Increase of insulin sensitivity by stevioside in fructose-rich chow-fed rats.

The intake of dietary fructose has undergone a marked increase around the world, especially the developed countries, in recent times. Stevioside, a glycoside contained in the leaves of Stevia rebaudiana Bertoni (Compositae), was used to screen the effect induced by a diet containing 60% fructose on insulin resistance in rats. Single oral administration of stevioside for 90 min decreased plasma glucose concentrations in a dose-dependent manner in rats receiving fructose-rich chow for four weeks. In addition, insulin action on glucose disposal rate was measured using the glucose-insulin index, the product of the areas under the curve of glucose, and insulin during the intraperitoneal glucose tolerance test. Oral administration of stevioside (5.0 mg/kg) in rats given four weeks of fructose-rich chow for 90 min reversed the value of glucose-insulin index, indicating that stevioside has the ability to improve insulin sensitivity in this insulin-resistant animal model. Time for the loss of plasma glucose lowering response to tolbutamide (10.0 mg/kg, i. p.) in fructose-rich chow fed rats was also markedly delayed by repeated stevioside treatment three times daily compared to the vehicle-treated group. The plasma glucose-lowering activity of tolbutamide was introduced to account for varying levels of endogenous insulin secretion, and is widely used as the indicator of insulin resistance development. Thus, it provided the supportive data that repeated oral administration of stevioside delayed the development of insulin resistance in rats on a high-fructose diet. Increased insulin sensitivity by stevioside administration was further identified using the plasma glucose-lowering action of exogenous insulin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Oral administration of stevioside at 0.2 mg/kg three times daily into STZ-diabetic rats for ten days increased the response to exogenous insulin. Taken together, this demonstrated that oral administration of stevioside improves insulin sensitivity, and seems suitable as an adjuvant for diabetic patients and/or those that consume large amounts of fructose.     

Improvement of insulin resistance by panax ginseng in fructose-rich chow-fed rats.

In an attempt to probe a new target for handling insulin resistance, we used Panax ginseng root to screen the effect on insulin resistance induced by fructose-rich chow in rats. Insulin action on glucose disposal rate was measured using the glucose-insulin index, which is the product of the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Oral administration of Panax ginseng root (125.0 mg/kg) into rats three times daily for three days after receiving fructose-rich chow for four weeks reversed the increased glucose-insulin index, indicating that Panax ginseng root has the ability to improve insulin sensitivity. In addition, the plasma glucose concentrations in rats repeatedly treated with Panax ginseng root were not elevated as markedly as those of the vehicle-treated group during the fructose-rich chow-feeding period. Also, the time in which the plasma glucose-lowering response to tolbutamide (10.0 mg/kg, i. p.) receded in fructose-rich chow fed rats was markedly delayed by repeated Panax ginseng root treatment compared to the vehicle-treated group. The plasma glucose-lowering activity of tolbutamide is believed to depend on the secretion of endogenous insulin, which is widely used as an indicator of insulin resistance development. Thus, it provided supportive data that oral administration of Panax ginseng root could delay the development of insulin resistance in rats. In conclusion, our results suggest that oral administration of Panax ginseng root improves insulin sensitivity and may be used as an adjuvant therapy for treating diabetic patients with insulin resistance.     

Increase of opioid mu-receptor gene expression in streptozotocin-induced diabetic rats.

Opioids play an important role in the regulation of glucose homeostasis. In the previous report, we showed that activation of opioid mu-receptors produced a plasma glucose lowering effect in diabetic rats lacking insulin. In the present study, we found that the response of opioid mu-receptor is more sensitive in streptozotocin-induced diabetic rats (STZ-diabetic rats) than in normal rats. Intravenous injection of loperamide, an agonist of opioid mu-receptors, induced a dose-dependent decrease of plasma glucose from 3 microg/kg to 60 microg/kg in fasting STZ-diabetic rats. However, loperamide decreased the plasma glucose of normal fasting rats at the doses of 0.3 mg/kg to 1.5 mg/kg, which were much higher than those needed to produce the same effect in diabetic rats. The plasma glucose-lowering action of loperamide at the dose effective in normal rats disappeared in opioid mu-receptor knockout mice, while the plasma glucose-lowering response to loperamide was still observed in wild-type mice. This opens the possibility of mediation through opioid mu-receptor in the plasma glucose-lowering action of loperamide. Moreover, the mRNA level of opioid mu-receptor in the liver markedly increased in STZ-diabetic rats compared to normal rats. Normalization of plasma glucose concentrations in STZ-diabetic rats with exogenous insulin or phlorizin reversed mRNA and protein levels of opioid mu-receptor in the liver after 4 days of treatment. This shows that correction of hyperglycemia in STZ-diabetic rats may reverse the higher gene expression of opioid mu-receptor. These results suggest that hyperglycemia is responsible for increase of opioid mu-receptor in STZ-diabetic rats.     

Antihypertensive effects of Dorstenia psilurus extract in fructose-fed hyperinsulinemic, hypertensive rats.

We examined the effect of methanol/methylene chloride extract of Dorstenia psilurus given by gastric intubation on systolic blood pressure, plasma glucose, insulin, cholesterol, triglycerides and creatinine in rats with fructose-induced hypertension. Male Wistar rats in groups of 6 animals each were fed fructose-rich diets or standard chow for 3 weeks and treated with 100 mg/kg/day or 200 mg/kg/day of plant extract or vehicle for 3 subsequent weeks. Systolic blood pressure was measured every three days using the indirect tail cuff method. Systolic blood pressure was higher in fructose-fed rats (142+/-2 mm Hg, p < 0.01) compared with the controls (112+/-2 mm Hg), and was lower in Dorstenia psilurus-treated groups (127+/-2 and 119+/-1 mm Hg for the dose of 100 and 200 mg/kg, respectively) compared with the fructose-fed rats. Plasma insulin, cholesterol and triglycerides were higher on the fructose-rich diet compared with the controls. Plasma insulin and cholesterol were lower in the Dorstenia psilurus-treated groups. These results suggest that, Dorstenia psilurus treatment could prevent and reverse high blood pressure induced by a diet rich in fructose probably by improvement of plasma insulin levels. The plant extract might prove useful in the treatment and/or prevention of hypertension.     

Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats

The present study was conducted to explore the effects of myricetin on insulin resistance in rats fed for 6 weeks with a diet containing 60% fructose. Repeated intravenous (i.v.) injection of myricetin (1 mg/kg per injection, 3 times daily) for 14 days was found to significantly decrease the high glucose and triglyceride levels in plasma of fructose chow-fed rats. Also, the higher degree of insulin resistance in fructose chow-fed rats as measured by homeostasis model assessment of basal insulin resistance was significantly decreased by myricetin treatment. Myricetin increased the whole-body insulin sensitivity in fructose chow-fed rats, as evidenced by the marked elevation of composite whole-body insulin sensitivity index during the oral glucose tolerance test. Myricetin was found to reverse the defect in expression of insulin receptor substrate-1 (IRS-1) and the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase) in soleus muscle of fructose chow-fed rats under the basal state, despite the protein expression of insulin receptor (IR). Increased basal phosphorylation of IR and IRS-1 as well as Akt was observed in parallel. The reduced level of insulin action on phosphorylation of IR, IRS-1 and Akt in soleus muscle of fructose chow-fed rats was reversed by myricetin treatment. Furthermore, myricetin treatment improved the defective insulin action on the translocation of glucose transporter subtype 4 (GLUT 4) in insulin-resistant soleus muscle. These findings indicate that myricetin improves insulin sensitivity through the enhancement of insulin action on IRS-1-associated PI 3-kinase and GLUT 4 activity in soleus muscles of animals exhibiting insulin resistance.     

Serotonin enhances beta-endorphin secretion to lower plasma glucose in streptozotocin-induced diabetic rats

Although serotonin, serotonin uptake inhibitors and serotonin precursors (including tryptophan or 5-hydroxytryptophan) are known to have hypoglycemic action in rodents or human, it is not clear whether serotonin has hypoglycemic effect in streptozotocin-induced diabetic rats (STZ-diabetic rats). The aim of this study was to investigate the action of serotonin in regulating the plasma glucose STZ-diabetic rats. Plasma glucose, insulin, beta-endorphin and adrenaline were assessed after intraperitoneal administration of serotonin. Serotonin produced hypoglycemic effects without altering plasma insulin and adrenaline levels but increasing beta-endorphin level in STZ-diabetic rats. The glycogen content in soleus muscle was increased at 90 min after application of serotonin (0.3 mg/kg) in STZ-diabetic rats. Dihydroergotamine (non-selective 5-HT receptor blocker) and pimozide (5-HT(7) receptor blocker) abolished the hypoglycemic effect of serotonin in STZ-diabetic rats. Serotonin-induced hypoglycemic effect in association with the increase of beta-endorphin release was abolished in bilaterally adrenalectomized STZ-diabetic rats. In isolated adrenal gland of STZ-diabetic rats, the increase of beta-endorphin secretion in response to serotonin was reduced by either dihydroergotamine or pimozide. Pretreatment with naloxone (1.0 mg/kg, i.p.) prevented serotonin-induced plasma glucose lowering effect in STZ-diabetic rats. The results demonstrated that serotonin may activate 5-HT(7) receptor on rat adrenal gland to enhance of beta-endorphin secretion, which then stimulates the opioid receptor to increase peripheral glucose utilization, resulting in decreased plasma glucose levels in STZ-diabetic rats.     

Metformin-like effects of Quei Fu Di Huang Wan, a Chinese herbal mixture, on streptozotocin-induced diabetic rat.

Effect on plasma glucose concentration of Quei Fu Di Huang Wan (Quei Fu DHW), the herbal mixture widely used to treat diabetic disorder in Chinese traditional medicine, was investigated in diabetic rats deficient in insulin. Changes of plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats) receiving repeated oral administration of Quei Fu DHW were determined. Also, the mRNA level (by Northern blotting) and protein level (by Western blotting) of phosphoenolpyruvate carboxykinase (PEPCK) in liver from STZ-diabetic rats were measured to compare differences between groups receiving repeated oral administration of Quei Fu DHW, metformin, and two active herbs (Zou Guei or Fuzei) at effective dosages. In STZ-diabetic rats, acute oral administration of Quei Fu DHW decreased the plasma glucose level significantly in a dose-dependent manner from 5 mg/kg to 26.0 mg/kg. Similar treatment with Quei Fu DHW also brought on a plasma glucose-lowering effect in normal rats, although the effectiveness was not as significant as in STZ-diabetic rats. Repeated oral treatment of Quei Fu DHW at 26 mg/kg every 8 h, three times daily for 3 days, produced a plasma glucose-lowering activity similar to that of metformin-treatment in STZ-diabetic rats. Oral administration of Zou Guei (Cinnamomi Cortex) or Fuzei (Aconiti Tuber), the individual constituent of Quei Fu DHW, at the dose of 50 mg/kg into STZ-diabetic rats for 3 days normalized hyperglycemia. Similar to the repeated treatment with Quei Fu DHW, Fuzei at the effective dose reversed the elevated mRNA and protein levels of PEPCK in liver from STZ-diabetic rats. This is consistent with findings that metformin restored the increased gene expression of PEPCK in liver from STZ-diabetic rats. However, the gene expression of PEPCK in STZ-diabetic rats was not influenced by similar treatment with Zou Guei. The present study found that oral administration of Quei Fu DHW could decrease hepatic gluconeogenesis in a way similar to metformin in lowering plasma glucose in diabetic rats lacking insulin. Thus, this preparation may be a helpful adjuvant for the treatment of diabetic disorders in clinical practice.     

Activation of mu-opioid receptors improves insulin sensitivity in obese Zucker rats

In the current study we investigated the effect of mu-opioid receptor activation on insulin sensitivity. In obese Zucker rats, an intravenous injection of loperamide (18 microg/kg, three times daily for 3 days) decreased plasma glucose levels and the glucose-insulin index. Both effects of loperamide were subsequently inhibited by the administration of 10 microg/kg of naloxone or 10 microg/kg of naloxonazine, doses sufficient to block mu-opioid receptors. Other metabolic defects characteristic of obese Zucker rats, such as defects in insulin signaling, the decreased expression of insulin receptor substrate (IRS)-1, the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3 kinase), and the glucose transporter subtype 4 (GLUT 4), and the reduction of phosphorylation in IRS-1 or Akt serine, were also studied. These defects were all reversed by loperamide treatment in a dose which overcame mu-opioid receptor blockade. Moreover, loss of tolbutamide-induced plasma glucose lowering action (10 mg/kg) in wild-type mice given a fructose-rich diet was markedly delayed by repeated treatment with loperamide; however, this delay induced by loperamide did not occur in mu-opioid receptor knockout mice. These results indicate an important role of peripheral mu-opioid receptors in the loperamide-induced improvement of insulin sensitivity. Our results suggest that activation of peripheral mu-opioid receptors can ameliorate insulin resistance in animals, and provide a new target for therapy of insulin resistance.     

Increase of beta-endorphin secretion by syringin, an active principle of Eleutherococcus senticosus, to produce antihyperglycemic action in type 1-like diabetic rats.

We employed streptozotocin-induced diabetic rats (STZ-diabetic rats) as type 1 diabetes-like animal models to investigate the mechanism(s) of antihyperglycemic action produced by syringin, an active principle purified from the rhizome and root part S of ELEUTHEROCOCCUS SENTICOSUS (Araliaceae). Bolus intravenous (i. v.) injection of syringin dose-dependently decreased the plasma glucose of STZ-diabetic rats in 30 minutes in a way parallel to the increase of plasma beta-endorphin-like immunoreactivity (BER). Syringin enhanced BER release from the isolated adrenal medulla of STZ-diabetic rats in a concentration-dependent manner from 0.001 to 10 micromol/l. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of syringin (1 mg/kg, i. v.) including the plasma glucose-lowering effect and the plasma BER-elevating effect. Also, syringin failed to lower plasma glucose in the presence of micro-opioid receptor antagonists and/or in the micro-opioid receptor knockout diabetic mice. In conclusion, the obtained results suggest that syringin can enhance the secretion of beta-endorphin from adrenal medulla to stimulate peripheral micro-opioid receptors resulting in a decrease of plasma glucose in diabetic rats lacking insulin.     

Release of beta-endorphin by prostaglandin E2 to lower plasma glucose in streptozotocin-induced diabetic rats.

In the present study, Wistar rats, which received a streptozotocin injection to induce diabetes (STZ-diabetic rats), a model similar to insulin-dependent diabetes mellitus (IDDM) or type 1 diabetes mellitus, were used to investigate the effect of prostaglandin (PG) E2 on plasma glucose. Intravenous injection of PGE2 produced a dose-dependent lowering of plasma glucose level in fasting STZ-diabetic rats after 60 min. In addition to the blockade of this hypoglycemic effect by guanethidine (a noradrenergic nerve terminal-blocking agent), prazosin at a dose effective to block alpha1-adrenoceptors abolished the action of PGE2. An increase of plasma norepinephrine (NE) was also observed in STZ-diabetic rats receiving PGE2 injections. Participation of sympathetic stimulation by PGE2 may thus be speculated. Also, the plasma glucose-lowering effect of PGE2 was also blocked by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptor. Injection of PGE2 increased plasma beta-endorphin-like immunoreactivity (BER) in STZ-diabetic rats, and this action was abolished by prazosin. Bilateral adrenalectomy resulted in the loss of this PGE2 effect, and no increase was seen in plasma BER with PGE2 in STZ-diabetic rats. Therefore, beta-endorphin from the adrenal gland appears to be responsible for the lowering of plasma glucose in STZ-diabetic rats by PGE2 through an increase of NE release to activate alpha1-adrenoceptors.     

Plasma glucose-lowering action of Hon-Chi in streptozotocin-induced diabetic rats.

Hon-Chi was used for anti-hyperglycemic activity screening in streptozotocin-induced diabetic rats (STZ-diabetic rats) in an attempt to develop new substances for handling diabetes. Mandarin Hon-Chi is red yeast rice fermented with Monascus pilous and Monascus purpureus. Single oral administration of Hon-Chi decreased plasma glucose in STZ-diabetic rats in a dose-dependent manner from 50 mg/kg to 350 mg/kg. Similar treatment with Hon-Chi also lowered the plasma glucose in normal rats as effectively as that produced in STZ-diabetic rats. In addition, oral administration of Hon-Chi at the highest dose (350 mg/kg) attenuated the elevation of plasma glucose induced by an intravenous glucose challenge test in normal rats. Moreover, mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) in liver from STZ-diabetic rats were reversed in a dose-dependent manner by the repeated oral treatment of Hon-Chi three times daily for two weeks. Otherwise, hyperphagia in STZ-diabetic rats was markedly reversed by similar repeated treatment of Hon-Chi. The obtained results suggest that oral administration of Hon-Chi could decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.     

Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.     

Infusion of beta-endorphin improves insulin resistance in fructose-fed rats.

In an attempt to probe the effect of beta-endorphin on insulin resistance, we used Wistar rats that were fed fructose-rich chow to induce insulin resistance. Insulin action on glucose disposal rate (GDR) was measured using the hyperinsulinemic euglycemic clamp technique, in which glucose (variable), insulin (40 mU/kg/min), and beta-endorphin (6 ng/kg/min) or vehicle were initiated simultaneously and continued for 120 min. A marked reduction in insulin-stimulated GDR was observed in fructose-fed rats compared to normal control rats. Infusion of beta-endorphin reversed the value of GDR, which was inhibited by naloxone and naloxonazine each at doses sufficient to block opioid mu-receptors. Opioid mu-receptors may therefore be activated by beta-endorphin to improve insulin resistance. Next, soleus muscle was isolated to investigate the effect of beta-endorphin on insulin signals. Insulin resistance in rats induced by excess fructose was associated with the impaired insulin receptor (IR), tyrosine autophosphorylation, and insulin receptor substrate (IRS)-1 protein content in addition to the significant decrease in IRS-1 tyrosine phosphorylation in soleus muscle. This impaired glucose transportation was also due to signaling defects that included an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and Akt serine phosphorylation. However, IR protein levels were not markedly changed in rats with insulin resistance. beta-endorphin infusion reversed the fructose-induced decrement in the insulin-signaling cascade with increased GDR. Apart from IR protein levels, infusion of beta-endorphin reversed the decrease in protein expression for the IRS-1, p85 regulatory subunit of PI3-kinase, and Akt serine phosphorylation in soleus muscle in fructose-fed rats. The decrease in insulin-stimulated protein expression of glucose transporter subtype 4 (GLUT 4) in fructose-fed rats returned to near-normal levels after beta-endorphin infusion. Infusion of beta-endorphin may improve insulin resistance by modulating the insulin-signaling pathway to reverse insulin responsiveness.     

Secretion of glucagon and insulin in hypophysectomized rats: effect of tolbutamide.

Normal and hypophysectomized (hypox) rats, fed ad libitum, received intraperitoneal injections of tolbutamide (75 mg/kg/day) or of saline for 6 weeks. 24 h after the last injection, blood samples were taken for glucose, insulin and glucagon determinations. In normal rats, tolbutamide treatment did not alter serum glucose, insulin and glucagon, although it suppressed the secretion of insulin and glucagon by the pancreatic islets. In hypox rats, tolbutamide decreased serum glucose and insulin, elevated serum glucagon and stimulated the secretion of glucagon, but not that of insulin by the pancreatic islets. In addition, tolbutamide treatment increased the glucagon response to arginine in normal, but not in hypox rats. The serum glucose response to arginine was decreased by tolbutamide treatment and by hypophysectomy and, thus, appeared independent of the glucagon rise or preexisting glucagon level. We conclude that tolbutamide treatment decreased the secretion of glucagon and insulin in normal rats and stimulated that of glucagon in hypox rats, perhaps because of the low levels of insulin in the serum and in the pancreas of the latter. Our results are compatible with the hypothesis that the pancreatic action of tolbutamide is influenced by the pituitary.     

Silymarin Induces Insulin Resistance through an Increase of Phosphatase and Tensin Homolog in Wistar Rats

Background and aims

Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown.

Methods

Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection.

Results

Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake.

Conclusions

Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients.     

Decrease of hypothalamic neuropeptide Y gene expression by vanadyl sulfate in streptozotocin-induced diabetic rats.

In an attempt to elucidate the effect of vanadium compounds on the gene expression of neuropeptide Y (NPY), vanadyl sulfate (VOSO4) was orally administrated at the dose of 1 mg/kg body weight into streptozotocin-induced diabetic rats (STZ-diabetic rats) three times daily for 1 week. We found a marked lowering of plasma glucose with a significant decrease of food and water intake in these STZ-diabetic rats treated with VOSO4, although the weight gain was unaffected. The increase of hypothalamic NPY, both the mRNA level and peptide concentration, in STZ-diabetic rats was also reduced by this oral treatment of VOSO4. However, similar treatment of VOSO4 in normal rats failed to modify the feeding behavior and hypothalamic NPY gene expression. These data suggest that decrease of hypothalamic NPY gene expression by VOSO4 is related to the recovery of hyperphagia in diabetic rats lacking insulin.     

Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus

The effect of 1 week clofibrate administration on glucose and insulin responses to oral glucose and to intravenous tolbutamide was evaluated in 21 patients with mild maturity-onset diabetes (fasting plasma glucose 108-152 mg/100 ml). After treatment, oral glucose tolerance and hypoglycaemic effect of tolbutamide were significantly improved; plasma insulin response was reduced after glucose and unmodified after tolbutamide; fasting plasma glucose was also significantly reduced. These findings did not correlate with the observed fall in serum lipids. Short-term clofibrate improves glucose metabolism in mild diabetes irrespective of its effects on lipid metabolism. It is suggested that the drug's action may be mediated by reduced insulin resistance.     

Selective potentiation of 5-methyl-2-(1-methylcyclohexyl)-4-oxazoleacetic acid (AD-4610) on glucose-induced insulin secretion

In the perfused pancreas from normal SD rats, AD-4610 (0.01-0.1 mM) potentiated biphasic insulin secretion induced by 7.5 mM of glucose. The concentration-response curve of insulin secretion to glucose was shifted leftwards with AD-4610 (0.1 mM) without altering either the threshold concentration of glucose to induce insulin secretion or the maximal insulin response to glucose, indicating increased sensitivity of the pancreatic B-cells to glucose. On the other hand, AD-4610 was 10-fold less effective in altering insulin secretion induced by arginine and glyceraldehyde. The effect of AD-4610 on insulin secretion and glucose metabolism was compared with that of tolbutamide in vivo. AD-4610 (100 mg/kg) potentiated insulin secretion induced by an intravenous glucose load, and also accelerated glucose metabolism without altering basal insulin secretion in normal rats. On the other hand, tolbutamide (20 mg/kg) increased basal insulin secretion, but slightly decreased glucose-induced insulin secretion. In yellow KK mice with hyperglycemia, AD-4610 (10-100 mg/kg) had a dose-dependent hypoglycemic action, but tolbutamide did not. Thus, AD-4610 stimulated insulin secretion in a glucose-dependent fashion and enhanced glucose metabolism in vivo. These results suggest that AD-4610 selectively potentiates glucose-induced insulin secretion by increasing the sensitivity of pancreatic B-cells to glucose and may be useful for treating human NIDDM through a different mechanism than that of tolbutamide.     

Plasma glucose-lowering effect of beta-endorphin in streptozotocin-induced diabetic rats.

The effect of beta-endorphin on plasma glucose levels was investigated in streptozotocin-induced diabetic rats (STZ-diabetic rats). A dose-dependent lowering of plasma glucose was observed in the fasting STZ-diabetic rat fifteen minutes after intravenous injection of beta-endorphin. The plasma glucose-lowering effect of beta-endorphin was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptors. Also, unlike wild-type diabetic mice, beta-endorphin failed to induce its plasma glucose-lowering effect in the opioid mu-receptor knock-out diabetic mice. In isolated soleus muscle, beta-endorphin enhanced the uptake of radioactive glucose in a concentration-dependent manner. Stimulatory effects of beta-endorphin on glycogen synthesis were also seen in hepatocytes isolated from STZ-diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid mu-receptors. In the presence of U73312, the specific inhibitor of phospholipase C (PLC), the uptake of radioactive glucose into isolated soleus muscle induced by beta-endorphin was reduced in a concentration-dependent manner, but it was not affected by U73343, the negative control of U73312. Moreover, chelerythrine and GF 109203X diminished the stimulatory action of beta-endorphin on the uptake of radioactive glucose at a concentration sufficient to inhibit protein kinase C (PKC). The data obtained suggest that activating opioid mu-receptors by beta-endorphin may increase glucose utilization in peripheral tissues via the PLC-PKC pathway to lower plasma glucose in diabetic rats lacking insulin.     

2型糖尿病伴发高血压大鼠模型的建立

目的：建立一种2型糖尿病伴发高血压大鼠的模型。方法：65只SD雄性大鼠,随机分为正常对照组、1% NaCl饮水组、20 mg/kg STZ-1% NaCl组、30 mg/kg STZ-1% NaCl组、40 mg/kg STZ-1% NaCl组（n=13）。除正常对照组大鼠普通饮食喂养外,其余各组大鼠以高脂饲料4周+普通饲料结合1% NaCl饮水9周喂养。第4周末链脲霉素（STZ）组大鼠分别腹腔注射STZ （20 mg/kg、30 mg/kg、40 mg/kg）。实验周期13周。检测大鼠一般状况、体重、平均摄食量、血糖、血压、血脂和血浆胰岛素水平。结果：与正常对照组和1% NaCl饮水组比较,在STZ注射后仅30 mg/kg STZ-1% NaCl组、40 mg/kg STZ-1% NaCl组大鼠体重减少（P<0.05）、平均食量、空腹和随机血糖均增加（P<0.05）;第4周起血压显著升高（P<0.05）,收缩压均值达到150 mmHg进入高血压期,并在其后5周（实验结束前）稳定于150~170 mmHg;第9周血浆胰岛素水平升高（P<0.05）,血浆甘油三酯（TG）水平下降（P<0.05）。结论：高脂饲料喂养4周+腹腔注射STZ 30~40 mg/kg结合1% NaCl饮水喂养,能诱导出2型糖尿病伴发高血压的大鼠模型。