Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats

Astragaloside IV (AGS-IV), a new glycoside of cycloartane-type triterpene isolated from the root of Astragalus membranaceus (Fisch.) Bunge, has been used experimentally for its potent immune-stimulating, anti-inflammatory, and antioxidative actions. A recent study has shown AGS-IV to be an aldose-reductase inhibitor and a free-radical scavenger. This study examined the effects of AGS-IV on motor nerve conduction velocity (MNCV), tailflick threshold temperature, biochemical indexes, and the histology of the sural nerve after diabetes was induced in rats with 75 mg/kg streptozotocin (STZ). AGS-IV (3, 6, 12 mg/kg, twice a day) was administered by oral gavage for 12 weeks after diabetes was induced. Compared with control (nondiabetic) rats, obvious changes in physiological behaviors and a significant reduction in sciatic MNCV in diabetic rats were observed after 12 weeks of STZ administration. Morphological analysis showed that AGS-IV suppressed a decrease in myelinated fiber area, an increase in myelinated fiber density, and an increase in segmental demyelination in diabetic rats. The protective mechanism of AGS-IV involved a decrease in declining blood glucose concentration and HbA1C levels, and an increase in plasma insulin levels. AGS-IV increased the activity of glutathione peroxidase in nerves, depressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes. Moreover, AGS-IV elevated Na+,K+-ATPase activity in both the nerves and erythrocytes of diabetic rats. These results indicate that AGS-IV exerts protective effects against the progression of peripheral neuropathy in STZ-induced diabetes in rats through several interrelated mechanisms.     

Effect of various nerve decompression procedures on the functions of distal limbs in streptozotocin-induced diabetic rats: further optimism in diabetic neuropathy

It is known that diabetic neuropathy is the result of endoneurial edema caused by various biochemical reactions triggered by hyperglycemia. This sequence of events can cause cessation of circulation at the perineurial level, or the tough layer, which is not resilient enough to spread intraneural pressure. Internal and external limiting structures create a double crush phenomenon to the nerve structure. Decompression of the nerve trunk at separate levels is one of the adjuncts to the overall treatment plan for diabetic neuropathy. In this study, the right sciatic nerves of 30 rats with streptozotocin-induced diabetes were used; three groups were created. In the control group, the sciatic nerves were explored and dissected only. In group II, tarsal tunnel release was performed and accompanied by epineurotomy of the sciatic nerve and its peroneal and tibial extensions. In group III, in addition to the procedures performed in group II, perineural sheaths, exposed through the epineurotomy sites at both the peroneal and tibial nerves, were incised for decompression of the fascicles. Improvement in diabetic neuropathy was evaluated by using footprint parameters. The last print length values, estimated according to the 38-month measurements, were 26.1 +/- 0.12 mm in the control group, 23.2 +/- 0.07 mm in group II, and 22.2 +/- 0.1 mm in group III. The toe spread and intermediate toe spread values of the groups were parallel to improvements in print lengths throughout the study. The best improvement was observed in the perineurotomy group. Finally, an electron microscopic study revealed variable degenerative changes in all groups, but they were milder in groups II and III. This experimental study reveals that adding internal decompression to external release doubled the effect in reducing derangement in the sciatic nerves of the rats and, in the authors' opinion, offers cause for further optimism in the treatment of diabetic neuropathy.     

A comparison of sciatic nerve neuropathy in diabetic and aged rats

We compared the development of sciatic nerve neuropathy in young diabetic rats with that in non-diabetic aged rats. Diabetes was induced in six-month old rats by injection with alloxan and was moderately controlled by single daily injections of insulin. Blood insulin levels in diabetic rats were significantly reduced compared to the aged animals, and glucose was significantly higher in diabetic rats. Sciatic nerve conduction velocities were measured monthly. Both motor and sensory conduction velocities decreased in the diabetic rats to a level that was similar to those in 36-month old rats. The decreases in conduction velocities in the diabetic rats were most dramatic during months 6 through 12 of diabetes. After 6 and 12 months of diabetes, sciatic nerves were examined by electron microscopy and compared to nerves from 24- and 36-month old rats respectively. Ultrastructural changes in the sciatic nerves of diabetic rats at 6 months included disruptions of myelin and dense axoplasm. In comparison, the 24-month old rats only had distorted contours of the nerve fibres. After 12 months of diabetes, the axoplasm had large spaces and the myelin was thickened and deformed. The axoplasm of 36-month old rats was normal in appearance; however the myelin sheath was thickened and split into layers. The Schwann cells were vacuolated and irregular in shape. These observations indicate that diabetes results in the early onset of age-like changes in the sciatic nerve. It suggests that the control of hyperglycemia in humans may preserve sciatic nerve structure and function.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.     

Pathomechanism of entrapment neuropathy in diabetic and nondiabetic rats reared in wire cages

To examine the pathomechanism of entrapment neuropathy associated with diabetes with special emphasis on the roles of mast cells and Tenascin-C using a rat model of Streptozotocin-induced diabetes. The roles of mast cells and Tenascin-C in development of tarsal tunnel syndrome were analyzed electrophysiologically and histologically in 20 male Ws/Ws-/-rats (mast cell deficient) and 20 of their male wild type counterparts (12-16 weeks old; 250-300 g). Rats were assigned randomly to one of the following three groups; diabetic group and nondiabetic group reared in cages with a wire grid flooring; non-diabetic group in cages with sawdust covered plastic flooring. No significant role for mast cells in entrapment neuropathy was found in the rats with streptozotocin-induced diabetes. Distal latency was prolonged in diabetic rats compared with nondiabetic rats, and positively correlated with increases in blood glucose levels. Tenascin-C expression levels in the endoneurium at the tarsal tunnel in diabetic rats were found to be correlated with distal latency. The anti-alpha-smooth muscle actin (alpha-SMA) positive myofibroblast was scattered in nerve fascicles overexpressing Tenascin-C. It seems likely that Tenascin-C expressing myofibroblasts constrict axons by inducing collagen contraction of the endoneurium. Our data indicate that metabolic and phenotypic abnormalities of endoneurium and perineum lie behind the vulnerability of diabetic patients to entrapment neuropathy.     

黄连素对糖尿病大鼠胰岛素抵抗的治疗作用

目的:探讨黄连素对链脲佐菌素所致糖尿病大鼠胰岛素抵抗的治疗作用。方法:采用链脲佐菌素腹腔注射的方式建立大鼠糖尿病模型,将实验大鼠分为5组:分别为模型组、黄连素低(100 mg/kg)、黄连素中(200 mg/kg)、黄连素高(300 mg/kg)剂量组和阳性对照组(二甲双胍:50 mg/kg),每组10只。另取10只正常大鼠作为正常组。黄连素低、中、高剂量组小鼠每天分别灌胃100、200和300 mg/kg黄连素;对照组每天灌胃二甲双胍50 mg/kg;正常组和模型组每天给予相同体积的生理盐水进行灌胃; 1次/天,连续灌胃4周。通过测定大鼠血FBG、果糖胺水平,OGTT实验,胰岛素(FINS)水平,并计算大鼠胰岛素抵抗指数(HOMA-IR)来评价黄连素对糖尿病大鼠胰岛素抵抗作用。结果:与正常组相比,给药前模型组大鼠静脉血FBG含量显著升高(P<0.05);与模型组比较,给药2周及以后给药4周后阳性对照组、黄连素中剂量组和高剂量组大鼠静脉血FBG含量均显著下降(P<0.05);给药4周后,阳性对照组、黄连素低、中、高剂量组OGTT实验结果显示在不同时间节点的血糖值均显著低于模...     

Effect of kolaviron on islet dynamics in diabetic rats

Kolaviron, a biflavonoid isolated from the edible seeds of Garcinia kola, lowers blood glucose in experimental models of diabetes; however, the underlying mechanisms are not yet fully elucidated. The objective of the current study was to assess the effects of kolaviron on islet dynamics in streptozotocin-induced diabetic rats. Using double immunolabeling of glucagon and insulin, we identified insulin-producing β- and glucagon-producing α-cells in the islets of diabetic and control rats and determined the fractional β-cell area, α-cell area and islet number. STZ challenged rats presented with islet hypoplasia and reduced β-cell area concomitant with an increase in α-cell area. Kolaviron restored some islet architecture in diabetic rats through the increased β-cell area. Overall, kolaviron-treated diabetic rats presented a significant (p < 0.05) increase in the number of large and very large islets compared to diabetic control but no difference in islet number and α-cell area. The β-cell replenishment potential of kolaviron and its overall positive effects on glycemic control suggest that it may be a viable target for diabetes treatment.     

Effect of dehydroepiandrosterone in hereditarily diabetic rats

Goto-Kakizaki rats (GK rats) were given access for 4 weeks to a diet enriched with dehydroepiandrosterone (DHEA, 0·2 per cent, w/w). The incorporation of DHEA in the food failed to affect significantly body growth, plasma D -glucose and insulin concentrations, pancreatic islet insulin content or the activity of both mitochondrial glycerophosphate dehydrogenase (mGDH) and NADP-malate dehydrogenase (malic enzme) in islet homogenates. DHEA however, increased the activity of mGDH and, at least in male rates, that of the malic enzyme also in the liver. It lowered the abnormally high basal insulin release otherwise found in the islets from diabetic rats, and, as judged from the ratio of insulin output at 16·7 mM /2·8 mM D -glucose, improved the cell responsiveness to the hexose. This coincided with a decreased plasma insulin/D -glucose ratio, suggesting that the major effect of DHEA was to increase the sensitivity to insulin of extrapancreatic targets, thus resulting in a secondary improvement of cell secretory behaviour. © 1997 John Wiley & Sons, Ltd.     

Calcium signaling in diabetic neuropathy

Diabetic neuropathy is a frequent complication of diabetes mellitus, for which no adequate clinical treatment is currently available. One of the main reasons for the absence of effective treatment of this disease is that information on how metabolic, vascular, and other abnormalities involved in the pathogenesis of diabetic neuropathy lead to dysfunction of nerve cells and pathways remains insufficient. Recent studies demonstrated that substantial abnormalities of calcium homeostasis in input neurons of the somatosensory nociceptive system are associated with many symptoms of diabetic neuropathy. Although proof of the causal linkage between calcium abnormalities and neuropathic complications is not conclusive, current research in neuroscience mostly indicates that such a linkage exists. Practically all known modifications of synaptic transmission in both central and peripheral nervous systems result from calcium-dependent modifications of the molecular players involved in this transmission. This is why the main goal of our review is to analyze in detail the fundamental cellular and molecular calcium-regulating mechanisms that are deteriorated in diabetes. As an important end-point of the proposed review, the capability of a widely used calcium channel blocker, nimodipine, to correct cytosolic and endoplasmic reticulum calcium abnormalities in neurons of the dorsal root ganglia and spinal dorsal horn and possible curative value of this agent in diabetic neuropathy are discussed.Neirofiziologiya/Neurophysiology, Vol. 36, No. 4, pp. 348–353, July–August, 2004.This revised version was published online in April 2005 with a corrected cover date.     

Clodronate changes neurobiological effects of pulsed magnetic field on diabetic rats with peripheral neuropathy

Several studies have reported that pulsed magnetic fields (PMFs) can be a choice of therapy for diabetic peripheral neuropathy. However, the exact underlying mechanism of PMF is still not known. The purpose of this study was, therefore, to investigate the effects of clodronate encapsulated with liposome, a specific agent depleting macrophage, on PMF-treated streptozotocin-induced type I diabetic rats with peripheral neuropathy. Effects of PMF, liposome-encapsulated clodronate (LEC) or their combined treatments were investigated in diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels, serum insulin level, and body mass. In diabetic rats, PMF exhibited a decrease in the blood glucose levels but did not change the serum insulin level. Both mechanical thresholds and thermal latencies of diabetic rats enhanced throughout the PMF treatment. During the PMF treatment, the administration of LEC suppressed the PMF-induced decrease in blood glucose level, PMF-induced increase in mechanical threshold and thermal latencies in diabetic animals. In addition, PMF reduced the LEC-induced increase in insulin levels of diabetic rats. Findings demonstrated that although effects of both PMF alone and LEC alone on diabetic animals are mostly positive, LEC may remove the therapeutic efficacies of PMF in combined treatment.     

Effect of glycine in streptozotocin-induced diabetic rats

Inadequate utilization of glucose in diabetes mellitus favors diverse metabolic alterations that play a relevant role in the physio-pathology of chronic complications of this disease. Streptozotocin-induced diabetic rats were treated daily with glycine (130 mM as optimal concentration) or taurine (40 mM) for six months. Groups of diabetic rats without treatment were used as controls. Glucose, total cholesterol, triacylglycerol, and glycated hemoglobin were determined periodically after inducing diabetes. Rats were killed after 6 months of treatment and histological analyses were performed. Diabetic groups that received glycine or taurine showed significant lower concentrations of glucose, total cholesterol, triacylglycerol, and glycated hemoglobin than diabetic control rats (P<0.05) after 6 months treatment. Histological analyses of diabetic rats showed pancreatic atrophy and necrosis, vacuolization, decrease of beta cells, and diffuse glomerulosclerosis. Diabetic rats treated with glycine or taurine showed less enlargement of the glomerular basal membrane than control diabetic rats. Our results suggest that glycine and taurine reduced the alterations induced by hyperglycemia in streptozotocin-induced diabetic rats probably due to inhibition of oxidative processes.     

Effect of lacidipine on ischaemic and reperfused isolated rabbit hearts

Lacidipine is a new developed dihydropyridine calcium-antagonist, showing a slow onset and long lasting-selective activity.To assess whether the administration of lacidipine protects the myocardium in a dose-dependent manner against ischaemia and reperfusion, isolated rabbit heart were infused with three different concentrations of lacidipine: 10^–10; 10^–9; 10^–8 M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity, ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP) and calcium were determined. Occurrence of oxidative stress during ischaemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutatione. Treatment with lacidipine at 10^–10 and 10^–9 M had no effects on the hearts when perfused under aerobic condition, whilst the higher dose reduced developed pressure of 36%. The ischaemic-induced deterioration of mitochondrial function was attenuated. On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores and mitochondrial function. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and of noradrenaline and oxidative stress were also significantly reduced. The effects of lacidipine were dose-dependent. The lower concentration (10^–10 M) failed to modify ischaemic and reperfusion damage. The dose of 10^–9 M was cardioprotective, but the best effect was found at 10^–8 M.It is concluded that lacidipine infusion provides a dose dependent protection of the heart against ischaemia and reperfusion. Because this protection occurred also at 10^–9 M, in the absence of negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy sparing effect or to improvement of oxygen delivery. From our data we can envisage two other major mechanism:-1) membrane protection-2) reduction of oxygen toxicity. The ATP sparing effect occurring at 10^–8 M is likely to be responsable for the further protection.     

Effect of dietary protein on cholesterol homeostasis in diabetic rats

Normal and streptozotocin (STZ)-diabetic rats were studied in order to examine the effects of altering the type of dietary protein on cholesterol homeostasis. Rats were fed a non-purified or a purified diet containing either casein or soybean protein. The results obtained on the specific aspects of lipid metabolism were remarkably similar in control rats fed the non-purified (Purina Lab Chow) diet or the purified diet with the soybean protein. However, most of the findings obtained with the above two groups were different from those obtained with rats fed the purified diet containing casein. In the latter group, plasma cholesterol was elevated following a 15-day feeding period as compared to the other two dietary groups. The excess plasma cholesterol in the casein-fed group was found in two lipoprotein fractions with densities of 1.023-1.045 g/ml and 1.045-1.086 g/ml, respectively. The latter lipoprotein fraction was also enriched with apolipoprotein E. The casein-fed animals also showed a lower fractional rate of plasma cholesterol esterification and an abnormal accumulation of cholesterol in the body despite inhibition of cholesterol synthesis in the liver and in the intestines. Twelve to 15 days after the induction of diabetes, plasma cholesterol increased to a similar extent in the rats on all three diets. However, the distribution of cholesterol among the lipoprotein fractions was markedly different. The percentage of cholesterol in fractions of d less than 1.086 g/ml was increased while that carried in the fraction of d 1.086-1.161 g/ml decreased in the rats fed the nonpurified diet and the casein diet. In contrast, there was no change in the distribution of lipoprotein cholesterol between the diabetic and the control rats fed the soybean protein diet. The hepatic synthesis of cholesterol was unaltered in diabetic rats fed the nonpurified diet and the purified diet with soybean protein, but was increased 2.4-fold in diabetic rats fed casein. Intestinal cholesterol synthesis was increased in all three dietary groups. The increase was highest in the rats fed casein and lowest in rats fed soybean protein. The rate of sterol synthesis in the kidneys was not significantly affected by the diet or diabetes. In all three dietary groups diabetes led to an abnormal accumulation of cholesterol in the body. This accumulation was highest in the casein-fed rats and lowest in those fed the soybean protein diet. The cholesterol content of the kidneys was markedly increased by dietary casein.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of cadmium on antioxidant status in alloxane-induced diabetic rats

Fifty-two healthy Swiss Male Albino rats aged two mo were used in this study. They were divided into four groups: control (C), diabetic (D), cadmium (Cd), and diabetic+Cd (D+Cd) groups. Diabetic condition was induced in D and D+Cd groups by administration of alloxane (5 mg/100 g). After this treatment, CD and D+Cd groups were injected with CdCl₂ ip (2 mg/kg/wk). At the end of the 2-mo experimental period, thiobarbituric acid reactive substances (TBARS), plasma and erythrocyte selenium (SE), plasma ceruloplasmin (Cp), and vitamin E (vit E) were determined in four groups of rats. The erythrocyte Se was lower in the experimental groups than in the controls. Plasma Se was significantly decreased in the D and D+Cd groups compared with the control group. Plasma Cp was unaltered. Plasma vit E was significantly decreased in Cd group in comparison with the C, D, and D+Cd groups.     

Cardiovascular autonomic neuropathy in spontaneously diabetic rats with and without application of EGb 761

Cardiovascular autonomic neuropathy causes abnormalities in the diabetic heart with various clinical sequelae, including exercise intolerance, arrhythmias and painless myocardial infarction. Little is known about (ultra)structural alterations of the myocardial nervous network. On the assumption that this diabetes-specific neuropathy develops due to permanently increased oxidative stress by liberation of oxygen-free radicals, adjuvant application of antioxidative therapeutics appears promising in preventing or delaying long-term diabetic complications. We have investigated the effects of Ginkgo biloba extract (EGb 761), a radical scavenger, against diabetes-induced myocardial nervous damage in spontaneously diabetic BioBreeding/Ottawa Karlsburg (BB/OK) rats. Morphological and morphometric parameters were evaluated by electron microscopy. We used immunohistochemistry to investigate protein expression of protein gene product 9.5, S100 protein, and thyroxin hydroxylase as a neuronal marker. Alterations of cardiac sympathetic activity were measured using the in vivo 123I-metaiodobenzyl-guanidine imaging, and the immunofluorescent labeling of beta1-adrenergic receptors and adenylate cyclase. Our results revealed that A) Diabetes results in slight to moderate ultrastructural alterations (hydrops, disintegration of substructure) of autonomic nerve fibers and related Schwann cells in untreated BB diabetic rats; B) Cardiac sympathetic integrity and activity is impaired due to alterations in the presynaptic nerve terminals and the postsynaptic ?1-AR-AC coupling system; C) Pre-treatment of diabetic myocardium with EGb results in an improvement of most of these parameters compared to unprotected myocardium. In conclusion, EGb may act as a potent therapeutic adjuvant in diabetics with respect to cardiovascular autonomic neuropathy, which may contribute to the prevention of late complications in diabetes.     

Pain modality and spinal glia expression by streptozotocin induced diabetic peripheral neuropathy in rats

Pain symptoms are a common complication of diabetic peripheral neuropathy or an inflammatory condition. In the most experiments, only one or two evident pain modalities are observed at diabetic peripheral neuropathy according to experimental conditions. Following diabetic peripheral neuropathy or inflammation, spinal glial activation may be considered as an important mediator in the development of pain. For this reason, the present study was aimed to address the induction of pain modalities and spinal glial expression after streptozotocin injection as compared with that of zymosan inflammation in the rat. Evaluation of pain behavior by either thermal or mechanical stimuli was performed at 3 weeks or 5 hours after either intravenous streptozotocin or zymosan. Degrees of pain were divided into 4 groups: severe, moderate, mild, and non-pain induction. On the mechanical allodynia test, zymosan evoked predominantly a severe type of pain, whereas streptozotocin induced a weak degree of pain (severe+moderate: 57.1%). Although zymosan did not evoke cold allodynia, streptozotocin evoked stronger pain behavior, compared with zymosan (severe+moderate: 50.0%). On the other hand, the high incidence of thermal hyperalgesia (severe+moderate: 90.0%) and mechanical hyperalgesia (severe+moderate: 85.7%) by streptozotocin was observed, as similar to that of zymosan. In the spinal cord, the increase of microglia and astrocyte was evident by streptozotocin, only microglia was activated by zymosan. Therefore, it is recommended that the selection of mechanical and thermal hyperalgesia is suitable for the evaluation of streptozotocin induced diabetic peripheral neuropathy. Moreover, spinal glial activation may be considered an important factor.     

Effect of FeSO4 treatment on glucose metabolism in diabetic rats

Iron, the prosthetic group of haemoglobin, was found to lower serum glucose levels of diabetic rats. Its regulative mechanism and effects on enzymatic activities of glucose metabolism are still unknown. In this study, the correlation between iron supply and enzymatic activities of glucose metabolism and respiratory chain were evaluated in liver and kidney tissues of alloxan induced-diabetic rats. After FeSO₄ and metformin administration, serum samples were collected for serum glucose and fructosamine level measurements. Kidney and liver tissues were excised at the end of the study for assaying enzymatic activities of isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH-dehydrogenase and cytochrome-c-oxidase. Results showed significantly decreased serum glucose and fructosamine levels in treatment groups and enhanced enzymatic activities of several proteins as compared with the diabetic control group. Therefore, these data suggested that FeSO₄ administration could increase the supply of oxygen, enhance enzymatic activities of glucose metabolism and the respiratory chain, accelerate glucose metabolism and consequently decrease serum glucose levels.     

Effect of clofibrate on lipid metabolism in streptozotocin diabetic rats.

The effect of clofibrate (CPIB) on lipid metabolism was studied in male rats rendered diabetic by intravenous injection of 80 mg/kg of streptozotocin. After 1 wk, the rats received by gastric intubation 242 mg/kg/day of CPIB for 7 days. Liver lipid concentration remained unchanged in experimental diabetes and after treatment with CPIB; however, due to decreased liver weight, total liver lipids were lower in diabetic rats. Elevation of cholesterol, phospholipids, and triglycerides in the serum of diabetic rats was reversed by CPIB treatment. Hepatic cholesterol synthesis in diabetic rats was suppressed to approximately 1/10 of that in normal rats. Treatment with CPIB abolished this residual cholesterogenic activity. Diabetes had no effect on intestinal cholesterol synthesis; a slight increase was noted after CPIB treatment. Basal and norepinephrine-induced lipolysis in fat pads was elevated in diabetic rats; CPIB had no effect on these changes. The data show that the elevated serum lipids in diabetic rats are lowered by treatment with C-IB. It was concluded that the hypocholesterolemic activity of clofibrate in rats is not caused by its suppression of hepatic cholesterol synthesis.