Inhalation toxicity studies of the alpha,beta-unsaturated ketones: 2-cyclohexene-1-one

2-Cyclohexene-1-one (CHX) is a cyclic alpha,beta-unsaturated ketone with broad human exposure. CHX is an environmental pollutant and is present in tobacco smoke and in soft drinks sweetened with cyclamate. Interest in the toxicity of this class of compounds is due to their structural similarity to the cytotoxin acrolein. In a pilot study, rats and mice were exposed to 0, 20, 40, or 80 ppm CHX for 6 h/day. The study was terminated after 4 days due to acute toxicity in the high-dose groups. In a subsequent 14-day study, mice and rats were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day. All animals survived exposure until terminal sacrifice. Body weights were not significantly different from controls after 14 days of exposure. Liver/body weights were increased in male and female mice exposed to 5 and 10 ppm, and in male and female rats exposed to 10 ppm CHX. Ninety-day toxicity studies were conducted to provide data required to design chronic toxicity and carcinogenicity studies of CHX if it is determined such studies are necessary. Groups of 10 male and female F-344 rats and B6C3F1 mice were exposed to 0, 2.5, 5, or 10 ppm CHX for 6 h/day for 13 wk. All animals survived until sacrifice. Body weights were not significantly different from controls after 13 wk of exposure. Liver weights were increased in male and female mice exposed to 5 and 10 ppm and in male and female rats exposed to 10 ppm CHX. No adverse effects on bone-marrow micronuclei, sperm motility, or vaginal cytology were observed. Microscopic lesions included hyperplasia, and squamous metaplasia in the nasal cavity in rats and mice of both sexes at all doses. Nasal-cavity erosion and suppurative inflammation also occurred in high-dose mice. Larynx and lung were not affected in either sex or species. Dose-related hepatic centrilobular cytoplasmic vacuolation was seen in male rats only. These data suggest that CHX acts as an alkylating agent primarily producing toxicity at the exposure site.     

Involvement of serotonin in zimelidine-induced hyperglycemia in mice

Effects of a selective serotonin reuptake inhibitor, zimelidine, on plasma glucose was studied in mice. Zimelidine dose-dependently induced hyperglycemia, although it did not change insulin levels. To determine the involvement of the serotonergic system in zimelidine-induced hyperglycemia, effects of the 5-HT depleter p-chlorophenylalanine(pCPA) were examined. pCPA significantly reduced zimelidine-induced hyperglycemia. This suggests that zimelidine-induced hyperglycemia is mediated by the serotonergic system through its 5-HT reuptake inhibition.     

Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice

Two hours following administration of a hepatotoxic dose of acetaminophen (500 mg/kg, i.p.) to mice, liver sections stained with periodic acid Schiff reagent showed centrilobular hepatic glycogen depletion. A chemical assay revealed that following acetaminophen administration (500 mg/kg) hepatic glycogen was depleted by 65% at 1 hr and 80% at 2 hr, whereas glutathione was depleted by 65% at 0.5 hr and 80% at 1.5 hr. Maximal glycogen depletion (85% at 2.5 hr correlated with maximal hyperglycemia (267 mg/100 ml at 2.5hr). At 4.0 hr following acetaminophen administration, blood glucose levels were not significantly different from saline-treated animals; however, glycogen levels were still maximally depleted. A comparison of the dose-response curves for hepatic glycogen depletion and glutathione depletion showed that acetaminophen (50–500 mg/kg at 2.5 hr) depleted both glycogen and glutathione by similar percentages at each dose. Since acetaminophen (100 mg/kg at 2.5 hr) depleted glutathione and glycogen by approximately 30%, evidence for hepatotoxicity was examined at this dose to determine the potential importance of hepatic necrosis in glycogen depletion. Twenty-four hours following administration of acetaminophen (100 mg/kg) to mice, histological evidence of hepatic necrosis was not detected and serum glutamate pyruvate transaminase (SGPT) levels were not significantly different from saline-treated mice. The potential role of glycogen depletion in altering the acetaminophen-induced hepatotoxicity was examined subsequently. When mice were fasted overnight, hepatic glutathione and glycogen were decreased by 40 and 75%, respectively, and fasted animals showed a dramatic increase in susceptibility to acetaminophen-induced hepatotoxicity as measured by increased SGPT levels. Availability of glucose in the drinking water (5%) overnight resulted in glycogen levels similar to those in fed animals, whereas hepatic glutathione levels were not significantly different from those of fasted animals. Fasted animals and animals given glucose water overnight were equally susceptible to acetaminophen-induced hepatotoxicity, as quantitated by increases in SGPT levels 24 hr after drug administration. The potential role of a reactive metabolite in glycogen depletion was investigated by treating mice with N-acetylcysteine to increase detoxification of the reactive metabolite. N-Acetylcysteine treatment of mice prevented acetaminophen-induced glycogen depletion.     

CCN2 protein is an announcing marker for cardiac remodeling following STZ-induced moderate hyperglycemia in mice

Diabetes causes changes in the myocardium, which are often called diabetic cardiomyopathy. This condition has been extensively investigated in animal models with high glucose levels. Nevertheless, it has not been investigated whether moderate hyperglycemia, in the absence of other features of metabolic syndrome, may also cause similar changes in the heart. The aim of the study was to assess changes in the myocardium in an animal model of mild type 1 diabetes. Moderate hyperglycemia was induced in 8- to 10-week-old male C57BL6J mice by 5 intraperitoneal injections of streptozotocin (40 mg/kg). After 16 weeks, they were sacrificed, and left ventricle (LV) dimensions and extent of cardiac fibrosis were assessed by morphometry. The abundance of CCN proteins in LVsamples was assessed using western blotting, while activity of metalloproteinase 2 was established in zymography. Real time PCR was used to investigate the expression of transforming growth factor β1 (TGFβ1) and atrial natriuretic peptide. Mice with moderate hyperglycemia presented comparable cardiac dimensions with fibrosis and hypertrophy parameters as the non-diabetic controls. However, the abundance of profibrotic CCN2 protein was significantly increased in hyperglycemic animals (1.67 ± 0.28 vs. 1 ± 0.47, p < 0.05). Interestingly, this change was independent from the TGFβ1 expression, as its RNAabundance was similar in both groups. Moderate hyperglycemia also caused an increase in the activity of the metalloproteinase 2 (1.21 ± 0.17 vs. 1 ± 0.07, p < 0.05).Despite diabetes, no profound changes in cardiac morphology were found. In our animal model, moderate hyperglycemia caused activation of a profibrotic gene expression program, which was counterbalanced by the increase of metalloproteinase activity.     

Phenoxazine derivatives 2-amino-4,4alpha-dihydro-4alpha-phenoxazine-3-one and 2-aminophenoxazine-3-one-induced apoptosis through a caspase-independent mechanism in human neuroblastoma cell line NB-1 cells

The aim of the present study was to determine whether phenoxazines such as 2-amino-4,4-alpha-dihydro-4alpha-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3) may suppress the proliferation of human neuroblastoma cell line, NB-1 that is refractory to chemotherapeutic agents, inducing apoptosis through the activation of caspase pathway or not. Phx-1 and Phx-3 suppressed the proliferation of NB-1 cells extensively dependent on dose and time. The IC50 of Phx-1 and Phx-3 was about 20 microM and 0.5 microM, respectively, when the cells were treated with Phx-1 or Phx-3 for 72 h. Phx-1 and Phx-3 caused the mixed types of cell death-apoptosis and necrosis-in NB-1 cells, which was detected by flow cytometry. The induction of apoptosis/necrosis caused by these phenoxazines seemed to be correlated dominantly with the caspase independent pathway, because the increased activity of effector caspase 3/7 in NB-1 cells caused by 50 microM Phx-1 or 20 microM Phx-3 was completely cancelled by the addition of z-VAD-fmk, a pan-caspase inhibitor, but such phenoxazines-suppressed viability of NB-1 cells was not recovered to normal levels by this inhibitor. The results of this study demonstrate that Phx-1 and Phx-3 have antitumor activity against the neuroblastoma cell line, NB-1, though the IC50 was extremely low for Phx-3, inducing the mixed types of cell death, apoptosis and necrosis, caspase-independently.     

Effects of the serotonergic anxiolytic buspirone on plasma glucose and glucose-induced hyperglycemia in mice

Effects of the serotonergic anxiolytic buspirone on plasma glucose and glucose-induced hyperglycemia were studied in mice. Buspirone did not affect plasma glucose levels of non-fasted mice, while it increased serum insulin levels. In fasted mice, buspirone significantly reduced glucose-induced hyperglycemia and enhanced insulin release elicited by glucose. This suggests that buspirone enhances insulin release, resulting in inhibition of glucose-induced hyperglycemia. The major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP) increased serum insulin levels and induced a slight hypoglycemia in non-fasted mice. 1-PP decreases glucose-induced hyperglycemia and amplifies insulin release elicited by glucose in fasted mice. Since buspirone is mainly metabolized to 1-PP and formation of 1-PP occurs quickly, the inhibitory effect of buspirone on glucose-induced hyperglycemia is likely mediated by 1-PP.     

Salicornia herbacea prevents high fat diet-induced hyperglycemia and hyperlipidemia in ICR mice

Salicornia herbacea L. (Chenopodiaceae) has been used as a seasoned vegetable by living in coastal areas. S. herbacea (SH) has been demonstrated to stimulate cytokine production, nitric oxide release, and to show anti-oxidative effect. In a series of investigations to develop potential anti-diabetic and/or anti-hyperlipidemic agents from Korean indigenous plants, 50% ethanol extract of Salicornia herbacea was found to prevent the onset of the hyperglycemia and hyperlipidemia induced by high fat diet in ICR mice. At 6 week old, the ICR mice were randomly divided into five groups; two control and three treatment groups. The control mice were to receive either a regular diet (RD) or high-fat diet (HFD), and the treatment groups were fed a high fat diet with either 350 mg/kg, 700 mg/kg of SH (SH350 and SH700) or 250 mg/kg of metformin (MT250) for a 10-week period. SH not only reduced body weight but also corrected associated hyperglycemia and hyperlipidemia in a dose dependent manner. SH exerted beneficial effects on the plasma glucose and lipid homeostasis possibly ascribed to its specific effects on lipogenesis related genes (SREBP1a, FAS, GAPT), and PEPCK, glucose 6-phosphatase gene expressions in liver. Ethanol extract of S. herbacea has potential as a preventive agent for type 2 diabetes (and possibly hyperlipidemia) and deserves future clinical trial.     

应用PD-1抑制剂后高血糖症1例

程序性细胞死亡蛋白1（PD-1）的单克隆抗体可以阻断PD-1与其配体之间的相互作用,恢复T细胞的抗肿瘤作用。PD-1抑制剂已被广泛批准用于治疗各种恶性肿瘤。有大量文献报道了信迪利单抗有令人满意的抗肿瘤作用,同时也报道出一些相关不良反应。由PD-1抑制剂引起的急性自身免疫性胰岛素依赖型糖尿病在儿童中非常罕见。现报道广东药科大学附属第一医院2021年11月收治的1例应用PD-1抗体后出现高血糖症儿童。     

Involvement of hyperglycemia in deposition of aggregated protein in glomeruli of diabetic mice

The aim of this study was to clarify the influence of hyperglycemia on the deposition of aggregated protein in the glomeruli of diabetic mice. KK-A(y) mice injected with aggregated bovine serum albumin accumulated more of it in the glomeruli than did ICR mice. There were no histological alterations in the glomeruli of KK-A(y) mice. KK-A(y) mice given voglibose in mouse-chow for 2 weeks had significantly reduced blood glucose, glycated albumin, and hemoglobin A(1C) levels compared with control mice. The voglibose-treated KK-A(y) mice were injected with aggregated bovine serum albumin and accumulated significantly less albumin in the glomeruli than did the control mice. Pioglitazone decreased blood glucose levels compared with the control, and reduced the glomerular deposition of aggregated albumin. Glomerular aggregated bovine serum albumin levels and blood glucose levels were reduced significantly by the injection of insulin. Six times more advanced glycation endproducts were produced from aggregated bovine albumin than from non-aggregated bovine albumin on incubation with glucose and L-lysine in vitro. Glucose-loaded ICR mice generated more advanced glycation endproducts from aggregated albumin, and had more aggregated bovine albumin in the glomeruli. It was suggested that hyperglycemia contributes to an increase in the deposition of aggregated protein in glomeruli even early on in diabetes.     

A phlorotannin constituent of Ecklonia cava alleviates postprandial hyperglycemia in diabetic mice

Context: 2,7″-Phloroglucinol-6,6′-bieckol is a type of phlorotannin isolated from brown algae, Ecklonia cava Kjellman (Phaeophyceae; Laminareaceae). 2,7″-Phloroglucinol-6,6′-bieckol mediates antioxidant activities. However, there has been no research on improving postprandial hyperglycaemia using 2,7″-phloroglucinol-6,6′-bieckol.

Objective: This study investigated the inhibitory effects of 2,7″-phloroglucinol-6,6′-bieckol on activities of α-glucosidase and α-amylase as well as its alleviating effect on postprandial hyperglycaemia in streptozotocin-induced diabetic mice.

Materials and methods: α-Glucosidase and α-amylase inhibitory assays were carried out. The effect of 2,7″-phloroglucinol-6,6′-bieckol on hyperglycaemia after a meal was measured by postprandial blood glucose in streptozotocin-induced diabetic and normal mice. The mice were treated orally with soluble starch (2?g/kg BW) alone (control) or with 2,7″-phloroglucinol-6,6′-bieckol (10?mg/kg bw) or acarbose (10?mg/kg BW) dissolved in 0.2?mL water. Blood samples were taken from tail veins at 0, 30, 60, and 120?min and blood glucose was measured by a glucometer.

Results: 2,7″-Phloroglucinol-6,6′-bieckol showed higher inhibitory activities than acarbose, a positive control against α-glucosidase and α-amylase. The IC₅₀ values of 2,7″-phloroglucinol-6,6′-bieckol against α-glucosidase and α-amylase were 23.35 and 6.94?μM, respectively, which was found more effective than observed with acarbose (α-glucosidase IC₅₀ of 130.04?μM; α-amylase IC₅₀ of 165.12?μM). In normal mice, 2,7″-phloroglucinol-6,6′-bieckol significantly suppressed the postprandial hyperglycaemia caused by starch. The 2,7″-phloroglucinol-6,6′-bieckol administration group (2349.3?mmol·min/L) had a lower area under the curve (AUC) glucose response than the control group (2690.83?mmol·min/L) in diabetic mice.

Discussion and conclusion: 2,7″-Phloroglucinol-6,6′-bieckol might be used as an inhibitor of α-glucosidase and α-amylase as well as to delay absorption of dietary carbohydrates.     

Wild ginseng prevents the onset of high-fat diet induced hyperglycemia and obesity in icr mice

Ginseng is a shade-loving perennial herb that is cultivated mainly in Korea, Japan, and China. The ginseng root has been used as a tonic remedy, and its antidiabetic activity has been demonstrated as early as 1920s. Although wild ginseng was anecdotally thought to be superior to cultivated ginseng as far as pharmacological properties were concerned, there have been no prior reports on the antidiabetic effect of wild ginseng. In this study, we investigated the preventative anti-diabetic and anti-obese effects of wild ginseng ethanol extract (WGEE). In the preventive experiment, WGEE co-administered with a high fat diet significantly inhibited body weight gain, fasting blood glucose, triglyceride, and free fatty acid levels in a dose dependent manner. WGEE-treated mice at doses of 250 and 500 mg/kg improved the insulin resistance index by 55% and 61% compared to the high fat diet (HFD) control, respectively. Diameters of white and brown adipocytes were also decreased by 62% and 46% in the WG500-treated group compared to those in HFD fed control mice. Taken together, WGEE has potential as a preventive agent for type 2 diabetes mellitus (and possibly obesity) and deserves clinical trial in the near future.     

The coupling of metabolic to secretory events in pancreatic islets: effects of 2-cyclohexene-1-one upon GSH content and secretory behaviour

The GSH content and GSH/GSSG ratio were decreased in rat pancreatic islets exposed to 2-cyclohexene-1-one (CHX; 1.0 mM), but the drug failed to affect the cytosolic NADH/NAD+ and NADPH/NADP+ ratios. This coincided with inhibition of D-glucose oxidation, whilst the oxidation of L-leucine and L-glutamine was little affected by CHX (1.0 mM). The release of insulin evoked by either D-glucose or 2-ketoisocaproate was inhibited by CHX (1.0 mM), whereas such was not the case for insulin secretion induced by L-leucine, alone or in combination with L-glutamine. The latter amino acid protected the B-cell against the inhibitory action of CHX upon glucose-stimulated insulin release. CHX severely altered the normal relationship between nutrient oxidation, [45Ca] net uptake and insulin release. Since CHX also inhibited insulin release evoked by non-nutrient secretagogues, it is speculated that GSH may be involved in several cytophysiological processes including the control of glycolysis, intracellular calcium distribution, and responsiveness to this cation of Ca2+-sensitive targets.     

Persistent correction of hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice by a non-conventional radical scavenger

We previously reported that in a diabetes mouse model, characterised by moderate hyperglycaemia and reduced β-cell mass, the radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate di-hydrochloride (IAC), a non-conventional cyclic hydroxylamine derivative, improves metabolic alterations by counteracting β-cell dysfunction associated with oxidative stress. The aims of this study were to ascertain whether the beneficial effects of IAC treatment could be maintained after its discontinuation and further elucidate the underlying mechanisms. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Diabetic mice were treated for 7 weeks with various doses of IAC (7.5, 15, or 30 mg/kg b.w./die i.p.) and monitored for additional 8 weeks after suspension of IAC. Then, pancreatic tissue was used for determination of β-cell mass by immunohistochemistry and β-cell ultrastructural analysis. STZ-NA mice showed moderate hyperglycaemia, glucose intolerance and reduced β-cell mass (25% of controls). IAC-treated STZ-NA mice (at both doses of 15 and 30 mg/kg b.w.) showed long-term reduction of hyperglycaemia even after discontinuation of treatment, attenuation of glucose intolerance and partial preservation of β-cell mass. The lowest IAC dose was much less effective. Plasma nitrotyrosine levels (an oxidative stress index) significantly increased in untreated diabetic mice and were lowered upon IAC treatment. At ultrastructural level, β cells of IAC-treated diabetic mice were protected against degranulation and mitochondrial alterations. In the STZ-NA diabetic mouse model, the radical scavenger IAC induces a prolonged reduction of hyperglycaemia associated with partial restoration of β-cell mass and function, likely dependent on blockade of oxidative stress-induced damaging mechanisms.     

Acanthopanax senticosus reverses fatty liver disease and hyperglycemia in ob/ob mice

Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the progression of NAFLD to end-stage disease associated with the development of cirrhosis and liver disease. In a previous experiment, 50% ethanol extract of Acanthopanax senticosus stem bark (ASSB) was found to reduce body weight and insulin resistance in high fat diet-induced hyperglycemic and hyperlipidemic ICR mice. To evaluate the anti-steatosis action of ASSB, insulin-resistant ob/ob mice with fatty livers were treated with ASSB ethanol extract for an 8 week-period. ASSB ethanol extract reversed the hepatomegaly, as evident in reduction of % liver weight/body weight ratio. ASSB ethanol extract also specifically lowered circulating glucose and lipids, and enhanced insulin action in the liver. These changes culminated in inhibition of triglyceride synthesis in non-adipose tissues including liver and skeletal muscle. Gene expression studies confirmed reductions in glucose 6-phosphatase and lipogenic enzymes in the liver. These results demonstrate that ASSB ethanol extract is an effective treatment for insulin resistance and hepatic steatosis in ob/ob mice by decreasing hepatic lipid synthesis.     

Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake

Many antipsychotic drugs disturb the regulation of glucose metabolism in patients treated for schizophrenia. The goal of the present studies was to determine if these antipsychotic drugs produce hyperglycemia in mice in relation to their ability to interfere with glucose uptake and utilization. Male C57BL/6 mice were injected with a panel of typical and atypical antipsychotic drugs and blood glucose levels were determined periodically over a 3- to 6-h time interval. The atypical drugs, clozapine, desmethylclozapine, quetiapine, and loxapine, and the original antipsychotic, chlorpromazine, induced significant hyperglycemia in the mice in accordance with their effects on glucose transport. By contrast, haloperidol and sulpiride, which have little effect on glucose uptake, did not induce hyperglycemia. Risperidone produced a modest elevation of blood glucose levels, but only at a low dose of the drug. Cytochalasin B, a specific inhibitor of the glucose transporter (GLUT) protein, produced significant hyperglycemia in the mice. Overall, there was a strong correlation between the ability of a drug to inhibit glucose transport in vitro and its ability to induce hyperglycemia in vivo. Finally, the drugs that produced hyperglycemia in mice have been linked to the development of diabetes in patients.     

The coupling of metabolic to secretory events in pancreatic islets: inhibition by 2-cyclohexene-1-one of the secretory response to cyclic AMP and cytochalasin B

In rat pancreatic islets perifused in the presence of 2-cyclohexene-1-one (CHX; 1.0 mM), the secretory response to either D-glucose or 2-ketoisocaproate, but not that evoked by the association of L-leucine and L-glutamine, was severely decreased. This coincided with a decreased stimulation of [45Ca] efflux from prelabelled islets, whereas the inhibitory action of D-glucose or 2-ketoisocaproate upon both [86Rb] and [45Ca] efflux appeared little or not affected. In the presence of D-glucose, the islets exposed to CHX were virtually unresponsive to either forskolin, theophylline or cytochalasin B. A severe decrease in the secretory response to forskolin was also observed in CHX-treated islets exposed to L-leucine and L-glutamine. Except for a somewhat lower sensitivity to NaF, no major change in adenylate cyclase activity or cyclic AMP production was observed in CHX-treated islets. The activity of protein kinase A was decreased in such islets but its responsiveness to cyclic AMP appeared unaltered. Transglutaminase activity was severely decreased in homogenates derived from CHX-treated islets. These findings suggest that CHX, possibly by lowering the GSH content of islet cells, impairs the functional capacity of the effector system for insulin release, in addition to and independently of any effect that it may exert upon nutrient catabolism and cationic fluxes in the islet cells.     

Inhibitory effects of the 5-HT(1A) receptor agonist buspirone on stress-induced hyperglycemia in mice: involvement of insulin and a buspirone metabolite, 1-(2-pyrimidinyl)piperazine (1-PP)

Effects of serotonergic anxiolytic buspirone on immobilization-induced hyperglycemia were studied in mice. Stress elicited hyperglycemia in mice. Pretreatment with buspirone significantly reduced immobilization-induced hyperglycemia. Buspirone increased serum insulin levels in both non- and stressed mice. The major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP) also increased and this further inhibited immobilization-induced hyperglycemia, since 1-PP increased serum insulin levels in both non-stressed and stressed mice, similar to the increases induced by buspirone. These results suggest that buspirone can reduce stress-induced hyperglycemia by facilitating insulin release. Moreover, 1-PP, a metabolite of buspirone may participate in the effects of buspirone. Since 1-PP is an antagonist of alpha(2) receptors, alpha(2) receptors may be related to effects of 1-PP.     

Effects of acute and chronic hyperglycemia on morphine-induced inhibition of gastrointestinal transit in mice

Using the charcoal meal test, the effects of morphine (3, 5 and 7 mg/kg) on gastrointestinal transit was assessed in normoglycemic as well as in acute and chronic hyperglycemic mice. Acute hyperglycemia was induced by intraperitoneal injection of glucose (5.04 g/kg), while chronic hyperglycemia was induced by streptozotocin injection (200 mg/kg i.p., 7-8 days before). Acute hyperglycemia augmented the inhibitory effect of morphine on gut transit, however, chronic hyperglycemia failed to modify the effects of morphine. The results indicate that hyperglycemia per se may not be the primary mechanism for the altered sensitivity to morphine in experimental models of diabetes.     

Chromium-induced hyperglycemia in the rat.

The acute administration of chromium chloride (Cr) produces hyperglycemia in rats. Adrenalectomy prevents the hyperglycemic effect but not the glucose intolerance. Subacute exposure of rats to Cr for 7--23 days does not change the resting blood glucose nor is there an acute or subacute effect on tolerance to glucose load. Administration of Cr does not influence acute insulin hypoglycemia. Thus contrary to Cr deficient animal, at the concentrations tested, Cr appears to be a hyperglycmiec agent to rats with minimal subacute effects.