Heung Yong Jin

Dipeptidyl Peptidase IV Inhibitor Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-β1 (TGF-β1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-β1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-β1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.

Effect of Dipeptidyl Peptidase-IV (DPP-IV) Inhibitor (Vildagliptin) on Peripheral Nerves in Streptozotocin-induced Diabetic Rats

BACKGROUND AND AIMS The aim of this study was to investigate the GLP-1 pathway effect on peripheral nerves using a DPP-IV inhibitor in streptozotocin (STZ)-induced diabetic rats. METHODS Adult male Sprague Dawley rats were divided into four groups and two groups (n=6 in each) were given a DPP-IV inhibitor of 0.3mg/kg/day or 10mg/kg/day dissolved in water. Intraepidermal innervation was quantified as nerve fiber abundance per unit length of epidermis (IENF/mm) following an immunohistochemical procedure using the polyclonal antibody of anti-protein gene product 9.5 (PGP 9.5). RESULTS Daily administration of DPP-IV inhibitor to the experimental diabetes model at doses of 10mg/kg for 32 weeks protected nerve fiber loss compared with untreated rats as follows (IENF/mm): normal (9.89+/-0.34), diabetes mellitus (DM) (8.42+/-0.28), DM with 0.3mg/kg DPP-IV inhibitor (9.88+/-0.38), and DM with 10mg/kg DPP-IV inhibitor (10.36+/-0.32) (p<0.05). There was a significant reduction (% change) in the decrease of intraepidermal nerve fiber density (IENFD) in the DPP-IV inhibitor-treated groups during the experimental period: normal (10.1%), DM (25.8%), DM with 0.3mg/kg DPP-IV inhibitor (13.3%), and DM with 10mg/kg DPP-IV inhibitor (7.9%) (p<0.05). CONCLUSIONS Our study suggests that a DPP-IV inhibitor may prevent peripheral nerve degeneration in a diabetes-induced animal model and support the idea that GLP-1 may be useful in peripheral neuropathy.

Neuroprotective effect of the glucagon-like peptide-1 receptor agonist, synthetic exendin-4, in streptozotocin-induced diabetic rats

BACKGROUND AND PURPOSE Glucagon‐like peptide‐1 (GLP‐1) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation. The aim of this study was to investigate the effect of the GLP‐1 pathway on peripheral nerves in streptozotocin‐induced diabetic rats.

The effect of α‐lipoic acid on symptoms and skin blood flow in diabetic neuropathy

Aims  Multiple pathogenic pathways are involved in diabetic neuropathy and diverse treatments have been tried without success. The aim of this study was to assess the effect of α‐lipoic acid on skin blood flow in patients with diabetic neuropathy.

Sulodexide prevents peripheral nerve damage in streptozotocin induced diabetic rats

We investigated whether sulodexide has additional protective effects against peripheral nerve damage caused by microvascular dysfunction in a rat model of diabetes. Female Sprague-Dawley (SD) rats were divided into the following 4 groups (n=7-9/group): Normal, Normal+Sulodexide (sulodexide 10mg/kg), diabetic group, and diabetic+Sulodexide (sulodexide 10mg/kg). We assessed current perception threshold, skin blood flow, superoxide dismutase, and proteinuria in experimental rats after oral administration of sulodexide for 20 weeks. We also performed morphometric analysis of sciatic nerves and intraepidermal nerve fibers of the foot. Superoxide dismutase activity in the blood and sciatic nerve were increased significantly after sulodexide treatment in the diabetic group. Current perception threshold was reduced at 2000 Hz (633.3 ± 24.15 vs 741.2 ± 23.5 μA, P<0.05) and skin blood flow was improved (10.90 ± 0.67 vs 8.85 ± 0.49 TPU, P<0.05) in the diabetic+Sulodexide group compared with the diabetic group. The mean myelinated axon area was significantly larger (56.6 ± 2.2 vs 49.8 ± 2.7 μm(2), P<0.05) and the intraepidermal nerve fiber density was significantly less reduced (6.27 ± 0.24 vs 5.40 ± 0.25/mm, P<0.05) in the diabetic+Sulodexide group compared to the diabetic group. Our results demonstrate that sulodexide exhibits protective effects against peripheral nerve damage in a rat experimental model of diabetes. Therefore, these findings suggest that sulodexide is a potential new therapeutic agent for diabetic peripheral neuropathy.

Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness

Despite the rapidly increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D), few treatment modalities are currently available. We investigated the hepatic effects of the novel thiazolidinedione (TZDs), lobeglitazone (Duvie) in T2D patients with NAFLD. We recruited drug-naïve or metformin-treated T2D patients with NAFLD to conduct a multicenter, prospective, open-label, exploratory clinical trial. Transient liver elastography (Fibroscan®; Echosens, Paris, France) with controlled attenuation parameter (CAP) was used to non-invasively quantify hepatic fat contents. Fifty patients with CAP values above 250 dB/m were treated once daily with 0.5 mg lobeglitazone for 24 weeks. The primary endpoint was a decline in CAP values, and secondary endpoints included changes in components of glycemic, lipid, and liver profiles. Lobeglitazone-treated patients showed significantly decreased CAP values (313.4 dB/m at baseline vs. 297.8 dB/m at 24 weeks; P = 0.016), regardless of glycemic control. Lobeglitazone improved HbA1C values (7.41% [57.5 mM] vs. 6.56% [48.2 mM]; P < 0.001), as well as the lipid and liver profiles of the treated patients. Moreover, multivariable linear regression analysis showed that hepatic fat reduction by lobeglitazone was independently associated with baseline values of CAP, liver stiffness, and liver enzymes, and metformin use. Lobeglitazone treatment reduced intrahepatic fat content, as assessed by transient liver elastography, and improved glycemic, liver, and lipid profiles in T2D patients with NAFLD. Further randomized controlled trials using liver histology as an end point are necessary to evaluate the efficacy of lobeglitazone for NAFLD treatment (Clinical trial No. NCT02285205).

Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes

DA-9801, a mixture of extracts from Dioscorea japonica Thunb. and Dioscorea nipponica Makino, was reported to have neurotrophic activity. Therefore, we investigated the therapeutic potential of DA-9801, in comparison with alpha lipoic acid (ALA), for peripheral nerves preservation in experimental diabetes. Experimental animals were divided into 4 groups, and each group was designated according to the type of treatment administered as follows: normal, DM, DM+DA-9801, and DM+ALA. After 16 weeks, response thresholds to tactile and thermal stimuli were higher in DM+DA-9801 group than in nontreated DM group. This degree of increase in DM+DA-9801 group indicates more therapeutic potency of DA-9801 than ALA. Western blot analysis showed more significant increase in NGF and decrease in TNF-α and IL-6 in DM+DA-9801 group than in DM or DM+ALA groups (P < 0.05). IENF density was reduced less significantly in the DM+DA-9801 group than in other DM groups (7.61 ± 0.32, 4.2 ± 0.26, and 6.5 ± 0.30 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Mean myelinated axonal area in the sciatic nerves was significantly greater in DM+DA-9801 group than in other DM groups (69.2 ± 5.76, 54.0 ± 6.32, and 63.1 ± 5.41 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Results of this study demonstrated potential therapeutic applications of DA-9801 for the treatment of diabetic peripheral neuropathy.

The Correlation and Accuracy of Glucose Levels between Interstitial Fluid and Venous Plasma by Continuous Glucose Monitoring System

Background Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects. Methods Thirty-two subjects were served with glucose solution contained same amount of test foods carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined. Results CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 ± 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day. Conclusion The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean.

Effect of rimonabant, the cannabinoid CB1 receptor antagonist, on peripheral nerve in streptozotocin-induced diabetic rat

The aim of this study is to investigate the effect of rimonabant, which has antiatherosclerotic and antiinflammatory properties, on peripheral neuropathy in a diabetic rat. Diabetic rat models were induced by treatment with streptozotocin and then either normal or diabetic rats were treated with an oral dose of 10mg/kg/day rimonabant or placebo for 24 weeks. We quantified the densities of intraepidermal (PGP9.5+) nerve fiber and total skin (RECA-1+) capillary length. We also measured the current perception threshold, as defined by the intensity of sine-wave stimulus, skin blood flow after treadmill running and TNF-alpha level in spinal cord tissue or plasma. After 24 weeks, rimonabant reduced the body weight and food intake in both diabetic and normal rats, but it had no effect on blood sugar levels. In addition, rimonabant treatment significantly improved the decreased intraepidermal nerve fiber density (5.53+/-0.12 vs. 4.36+/-0.27/mm, P<0.05) and alleviated the increased current perception threshold in rimonabant-treated versus control diabetic rats. These responses were closely associated with the attenuation of skin capillary loss (1.98+/-0.07 vs. 1.67+/-0.10 mm/mm(2), P<0.05), increase in skin blood flow (14.93+/-1.08 vs. 12.07+/-0.87 TPU, P<0.05) and reduction in TNF-alpha level in tissue (70.10+/-4.99 vs. 91.18+/-3.34 pg/mg, P<0.05) in rimonabant-treated diabetic rats compared with placebo. These findings suggest that rimonabant can be beneficial for treatment of diabetic peripheral neuropathy, possibly due to its potential role in micro- and macrovessel protection and its anti-inflammatory properties.

The impact of glycemic variability on diabetic peripheral neuropathy.

Mean glucose values alone cannot explain the patterns of morbidity and mortality due to dysglycemia in diabetes. Development of continuous glucose monitoring systems has improved the analysis and interpretation of glycemic variability. The roles of glycemic components other than constant hyperglycemia in diabetic complications must be investigated because large clinical studies have indicated that risk factors besides the average glucose value of HbA1c are involved in chronic macrocomplications/microcomplications of diabetes. Among these complications, the pathogenesis of diabetic peripheral neuropathy is particularly complex, and several factors related to glucose and nonglucose pathways have been suggested as risk factors. There is little information regarding the effect of glycemic variability on diabetic peripheral neuropathy, unlike other microvascular complications of retinopathy and nephropathy, and whether glycemic variability causes harmful effects is still a matter of debate. In this review, we discuss the relationships between glycemic variability and diabetic peripheral neuropathy, focusing on somatosensory peripheral neuropathies rather than autonomic neuropathies.