Long-term effects of vanadyl treatment on streptozocin-induced diabetes in rats

The vanadate and vanadyl forms of vanadium have been shown by many investigators to have insulinlike effects on glucose metabolism. Many investigators have shown that vanadium, or its salts, counteracts the hyperglycemia associated with streptozocin-induced diabetes (STZ-D) in the rat, although insulin secretion remains depressed. Studies of the action of vanadate on insulin secretion and glucose metabolism have not addressed the question of possible long-term effects of this compound on glucose metabolism extending beyond the period of oral administration. This study was undertaken to assess the effects of treatment (3 wk) and withdrawal of vanadyl sulfate (13 wk) on glucose metabolism, insulin secretion, and islet insulin content of STZ-D rats. Our results indicate that STZ-D rats that have had blood glucose levels normalized by 3 wk of vanadyl treatment remain normoglycemic after 13 wk of withdrawal from treatment. Normal glucose tolerance was observed in vanadyl-treated diabetic animals despite depressed fasting and glucose-stimulated plasma insulin levels. Insulin secretion from the isolated perfused pancreas was greater after vanadyl treatment than in untreated diabetic rats, although it was only 12% of values from controls. Three weeks of vanadyl treatment of STZ-D rats, followed by 13 wk of withdrawal, yielded islets close in size and insulin content of control islets, even though in vivo and in vitro insulin secretion was impaired. This study has shown that short-term vanadyl treatment of STZ-D rats yields normalization of glucose tolerance and protection of islets from destruction by STZ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasopressin in rats with genetic and streptozocin-induced diabetes

Rats were administered streptozocin (STZ; 50 or 75 mg/kg i.v., tail vein) or vehicle. Approximately 2 wk later, venous and arterial catheters was implanted for subsequent (24 h later) vasopressin, electrolyte, and hemodynamic measurements. STZ-induced diabetic (STZ-D) rats demonstrated a dose-dependent increase in the plasma glucose concentration, plasma osmolality, and plasma vasopressin concentration. Mean arterial blood pressure (MABP) was unchanged, but heart rate was reduced. Diabetes-prone BB rats, maintained on or withdrawn from insulin treatment for 24-48 h, and diabetes-resistant rats were instrumented and studied as above. Spontaneous-diabetes-prone rats demonstrated increase in plasma glucose concentration and plasma osmolality similar to STZ-D rats but had significantly greater plasma vasopressin concentrations. The significant decrease in MABP observed in these animals probably contributed to the enhanced vasopressin response. We conclude that both osmotic and cardiovascular parameters play important roles in vasopressin secretion in diabetic rats.     

Skeletal muscle proteolysis in rats with acute streptozocin-induced diabetes

Skeletal muscle proteolysis was studied in rats 1 day after induction of diabetes with 65 mg/kg streptozocin. An evisceration procedure, including functional hepatectomy-nephrectomy, was performed, and the rate of proteolysis in the remaining tissues, primarily skeletal muscles, was evaluated over 2 h. With cycloheximide to block protein synthesis, total protein breakdown was measured from the rate of rise in plasma tyrosine concentration. The rate of degradation of contractile (myofibrillar) protein was estimated from the rate of rise in plasma concentration of 3-methylhistidine released from the breakdown of actomyosin. Compared with nondiabetic control preparations, the total protein degradation rate was increased 30% by diabetes (P less than .001), and myofibrillar catabolism was accelerated by 60% (P less than .005). In diabetes, the increase in proteolysis was accompanied by reductions in circulating insulin to 25-50% of normal level, whereas food intake did not differ from control. Treatment of diabetic rats with exogenous insulin, including acute infusions postoperatively, completely reversed the proteolytic effects of diabetes. The findings demonstrate that the hypoinsulinemia of acute diabetes increases the catabolism of skeletal muscle protein and that the inhibitory effect of normal levels of insulin includes a specific action to restrain myofibrillar proteolysis.     

Effect of streptozocin-induced diabetes on insulin-receptor tyrosine kinase activity in obese Zucker rats

We examined insulin binding, insulin-stimulated autophosphorylation, and phosphorylation of poly(Glu.Na,Tyr)4:1 by liver and skeletal muscle insulin receptor from lean, obese, and obese streptozocin-induced diabetic Zucker rats. Induction of diabetes with streptozocin (30 mg/kg) lowered the lasting insulin level from 11.4 to 3.8 ng/ml, which was not significantly greater than the lean control level. Autophosphorylation and tyrosine kinase activity of liver insulin receptors were increased 70-100% in the obese control group (relative to lean rats), but diabetes reversed this hyperresponsiveness to insulin. In muscle, obesity was associated with a 40-50% decrease in autophosphorylation and tyrosine kinase activity, which was also reversed in the diabetic state. Autophosphorylation and tyrosine kinase activity were significantly correlated in liver and muscle and were also correlated with fasting insulin levels. These data suggest that insulin-receptor tyrosine kinase activity is regulated differently in liver and muscle and that the abnormalities in kinase activity associated with the obese Zucker rat are at least partly secondary to hyperinsulinemia.     

Cerebral taurine transport is increased during streptozocin-induced diabetes in rats.

Taurine is a cerebral osmolyte whose intracellular content changes in parallel with plasma osmolality. We conducted experiments to assess whether cerebral taurine transport is modified during chronic hyperglycemia. Rats with STZ-induced diabetes were studied after 1 wk of sustained hyperglycemia. Cerebral taurine uptake in synaptosomes (metabolically active nerve terminal vesicles) was measured using a rapid filtration technique. The synaptosomes were isolated by homogenization of the brain and purification on discontinuous Ficoll gradients (n = 8 synaptosome preparations). Diabetic rats (n = 13) displayed a 15-25% increase in synaptosomal taurine uptake compared with normoglycemic control animals (n = 12) at all time points assayed between 5 and 120 min. Thus, after a 30-min incubation, cerebral taurine uptake increased from a control level of 3.53 +/- 0.23 to 4.10 +/- 0.24 mumol/mg protein (n = 10) in hyperglycemic rats, P less than 0.03. The magnitude of the plasma-to-brain cell taurine gradient was unchanged in diabetic animals. The intrasynaptosomal taurine concentration (approximately 2 microM) and taurine efflux from the synaptosomes were no different in hyperglycemic versus control rats; efflux amounted to less than 2.5% of the uptake value at corresponding time points. Maximal brain taurine uptake under both control and experimental hyperglycemic conditions required the presence of external Na+ and Cl-. Synaptosomal taurine transport was reduced by competing beta-amino acids such as beta-alanine, beta-aminoisobutyric acid, and hypotaurine (P less than 0.01). Addition of oubain and the anionic binding site inhibitors, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid and 4,4'diisothio-cyanatostilbene-2,2'-disulfonic acid, also decreased cerebral taurine uptake under normoglycemic and hyperglycemic conditions (P less than 0.01). The increased synaptosomal taurine uptake by diabetic rats was not a result of generalized membrane dysfunction because glycine transport was not elevated in hyperglycemic rats. The enhanced transport rate was attributable to a 35 and 81% increase in the Vmax of the high- and low-affinity taurine transporters, respectively (P less than 0.01), without significant change in the Km of the carrier systems. Treatment of hyperglycemic rats (n = 5) with ultra-long-acting insulin to normalize the serum glucose concentration restored synaptosomal taurine uptake to the level observed in normoglycemic controls. The effect of insulin was attributable to correction of hyperglycemia, because addition of insulin (500 mU/ml) to the in vitro assay system did not alter synaptosomal taurine uptake.(ABSTRACT TRUNCATED AT 400 WORDS)     

Altered protein phosphorylation in sciatic nerve from rats with streptozocin-induced diabetes

The effect of experimental diabetes on the phosphorylation of proteins in the rat sciatic nerve was studied. Nerves from animals made diabetic with streptozocin were incubated in vitro with [32P]orthophosphate and divided into segments from the proximal to the distal end, and proteins from each segment were then separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The principal labeled species were the major myelin proteins, P0, and the basic proteins. After 6 wk of diabetes, the incorporation of isotope into these proteins rose as a function of distance along the nerve in a proximal to distal direction and was significantly higher at the distal end compared with incorporation into nerves from age-matched controls. The overall level of isotope uptake was similar in nerves from diabetic animals and weight-matched controls. The distribution of 32P among proteins also differed in diabetic nerve compared with both control groups in that P0 and the small basic protein accounted for a greater proportion of total label incorporated along the entire length of nerve. In contrast to intact nerve, there was no significant difference in protein phosphorylation when homogenates from normal and diabetic nerve were incubated with [32P]-gamma-ATP. The results suggest that abnormal protein phosphorylation, particularly of myelin proteins, is a feature of experimental diabetic neuropathy and that the changes are most pronounced in the distal portion of the nerve.     

Insulinlike effects of sodium selenate in streptozocin-induced diabetic rats.

Treatment of streptozocin (STZ)-induced diabetic rats with sodium selenate (10-15 mumol.kg-1.day-1) for 7 wk resulted in a decrease in plasma glucose, food intake, and water intake to control or near control levels. Plasma insulin was reduced in control rats given sodium selenate to the level found in the diabetic and treated diabetic group. Treatment did not affect control rats with regard to the other measurements cited. Sodium selenate enhanced weight gain in responding diabetic rats to that seen in controls; sodium selenate's actions thus resembled those of insulin. Thus selenate, like vanadium, appears to have insulinlike effects when administered in vivo.     

Relationship between renal function and metabolic alterations in early streptozocin-induced diabetes in rats

To investigate the temporal relationship of diabetes-induced renal growth and its associated metabolic alterations to the early development of renal hyperfunction, parallel functional and metabolic studies were performed shortly after the onset of diabetes in rats. Hyperglycemia and hypoinsulinemia were evident 18 h after streptozocin injection, and significant hyperglucagonemia and acidosis were present at 36-48 h. Glomerular filtration rate (GFR), expressed per unit of body weight, first increased at 3 days of diabetes [1.35 +/- 0.07 (SE) (N = 14)] and was 18% greater than in controls [1.14 +/- 0.03 ml X min-1 X 100 g-1 (SE) (N = 38)] (P less than .005). Renal enlargement preceded GFR changes, so that GFR per unit of kidney weight was lower at 48 h in diabetics [1.31 +/- 0.06 (SE) (N = 16)] than in controls [1.54 +/- 0.04 ml X min-1 X g-1 (SE) (N = 38)] (P less than .01). Nucleotide and RNA metabolism was studied in the renal cortex after infusion of radio-labeled orotate or adenine. Rate of RNA synthesis, total cellular RNA, and the pools of ATP, UTP, and uridine 5'-diphospho-N-acetyl glucosamine were significantly increased 13-51% in 48-h diabetics. Nucleotide precursor incorporation was significantly increased only in uracil ribonucleotides. The increase in uracil ribonucleotide pool exceeded the degree of cell hypertrophy. Our studies indicate that renal hypertrophy and specific increases in uracil ribonucleotide synthesis precede functional changes in early diabetes. Renal metabolic changes may be the critical primary factors in diabetic nephropathy.     

Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozocin-induced diabetes in rats

The brains of rats with streptozocin-induced diabetes treated with a low-dose insulin regimen (1 IU/day) were studied with morphometric techniques. After 1 yr of diabetes, brain weight decreased slightly (1350 +/- 71 vs. 1521 +/- 55 mg, 2P less than .01) as did the volume of the neocortex (498 +/- 36 vs. 567 +/- 40 mm3, 2P less than .05). A significant loss of neocortical neurons occurred (38 +/- 2 X 10(6) vs. 46 +/- 3 X 10(6), 2P less than .01), and the length of the capillary network in the neocortical tissue shortened disproportionately (405 +/- 102 vs. 631 +/- 47 m, 2P less than .01), leading to increased diffusion distance. The mechanisms underlying cerebral loss in this model are unknown, but abnormalities of the vascular supply with prolongation of the route of diffusion might play a role.     

Tyrosine hydroxylase activity in sympathetic nervous system of rats with streptozocin-induced diabetes

The activity of tyrosine hydroxylase (TOH), the rate-limiting enzyme in norepinephrine biosynthesis, was measured in selected sympathetic ganglia to develop a quantitative measure of sympathetic autonomic neuropathy in streptozocin-induced diabetic rats. Surprisingly, TOH activity was elevated twofold in diabetic prevertebral ganglia innervating the alimentary tract (i.e., superior mesenteric, celiac, and inferior mesenteric), which has terminal processes that develop neuroaxonal dystrophy in this model system. TOH activity of paravertebral ganglia (i.e., superior cervical and stellate) with nonalimentary targets was not increased in the same animals. Increased TOH activity in the prevertebral ganglia 1) developed within the 1st wk of diabetes and persisted for 10 mo, 2) did not represent a change in TOH affinity for d-1,6-methyl-5,6,7,8- tetrahydropterine cofactor, 3) was prevented by both nicotinamide pretreatment and early institution of insulin therapy, and 4) did not develop as a result of classical transsynaptic induction. Pair-feeding experiments confirmed that the most likely cause of increased TOH activity in this system was the marked hypertrophy and hyperplasia of the diabetic bowel resulting from compensatory hyperphagia. We conclude that TOH activity does not represent a suitable marker for sympathetic autonomic neuropathy in this experimental system. Rather, the increase appears to be an example of a selective increase in the synthesis of neurotransmitter enzymes, possibly in response to increased trophic support provided by the expanded target, i.e., the hypertrophic gut. The additional synthetic stress imposed on prevertebral neurons by the expansion of the innervation of the alimentary target coupled with the complex diabetic metabolic milieu may contribute to the development and selective distribution of dystrophic axonopathy to the innervation of the alimentary tract.     

Additive hypoglycemic effects of drugs that modify free-fatty acid metabolism by different mechanisms in rats with streptozocin-induced diabetes

In this study the effect of two drugs [etomoxir and nicotinic acid (NA)] on plasma glucose, free-fatty acid (FFA), and triglyceride (TG) concentrations was determined in rats with streptozocin (STZ)-induced diabetes. The two compounds modify FFA metabolism by different mechanisms, etomoxir (ethyl-2-[6-(4-cholorophenoxyl)-hexyl]oxirane-2-carboxylate) by inhibiting hepatic fatty acid oxidation, and NA by inhibiting lipolysis in adipose tissue. Diabetes was induced in male Sprague-Dawley rats, weighing approximately 400 g, by STZ injection (30 mg/kg i.v.), and the metabolic effects of the two drugs were studied 7-10 days later. The acute administration of either etomoxir or NA lowered plasma glucose concentrations in diabetic rats by approximately 150 mg/dl (P less than .001) in 4 h. However, the two drugs differed dramatically in their effects on plasma FFA and TG concentrations. Specifically, etomoxir produced striking increases in plasma FFA and TG concentrations, whereas NA administration caused a marked decrease. However, when NA was given in conjunction with etomoxir, NA prevented the increase in plasma FFA and TG concentration seen with etomoxir; the combination of NA and etomoxir approximately doubled the decrease in plasma glucose concentration produced by NA or etomoxir when given alone. Because plasma insulin concentrations did not change in response to either drug, whether administered singly or in combination, these metabolic effects do not result from a change in insulin secretion. These results suggest that modulation of FFA metabolism at the level of the adipocyte or the liver can have dramatic effects on carbohydrate and lipid metabolism.     

Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozocin-induced diabetic rats

The effect of oral administration of sodium orthovanadate for 5 wk on hepatic glycogen metabolism was studied in control and streptozocin-induced diabetic rats. Diabetes caused hyperglycemia (5-fold increase), hypoinsulinemia (85% decrease), and hyperglucagonemia (4-fold increase). There were also marked decreases in liver glycogen and activities of glycogen-metabolizing enzymes in liver. Although vanadate administration in control animals showed no significant effect on the various parameters measured except for a 70% decrease in plasma insulin, this treatment in diabetic rats restored these parameters to near control values. In diabetic rats, glycogen synthase a and the activity ratio (activity of glycogen synthase a divided by activity of total glycogen synthase) decreased to 30% of control levels and were restored to approximately 70-80% of control values after vanadate administration. A similar pattern was observed for the activity of synthase phosphatase. The activities of glycogenolytic enzymes, i.e., phosphorylase (activity of phosphorylase a and activity of total phosphorylase), phosphorylase kinase, and protein kinase (in presence or absence of cAMP), were significantly decreased by 40-70% in diabetic rats. These enzyme activities were recovered to 70-100% of control values after vanadate treatment. Phosphorylase phosphatase was not altered by diabetes, but the vanadate treatment of both groups, i.e., control and diabetic rats, showed a 25% increase in its activity (P less than 0.01). In conclusion, these results show insulinlike in vivo action of vanadate on various parameters related to hepatic glycogen metabolism.     

Effects of streptozocin-induced diabetes on sympathetic and parasympathetic stimulation of parotid salivary gland function in rats

Diabetes was induced with streptozocin in male Wistar rats. After 4-6 mo, parotid salivary flow was induced by stimulating bipolar electrodes (3-5 V for 2 ms) on either the auriculotemporal nerve (5 Hz) or the cervical sympathetic trunk (10 Hz). During parasympathetic stimulation, flow rates were 443 +/- 287 microliters/30 min in diabetic animals compared to 657 +/- 134 microliters/30 min in controls (P less than .01). Although parotid flow rates during parasympathetic stimulation were well maintained in controls, they decreased rapidly in most diabetic rats. Parotid secretory response to sympathetic stimulation was also reduced in diabetic compared with control animals (40 +/- 16 microliters/30 min and 82 +/- 50 microliters/30 min, respectively, P less than .01). In contrast to results obtained with direct neural stimulation, no differences in threshold dose or total saliva were observed when cholinergic (methacholine) and peptidergic (physalaemin) agonists were administered intravenously. Response threshold for an adrenergic agonist (epinephrine) was significantly increased in diabetes. Electron microscopy showed axoplasmic abnormalities in nonmyelinated axons in diabetic glands but not in control glands. Although most nerve profiles appeared normal, neuroaxonal abnormalities were found in every diabetic animal. The ultrastructural findings and the similar responses to methacholine and physalaemin suggest that autonomic neuropathy may be a factor in the abnormal response of the parotid gland to parasympathetic nerve stimulation.     

Chronic undernutrition accentuates insulin deficiency in rats with mild streptozocin-induced diabetes.

The effect of chronic undernutrition on coexisting diabetes mellitus was studied in pair-fed littermate rats with mild streptozocin-induced diabetes. They were either fed ad libitum or 50% food restricted for 9 wk. Undernourished diabetic rats, in which weight gain was reduced by 40%, had significantly higher glucose intolerance (mean +/- SE, fractional rate of glucose disappearance during glucose tolerance test [Kgtt] 1.77 +/- 0.16) than diabetic littermates fed ad libitum (2.33 +/- 0.21, P less than 0.05) or nondiabetic controls (3.8 +/- 0.7, P less than 0.01). The total area under the insulin response curve was significantly reduced in both groups of diabetic rats, but the undernourished group showed a 45% greater reduction in overall secretion than normally nourished diabetic littermates (21.3 +/- 2.7 vs. 39.4 +/- 6.3 nM.min in the diabetic group, P less than 0.01, and 65.7 +/- 6.1 nM.min in controls). There was also a marked reduction in first-phase insulin secretion in the undernourished rats (4.75 +/- 0.24 vs. 9.84 +/- 1.36 nM, P less than 0.05, and 14.3 +/- 1.8 nM, P less than 0.01, respectively, in normally nourished diabetic littermates and controls). After refeeding, a significant improvement occurred in Kgtt (to 2.67 +/- 0.24, P less than 0.01) and first-phase insulin secretion (to 9.69 +/- 1.65 nM, P less than 0.05). The postrefeeding values were not different from those in the normally nourished diabetic littermates, indicating that the effect was fully reversible and solely attributable to undernutrition rather than to enhanced beta-cell cytotoxicity from streptozocin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of glutamine-enriched feeding on incisional healing in rats

Glutamine (Gln), which is the most abundant free amino acid in the circulation, and also a primary fuel for rapidly dividing cells, was used to determine its effects on incisional healing. The effect of Gln-enriched feeding was investigated using tensile strength measurement, which reflects the quality and speed of regeneration, and by the measurement of tissue hydroxyproline level which correlate directly with the collagen content of wounds. Forty albino Wistar rats in four equal groups received a special diet 7 days prior to surgery and 7 days after surgery. On the 7th day of study a 5-cm dorsal midline skin incision was made and then closed by interrupted sutures. Group 1 received a normal diet for all 14 days; group 2 received a Gln-enriched diet 7 days prior to surgery and a normal diet 7 days after surgery; group 3 received a normal diet prior to surgery and a Gln-enriched diet after surgery; group 4 received a constant Gln-enriched diet. On the 7th postoperative day, tensile strength measurements and hydroxyproline level analyses were done. A preoperative Gln-enriched diet did not show any significant improvement in the tensile strength and hydroxyproline levels on the 7th postoperative day, but a pre- and postoperative, and a postoperative Gln-enriched diet significantly improved the tensile strength and hydroxyproline levels when compared with the normal diet group (P<0.0001). These findings show that wound healing is better when Gln was added in the postoperative, or both pre- and postoperative periods, but not when only added in the preoperative period. Received: 18 May 1998 / Accepted: 16 November 1998     

Uteroplacental hemodynamic disturbances in establishment of fetal growth retardation in streptozocin-induced diabetic rats

This study examined the relationship between uteroplacental blood flow and fetal hypotrophy in streptozocin-induced diabetic rats (40 mg/kg body wt i.v.). Our results showed that, in diabetic rats, fetal hypotrophy was associated with a significant reduction in arterial blood velocity in the uterine artery (P less than 0.001), placenta (P less than 0.01), umbilical artery (P less than 0.01), and fetal aorta (P less than 0.05). This was not observed when diabetic rats were treated with insulin. Treatment of rats with the alpha 1-blocking vasodilator nicergoline restored fetal growth and arterial blood velocity to control values without affecting the degree of hyperglycemia. Nicergoline in control rats did not change fetal weight and caused only minor hemodynamic changes on presumably already maximally vasodilated arteries. We concluded that the uteroplacental hemodynamic disturbances observed in diabetic rats play a major role in the establishment of fetal growth retardation.     

Myofibrillar protein breakdown in skeletal muscle is diminished in rats with chronic streptozocin-induced diabetes

Previous reports have suggested that insulin may not regulate the breakdown of myofibrillar proteins in skeletal muscle. To further test the role of insulin, insulinopenia was produced by treating rats with streptozocin. After treatment, protein breakdown in skeletal muscle was evaluated with the isolated perfused rat hindquarter preparation. After the inhibition of protein synthesis with cycloheximide, total and myofibrillar protein breakdown were assessed by measuring the release of tyrosine and 3-methylhistidine, respectively, in the perfused hindquarters of diabetic and age-matched control rats. Streptozocin-induced (65 mg/kg) diabetes (3- to 28-day duration) resulted in hyperglycemia, hypoinsulinemia, hyperphagia, increased plasma lipid levels, arrested body and muscle growth, and increased urea and 3-methylhistidine excretion. Despite this, protein breakdown in skeletal muscle diminished. The release of 3-methylhistidine by the perfused hindquarters of diabetic rats decreased, whereas the release of tyrosine remained unchanged, suggesting that the breakdown of myofibrillar proteins was affected specifically. 3-Methylhistidine (unbound) levels in skeletal muscle of unperfused diabetic rats as well as in skin decreased, whereas they increased twofold in the gastrointestinal tract. More severe diabetes (125 mg/kg streptozocin), which resulted in ketoacidosis, augmented protein breakdown in muscle; however, this response was due to a marked fall in food consumption (it was also evident when control rats were pair fed). These data reinforce previous conclusions that insulin does not play a major role in the regulation of myofibrillar protein breakdown in skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes

The effect of insulin or glutathione treatment on glutathione content of liver and jejunal mucosa and on superoxide dismutase (SOD) activity of liver, kidney, and erythrocytes was investigated in pair-fed animals with streptozocin (STZ)-induced diabetes. Diabetes lowered hepatic glutathione concentration, but glutathione concentration of the jejunal mucosa was not affected. Insulin, but not oral glutathione, restored hepatic glutathione concentration to normal levels. Diabetes depressed activity of the cytosolic form of SOD in liver, kidney, and erythrocyte. Treatment of diabetic rats with oral glutathione or intramuscular insulin increased cytosolic SOD activity of renal cortex and liver (but not erythrocytes) to control levels. These results suggest a link between glutathione metabolism and cytosolic SOD activity in diabetes.