Diabetes & Metabolism Journal

Original Articles

Protective Effects of Lithospermic Acid B on Diabetic Nephropathy in OLETF Rats Comparing with Amlodipine and Losartan.: Eun Seok Kang, Beom Seok Kim, Chul Hoon Kim, Gi Ho Seo, Seung Jin Han, Sung Wan Chun, Kyu Yeon Hur, Chul Woo Ahn, Hunjoo Ha, Mankil Jung, Bong Soo Cha, Hyun Chul Lee; Korean Diabetes J. 2008;32(1):10-20. Published online February 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.1.10

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BACKGROUND
Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhizae, has been reported to have renoprotective effects in type 1 and type 2 diabetic animal models. We examined the effects of LAB on the prevention of diabetic nephropathy compared with amlodipine, a calcium channel blocker, and losartan, an angiotensin receptor blocker, in Otsuka Long-Evans-Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. METHODS: LAB (20 mg/kg), amlodipine (10 mg/kg), or losartan (10 mg/kg) was given orally once daily to 10-week-old male OLETF rats for 28 weeks. RESULTS: None of LAB, losartan, and amlodipine exhibited effects on blood glucose levels. Treatment with amlodipine or losartan resulted in similar reductions in blood pressure; however, LAB was less effective in lowering blood pressure. Albuminuria was markedly suppressed by losartan and LAB, but not by amlodipine. LAB treatment decreased levels of renal lipid peroxidation, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 (TGF-beta1). CONCLUSION: These results suggest that LAB has beneficial effects on the diabetic nephropathy in OLETF rats by decreasing oxidative stress and inflammation as potent as losartan.

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An Overview on Naturally Occurring Phytoconstituent: Lithospermic Acid
Bhupesh Chander Semwal, Amjad Hussain, Sonia Singh
The Natural Products Journal.2024;[Epub] CrossRef

Thiazolidinediones on Insulin Resistance and Insulin Secretion in Obese Diabetic OLETF Rats.: Jung hyun Noh, Seung hyun Hong, Kyoung hee Lee, Kyoung Min Min, Tae young Yang, Myung shik Lee, Kwang won Kim, Moon kyu Lee; Korean Diabetes J. 2007;31(1):33-43. Published online January 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.1.33

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Abstract PDF: BACKGROUND
Thiazolidinediones are synthetic peroxisome proliferator-activated receptor-gamma agonists that decrease insulin resistance but, as in vitro and in vivo studies suggest, may have direct beneficial effects on pancreatic beta cells. Here, we investigated the effects of thiazolidinediones (TZDs) on the insulin resistance, beta-cell mass and insulin secretion in obese diabetic OLETF rats. METHODS: We studied insulin resistance (by hyperinsulinemic euglycemic clamp) and insulin secretion (by hyperglycemic clamp) in TZDs administered OLETF and LETO rats. Histologic alterations of the islets were observed and beta-cell mass was also measured by point counting method. RESULTS: Chronic administration of troglitazone (TGZ, 0.15%) or pioglitazone (PGZ, 0.02%) prevented the development of glucose intolerance in OLETF rats, as assessed by oral glucose tolerance test. There was significant difference in submaximal glucose infusion rate between TGZ-treated and untreated OLETF rats during euglycemic clamp studies at 24 weeks of age. At 16 and 24 weeks of ages, beta-cell mass significantly increased in TGZ-treated OLETF rats compared to untreated animals. At 19 weeks and 30 weeks of age, first-phase insulin secretion was not different in PGZ-treated OLETF rats from untreated OLETF rats during hyperglycemic clamp study. At 30 weeks of age, late-phase insulin secretion was decreased in PGZ-treated OLETF rats compared to untreated OLETF rats. The expression of alpha-smooth muscle actin, a marker of activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets was suppressed by TGZ treatment at 24 weeks of age. CONCLUSION: The treatment of TGZ prevented the development of diabetes, and increased insulin sensitivity and pancreatic beta-cell mass in OLETF rats. These results might be related with the suppression of pancreatic stellate cells. Insulin secretion was not affected by PGZ treatment.

Effects of Caloric Restriction on the Expression of PGC-1 and PPARs mRNA in Liver of Otsuka Long-Evans Tokushima Fatty Rats.: Sang Yong Kim, Jin Hwa Kim, Hak Yeon Bae, Byoung Rai Lee; Korean Diabetes J. 2006;30(3):161-169. Published online May 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.3.161

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Abstract PDF: BACKGROUND
Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. PPARgamma-coactivator 1 (PGC-1) and Peroxisome proliferator -activated receptors (PPARs) costimulate the expression of key enzymes of gluconeogenetic pathway. This study was performed to evaluate the response to dietary caloric restriction (CR) on the PPARs and PGC-1 expression in liver of diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Diabetic OLETF rats (male, 24 weeks) and Long-Evans Tokushima Otsuka (LETO) rats (male, 24 weeks) were used in this study. Liver PPARs and PGC-1 mRNA, and blood glucose levels were investigated at 1, 2, and 3 weeks after the beginning of 30% CR. PPARs and PGC-1 mRNA were determined by RT-PCR and blood glucose levels were measured by spectrophotometric assay. RESULTS: The liver PGC-1 mRNA expressions were increased to 19% in non-diabetic LETO rats but significant change was not observed in diabetic OLETF rats by 30% CR. The liver PPARgamma mRNA expressions were not changed in non-diabetic LETO rats but increased to 23% in diabetic OLETF rats by 30% CR. The difference of PPARalpha and PPARbeta mRNA expressions in liver of OLETF and LETO rats were not observed. CONCLUSION: The liver PPARgamma and PGC-1 expression response to CR are altered in OLETF rats compared to in LETO rats. These findings suggested that PPARgamma and PGC-1 expression control system altered in diabetic OLETF rat liver and altered PPARgamma and PCG-1 expression may some roles on the aberrantly activated gluconeogenesis in diabetes mellitus.

The long-term effect of ramipril on Gialpha2-protein and Protein Tyrosine Phosphatase 1B in an animal model of type 2 diabetes(OLETF rat).: Jung Min Lee, Ok Ki Hong, Hyuk Sang Kwon, Sung Dae Moon, Sang Ah Chang, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Sung Koo Kang; Korean Diabetes J. 2006;30(1):25-38. Published online January 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.1.25

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Abstract PDF: BACKGROUND
The regulation of tyrosine phosphorylation/dephosphorylation is an important mechanism in various intracellular metabolism. Also impaired insulin signal transduction is important in pathogenesis of type 2 diabetes. It has been reported that PTP1B is a negative regulator of insulin action, and Gialpha2-protein is related to the regulation of PTP1B. Herein we investigated the long-term effects of ramipril on PTP1B/insulin signal protein interaction and the relation between Gialpha2 and PTP1B in animal model of type 2 diabetes (OLETF rat). METHODS: OLETF rats and age-matched LETO rats were divided into two groups. One group of rats received ramipril (10 mg/kg body weight) for 12 weeks, and another group did not. Finally, each group was divided into 2 subgroups, with or without insulin injection intravenously, before sacrifice. After sacrifice, tissues extracts of liver, hind limb muscle, and epididymal fat were obtained for quantification of PTP1B, Gialpha2, and several insulin signal proteins by western blotting. RESULTS: In liver and muscle, the levels of basal PTP1B and activated PTP1B of OLETF rats treated with ramipril and insulin were significantly decreased. The levels of Gialpha2, activated IRS-2, and activated p-85alpha were significantly increased in OLETF rats treated with ramipril and insulin. In adipose tissue, the levels of Gialpha2 and activated p-85alpha of OLETF rats treated with ramipril and insulin were slightly increased as in liver and muscle. But, the levels of basal PTP1B and activated PTP1B were significantly increased. And, the levels of activated IRS-1 and activated IRS-2 were decreased. CONCLUSION: These results suggest that the improvement of insulin sensitivity by treatment with ramipril was related to the decreased level of activated PTP1B. Also, we could suggest that the changes of activated PTP1B level was related with the changes of Gialpha2-protein. However, the results of adipose tissue were different from those of liver and muscle. So it seemed likely that there would be various major modulators for regulation of insulin signal pathway according to tissue.

Protective Effects of Lithospermate B on Diabetic Nephropathy in OLETF Rat.: Hyun Joo Lee, Geun Taek Lee, Eun Seok Kang, Kyu Yeon Hur, Zheng Shan Zhao, Chul Woo Ahn, Hun Joo Ha, Man Kil Jung, Bong Soo Cha, Hyun Chul Lee; Korean Diabetes J. 2005;29(4):322-332. Published online July 1, 2005

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Abstract PDF: BACKGROUND
Magnesium lithospermate B(LAB), an active component isolated from Salvia milltiorrhizae, has been reported to have renoprotective effects in type 1 diabetic animal model. The purpose of this study was to examine the effects of LAB on the prevention of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty(OLETF) rat which is regarded as an animal model of type 2 diabetes. METHODS: Ten microgram of LAB/kg or Vehicle(PBS) was given orally once daily to 10-week-old male OLETF rats and LETO rats for 40 weeks. Intra-peritoneal glucose tolerance test was performed at 50 weeks. 24 hr urinary protein excretion amounts were measured. Lipid peroxidation, TGF-beta1 and ED-1 of renal cortex were measured. RESULTS: The mean body weight of LAB+OLETF was not significantly different from that of OLETF rats. LAB treatment decreased proteinuria, lipid peroxidation, and free fatty acid in OLETF rats without decrease in the plasma glucose concentration. Also, LAB inhibited the progression of glomerular hypertrophy and mesangial expansion. LAB effectively decreased ED-1 positive cells, ECM expansion, and TGF-beta1 level in the renal cortex of OLETF rats. CONCLUSIONS: These results suggest that the beneficial effects of LAB on the diabetic renal damage in the OLETF rats may depend on a mechanism of decreasing oxidative stress. LAB might be a new therapeutic agent for the prevention of nephropathy in type 2 diabetes as well as type 1 diabetes.

Taurine-Mediated Restoration of Glucose Sensitivity of Pancreatic Beta Cells in OLETF Rats.: So Yeon Kim, Keun Gyu Park, In Kyu Lee, Seong Il Nam, Dae Kyu Song; Korean Diabetes J. 2005;29(3):198-205. Published online May 1, 2005

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Abstract PDF: BACKGROUND
An OLETF(Otsuka Long-Evans Tokushima Fatty) rat is a model of type 2 diabetes that is characterized by obesity-induced insulin resistance. Taurine has been known to be beneficial for type 2 diabetes. This study evaluated the potential taurine effect on the insulin response to high glucose in the islets of OLETF rats. METHODS: One percent of taurine was put in the drinking water for the taurine group of OLETF rats at the time of their being 20 to 39 weeks of age. At 40 weeks, the pancreatic islets and beta cells were obtained to measure the glucose-stimulated insulin secretion(GSIS) and the ATP-sensitive K+(KATP) channel current. RESULTS: Taurine supplementation had no effect on the weight change of the rats when this was measured weekly from 20 to 39 weeks(mean+/-SE: 702+/-19g in the control group vs. 688+/-18g in the taurine group at the 39th week). However, the GSIS was significantly potentiated in the taurine-treated rats(8.9+/-1.3% vs. 13.2+/-3.2% of the total secreted at 15 mM glucose for 1h). The glucose-induced KATP channel inhibition in the beta cells was also greater in the taurine group. CONCLUSION: Taurine supplementation is a beneficial tool for the restoration of GSIS in the pancreatic islet of the OLETF rats. Maintenance of blood taurine level may be important in treating type 2 diabetic patients, who are subject to a low blood level of taurine

High Carbohydrate Diet Effects on the Development of Diabetes Mellitus and Modification of Pancreatic Islets in OLETF Rats.: Sung Ki Kim, Seong Bin Hong, Hwi Ra Park, Eun A Kim, Kyung Wook Lee, Moon Suk Nam, Yong Seong Kim; Korean Diabetes J. 2004;28(3):187-198. Published online June 1, 2004

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Abstract PDF: BACKGROUND
Diet has long been believed to be an important risk factor for type 2 diabetes. The composition of carbohydrates in the diet was higher in the past, where as now it is considerably reduced in the diet of Korean peoples, which is probably associated with the risk of developing type 2 diabetes. The aim of the present study was to investigate the long-term effect of high carbohydrate/low protein diets on the glucose and lipid metabolism and the pancreatic islet in OLETF(Otsuka Long-Evans Tokushima Fatty) rats, the animal model of type 2 diabetes. METHODS: Seven week old male OLETF rat were fed a high carbohydrate/low protein diet(carbohydrate 71.0%, fat 14.5%, protein 14.5%) as the experimental group, with an ordinary chow diet(carbohydrate 63.5%, fat 14.5%, protein 22%) fed to the controls. The plasma insulin, lipid profiles, free fatty acid and oral glucose tolerance were analyzed at 16 and 32 weeks. After the glucose tolerance test, the pancreas was excised, and immunohistochemical staining was conducted for the islet morphology and insulin mRNA to quantify the insulin secretory capacity. RESULTS: The basal glucose levels tended to be higher in the control group, but with no significant statistical difference. There were no differences in the serum insulin, total cholesterol, triglyceride, HDL-cholesterol and plasma free fatty acid levels between the two groups. The pancreatic islets of the control group showed multilobulation, with fibrotic changes; where as those of the experimental group were maintained normal profiles. A higher expression of insulin mRNA was observed in the experimental than in the control group. CONCLUSION: A high carbohydrate diet induced lower body weight increases, and protected against beta cell injury and decreased the development of abnormal glucose tolerance in OLETF rats. This may explain the growing incidence of diabetes with respect to the change in carbohydrate composition in the diet of Korean peoples. However, whether the protective effect of a high carbohydrate diet, against the development of diabetes in OLETF rats, can be attributed to small weight increases or if the change in food composition itself, or both needs to be determined.

Effect of Heat Shock on the Vascular Reactivity and Expression of Heat Shock Protein in an Animal Model of Type 2 Diabetes Mellitus (OLETF rat).: Soon Hee Lee, Sung Woo Ha, Bo Wan Kim; Korean Diabetes J. 2003;27(3):199-212. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Heat shock proteins (HSPs) are highly expressed in cardiovascular tissues, with heat shock possibly modulating the vascular reactivity to vasoactive agents. An abnormal vascular reactivity has been shown in diabetes, and may be closely associated to diabetic vascular complications. The aim of this study was to investigate the effects of heat shock on the vascular reactivity and the expression of HSP70 in the isolated aortae of OLETF rats, a commonly used animal model for type 2 diabetes mellitus, and LETO rats, as age matched controls. METHODS: In 4 ring segments of the thoracic aorta isolated from each rat, the endothelium was denuded in 2 (EC-) and reserved in the other 2 (EC+). To induce heat shock, the aortic rings were exposed to 42 degrees C for 45 minutes. The vascular reactivity responses to various vasoactive agents were measured by organ chamber studies, and by changes in the HSP expression, using Western blotting of the aortic rings in the OLETF rats and controls. RESULTS: The contractile responses to KCl became apparent 4 hours after the end of the heat shock induction. After heat shock, the phenylnephrine-induced contractile responses were similarly increased in the OLETF rats and the controls, but the increase was more significant in the EC(-) than the EC(+) rings, in both the OLETF rats and the controls. The relaxative responses to either acetylcholine (ACh) in the EC(+) aortic rings, or to sodium nitroprusside in the EC(-) rings, were not significantly affected by the heat shock treatment in either the OLETF rats or the controls, although the maximal relaxative response to ACh before the induction of the heat shock was lower in the aortic rings of the OLETF rats than in the controls. The HSP70 levels before the heat shock were higher in the aortic rings of the OLETF rats than in the controls, whereas those after heat shock were higher than those before in both the OLETF rats and the controls. The increase in the expression of HSP70 following the heat shock was higher in rings of the controls than in those of the OLETF rats. The HSP70 levels following the heat shock were increased to a greater extent in the EC(+) than the EC(-) rings of both the OLETF rats and the controls. CONCLUSION: These results suggest that the vascular reactivity to heat shock was decreased to a greater extent in the aortae of OLETF rats than in those of the controls, and that HSP70 seems to play an important role in the vascular response to heat shock through interaction of the endothelium and the smooth muscle.

Mechanism of Impaired Endothelium-dependent Vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats .: Kook Jin Chun, Seok Man Son, In Ju Kim, Chi Dae Kim, Seok Dong Yoo, Yong Ki Kim; Korean Diabetes J. 2002;26(1):47-57. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several long-term animals hyperglycemia models and human diabetic patients. Since oxidative stress has been implicated as a contributor to impaired vascular function, the mechanism of an impaired endothelium-dependent vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats was investigated. METHODS: This present study was undertaken to characterize both the vascular production and the enzymatic source of the superoxide anion in the type 2 diabetic rats. RESULTS: In the thoracic aortas of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared to that of the control rats (LETO, Long-Evans Tokushima Otsuka) in association with a significant increase in superoxide production (2421.39+/-07.01 nmol/min/mg). There was no difference in eNOS expression between the OLETF rats and LETO rats. The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI, 10 mol/L), NAD (P)H oxidase inhibitor. In line with these results, studies using various enzyme inhibitors such as DPI, allopurinol, rotenone and L-NMMA suggest that the main source of superoxide anions in the aorta is NAD (P)H oxidase. CONCLUSION: These results suggest that enhanced NAD(P)H oxidase activity and reduced nitric oxide (NO) availability through an interaction between NO and superoxide anion contribute to the impaired endothelium-dependent vasodilation in OLETF rats.

The Effect of Long-term Treatment of Ramipril on Glucose Tolerance and Pancreatic Islets in Type 2 Diabetes Animal Model (OLETF Rats).: Seung Hyun Ko, Kun Ho Yoon, Myung Mi Kim, Yu Bae Ahn, Ki Ho Song, Soon Jib Yoo, Hyun Shik Son, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(6):469-482. Published online December 1, 2001

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Abstract PDF: BACKGROUND
In a Heart Outcomes Prevention Evaluation HOPE study, ramipril, a long- acting angiotensin-converting enzyme (ACE) inhibitor, significantly reduced the death rates the number of myocardial infarctions, strokes, heart failure as well as the risk of complications related to diabetes and of diabetes itself. However, it is known that ACE inhibitors improve glucose tolerance or insulin sensitivity or reduce the incidence of diabetes. METHODS: 24 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 400~450 g were used in this study. 4 groups of rats were examined in parallel for 40 weeks. The OLETF rats were randomized for treatment with an aqueous solution of ramipril ( 5mg/Kg) daily [OL (RMP), n=10)] and with saline [OL(CON), n=10)]. The LETO rats were also randomized in the same was as the OLETF rats (LT (RMP), n=10, LT (CON), n=10). The blood glucose level, body weight, systolic and diastolic blood pressure was assessed every month. At 3 and 6 months, the 24hrs urinary protein concentration was measured, and as insulin tolerance test and oral glucose tolerance test were conducted in all experimental groups. After 6 months, the body weight was matched for 2 months in each corresponding group. Subsequently, a 15% sucrose loading was done for 2 months. After the glucose tolerance test, the pancreas was excised and immunohistochemical staining was conducted for insulin to quantify the beta cell mass by a point-counting method. In addition, the islet morphology was evaluated in the pancreas. RESULTS: Ramipril treatment for a period of 6 months improved the 2hr blood glucose level, the area under the glucose curve in the oral glucose tolerance test, insulin sensitivity in addition to lowering significantly systolic and diastolic blood pressure and 24hrs urinary protein level significantly in OLETF rats. Of note, a lower weight gain was observed in both the ramipril-treated animals at 6 months. After weight matching, the AUCg and 2hr blood glucose level values were similar between the corresponding groups, but a 15% sucrose loading worsened the AUCg value. Histologically, the islets were less disorganized and the extent of fibrosis was lower in the ramipril- treated OLETF rats in the trichrome stain. CONCLUSION: Long-term treatment of ramipril, a long acting angiotensin-converting enzyme inhibitor may be useful for suppressing weight gain and proteinuria in addition to having aprotective effect on the islet to harmful stimuli such as hyperglycemia.

Chronic Diabetic Complications in the Insulin- Treated Animal Model of Type 2 Diabetes Mellitus.: Jee Won Park, Sung Kyu Lee, Hyo Jung Kim, Hae Lim Noh, Chang Young Hah, Su Jin Lee, Yoon Sok Chung, Kwan Woo Lee, Hyun Man Kim, Eun Ju Paek; Korean Diabetes J. 2001;25(3):200-210. Published online June 1, 2001

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Abstract PDF: BACKGROUND
Non-Insulin Dependent Diabetes Mellitus (NIDDM) is a characterized by insulin resistance and impairment of beta cell function. OLETF male rat usually developed NIDDM and obesity at 20 weeks old spontaneously. It is a metabolically characterized by insulin resistance in onset of early disease. However, body weight and insulin secretory function was gradually reduced during the diabetes developed. These characteristics of disease is similar to Korean type 2 diabetic patients. NIDDM patients in Korea are thought to be different from traditional NIDDM in western countries. They are non obese type and also has reduced insulin secretory function compared to western countries. These patients are not easily managed on diet and/or oral hypoglycemic agent. Reduced C-peptide and insulin concentrations in these patients are similar to patients with IDDM. In these patients, insulin therapy is effective to control glucose level. Therefore, we investigated the effect of insulin and oral hypoglycemic therapy to glucose control and severity of chronic complications in OLETF male rats of 6weeks (42 weeks old) and 14 weeks (50 weeks old) treated groups. MATERIAL AND METHODS: The OLETF male rats which are 36 weeks old is diagnosed to NIDDM. A total of 20 rats were stratified into the three groups: control group (n=3), OHA's group; rats treated by OHA's (n=3) and insulin group; rats treated with insulin (n=4). We evaluated anthropometry, fasting glucose and 75 gram OGATT, nerve conduction studies, sclerotic degree of kidney and thickness of carotid arteries at 42 and 50 weeks old. RESULTS: In the 42 weeks old groups (6 weeks treated group), there was a significant difference in weight gain in group 3 but no differences were observed in kidney tissue pathology and thickness of carotid arteries. In the 50 weeks old groups (14 weeks treated group), there were also no changes in the kidneys and arteries, but weight gain and peak amplitude in NCV was significantly higher in insulin - treated group. CONCLUSIONS: OLETF male rats as NIDDM animal mocel, with late stage diabetic complications show weight loss and decreased insulin secretory capacity. Insulin treated group shows improved blood glucose control. Also it showed improved severity of diabetic neuropathy.

Effects of Cilostazol on Insulin Resistance in OLETF Rats.: Sung Rae Kim, Ki Hyun Baek, Seung Hyun Ko, Jung Min Lee, Sang Ah Chang, Yoo Bae Ahn, Soon Jib Yoo, Jong Min Lee, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(1):63-70. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance is one of the major pathophysiology of type 2 diabetes mellitus. It is reported that cilostazol and cyclic AMP phosphodiesterase inhibitor has the anti-platelet effect as well as an improvement of hypertriglyceridemia in addition to vasodilatation. Furthermore, the previous reports indicated that there is a positive relationship between insulin resistance and dyslipidemia. Thus, we investigated the effects of cilostazol on insulin resistance in OLETF rats using the euglycemic hyperinsulinemic glucose clamp technique, and lipid levels. METHODS: Fifteen five months old OLETF rats were fed for 4 weeks(8 treated with cilostazol and 7 were control), and compare to 20 same aged LETO rats (8 treated with cilostazol and 12 were control) through the glucose infusion rate on euglycemic hyperinsulinemic glucose clamp and lipid profiles. RESULTS: The glucose infusion rate was higher in the cilostazol treated OLETF rats than in the non-cilostazol treated OLETF rats (0.021+/-0.0031 vs 0.027+/-0.0036 mL/min). The levels of free fatty acids (2424.8+/-652.7 vs 1061.8+/-223.2 Eq/L), total cholesterol (145.7+/-17.9 vs 115.4+/-7.6 mg/dL) and triglyceride (146.5+/-46.6 vs 76.1+/-12.5 mg/dL) of cilostazol treated OLETF rats were significantly lower than those of non-cilostazol treated OLETF rats. CONCLUSION: This study result suggest that cilostazol may improve the insulin resistance through the improvement of dyslipidemia in OLETF rats.

Effect of Glycosaminoglycan on Proteinuria and Urinary N-acetyl- -D-Glucosaminidase Excretion in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats.: Kyung Mook Choi, Dae Ryong Cha, Sang Youb Han, Dong Rim Kim, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi; Korean Diabetes J. 2000;24(5):533-540. Published online January 1, 2001

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Abstract: BACKGROUND
Increased loss of proteoglycan (PG) characterized by an increased loss of anionic charges in the basement membrane has been considered as one of main factors causing urinary loss of albumin. The glycosaminoglycans (GAGs) are linear polymers of repeated disaccharides and the GAG chains are covalently bound to core proteins, forming proteoglycans. It is known that urinary N-acetyl- -D-glucosaminidase (NAG) excretion is a sensitive marker of renal damage and is increased before other renal functional parameters. The aim of this study was to investigate whether GAG treatment is capable of influencing urinary protein and NAG excretion in Otsuka Long-Evans Tokushima Fatty (OLETF) rats which are known as type 2 diabetic animal model. METHODS: Fifteen male OLETF rats and twenty male Long-Evans Tokushima Otsuka (LETO) rats were used for this study. LETO rats are non-diabetic control rats. All OLETF rats were randomly assigned to 2 groups: control group (n=10) given only tap water and GAG group (n=5) feeding with GAG 10 mg/kg from 7 weeks to 55 weeks of age. Measurement of body weight, blood glucose, serum BUN and creatinine was performed periodically. 24-hour urine collection for measurement of urinary protein and NAG excretion was done at 17, 25, 37, 46, 55 weeks of age. RESULTS: 1) OLETF rats showed higher body weight, blood glucose, 24-hour urinary protein and NAG excretion compared with LETO rats. But serum concentration of BUN and creatinine were not different between OLETF and LETO rats. 2) GAG-treated OLETF rats exhibited lower urinary protein/creatinine excretion (17.48+/-0.50 vs 22.49+/-0.11 mg/mg Cr, p< 0.05) and NAG (17.40+/-5.94 vs 43.73+/- 7.44 nmol/h/mg Cr, p< 0.05) excretion compared with non-treated OLETF rats. But body weights, blood glucose, serum concentration of BUN and creatinine were not different between GAG-treated OLETF rats and non-treated OLETF rats. CONCLUSION: 1) The urinary excretion of NAG may be a possible early marker of diabetic nephropathy in OLETF rats. 2) Urinary protein and NAG excretion were decreased in the GAG-treated OLETF rats. GAG seems to have a protective effect against development of diabetic nephropathy.

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