitis after five daily injections of STZ (40 mg.kg-1.day-1). Syngeneic islet transplants beneath the renal capsule developed insulitis when the islets were transplanted 10-14 days before the daily injections of STZ. In contrast, insulitis of the grafts did not occur when the syngeneic transplants were done 3 days after the five daily injections of STZ. If the donor islets were incubated in vitro with 0.5 mg/ml STZ for 1 h at 37 degrees C and then transplanted after the low-dose STZ administration of the recipients, then a definite insulitis was present in the syngeneic transplants. These findings indicated that this brief exposure to STZ in vitro was sufficient to permit immunologic recognition of the grafts. In vitro STZ-exposed islets transplanted into high-dose STZ-induced diabetic mice also developed insulitis, whereas STZ-exposed islets transplanted into alloxan-induced diabetic mice did not. Donor islets incubated in vitro with STZ and transplanted into unexposed mice did not develop insulitis in the grafts. Thus, preexposure of the recipient to STZ is essential to the development of insulitis within in vitro STZ-exposed islet grafts. This is also specific to islets because in vitro STZ-exposed thyroid tissue transplanted into low-dose STZ recipients failed to exhibit a thyroiditis. These data are consistent with the idea that STZ immunologically alters the beta-cell by inducing an antigenic change.

β-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.

Capillary area in early low-dose streptozocin-treated mice

It has been reported that vasoconstriction of intra-islet capillaries plays an important role in the initiation of the insulitis seen in the islets of Langerhans of diabetic animals. Nevertheless, only a few studies have concentrated on islet vessels. This led us to perform an experiment with the aim to compare the islet capillary area of normal untreated and multiple low-dose streptozocin (LDS) (40 mg/kg b.wt. i.p./5 days)-treated mice. In order to identify endothelial cells a method devised by Gomori, based on the fact that these cells present alkaline phosphatases on their surface, was used. Results revealed that in LDS-treated animals the capillary area per islet is significantly reduced when compared to the vascular area of controls (p less than 0.05). This could be due to a vasoconstriction phenomenon that occurs in the islet capillaries after the streptozocin administration and before the appearance of any inflammation. Our findings could demonstrate that vasoconstriction events are involved in initiation of the diabetic disease.

Decreased Insulin- and Glucagon-Pulse Amplitude Accompanying β-Cell Deficiency Induced by Streptozocin in Baboons

The effect of beta-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of beta-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate. Highly regular pulses were less prevalent in baboons compared with rhesus monkeys and humans, but the mean frequency was similar and was not affected by treatment. The principal effect of beta-cell destruction was to proportionately reduce the pulse amplitude of insulin (-39%, P less than .003) without detectable change in pulse frequency, interhormonal phase relationship, or the regularity of pulses. Glucagon-pulse amplitude also fell (-19%, P less than .09), but not significantly. However, glucagon-pulse amplitude was strongly correlated with insulin-pulse amplitude (r = -.59, P less than .002), whereas mean fasting plasma concentrations of insulin and glucagon were not significantly changed after treatment. Because streptozocin affects only the beta-cell, the data indicate a major influence of the insulin pulse on the alpha-cell secretory pulse. The data do not support the presence of a separate pacemaker for the alpha-cell but do not eliminate this possibility. The strong correlation of reduction in insulin-pulse amplitude with increasing fasting glucose and decreasing glucose disappearance lends support to growing evidence that the pattern of insulin secretion is an important determinant of normal glucose homeostasis.

A signoidal relationship between liver stearoyl CoA desaturase activity and serum hormone concentrations caused by streptozocin and its antagonists

Stearoyl CoA desaturase activity in liver microsomes, and insulin, thyroxine, and triiodothyronine levels in serum were measured after administration of streptozocin (STZ) and its antagonists to rats. The effect of STZ, which caused hyperglycemia and inhibited the desaturase activity, was antagonized by 2-desoxyglucose and 3-O-methyl-glucose; 1-O-methyl-3-desoxyglucose and 1-O-methyl-3-O-methylglucose were without any effect. The enzyme activity plotted against insulin levels showed a broad sigmoidal curve, whereas the activities versus thyroid hormone levels showed steeper sigmoidal curves.

Influence of Lactation on Morphometric and Secretory Variables in Pancreatic β-Cell of Mildly Diabetic Rats

In nondiabetic rats, lactation accelerates the restoration of pancreatic beta-cell function after the period of increased secretory activity associated with pregnancy. To investigate whether a comparable situation prevails in mildly diabetic animals, streptozocin (22.5 mg/kg body wt) was administered to female rats at the onset of pregnancy. Plasma glucose and insulin concentrations, content and release of insulin in isolated islets, total mass and volume density of both the endocrine pancreas and granulated beta-cells, and ultrastructural prevalence of light and dark secretory granules were measured on the 20th day of pregnancy and in lactating and nonlactating animals 20 days after delivery. In the mildly diabetic animals, the changes in endocrine pancreatic function normally associated with pregnancy and lactation were greatly attenuated, albeit not completely eliminated. We propose that the increased biosynthetic and secretory activity imposed on surviving beta-cells after streptozocin administration tends to mask the adaptative changes in beta-cell function otherwise seen during the postpartum and lactation period.

Decreased myo-inositol content and Na+-K+-ATPase activity in superior cervical ganglion of STZ-diabetic rat and prevention by aldose reductase inhibition.

Decreased sciatic nerve myo-inositol content and Na+-K+-ATPase activity have been associated with slowing of motor nerve conduction in the acutely diabetic rat and have been invoked as possible pathogenic factors in diabetic peripheral neuropathy. Aldose reductase inhibitors prevent these abnormalities in peripheral nerves of the streptozocin (STZ)-diabetic rat. Whether an analogous biochemical abnormality occurs in the autonomic nervous system and plays a role in the development of diabetic autonomic dysfunction is unknown. Therefore we examined the effect of 8 wk of untreated STZ diabetes and administration of 20 mg X kg-1 X day-1 of the aldose reductase inhibitor sorbinil on myo-inositol level and Na+-K+-ATPase activity in rat superior cervical ganglia. Both myo-inositol concentration and Na+-K+-ATPase activity were reduced in ganglia from untreated STZ-diabetic rats, and sorbinil administration prevented these abnormalities. Thus, a sorbinil-responsive metabolic defect involving myotional abnormalities in the somatic and autonomic nervous systems in diabetes.