Effect Of Streptozotocin-induced Diabetes Mellitus Research Articles

Association between Disturbances in Polyunsaturated Fatty Acid Metabolism and Development of Oxidative Stress during Experimental Diabetes Mellitus.

We studied the effect of streptozotocin-induced diabetes mellitus on the level of glycemia and some other indices of lipid metabolism, including fatty acid metabolism and LPO intensity, during the development of diabetes mellitus in rats. Even at the early terms of diabetes development, hypertriglyceridemia and hypercholesterolemia were accompanied by changes in the blood content of fatty acid (at the expense of ω3 and ω6 fatty acids) that persisted throughout the observation period. Intensification of LPO against the background of suppressed activity of antioxidant enzymes and reduced level of ω3 fatty acids attested to the development of oxidative stress. These data attest to antioxidant property of ω3 fatty acids, which is seen from positive correlations between these fatty acids and activity of antioxidant enzymes.

Effect of Lipoic Acid on Serum Paraoxonase-1 and Paraoxonase-3 Protein Levels and Activities in Diabetic Rats.

The aim of the present study was to investigate the effect of streptozotocin-induced diabetes mellitus and lipoic acid treatment on serum paraoxonase-1 and paraoxonase-3 protein levels and paraoxonase, arylesterase and lactonase activities.36 rats were equally and randomly divided into 4 groups as control, lipoic acid, diabetes and diabetes+lipoic acid. To induce diabetes, a single dose of streptozotocin (40 mg/kg) was injected intraperitoneally to diabetes and diabetes+lipoic acid groups. Lipoic acid (10 mg/kg/day) was injected intraperitoneally for 14 days to lipoic acid and diabetes+lipoic acid groups. Serum PON1 and PON3 protein levels were measured by western blotting. Serum paraoxonase, arylesterase and lactonase activities were determined by the measuring initial rate of substrate (paraoxon, phenylacetate and dihydrocoumarin) hydrolysis.Streptozotocin-induced diabetes mellitus caused a significant decrease whereas lipoic acid treatment caused a significant increase in serum PON1 and PON3 protein levels and paraoxonase, arylesterase and lactonase activities. The increase percent of serum PON3 protein was higher than that of serum PON1 protein and the increase percent of serum lactonase activity was higher than that of serum paraoxonase and arylesterase activities in diabetes+lipoic acid group.We can report that, like PON1 protein, PON3 protein and actually its lactonase activity may also have a role as an antioxidant in diabetes mellitus and lipoic acid treatment may be useful for the prevention of the atherosclerotic complications of diabetes by increasing serum PON1 and PON3 protein levels and serum enzyme activities.

Comparative Effects of Antidiabetic Drug, Metformin and Deferoxamine, on the Hepatotoxic and Nephrotoxic Side Effects of Streptozotocin-induced Diabetes Mellitus in Rats

Aims: The present study compared the effects of metformin (met) and deferoxamine (DFX) on the hepatotoxic and nephrotoxic side effects of streptozotocin experimental diabetes in rats using serum biochemical and histopathological indicators.Study Design: Following induction of diabetes, animals were randomly and evenly distributed into four groups A, B, C and D of six rats each (n=6). Experimental diabetes was induced in overnight fasted rats by a single dose i.p each of nicotinamide and, 15min after, STZ followed by administration of the antidiabetic drug, met (os, 250mg/kgb.wt) and iron chelating drug, DFX (i.p,150mg/kgb.wt), daily for 14 days. Blood and histological samples were collected and prepared for biochemical and histopathological analysis of indicators of cytotoxic side effects.Results: STZ caused cytotoxic effects on the liver and kidney of experimental rats, indicative of cellular leakage and loss of the functional integrity of the cell membranes. Metformin and deferoxamine both effectively reversed the hepatotoxic side effects of STZ-induced diabetes as determined by serum activities of ALP, AST and ALT and histopathological presentation. However, whereas metformin effectively reversed the STZ induced side effects on the kidney as determined by serum creatinine level and histopathological indicators, DFX did not.Conclusion: It is concluded that metformin has a markedly higher potency than DFX in mitigation of hepatic and renal tissue derangement, as determined by both serum biomarkers and tissue histology.

Impact of Momordica Charantia (Karela) on the Proportion of Hepatocytes with Intranuclear Inclusions in the StreptozotocinInduced Diabetic Rats

Background: Momordica charantia has some hypoglycemic properties.Objective: The purpose of the present study was to find out the impact of Momordica charantia (karela) on the proportion of hepatocytes in the Streptozotocin-induced diabetic rats.Methodology: This was an animal study carried out in the Department of Anatomy at Bangabandhu Sheikh Mujib Medical University (BSMMU) and Bangladesh Institute of Research & rehabilitation in Diabetes, Endocrine & metabolic Disorders (BIRDEM), Dhaka. Healthy young Long Evans rats of male sex weighing 150 to 280gm with an age range of 10 to 12 weeks were used in this study. The rats were divided into 4 equal groups depending upon their different sorts of dietary feedings and drug treatment. The variation of different proportion of hepatocytes with intranuclear inclusions in different groups of rat was monitored.Result: Sixty five rats were included in this study. Mean proportion of hepatocytes with intranuclear inclusions on day 51 from Streptozotocin/vehicle injection in the control group which was known as Group-A was 0. In untreated diabetic group the mean proportion of hepatocytes with intranuclear inclusions was 3.71 ± 0.82. On the other hand, in the insulin-treated diabetic rats the mean proportion of hepatocytes with intranuclear inclusions was 0 and in the karela-treated diabetic rats, the proportion of hepatocytes with intranuclear inclusions was 0. The value in the insulin-treated diabetic rats (p=0.0001) and in the karela-treated diabetic rats (p= 0.0001) were significantly lower than that of the untreated diabetic rats; however, there was no significant difference between the insulin-treated diabetic rats & the karela-treated diabetic rats (P>0.05) in this regard.Conclusion: Karela showed a tendency of acting against hyperglycemic effects of Streptozotocin-induced diabetes mellitus and also acting against the rise in proportion of hepatocytes with intranuclear inclusions in Streptozotocin-induced diabetes mellitus.DOI: http://dx.doi.org/10.3329/jssmc.v5i2.20761J Shaheed Suhrawardy Med Coll, 2013;5(2):84-86

Dysfunction of Membrane-Receptor System of Blood Cells and Kidney Tissue in Experimental Diabetes Mellitus

The effect of streptozotocin-induced diabetes mellitus on some parameters of energy metabolism and functional status of cell membranes was studied in experiments on rats. It was found that the development of diabetes mellitus is associated with dramatic changes in the metabolism of blood cells and kidney tissue: inhibition of aerobic ATP synthesis, accumulation of lactate, uncoupling of oxidative phosphorylation, and development of lactic acidosis. Diabetes mellitus leads to restructuring of membrane lipids, changes in microviscosity, and suppression of insulin receptors and membrane-bound Na(+), K(+)-ATPase, and Ca(2+)-ATPase. Sharply increased levels of LPO products and lactic acidosis during DM indicate an imbalance in the LPO-antioxidant system and development of oxidative stress.

Effect of streptozotocin-induced diabetes mellitus on the cerebellar cortex of adult male albino rats

Effect of streptozotocin-induced diabetes mellitus on the cerebellar cortex of adult male albino rats

Enhanced Diabetes-Induced Cataract in Copper-Zinc Superoxide Dismutase–Null Mice

Oxidative stress is thought to contribute to diabetes-induced cataract, and the authors have previously demonstrated that lenses from mice lacking the antioxidant enzyme copper-zinc superoxide dismutase (SOD1) show elevated levels of superoxide radicals and are more prone in vitro to develop glucose-induced cataract than are wild-type lenses. In the present study the effect of streptozotocin-induced diabetes mellitus on cataract formation in SOD1-null and wild-type mice in vivo was examined. Eight weeks after diabetes was established by repeated intraperitoneal streptozotocin injections, the mice were killed and the lenses removed and photographed in retroillumination. The cataract was quantified from the photographs by digital image analysis and the lens contents of glutathione (GSH) as well as the lens protein carbonyl contents suggestive of protein oxidation were analyzed. The streptozotocin-induced diabetic SOD1-null mice developed more cataract than the diabetic wild-type mice. Also, lens GSH levels were lower in the diabetic SOD1-null mice than in the nondiabetic SOD1-null mice. However, the protein carbonyls were equally raised in the diabetic mice of both genotypes. The increased cataract formation and the compromised antioxidant capacity found in the diabetic SOD1-null lenses thus emphasize the involvement of superoxide radicals in diabetes-induced cataract.

Streptozotocin-induced diabetes is associated with changes in NGF levels in pancreas and brain.

Type 1 diabetes mellitus (DM), a "classical" result of a pancreatic-beta cell damage, is associated with various metabolic, neuronal, endocrine and immune alterations at cellular, tissue and organ levels. Nerve growth factor (NGF) is one of the most extensively studied neurotrophic factors, which is produced and released by numerous cells including the pancreatic beta cells. NGF plays an important role during brain development and may be able to delay or even reverse damaged forebrain cholinergic neurons that undergo degeneration in aged animals and in Alzheimer's disease (AD). Recent reports indicate that experimentally induced DM in rodents can cause brain biochemical and molecular alterations similar to those observed in sporadic AD. Given the importance of NGF in the pathophysiology of brain cholinergic neurons, we looked for NGF changes in the pancreas and brain of diabetic rats. The aim of this study was, therefore, to investigate the effect of streptozotocin-induced DM on NGF and NGF receptor expression in pancreas and brain. The results showed that DM is associated with altered NGF, NGF-receptor expression in both pancreas and brain.

Effects of streptozotocin-induced diabetes mellitus on some bone turnover markers in the vertebrae of ovary-intact and ovariectomized adult rats

Diabetes mellitus and estrogen deficit are known causes of osteopenia in animal models as well as in humans. In the present work, the combined effect of ovariectomy and diabetes was investigated. Diabetes was induced in ovary-intact and ovariectomized female Wistar rats with a single injection (50 mg/kg body weight, i.p.) of streptozotocin. The rats were administered insulin (I) daily or 17-beta estradiol (E2) on alternate days for a period of 35 days and sacrificed. Serum calcium (Ca2+), phosphorus (P), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), vertebral ALP, collagen, and glycosaminoglycans were estimated. The levels of serum Ca2+ and P increased in diabetic rats, but decreased after I or E2 treatments. Serum ALP and TRAP activity increased in the ovary-intact and ovariectomized diabetic rats. Vertebral ALP activity increased in ovariectomized diabetic rats, but decreased in diabetic rats, which were treated with I or E2. In the vertebrae, TRAP activity was elevated as a result of diabetes, but this was prevented by insulin or estradiol. Diabetes induced a decrease in total collagen in the vertebrae, while I or E2 treatment induced an increase. The levels of chondroitin sulphate and heparan sulphate decreased significantly in the vertebrae of both ovary-intact and ovariectomized diabetic rats, while hyaluronic acid increased. In conclusion, diabetes and ovariectomy each seem to affect the process of matrix formation and mineralization in the bone, and this is aggravated by the combination of diabetes and ovariectomy. The effects of I and E2 were similar, and both hormones reversed the changes brought about by diabetes.

DIABETES INDUCED DECREASE IN DETRUSOR SMOOTH MUSCLE FORCE IS ASSOCIATED WITH OXIDATIVE STRESS AND OVERACTIVITY OF ALDOSE REDUCTASE

Bladder dysfunction is one of the complications of diabetes. We determined whether diabetic induced bladder dysfunction is associated with decreased detrusor smooth muscle contractility, hyperglycemia induced over expression of aldose reductase (AR) and increased sorbitol production. In addition, we compared oxidative stress in the detrusor smooth muscle in diabetic rabbits with that in normal rabbits by estimating lipid peroxidation. Diabetes was induced in New Zealand White, age matched male rabbits by intravenous injection of alloxan (100 mg/kg body weight). Normal and sucrose drinking rabbits served as controls. Six months after the induction of diabetes rabbits with a blood glucose level of 400 mg/dl or higher were sacrificed and detrusor smooth muscle tissue was isolated. Detrusor was analyzed for force generation, lipid peroxidation products using malondialdehyde as a biomarker, and AR expression and function by reverse transcriptase-polymerase chain reaction and sorbitol levels, respectively. The mean maximum force +/- SE produced by detrusor muscle strips in response to 125 mM KCl was 17.50 +/- 1.66, 17.56 +/- 1.23 and 7.51 +/- 2.56 gm/100 mg tissue in normal, sucrose drinking and diabetic rabbits, respectively, representing a 57% force decrease in diabetic subjects. Bethanechol elicited force decreased 40% (26.52 +/- 3.21, 27.3 +/- 2.87 and 16.32 +/- 1.67 gm/100 mg tissue, respectively, in normal, sucrose drinking and diabetic rabbits) in diabetic vs control subjects. Concomitant with the force decrease, the expression of AR, sorbitol content and lipid peroxidation products were increased. Diabetes induced a decrease in detrusor smooth muscle force. This was associated with an increase in lipid peroxides and sorbitol concomitant with over expression of AR and polyol pathway activation. Our data suggest that these changes might contribute to oxidative stress and decreased contractility of detrusor smooth muscle, leading to bladder dysfunction.

Effect of streptozotocin-induced diabetes mellitus on alveolar bone deposition in the rat

Effects of diabetes on alveolar bone remodelling were assessed by quantitative histology and a chronological lead-labelling technique. Experimental diabetes was induced by a single dose of 40 mg/kg of streptozotocin. Remodelling of the alveolar wall surrounding the root of mandibular first molar was studied in control rats fed ad libitum, and in diabetic and insulin-treated diabetic rats 24 days after the induction of diabetes. The volumes of bone formation on the mesial side of the alveolar wall were evaluated over a 10-day period by chronological lead-labelling and computer image analysis. For a histometric measure of bone-resorption, the number of osteoclasts along the distal surface of the alveolar wall was counted. The volume of bone formed and the number of osteoclasts were significantly lower in the diabetic rats than in the controls, but insulin treatment of diabetic rats normalised these histomorphometric measures of bone turnover. These results demonstrate that streptozotocin-induced diabetes mellitus reduces the rate of bone turnover in the alveolar wall surrounding the root, which reduction is corrected by treatment with insulin.

Lower faecal egg excretion in chemically-induced diabetic mice infected with Schistosoma mansoni due to impaired egg maturation.

The effect of streptozotocin-induced diabetes mellitus was studied in mice infected with Schistosoma mansoni. Faecal egg excretion was lower in diabetic mice but worm load and total amount of eggs in the intestine tissue were equal to the control group. Evaluation of an oogram showed a great number of immature dead eggs and a low number of mature eggs in diabetic mice. It was therefore concluded that faecal egg excretion was lower in diabetic mice due to impaired egg maturation.

LOSS OF KIDNEY IGF-1 RECEPTORS IN EXPERIMENTAL LONG-TERM DIABETIC RATS

The present study was undertaken to assess the long-term effects of streptozotocin-induced diabetes mellitus on insulin-like growth factor-1 (IGF-1) receptors in rat kidneys. Morphological changes were also evaluated using light and electron microscopy. Using receptor autoradiography the levels of IGF-1 were investigated in rat kidneys diabetic for eight months and controls. Sections from both diabetic and control rats were stained with haematoxylin and eosin for morphological studies. Ultra-thin kidney sections were examined using a transmission electron microscope. IGF-1 receptors were significantly lower in the cortex and the medulla of the diabetic rats compared with controls. Morphological differences between normal and diabetic kidneys were observed in both the cortex and medulla. Glomerular changes and necrosis of the renal cortical and medullary parenchyma were demonstrated in the diabetic rats. Necrosis of cells of the collecting ducts and loops of Henle could explain the loss of IGF-1 receptor concentration in the medulla. Shrinkage of glomeruli and normal proximal convoluted tubules of diabetic kidneys were also observed. Our results also revealed extensive damage to the distal convoluted tubules that have not been reported to possess any insulin-like growth factor-1 receptors. Our results demonstrate a reduction of kidney IGF-1 receptors after long-term diabetes mellitus possibly because of the extensive morphological loss of renal tissue. It could be speculated that early administration of IGF-1 might be useful in longterm diabetes mellitus to prevent the degeneration and/or help regeneration of damaged renal tissue.

Regulation of insulin-stimulated tyrosine phosphorylation of Shc and Shc/Grb2 association in liver, muscle, and adipose tissue of epinephrine- and streptozotocin-treated rats.

Shc protein phosphorylation has been extensively characterized as the initial step that activates a complex mitogenic pathway through its association with Grb2. In the present study, we investigated the adrenergic control of insulin-induced Shc phosphorylation and Shc-Grb2 association, and the modulating effect of streptozotocin-induced diabetes mellitus on Shc phosphorylation and Shc/Grb2 association. Acute treatment with epinephrine, which leads to a normoglycemic insulin-resistant state, does not affect insulin-induced Shc tyrosine phosphorylation or Shc-Grb2 association in liver, muscle, or fat. By contrast, a significant increase in insulin-induced Shc phosphorylation is observed in liver and muscle of rats treated with streptozotocin. The association of Shc/Grb2 is also increased in both tissues following insulin treatment. These data suggest that while epinephrine preserves the insulin-induced phosphorylation of Shc and the mitogenic pathway stimulated by Shc-Grb2 association, treatment with streptozotocin leads to a tissue-specific increase in the activity of the initial step that ultimately results in the activation of the Shc/Grb2 mitogenic pathway.

The effect of streptozotocin-induced diabetes mellitus on substance P and calcitonin gene-related peptide expression in the rat trigeminal ganglion

Substance P (SP) and calcitonin gene-related peptide (CGRP) constitute the main sensory peptides in the trigeminal ganglion (TG). The objective of this study was to characterize peptidergic changes in the streptozotocin-induced diabetes mellitus rat model both quantitatively and qualitatively. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg) and the levels of SP and CGRP were measured by means of radioimmunoassay (RIA) in a time-dependent manner. Peptide immunoreactivities were characterized by high pressure liquid chromatography (HPLC). The expression of both neuropeptides was examined 5 weeks after streptozotocin injection using in situ hybridization with 35 S -labelled oligonucleotides. Saline-injected rats served as controls. SP was significantly decreased in the diabetic rat TG, i.e., a 44.6% (±10.9) decrease after 1 week, 40.2% (±11.8) after 3 weeks and 72.3% (±14.6) after 5 weeks. CGRP was decreased only after 5 weeks (19.6% decrease ±3.9), whereas at later stages, both peptide levels returned to normal values. HPLC revealed one major peak coeluting with the synthetic peptides. By using in situ hybridization, a significantly increased signal of both peptide-encoding mRNAs was found (43.8%), which seems to act to restore a diabetes-associated depletion of neuropeptides in the diabetic rat TG. The decreased SP- and CGRP levels in the diabetic rat TG reflect a diabetes-associated deficit which may be clinically relevant. Diabetes mellitus is associated with a variety of ocular complications, even corneal complications, including decreased corneal sensitivity, which in many ways resemble those after interruption of the normal trophic innervation of the eye. Our results point to reduced availability of neuropeptides for corneal innervation and may thus support the idea of a partial loss of trophic influences from the trigeminal nerve in diabetics.

The effect of diabetes mellitus on histopathological changes in the tissues under denture base bearing masticatory pressure.

The effect of streptozotocin-induced diabetes mellitus on histopathological changes in tissues bearing masticatory pressure exerted through an experimental denture base has been studied in animal specimens. Experimental dentures, which prescribed the masticatory pressure by the amount of subsidence of the denture base (100, 50 or 13 microm), were constructed for the hard palate of the molar regions of rats. It was revealed that streptozotocin-induced diabetes mellitus (1) weakened the intercellular junctions in the epithelium and gradually enhanced this state with time, (2) lessened the atrophic and proliferative reactions in the epithelial ridge and prolonged their appearance period, (3) enhanced the compression of lamina propria mucosae and prolonged the appearance period of this reaction, (4) enhanced the inflammatory change and extended its appearance period, (5) lowered the threshold for the inflammatory reaction induced by the masticatory pressure, (6) increased the number of osteoclasts and prolonged the period of their presence, (7) lowered the threshold for osteoclastic bone resorption induced by the masticatory pressure, (8) inhibited the appearance of osteoblasts following the disappearance of osteoclasts and (9) accelerated the decline rate of masticatory pressure exerted to the denture supporting tissues. Therefore, it can be concluded that the streptozotocin-induced diabetes mellitus in the animals tested deteriorated the tolerance of the denture supporting tissues to masticatory pressure.

Small intestinal Na+,K+-adenosine triphosphatase activity and gene expression in experimental diabetes mellitus.

The Na+,K+-ATPase plays a key role in the absorption of electrolytes, water, and nutrients from the small intestine. The effect of streptozotocin-induced diabetes mellitus (STZ-DM) on the activity and expression of Na+,K+-ATPase in the rat small intestine was examined in the present study. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (75 mg/kg) and control and STZ-DM rats were killed at day 30 (chronic diabetic state). Levels of Na+,K+-ATPase activity and numbers of sodium pumps were increased two- to threefold in the jejunum and ileum. Sodium pump kinetics were unaltered in STZ-DM. The levels of Na+,K+-ATPase alpha1 and beta1 isoform protein, corresponding mRNAs, and levels of transcription were increased in the jejunal and ileal mucosa of the chronically diabetic rat. The increases in Na+,K+-ATPase functional activity, protein expression, and mRNA were most marked at the level of the ileal mucosa. While a proximal to distal gradient in Na+,K+-ATPase activity and subunit isoform protein levels were observed in both control and diabetic rats, levels of subunit isoform mRNA abundance were similar in both regions of the small intestine in both groups of rats. The alterations in small intestinal Na+,K+-ATPase expression in the chronic diabetic state appear to involve alterations in transcriptional and posttranscriptional events and may likely represent an adaptive response that leads to increased Na+-coupled monosaccharide absorption in the context of a perceived state of nutrient depletion.

Elevation of [Ca2+]i of renal proximal tubular cells and down-regulation of mRNA of PTH-PTHrP, Via and AT1 receptors in kidney of diabetic rats

An elevation in intracellular calcium ([Ca2+]i) in rats with chronic renal failure and elevated blood levels of PTH is associated with down-regulation of the mRNA of many proteins. Similarly, in phosphate depleted animals that have normal renal function and low blood levels of PTH, [Ca2+]i is elevated and the mRNA of PTH-PTHrP receptor is down-regulated. The effect of elevation in [Ca2+]i on molecular machinery of many proteins may represent a generalized phenomenon. Diabetes mellitus may also be associated with a rise in [Ca2+]i and therefore down-regulation of the mRNA of proteins may also occur. The present study examined the effect of streptozotocin-induced diabetes mellitus in rats on the [Ca2+]i of the renal proximal tubular cells and on their mRNAs of the PTH-PTHrP, V1a and AT1 receptors. The basal levels of [Ca2+]i of these cells increased significantly (P < 0.01) after one day of diabetes and remained elevated thereafter. There was a significant (r = 0.67, P < 0.01) direct correlation between the [Ca2+]i of the cells and blood levels of glucose up to 350 mg/dl, and the value of [Ca2+]i plateaued with higher concentrations of glucose. Three days of amlodipine therapy prevented and reversed the elevated levels of [Ca2+]i despite marked hyperglycemia. The mRNA of all three receptors in the kidney were down-regulated and this defect was prevented by amlodipine which normalized the [Ca2+]i of the cells. The results show that: (1) the hyperglycemia of IDDM in rats causes a significant elevation in the basal levels of [Ca2+]i of the renal proximal tubular cells and down-regulation of their mRNA of PTH-PTHrP, V1a and AT1 receptors; (2) normalization of the [Ca2+]i of these cells by treatment of the diabetic rats with amlodipine prevented the elevation of [Ca2+]i and the down-regulation of the mRNA of these receptors; (3) these effects occurred in the presence of normal renal function and normal blood of PTH and phosphorus.

Impaired myelinated fiber regeneration following freeze-injury in rats with streptozotocin-induced diabetes: involvement of the polyol pathway

This study examined the effects of streptozotocin-induced diabetes mellitus and aldose reductase inhibitor (ZD5522) treatment on myelinated fiber regeneration in rats. After 2 months of diabetes, with or without ZD5522 treatment (10 mg · kg −1 · day −1) from induction, sciatic nerve degeneration was initiated by a punctate lesion using a liquid NZ 2 cooled probe. Regeneration was studied over a subsequent 14-day period using in vitro electrophysiological techniques. There was a 21.4% ( P < 0.001) deficit in the maximum fiber regeneration distance in diabetic rats, 14 days postlesion. This was partially (64.9%, P < 0.01) prevented by aldose reductase inhibitor treatment, the resultant regeneration distance being not significantly different from that of age-matched nondiabetic control rats. The regeneration rate, assessed from data collected 4, 9 and 14 days postlesion, was 23.7% ( P < 0.001) reduced by diabetes and ZD5522 treatment provided 73.1% protection ( P < 0.01). We conclude that polyol pathway activity is involved in impaired regeneration in experimental diabetes, potential pathophysiological mechanisms involving a reduction in neurotrophic support and impaired endoneurial blood supply.

Effect of streptozotocin-induced diabetes mellitus on release of vasoactive intestinal polypeptide from rodent small intestine.

Representative longitudinal muscle strips (6 x 10 mm) from proximal and distal small intestine were excised from control and streptozotocin-treated rats after one month of untreated and insulin-treated diabetes. Untreated diabetes significantly reduced tissue concentrations of vasoactive intestinal polypeptide (VIP) at both intestinal loci. Insulin treatment of the diabetic animals restored tissue VIP concentrations to control group levels, although the beneficial effect of insulin treatment was only significant in the duodenum. Spontaneous release of VIP was significantly attenuated by untreated diabetes at both intestinal sites. In the duodenum, insulin treatment of the diabetic animals restored VIP release to levels indistinguishable from control group values. In the ileum, insulin treatment produced levels of VIP release that were not significantly different from those of the control and untreated diabetic groups. Tetrodotoxin (5 x 10(-6) M) significantly--but incompletely--inhibited VIP release from control group animals at both intestinal sites. These observations indicate that diabetes mellitus significantly diminishes VIP tissue concentrations and release from intestinal myenteric nerves. These abnormalities improve with insulin treatment. However, the mechanisms of VIP release from proximal and distal intestine appear to differ not only in their response to the diabetic state, but also in their response to insulin treatment.