• Advances in Traditional Medicine
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• v.9 no.1
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• pp.20-38
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• 2009

The objectives of this study were to determine the effect of herb formula HDDM, a modification of Huangdan decoction that has been shown to be effective in the treatment of glomerulonephritis and chronic renal failure, on the blood glucose levels in multiple low doses (MLD; 50 mg/kg for five consecutive days) of streptozotocin (STZ)-treated female B6C3F1 mice. Initial studies were performed to compare diabetes induction in five strains (e.g., B6C3F1, NOD, CD-1, C3H/HeN and C57BL/6) of mice by MLD-STZ, and immune changes following the treatment. The results suggested that the order of susceptibility to diabetes induction was NOD $\approx$ CD-1 > B6C3F1 $\approx$ C3H > C57BL/6. Furthermore, STZ modulation of T cell development, differentiation and activation might play a role in diabetes induction by MLD-STZ treatment. MLD-STZ-induced diabetes in female B6C3F1 mice was moderate, which allowed the evaluation of drug-induced protection or exacerbation of diabetes to be performed. As such, modulation of blood glucose by HDDM, which consisted of Da Huang (Radix Et Rhizoma Rhei), Huang Qi (Radix Astragali Seu Hedysari), Dan Shen (Radix Salviae Miltiorrhizae), Yin Yang Huo (Herba Epimedii), Yi Yi Ren (Semen Coicis or Coix lacryma-jobi), Mai Dong (Radix Ophiopogonis) and Shan Zhu Yu (Fructus Corni), was evaluated in MLD-STZ-treated female B6C3F1 mice. The results suggested that HDDM could lower the blood glucose levels, but it had no immunomodulatory activities. Additionally, HDDM-treated mice exhibited improved glucose tolerance. In conclusion, these studies have suggested that MLD-STZ-induced diabetes in female B6C3F1 mice is a useful model to evaluate drug modulation of diabetes, and that the herb formula HDDM possesses anti-diabetic effects.

• Archives of Pharmacal Research
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• v.23 no.6
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• pp.626-632
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• 2000

Brazilin, an active principle of Caesalprenia sappan, was examined for its immunopotentiating effects in multiple low dose streptozotocin (MLD-STZ) induced type diabetic mice. Brazilin was intraperitoneally administered for 5 consecutive days to MLD-STZ induced type 1 diabetic mice. Delayed type hypersensitivity, Con A-induced proliferation of splenocytes and mixed lymphocyte reaction, which had been decreased in diabetic mice, were significantly recovered by the administration of brazilin. Brazilin increased IL-2 production without affecting suppressor cell activity. Con A-induced and IL-2-induced expression of high affinity IL-2 receptors were also enhanced by brazilin. These results indicate that brazilin augments cellular immune responses, which are suppressed in the MLD-STZ induced type I diabetic mice, by increasing IL-2 production and responsiveness of immune cells to IL-2.

• Archives of Pharmacal Research
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• v.26 no.7
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• pp.559-563
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• 2003

Cytokines produced by immune cells infiltrating pancreatic islets have been incriminated as important mediators of $\beta$-cell destruction in insulin-dependent diabetes mellitus. In non insulin-dependent diabetes, cytokines are also associated with impaired $\beta$-cell function in high glucose condition. By the screening of various natural products blocking $\beta$-cell destruction, we have recently found that epigallocatechin gallate (EGCG) can prevent the in vitro destruction of RINm5F cell, an insulinoma cell line, that is induced by cytokines. In that study we suggested that EGCG could prevent cytokine-induced $\beta$-cell destruction by down-regulation of nitric oxide synthase (NOS) through inhibition of NF-kB activation. Here, to verify the in vivo antidiabetogenic effect of EGCG, we examined the possibility that EGCG could also prevent the experimental autoimmune diabetes induced by the treatment of multiple low doses of streptozotocin (MLD-STZ), which is recognized as an inducer of type I autoimmune diabetes. Administration of EGCG (100 mg/day/kg for 10 days) during the MLD-STZ induction of diabetes reduced the increase of blood glucose levels caused by MLD-STZ. Ex vivo analysis of $\beta$-islets showed that EGCG downregulates the MLD-STZ-induced expression of inducible NOS (iNOS). In addition, morphological examination showed that EGCG treatment ameliorated the decrease of islet mass induced by MLD-STZ. In combination these results suggest that EGCG could prevent the onset of MLD-STZ-induced diabetes by protecting pancreatic islets. Our results therefore revealed the possible therapeutic value of EGCG for the prevention of diabetes mellitus progression.

• Journal of Ginseng Research
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• v.27 no.2
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• pp.56-61
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• 2003

This study was designed to compare the antidiabetic activities between Ginseng Radix Alba (GRA), Ginseng Radix Rubra (GRR) and Panax Quinquefoli Radix (PQR) in multiple low dose (MLD) streptozotocin (STZ) (20 mg/kg i.p injection far 5 days) induced diabetic rats. In the glucose tolerance test, 500 mg/kg of each ginseng ethanol extract was administered intraperitoneally 30 min before glucose challenge. While GRA failed to lower blood glucose level, GRR and PQR both significantly prevented the hyperglycemia when compared with the control group. In the MLD STZ-induced diabetic rats, 300 mg/kg of each ginseng ethanol extract was administered intraperitoneally for 2 weeks. Plasma glucose and insulin levels were markedly improved in all treatment groups. While GRR showed the highest antidiabetic activity, and GRA and PQR revealed somewhat equipotent antidiabetic activities, but less than that in GRR-treated group as far as blood parameters and diabetic symptoms such as polyphagia and polydipsia are concerned. Blood glucose levels were closely associated with plasma insulin levels, and this result may suggest that ginseng ethanol extracts showed the activity to enhance insulin secretion as well as preventing destruction of pancreatic islet cells. To elucidate the relationship between antidiabetic activity and ginsenoside profiles, seven major ginsenosides were quantified by HPLC. We figured out the fact that protopanaxatriol (PPT): proptopanaxadiol (PPD) ratio might play an important role in its hypoglycemia effects.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.261.2-261.2
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• 2002

Hypoglycemic effect of GRA was examined in multiple low dose(MLD) streptozotocin(STZ)-induced diabetic rats with regard to time of administration. Experimental methods: 20 mg/kg of STZ in 100 mM citrate buffer(pH 4.5) was injected intraperitoneally for 5 consecutive days. In co-treatment groups, GRA was administered intraperitoneally for 3 weeks at dose of 150 or 300 kg/kg. (omitted)

• YAKHAK HOEJI
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• v.48 no.4
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• pp.247-253
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• 2004

We investigated the hypoglycemic effect of formula containing Euonymus alatus (EA) and Mori Folium (MF) in multiple low dose (MLD) streptozotocin (STZ)-induced diabetic rats. In order to iduce hyperglycemic state 25 mg/kg of STZ was injected intraperitoneally for 5 consecutive days. SD rats were randomly divided into diabetic control and treatment groups. Treatment groups were administered with either 250 mg/kg of EA and 250 mg/kg of MF (E1Ml), or 500 mg/kg of EA mixed with same dose of MF (E2M2) for 3 weeks. Blood glucose levels and body weights were measured every 5th or 6th day. E1Ml and E2M2 both significantly reduced food intake, water intake, and fasting blood and urine glucose levels as compared to those in diabetic control group in a dose dependent manner. Body weight in diabetic control group was increased slightly after 3 weeks. Treatment group, however, showed gradual increase in body weights during 3 week-period. While plasma insulin levels of the diabetic control group were decreased to the level of 387$\pm$14 pg/ml from 534$\pm$36 pg/ml, those levels in E1Ml and E2M2-treated groups were both markedly increased by 13% and 26%, respectively. Urine glucose levels in E1Ml and E2M2-treated groups were also remarkably reduced by 17 and 26% compared to the levels of diabetic control group. While expression of membrane-bound glucose transporter-4 (GLUT-4) protein in skeletal muscle was reduced by 45% in diabetic control compared to the normal control, GLUT-4 protein expressions in E1Ml and E2M2-treated groups were augmented by 2 and 3.5 times compared to the diabetic control, respectively. Pancreatic HE staining experiments showed that E2M2-treated group revealed much less infiltrated mononuclear cells, indicating that E2M2 efficiently blocked insulitis induced by multiple low dose streptozotocin. Taken together, we conclude that formula containing EA and MF may prevent or delay the development of hyperglycemia through overexpression of GLUT-4 protein in skeletal muscle and prevention of insulitis.

• 한국인삼전략화협의회:학술대회논문집
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• v.2003 no.09
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• pp.77-88
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• 2003

"Ginseng (Panax ginseng C.A. Meyer) has been a popular herbal remedy used in eastern Asian cultures for thousands of years, and a number of health claims are made for it. Modern therapeutic claims for ginseng refer to vitality, immune function, cancer, cardiovascular diseases, diabetes and sexual function. These claims are mostly based on uncontrolled or non-randomized studies. Among modern therapeutic claims, however, therapeutic effects for diabetes can reasonably be accepted. Following experiment was done recently in our lab: this study was designed to compare the antidiabetic activities between Ginseng Radix Alba (GRA), Ginseng Radix Rubra (GRR) and Panax Quinquefoli Radix (PQR) in multiple low dose (MLD) streptozotocin (STZ) (20mg/kg i.p injection for 5 days) induced diabetic rats. In the glucose tolerance test, 500mg/kg of each ginseng ethanol extract was admoinistered intraperitoneally 30min before glucose challenge. While GRA failed to lower blood glucose level, GRR and PQR both significantly prevented the hyperglycemia when compared with the control group. In the MLD STZ-induced diabetic rats, 300 mg/kg of each ginseng ethanol extract was administered intraperitoneally for 2 weeks. Plasma glucose and insulin levels were markedly improved in all treatment groups. While GRR showed the highest antidiabetic activity, and GRA and PQR revealed somewhat equipotent antidiabetic activities, but less than that in GRR-treated group as for as blood parameters and diabetic symptoms such as polydipsia are concerned. Blood glucose levels were closely associated with plasma insulin levels, and this result may suggest that ginseng ethanol extracts showed the activity to enhance insulin secretion as well as preventing destruction of pancreatic islet cells. To elucidate the relationship between antidiabetic activity and ginsenoside profiles, seven major ginsenoside were quantified by HPLC. We figured out the fact that protopanaxatriol (PPT) : proptopanaxadiol (PPD) ratio might play an important role in its hypoglycemia effects."

• Journal of Ginseng Research
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• v.26 no.4
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• pp.191-195
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• 2002

In this study, we like to examine whether Panax ginseng water extract (PGWE) exerts antidiabetic activities in prevention and treatment modes in multiple low dose (MLD) streptozotocin (STZ) (20 mg/kg i.p injection for 5 days) induced diabetic SD rats. In the prevention mode,150 mg/kg of GRWE was administered intraperitoneally with STG for 3 weeks, and this group is called CO 150. In the treatment mode, we started to administer the same dose of PGWE on day 8 and for 3 weeks, and this group is called POST150. PGWE exerted significant hypoglycemic activities in both prevention (normal control, 97 ${\pm}$ 6 mg/dl; diabetic control, 331${\pm}$23; CO150, 211${\pm}$37) and treatment groups (normal control, 128${\pm}$4 mg/dl; diabetic control, 392${\pm}$33: POST150, 263${\pm}$44). Of great importance is the fact that plasma insulin levels in both groups were markedly increased as compared to the diabetic control (normal control,428.7${\pm}$62.1 pg/dl; diabetic control, 167.0${\pm}$91.7; CO150, 377.6${\pm}$68.7 in prevention mode, and in treatment mode normal control 417.9${\pm}$84.6 pg/dl; diabetic control, 166.1${\pm}$104.7; POST150, 315.2${\pm}$47.4). Blood glucose levels were closely associated with plasma insulin levels, and this result may suggest that PGWE showed the activity to enhance insulin secretion as well as preventing destruction of pancreatic islet cells. Food and water intakes were also determined at the last week of treatment i n both groups. Characteristic symptoms of diabetes were significantly improved in both groups. In the prevention mode, water intake (ml/rat/day) in normal control was increased from 30.6${\pm}$1.5 to 122.2${\pm}$3.4 in diabetic control rats. In the CO150-treated group, water intake was dramatically reduced to 68.3${\pm}$4.4 (p<0.001 vs. diabetic control). In the treatment mode, POST-treated group also reduced the water intake from 128.9${\pm}$2.2 to 113.3${\pm}$1.7. Taken together, our data suggest that PGWE showed comparable antidiabetic activities in prevention and treatment modes. Therefore, PGWE may have a potential as a prophylactic as well as therapeutic agent fur type 2 diabetes mellitus (T2DM).

• Korean Journal of Pharmacognosy
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• v.33 no.4 s.131
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• pp.337-342
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• 2002

The effect of water extract composed of panax ginseng radix rubra, acanthopanacis cortex, and cordyceps (PAC) on diabetic animal models were investigated in two different diabetic animal models. FAC water extract significantly reduced the plasma glucose levels on day 30 as compared with the diabetic control group in $KKA^Y$ obese, hyperglycemic and hyperglycemic and hyperinsulinemic mice, and also reduced the plasma glucose levels as well as total cholesterol in multiple low dose (MLD) strep tozotocin-induced diabetic SD rats. PAC water extract also showed an inhibitory effect on reduction of body weight and on development of MLD STZ-induced diabetic state. Elevated kidney hypertrophy, which is a characteristic feature shown in early stage of diabetic nephropathy and calculated as the ratio of kidney mass (g) relative to the body weight (g), was also markedly improved in PAC water extract- treated group as compared to the diabetic control group. Taken together, these data suggest that PAC water extract may have a potential as a antidiabetic agent in type 2 diabetes mellitus.

• YAKHAK HOEJI
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• v.46 no.6
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• pp.411-415
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• 2002

We compared the hypoglycemic effects of Ginseng Radix Alba (GRA) and Mori Folium (MF) in multiple low dose (MLD) streptozotocin(STZ)-induced diabetic rats. In order to induce hyperglycemic state 25 mg/kg of STZ was injected intraperitoneally for 5 consecutive days. SD rats were randomly divided into diabetic control and treatment groups. Treatment groups were administered with either 500 mg/kg of GRA (G500), 500 mg/kg of MF (M500), or 250 mg/kg of GRA mixed with same dose of MF (GM250) for 3 weeks. Blood glucose level and body weight were measured every 5th day. G500 and M500 both significantly reduced blood glucose levels as compared to the diabetic control group (diabetic control, 458.3$\pm$25.4 mg/dl; G500, 275.0$\pm$12.0; M500, 278.0$\pm$15.4; GM250, 324.0$\pm$18.4). While body weight in diabetic control group was decreased slightly after 3 weeks, treatment groups showed gradual increases of body weight during 3 week-period. Plasma insulin level was increased by treatment with GRA, but those levels in M500 and GM250 groups were similar to the diabetic control (normal control, 32.0$\pm$13.9 $\mu$IU/mι; diabetic control, 12.4$\pm$1.9; G500, 17.5$\pm$3.4; M500, 11.1$\pm$3.2; GM250, 10.5$\pm$t3.7). Urine glucose levels were also remarkably reduced in all treatment groups (normal control, 0.0$\pm$0.0 g/day; diabetic control, 11.4$\pm$2.5; G500, 4.9$\pm$0.2; M500, 5.7$\pm$1.6 ; GM250, 8.2$\pm$0.2). At the second and third week of the treatment, food and water intakes were determined. At the third week, food and water intakes were significantly decreased in all treatment groups. Taken together, we may conclude that GRA and MF alone may prevent or delay the development of hyperglycemia, however, synergistic hypoglycemic activity was not be seen in group treated with mixed formula of GRA and MF when compared to GRA or MF alone.