Hydrazonopropionic acids, a new class of hypoglycemic substances. 4. Hypoglycemic effect of 2-(3-methyl-cinnamylhydrazono)-propionate in the rat and guinea pig

The hydrazone-compound 2-(3-methyl-cinnamylhydrazono)-propionate (MCHP) significantly lowered the blood glucose concentration in fasted guinea pigs and rats. A significant decrease of blood glucose levels was observed in fasted guinea pigs already after an intraperitoneal injection of 20.5 mumol/kg MCHP, while much higher doses (about 1000 mumol/kg) were necessary to produce a hypoglycemic effect in the fasted rat. After oral administration MCHP (82.0 mumol/kg) significantly decreased the blood glucose concentration in guinea pigs. Furthermore MCHP caused a dose-dependent increase of plasma free fatty acid concentrations in guinea pigs and rats. In addition, MCHP decreased the concentrations of blood ketone bodies, plasma cholesterol and intrahepatic acetyl-coenzyme A in the guinea pig. All of these findings appear to be due to a reduced fatty acid utilization in the presence of MCHP resulting presumably in an intramitochondrial deficiency of acetyl-CoA. At hypoglycemic effective doses the intramitochondrial and cytoplasmatic redox ratios as well as the hepatic ATP/ADP ratio were not influenced by MCHP in fasted guinea pigs. Even at large doses (123 mumol/kg) MCHP decreased the activity of monoamino oxidase in guinea pigs only by less than 15%. Furthermore MCHP showed under our experimental conditions no relevant influence on the activity of various liver enzymes in plasma, the plasma concentration of creatinine, the plasma triglyceride-glycerol level and on the intrahepatic triglyceride-glycerol concentration of fasted guinea pigs. It is concluded that MCHP meets basic requirements for a potential oral antidiabetic agent.     

β-Conglycinin Lowers Very-Low-Density Lipoprotein-Triglyceride Levels by Increasing Adiponectin and Insulin Sensitivity in Rats

The relationship between insulin sensitivity and the plasma triglyceride-lowering effect induced by β-conglycinin was investigated. Male Wistar rats (19 weeks old) were fed diets containing casein, soy protein isolate, or β-conglycinin for 4 weeks. In oral glucose administration, the β-conglycinin-fed rats showed a significant decrease in the area under the glucose curve (0–60 min) as compared with the casein-fed rats. The hypoglycemic effect was significantly higher in the β-conglycinin-fed rats than in the casein-fed rats at 30 min after intraperitoneal insulin injection. The liver sterol regulatory element-binding-protein-1 mRNA expression level was significantly lower and the plasma adiponectin concentration was significantly higher in the β-conglycinin-fed rats than in the casein-fed rats. The hypotriglyceridemic effect of β-conglycinin depended on a significant decrease in the concentration of very-low-density-lipoprotein triglycerides. These results indicate that β-conglycinin increases adiponectin levels and improves glucose tolerance. The ability of β-conglycinin to lower plasma lipid levels might be due to increased insulin sensitivity of the liver.     

Effect of liver glycogen content on glucose production in running rats

The influence of supranormal compared with normal hepatic glycogen levels on hepatic glucose production (Ra) during exercise was investigated in chronically catheterized rats. Supranormal hepatic glycogen levels were obtained by a 24-h fast-24-h refeeding regimen. During treadmill running for 35 min at a speed of 21 m/min, Ra and plasma glucose increased more (P less than 0.05) and liver glucogen breakdown was larger in fasted-refed compared with control rats, although the stimuli for Ra were higher in control rats, the plasma concentrations of insulin and glucose being lower (P less than 0.05) in control compared with fasted-refed rats. Also, plasma concentrations of glucagon and both catecholamines tended to be higher and muscle glycogenolysis lower in control compared with fasted-refed rats. Lipid metabolism was similar in the two groups. The results indicate that hepatic glycogenolysis during exercise is directly related to hepatic glycogen content. The smaller endocrine glycogenolytic signal in face of higher plasma glucose concentrations in fasted-refed compared with control rats is indicative of metabolic feedback control of glucose mobilization during exercise. However, the higher exercise-induced increase in Ra, plasma glucose, and liver glycogen breakdown in fasted-refed compared with control rats indicates that metabolic feedback mechanisms are not able to accurately match Ra to the metabolic needs of working muscles.     

Enzymatic,metabolic and secretory perturbations in pancreatic islets of thyroidectomized rats

In thyroidectomized rats, the activity of FAD-linked glycerophosphate dehydrogenase was severely diminished in liver homogenates but not affected significantly in pancreatic islet homogenates, whilst the activity of 2-ketoglutarate dehydrogenase was decreased modestly in both liver and islet homogenates. Likewise, in intact islets of thyroidectomized rats, the generation of³HOH from [2-³H]glycerol was not decreased, and the ratio between oxidative and total glycolysis not significantly lower than in islets from sham-operated rats, at least in the presence of a high concentration of D-glucose. Nevertheless impaired oxidation of both D-[3,4-¹⁴C]glucose and D-[6-¹⁴C]glucose was observed in islets of thyroidectomized rats, the relative magnitude of such a decrease being more pronounced at a low than at a high D-glucose concentration. Such metabolic anomalies coincided with a lower level of plasma insulin and a decreased output of insulin by islets incubated at low (2·8 mM ), but not higher, concentrations of D-glucose. It is concluded that hypothyroidism does not mimic the deficiency in islet FAD-linked glycerophosphate dehydrogenase activity found in rats with inherited or acquired non-insulin-dependent diabetes.     

Oral glucose decreases hepatic extraction of insulin.

Peripheral venous (plasma) insulin and C-peptide concentrations were measured in eight normal subjects given oral or intravenous glucose sufficient to produce similar plasma glucose concentrations. The expected increased insulin response to oral as compared with intravenous glucose was not matched by a comparable increase in C-peptide concentration. The ratio of insulin to C-peptide concentrations doubled 30 minutes after oral glucose was given; no comparable rise was seen with intravenous glucose (p = 0.01). This finding is interpreted as evidence for decreased hepatic extraction of insulin after administration of oral glucose. Such a decrease could account for at least half of the well known difference in peripheral insulin concentrations after administration of oral as compared with intravenous glucose.     

Effects of glucose infusion in exercising rats

To determine whether feedforward control of liver glycogenolysis during exercise is subject to negative feedback by elevated blood glucose, glucose was infused into exercising rats at a rate that elevated blood glucose greater than 10 mM. Liver glycogen content decreased 22.4 mg/g in saline-infused rats compared with 13.6 mg/g in glucose-infused rats during the first 40 min of treadmill running (21 m/min, 15% grade). Liver adenosine 3',5'-cyclic monophosphate (cAMP) concentration was significantly lower in the glucose-infused rats during the exercise bout. The concentration of hepatic fructose 2,6-bisphosphate remained elevated throughout the exercise bout in glucose-infused rats but decreased markedly in saline-infused rats. Plasma insulin concentration was higher and plasma glucagon concentration lower in glucose-infused rats than in saline-infused rats during exercise. Early in exercise, liver glycogenolysis proceeds in the glucose-infused rats despite the fact that glucose and insulin concentrations are markedly elevated and liver cAMP is unchanged from resting values. These observations suggest the existence of a cAMP-independent feedforward system for activation of liver glycogenolysis that can override classical negative feedback mechanisms during exercise.     

Defect in glucokinase translocation in Zucker diabetic fatty rats

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; micromol.kg(-1).min(-1)) were slightly higher in ZDF (8.4 +/- 0.3 and 53 +/- 7, respectively) than in lean rats (6.2 +/- 0.2 and 45 +/- 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 +/- 350) than in lean rats (150 +/- 14). The ratio of hepatic uridine 5'-diphosphate-glucose 3H specific activity to plasma glucose 3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (micromol.kg(-1).min(-1)), and hepatic glucose cycling (micromol.kg(-1).min(-1)) were higher in ZDF (35 +/- 5, 87 +/- 16, and 33 +/- 10, respectively) compared with lean rats (18 +/- 3, 56 +/- 6, and 11 +/- 2, respectively). [3H]glucose incorporation into glycogen (micromol glucose/g liver) was similar in lean (1.0 +/- 0.7) and ZDF (1.6 +/- 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (micromol.kg(-1).min(-1)), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (micromol glucose/g liver) were markedly higher in lean (191 +/- 22, 62 +/- 3, and 5.0 +/- 1.4, respectively) but similar in ZDF rats (100 +/- 6, 37 +/- 3, and 1.4 +/- 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.     

The effect of magnesium deficiency on glucose stimulated insulin secretion in rats

Weanling Sherman rats were pair-fed for 8 days on a control or a magnesium deficient diet containing 70.5% sucrose. After a 12-hour fast, the rats were injected intraperitoneally with glucose (250 mg/100 g body weight) and arterial blood was drawn at 0, 15, 30, 60, 90 minutes after injection. Before glucose loading, in magnesium deficient rats, plasma magnesium levels were significantly increased. The plasma triglyceride concentration was significantly higher in magnesium deficient rats compared to controls. After glucose loading, in the control group, the plasma insulin concentrations increased to 67.9 +/- 5.8 microU/ml at 15 minutes and returned to pretreatment levels by 30 minutes; in the magnesium-deficient rats, the plasma insulin levels were significantly lower at 15 minutes 32.9 +/- 5.6 microU/ml (P less than 0.01) and returned more slowly to the pre-challenge level. No significant differences were observed in plasma glucose levels between the two groups of rats.     

Hepatic glycogen breakdown is implicated in the maintenance of plasma mannose concentration

D-mannose is an essential monosaccharide constituent of glycoproteins and glycolipids. However, it is unknown how plasma mannose is supplied. The aim of this study was to explore the source of plasma mannose. Oral administration of glucose resulted in a significant decrease of plasma mannose concentration after 20 min in fasted normal rats. However, in fasted type 2 diabetes model rats, plasma mannose concentrations that were higher compared with normal rats did not change after the administration of glucose. When insulin was administered intravenously to fed rats, it took longer for plasma mannose concentrations to decrease significantly in diabetic rats than in normal rats (20 and 5 min, respectively). Intravenous administration of epinephrine to fed normal rats increased the plasma mannose concentration, but this effect was negated by fasting or by administration of a glycogen phosphorylase inhibitor. Epinephrine increased mannose output from the perfused liver of fed rats, but this effect was negated in the presence of a glucose-6-phosphatase inhibitor. Epinephrine also increased the hepatic levels of hexose 6-phosphates, including mannose 6-phosphate. When either lactate alone or lactate plus alanine were administered as gluconeogenic substrates to fasted rats, the concentration of plasma mannose did not increase. When lactate was used to perfuse the liver of fasted rats, a decrease, rather than an increase, in mannose output was observed. These findings indicate that hepatic glycogen is a source of plasma mannose.     

Regulation of glycogenolysis in the liver of the newborn rat in vivo inhibitory effect of glucose

Newborn rats were injected immediately after delivery with glucose or glucose plus mannoheptulose, and the time-courses of liver glycogen, plasma glucose, insulin and glucagon concentration were studied. The administration of glucose prevented both liver glycogenolysis and the increase in plasma glucagon concentration which normally occurs immediately after delivery. In addition, the administration of glucose prevented the decrease of plasma glucose and insulin concentration which normally occurs during the first hour of extrauterine life. Supplementation of glucose with mannoheptulose prevented the increase of plasma insulin concentrations caused by the administration of glucose; liver glycogenolysis, however, was not stimulated in these circumstances. The increase in the rate of glycogenolysis caused by the administration of glucagon was prevented in newborn rats previously treated with glucose. These results suggest that glucose exerts an inhibitory effect on the stimulation of neonatal liver glycogenolysis by glucagon.     

Comparison of the chromium distribution in organs and subcellular fractions of normal and diabetic rats by using enriched stable isotope Cr-50 tracer technique

The enriched stable isotope⁵⁰Cr(III) tracer technique combined with neutron activation analysis was used to examine the intracellular distribution of Cr(III) in the liver, pancreas, testes, and kidney homogenates of both normal and diabetic rats. Our new results showed that the nucleic fraction has the highest Cr concentration in the liver cell of both normal and diabetic rats. The diabetic rats retain more Cr in the mitochondrial and lysosomal fractions of liver homogenate than the normal. This is likely an indication of chromium participating in the glucose or lipid metabolism to compensate the low level of insulin in the body of diabetic rats. The concentrations of Cr in the subcellular fractions of pancreas, testes, and kidney in the normal rats are higher than those in the diabetic rats, which favor the hypothesis that Cr(III) plays its biological function via interaction with the insulin-sensitive tissues or enhancement of the sensitivity of the insulin receptor.     

Small doses of intracarotid insulin do not lower plasma glucose in the rat

We sought to confirm the observation that 500 microU of insulin injected into the carotid artery of rats lowers plasma glucose by approximately 20 mg/dl within 2 minutes. In our hands, glucose concentrations fell gradually by approximately 20-25 mg/dl over a 45-60 minute period after insertion of a carotid artery cannula. This occurred whether 500 microU of insulin and/or anti-insulin serum or saline were injected toward the heart. There was no change in glucose concentrations following injection of 500 microU of insulin toward the head 45 minutes after insertion of the cannula. Thus, the hypoglycemic response to small amounts of insulin administered to the head via the carotid artery must be very sensitive to factors that are currently difficult to recognize.     

Derangement in hepatic enzymes caused by sucrose-drinking and its implication for the development of hyperglycemia in female Wistar fatty rats

Eight-week-old, female Wistar fatty rats and their lean littermates were given a 30% sucrose solution in addition to a laboratory chow diet and water for 7 weeks. The fatty rats were hyperinsulinemic and hyperlipidemic, but normoglycemic when they drank only water. The hepatic activities of insulin-inducible glucokinase (GK), pyruvate kinase (PK), and malic enzyme (ME) were higher in the fatty rats than in the lean rats, whereas the insulin-suppressible glucose-6-phosphatase (G6Pase) activity was similar in both types of rats, indicating the normal response of hepatic enzymes to hyperinsulinemia in the fatty rats. When they drank the sucrose solution, the fatty rats, but not the lean rats, developed hyperglycemia over 200 mg/dl. Plasma insulin and triglyceride concentrations increased in both types of rats. Although the hepatic activities of GK, PK, and ME in the lean rats, and PK and ME in the fatty rats increased in response to the increase in plasma insulin, GK activity decreased in the fatty rats. On the other hand, G6Pase activity increased in both types of rats. As a result, the G6Pase/GK ratio, which may reflect net glucose handling in the liver, increased twofold in the fatty rats, but did not alter in the lean rats. From these findings, we conclude that sucrose ingestion induces an increase in hepatic glucose production through derangement of the hepatic enzyme profile and that the resultant decrease in hepatic glucose handling may be one of the pathogenic factors participating in the development of hyperglycemia in Wistar fatty rats.     

Nutritionally induced changes in the peroxisome proliferator-activated receptor-alpha gene expression in liver of suckling rats are dependent on insulinaemia

It was previously found that the expression of peroxisome proliferator-activated receptor-alpha (PPARalpha) was markedly augmented in the liver of suckling rats, in comparison to the fetuses and most notably to adult rats and it paralleled similar changes in hepatic lipid concentration. To determine whether these changes could be related to the high lipid content of the maternal milk and/or to hormonal status, the role of changes in nutrient availability and in plasma insulin concentration on liver expression during the perinatal stage in vivo in the rat was studied. When suckling rats were weaned on day 17, instead of on day 20, the level of hepatic PPARalpha mRNA decreased earlier than in rats weaned later. When 10-day-old rats were force-fed with either glucose or Intralipid or a combination of both diets, it was found that, at similar low levels of plasma insulin, a high level of FFA stimulated PPARalpha expression, whereas, at similar high plasma FFA concentrations, an elevated insulin level attenuated the increase in PPARalpha expression. It is proposed that both the high lipid intake and decreased plasma insulin level are responsible for the high PPARalpha expression detected in rat neonates.     

Rapid effects of insulin and glucose on the hepatic incorporation of gluconeogenic substrates into glyceride glycerol and glycogen

1. The hepatic utilization of gluconeogenic substrates was investigated shortly after portal infusion of either insulin or glucose in fasted rats. 2. After 20 min of insulin infusion blood glucose concentration decreased. However, neither glucose generation from precursors such as alanine or pyruvate nor their incorporation into fatty acids was modified. Under these conditions, insulin rapidly increased the incorporation of gluconeogenic substrates into the hepatic glyceride glycerol fraction. Insulin treatment led to a decrease in substrate incorporation into liver glycogen. 3. After 20 min of portal glucose infusion both plasma insulin and glucose concentrations increased and the incorporation of pyruvate into hepatic glyceride glycerol and into glycogen was also stimulated. 4. A close relationship was observed between blood glucose concentrations and the level of incorporation of gluconeogenic substrates into liver glycogen. 5. In conclusion, during fasting insulin stimulates the incorporation of gluconeogenic substrates into the glycerol moiety of hepatic glycerides, which may be the preferential mechanism through which fatty acid esterification is accomplished during refeeding. This effect of insulin is rapid and detected even before other classical modifications induced by the hormone such as gluconeogenesis inhibition or lipogenesis activation. Furthermore, the effect is not related to insulin-induced hypoglycemia since glucose infusion mimics insulin action on glyceride glycerol synthesis.     

Chlorogenic acid modifies plasma and liver concentrations of: cholesterol,triacylglycerol, and minerals in (fa/fa) Zucker rats

Chlorogenic acid, a phenolic compound found ubiquitously in plants, is an in vitro antioxidant and metal chelator. Some derivatives of chlorogenic acid are hypoglycemic agents and may affect lipid metabolism. Concentrations of cholesterol and triacylglycerols are of interest due to their association with diseases such as non-insulin-dependent-diabetes- mellitus and obese insulin resistance. As little is known about the effects of chlorogenic acid in vivo, studies using obese, hyperlipidemic, and insulin resistant (fa/fa) Zucker rats were conducted to test the effect of chlorogenic acid on fasting plasma glucose, plasma and liver triacylglycerols and cholesterol concentrations. Aditionally, the effects of chlorogenic acid on selected mineral concentrations in plasma, spleen, and liver were determined. Rats were implanted with jugular vein catheters. Chlorogenic acid was infused (5 mg/Kg body weight/day) for 3 weeks via intravenous infusion. Chlorogenic acid did not promote sustained hypoglycemia and significantly lowered the postprandial peak response to a glucose challenge when compared to the same group of rats before Chlorogenic acid treatment. In Chlorogenic acid-treated rats, fasting plasma cholesterol and triacylglycerols concentrations significantly decreased by 44% and 58% respectively, as did in liver triacylglycerols concentrations (24%). We did not find differences (p > 0.05) in adipose triacylglycerols concentration. Significant differences (p < 0.05) in the plasma, liver, and spleen concentration of selected minerals were found in chlorogenic acid-treated rats. In vivo, chlorogenic acid was found to improve glucose tolerance, decreased some plasma and liver lipids, and improve mineral pool distribution under the conditions of this study.     

Diminished hormonal responses to exercise in trained rats

Male rats (120 g) either were subjected to a 12-wk physical training program (T rats) or were sedentary controls (C rats). Subsequently the rats were killed at rest or after a 45- or 90-min forced swim. At rest, T rats had higher liver and muscle glycogen concentrations but lower plasma insulin. During exercise, blood glucose increased 60% in T rats but decreased 20% in C rats. Plasma glucagon and insulin concentrations did not change in T rats but plasma glucagon increased and insulin decreased markedly in C rats. Plasma epinephrine (90 min: range, 0.78-2.96 ng-ml-1, (T) vs. 4.42-15.67 (C)) and norepinephrine (90 min: 0.70-2.22 (T) vs. 2.50-6.10 (C)) were lower in T than in C rats. Hepatic glycogen decreased substantially and, as with muscle glycogen, the decrease was parallel in T and C rats. The plasma concentrations of free fatty acids were higher but lactate and alanine lower in T than in C rats. In trained rats the hormonal response to exercise is blunted partly due to higher glucose concentrations. In these rats adipose tissue sensitivity to catecholamines is increased, and changes in glucagon and insulin concentrations are not necessary for increased lipolysis and hepatic glycogen depletion during exercise.     

Pathogenesis of hyperglycemia in genetically obese-hyperglycemic rats, Wistar fatty: presence of hepatic insulin resistance

The present studies were designed to clarify the contribution of the liver to the development of hyperglycemia in Wistar fatty rats. The hepatic activities of insulin-inducible enzymes involved in glycolysis (glucokinase; GK and pyruvate kinase) and lipogenesis (glucose-6-phosphate dehydrogenase), were higher in fatty rats than in lean rats at 4 and 8 weeks of age because of the higher insulin levels in the former. Thereafter, the GK activities of fatty rats decreased slightly in spite of severe hyperinsulinemia, and did not differ from those of lean rats. In addition, fatty rats had higher levels of insulin-suppressible gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and fructose-1, 6-diphosphatase. These findings indicate that the hepatic enzymes of fatty rats are resistant to insulin. This postulation was supported by the fact that the hepatic enzyme activities of fatty rats showed a lower response to changes in plasma insulin levels produced by fasting and refeeding. The G6Pase/GK ratio, which indicates net glucose handling in the liver, increased in fatty rats and decreased in lean rats with advancing age, suggesting that hepatic glucose production in fatty rats becomes dominant with advancing age. The changes in hepatic glycolytic intermediates supported this suggestion; the glycolytic steps both from glucose to glucose-6-phosphate and from phospho-enolpyruvate to pyruvate in fatty rats were accelerated at 5 weeks of age, but suppressed at 12 weeks of age. These results indicate that insulin resistance in the hepatic enzyme regulation may contribute to the development of hyperglycemia in Wistar fatty rats.     

Cerebral Oxidative Metabolism and Blood Flow During Acute Hypoglycemia and Recovery in Unanesthetized Rats

Abstract: Progressive neurological depression leading to coma was produced in unanesthetized rats at a constant level of hypoglycemia induced by insulin. High-energy phosphate concentrations in brain remained normal during hypoglycemic lethargy, but ATP declined by 6% during stupor and by 40% during coma that was characterized by an isoelectric EEG. Cerebral blood flow (CBF) remained normal during hypoglycemia whereas the cerebral metabolic rates for oxygen (CMRo₂) and glucose (CMR_glucose) decreased by 45 and 73%, respectively, indicating oxidation of nonglucose fuels. A plot of CMRo₂ and CMR_glucose versus plasma glucose indicated increasing oxidation of alternate substrates (elevated CMRo²/CMR_glucose) at plasma glucose concentrations below 2.5 mm . The cerebral uptake of β-hydroxybutyrate increased during hypoglycemic stupor and its complete oxidation could account for the CMRo₂ in excess of glucose utilization. Brain ammonia, a byproduct of amino acid metabolism, reached a level during hypoglycemic coma sufficient to produce coma in normoglycemic animals. The rate and degree of recovery after glucose administration depended on the duration of hypoglycemia and the pretreatment neurological state of the animal. Following 10 min of glucose infusion, ATP levels that were modestly depressed in stuporous rats recovered fully, paralleling the animals' apparently full neurological recovery. Rats that had been in hypoglycemic coma for 1 min or less fully recovered high-energy phosphate concentrations in brain. However, when normalization of plasma glucose was delayed for more than 1 min of coma, the CMRo₂ remained depressed, CBF decreased to 40% of control, and high-energy substrates failed to normalize. In keeping with the depression of oxidative metabolism and blood flow, neurological function and the EEG remained abnormal even after 1 h of glucose infusion. The findings suggest that irreversible brain injury may develop within the first minutes of hypoglycemic coma.     

Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats

We investigated the antihyperglycemic effect of p-methoxycinnamic acid (p-MCA), a cinnamic acid derivative, on plasma glucose and insulin concentrations, activities of hepatic glucose-regulating enzymes and hepatic glycogen content in normal and streptozotocin (STZ)-induced diabetic rats. p-MCA (10-100 mg/kg, PO) dose-dependently decreased plasma glucose concentration in both normal and diabetic rats in the oral glucose tolerance test. To investigate the chronic effects of p-MCA on glucose metabolism, p-MCA (40 mg/kg, PO) was administered to normal and diabetic rats once a day for 4 weeks. p-MCA reduced plasma glucose concentration in diabetic rats, which was observed during the 4-week study. However, p-MCA treatment did not change plasma glucose concentrations in normal rats during the 4-week study. p-MCA also reduced the excessive activities of hepatic glucose-6-phosphatase, hepatic hexokinase, glucokinase and phosphofructokinase in diabetic rats and increased hepatic glycogen in these rats. In p-MCA-treated normal rats, there were no changes in the activities of hepatic glucose-regulating enzymes, hepatic glycogen and glucose-6-phosphate. Our findings suggested that p-MCA exert its antihyperglycemic effect by increasing insulin secretion and glycolysis, and by decreasing gluconeogenesis.