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Original Article
Ruboxistaurin for the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review of Randomized Clinical Trials
Dipika Bansal, Yogesh Badhan, Kapil Gudala, Fabrizio Schifano
Diabetes Metab J. 2013;37(5):375-384.   Published online October 17, 2013
DOI: https://doi.org/10.4093/dmj.2013.37.5.375
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  • 48 Citations
AbstractAbstract PDFPubReader   
Background

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. Protein kinase C (PKC) inhibitor's has been thought to be a potential disease modifying drug's in DPN as it slows or reverse neuropathy's progression. To assesses the efficacy and safety of ruboxistaurin on the progression of symptoms, signs, or functional disability in DPN.

Methods

A systematic review of the literature databases like PubMed, ProQuest, EBSCO, EMBASE, and Cochrane Central was performed up to August 2012. We included randomized controlled trials (RCTs) comparing PKC inhibitor ruboxistaurin (RBX) with control and lasting at least 6 months. Our primary outcome measure was change in neurological examination, measured by neurological total symptom score (NTSS) and vibration detection threshold (VDT). Secondary outcome measures were total quality of life (QoL), skin microvascular blood flow and others.

Results

Six RCTs were included in review. Change in neurological function assessed by NTSS was reported in six studies, out of which significant difference between the RBX and placebo group seen in four studies favouring treatment group while remaining two studies reported no significant difference. VDT was assessed in only one study in which no significant difference seen between RBX and placebo group. Two studies reported significant improvement in QoL data. Safety data was reported in only two studies in which none of side effect was related to RBX.

Conclusion

RBX had effects on DPN in some studies, but the evidence is not enough for meta-analysis and firm conclusion.

Citations

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Review
The Role of Oxidative Stress in the Pathogenesis of Diabetic Vascular Complications
Shuji Sasaki, Toyoshi Inoguchi
Diabetes Metab J. 2012;36(4):255-261.   Published online August 20, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.4.255
  • 3,345 View
  • 60 Download
  • 58 Citations
AbstractAbstract PDFPubReader   

Oxidative stress has been paid increasing attention to as an important causative factor for diabetic vascular complications. Among possible various sources, accumulating evidence has indicated that NAD(P)H oxidase may be the most important source for reactive oxygen species production in diabetic vascular tissues. The mechanisms underlying activation and up-regulation of NAD(P)H oxidase has been supposed to be mediated by high glucose-induced protein kinase C (PKC) activation. In this review article, activation of local renin-angiotensin II system induced by chymase activation is also shown to amplify such a PKC-dependent activation of NAD(P)H oxidase. Additionally, human evidence showing the beneficial effect of antioxidants on diabetic vascular complications. Bilirubin has been recognized as a strong endogenous antioxidant. Here markedly lower prevalence of vascular complications is shown in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation. Lastly, statin, angiotensin II receptor blocker, chymase inhibitor, bilirubin and biliverdin, PKC β isoform inhibitor, and glucagon-like peptide-1 analog, are shown to serve as antioxidants and have some beneficial effect on diabetic vascular complications, via inhibiting PKC-NAD(P)H oxidase activation, supporting the notion that this mechanism may be an effective therapeutic target for preventing diabetic vascular complications.

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Original Articles
Migration of Vascular Smooth Muscle Cells by High Glucose is Reactive Oxygen Dependent.
Yong Seong An, Ji Hae Kwon, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son
Korean Diabetes J. 2008;32(3):185-195.   Published online June 1, 2008
DOI: https://doi.org/10.4093/kdj.2008.32.3.185
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AbstractAbstract PDF
BACKGROUND
Oxidative stress contributes to vascular diseases in patients with diabetes. As the mechanism of development and progression of diabetic vascular complications is poorly understood, this study was aimed to assess the potential role of hyperglycemia-induced oxidative stress and to determine whether the oxidative stress is a major factor in hyperglycemia-induced migration of vascular smooth muscle cells (VSMCs). METHODS: We treated primary cultured rat aortic smooth muscle cells for 72 hours with medium containing 5.5 mM D-glucose (normal glucose), 30 mM D-glucose (high glucose) or 5.5 mM D-glucose plus 24.5 mM mannitol (osmotic control). We measured the migration of VSMCs and superoxide production. Immunoblotting of PKC isozymes using phoshospecific antibodies was performed, and PKC activity was also measured. RESULTS: Migration of VSMCs incubated under high glucose condition were markedly increased compared to normal glucose condition. Treatment with diphenyleneiodonium (DPI, 10 micromol/L) and superoxide dismutase (SOD, 500 U/mL) significantly suppressed high glucose-induced migration of VSMCs. Superoxide production was significantly increased in high glucose condition and was markedly decreased after treatment with DPI and SOD. High glucose also markedly increased activity of PKC-delta isozyme. When VSMCs were treated with rottlerin or transfected with PKC-delta siRNA, nitro blue tetrazolium (NBT) staining and NAD(P)H oxidase activity were significantly attenuated in the high glucose-treated VSMCs. Furthermore, inhibition of PKC-delta markedly decreased VSMC migration by high glucose. CONCLUSION: These results suggest that high glucose-induced VSMC migration is dependent upon activation of PKC-delta, which may responsible for elevated intracellular ROS production in VSMCs, and this is mediated by NAD(P)H oxidase.
Cell Cycle Progression of Vascular Smooth Muscle cell Through Modulation of p38 MAPK and GSK-3beta Activities Under High Glucose Condition.
Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son
Korean Diabetes J. 2005;29(5):418-431.   Published online September 1, 2005
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AbstractAbstract PDF
BACKGOUND: Macroangiopathy, with atherosclerosis, is the leading cause of mortality and morbidity in diabetic patients. Vascular smooth muscle cells play a crucial role in atherosclerosis, as they proliferate, migrate and express genes that encode inducible growth factors. However, the mechanisms induced by hyperglycemia that accelerate the proliferative change of vascular smooth muscle cells in diabetes remain unclear. This study was aimed at clarifying the respective roles of hyperglycemia in the acceleration of vascular complications in diabetes, examine the effects of hyperglycemia on vascular smooth muscle cell proliferation and the possible underlying mechanisms, including cell cycle progression. METHODS: Primary cultured rat aortic RASMs were exposed to normal glucose(5 mmol/L D-glucose), high glucose(30 mmol/L D-glucose) or an osmotic control (5mmol/L D-glucose plus 24.5 mmol/L mannitol) for 72 hours. The effect of high glucose on cell proliferation was determined by assessing the cell count and BrdU incorporation. Proteins involved in the cell proliferation pathway (PDK1, Akt/PKB, p42/44 MAPK, p38 MAPK, GSK-3beta) and those in cell cycle progression (cdk4, cyclin D, cdk2, cyclin E and ppRb phosphorylation) were determined by Western blot analysis. cdk4 kinase and PKC activity assays were also performed. RESULTS: A high level of glucose increased both the cell count(P<0.01) and BrdU incorporation(P<0.01). The PDK1, Akt/PKB and p42/44 MAPK activities were not significantly increased. A high level of glucose significantly increased the activities of p38 MAPK (P<0.01) and GSK-3beta(P<0.05) and the expressions of cdk4, cyclin D and ppRb phosphorylation. The cdk4 (P<0.01) and PKC (P<0.05) activities were also significantly increased. The inhibition of protein kinase C with GF109203X markedly reduced the phosphorylations of p38 MAPK and GSK-3betaand the expressions of cdk4 and cyclin D. In addition, pretreatment with GF109203X decreased the cell number in response to a high glucose level. CONCLUSION: These findings suggest that a high level of glucose increases vascular smooth muscle cell proliferation, with the possible mechanism further increases the G1 to S phase cell cycle progression via the activation of PKC, p38 MAPK and GSK-3beta.
Effect and Mechanism of Vascular Endothelial Growth Factor on Endothelial Nitric Oxide Synthase Expression in Aortic Endothelial Cells.
Soon Hee Lee, Jung Guk Kim, Joong Yeol Park, Sung Woo Ha, Bo Wan Kim
Korean Diabetes J. 2002;26(5):396-404.   Published online October 1, 2002
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AbstractAbstract PDF
BACKGROUND
Vascular endothelial growth factor (VEGF), a soluble angiogenic factor produced by many tumor and normal cells, is a potent angiogenic and vascular permeability factor. VEGF plays a key role in both pathological and physiological angiogenesis. There are many recent findings regarding the role of VEGF in diabetic microvascular and macrovascular diseases. Many approaches with VEGF-related therapies begin to treat and prevent these complications and have been used for the treatment of microvascular complications such as diabetic retinopathy, whereas VEGF agonists have been used to treat macrovascular complications such as myocardial infarction and peripheral limb ischemia. Nitric oxide (NO) is known to mediate many physiological and pathological functions, including modulation of vascular tone, permeability, and capillary growth. Recent reports indicate that NO may play an intimate role in VEGF signaling. Therefore, we hypothesized that the expression of eNOS may be regulated by VEGF. The objectives of the present study were to determine whether VEGF up-regulates the expression of endothelial NO synthase (eNOS) in endothelial cells and to elucidate the mechanism that mediate this response. METHODS: Endothelial cells were isolated from bovine aortae. The expression of eNOS was assessed by Northern blotting analysis. To evaluate the mechanism of VEGF-induced eNOS expression, endothelial cells were conditioned with VEGF and pretreated with phorbol-12-myristate acetate (PMA), a protein kinase C (PKC) activator, or GF109203X (GFX), a PKC inhibitor. The changes of eNOS gene expression. RESULTS: VEGF significantly increased the expression of eNOS mRNA in bovine aortic endothelial cells (BAEC) in time and dose dependent manners. PMA increased the expression of eNOS mRNA, as well as the VEGF-induced expression of eNOS mRNA in endothelial cells, while inhibition of the PKC activity, with the GFX blocked the upregulation of the VEGF-induced eNOS mRNA. CONCLUSION: The results suggest that VEGF upregulates eNOS gene expression in aortic endothelial cells, by a PKC dependent pathway and, eNOS may be important in the development of VEGF-induced angiopathy.
Effect of Protein Kinase C Inhibitor on Glucose Transporter-1 (GLUT1) Expression in Cultured Rat Mesangial Cells.
Ie Byung Park, Dae Ryong Cha, Dong Rim Kim, Sin Gon Kim, Dong Hyun Shin, Kyung Mook Choi, Nan Hee Kim, Sei Hyun Baik, Dong Seop Choi
Korean Diabetes J. 2001;25(3):218-229.   Published online June 1, 2001
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AbstractAbstract PDF
BACKGROUND
Recent studies have suggested that increased glucose uptake via GLUT1 may be a major determinant of glucose utilization and extracellular matrix formation in mesangial cells. This study was to evaluate the effect of protein kinase C inhibitor on glucose transporter-1 (GLUT1) expression in cultured rat mesangial cells. METHODS: The GLUT1 expression was evaluated in mesangial cells exposed to various glucose concentrations of media (5.5 mM, 15 mM or 30 mM) and incubation times (6 hr, 24 hr or 72 hr) by semiquantitative RT-PCR and western blot analysis. The effect of protein kinase C (PKC) inhibitor, calphostin C and phorbol 12-myristate 13-acetate (PMA) on GLUT1 expression was also evaluated under the same conditions. RESULTS: The GLUT1 mRNA expressions were significantly increased in MG (15 mM) and HG (30 mM) than those in NG (5.5 mM) with incubation of 6 hr, 24 hr and 72 hr, respectively. In HG media, the GLUT1 mRNA expression with incubation of 24 hr and 72 hr were significantly increased than that with incubation of 6 hr, respectively. In HG media, the GLUT1 mRNA expressions were significantly reduced in calphostin C and PMA treated groups compared with those in untreated groups. In western blot analysis of HG media, GLUT1 proteins were identified in PMA- or calphostin C-untreated group and PMA 6 hr treated group, but not identified in PMA 24 hr treated group and in calphostin C-treated groups with incubation of 6 hr and 24 hr. CONCLUSION: PKC inhibitors decrease glucose-induced GLUT1 expression under high glucose concentration in mesangial cells. These results suggest that PKC pathway may regulate GLUT1 expression under high glucose concentration in cultured rat mesangial cells.
Effect of Protein Kinase C Inhibitors on Expression of TGF-betamRNA in Cultured Mesangial Cells Under High Glucose Concentration.
Yoon Sang Choi, Dong Seop Choi
Korean Diabetes J. 1999;23(5):635-646.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
Diabetic nephropathy is characterized by hypertrophy of both glomerular and tubular elements, thickening of the glomerular and tubular basement membranes, progressive accumulation of extracellular matrix components in mesangium, and tubulointerstitial fibrosis. Hyperglycemia increases the level of diacylglycerol (DAG) and activates protein kinase C (PKC) in mesangial cells and other vascular tissues. PKC activation regulates a number of vascular functions such as vascular permeability, contractility, cellular proliferation, basement membrane synthesis, signal transduction mechanisms for hormones and growth factors, In addition, glomerular mesangial cells play an important role in the development of diabetic nephropathy. Mesangial cells have many functions such as contractile properties, phagocytosis of macromolecules, synthesis of matrix proteins, and production of and response to growth factors (e.g., PDGF, TGF beta). Also, these growth factors play important roles for mesangial cell proliferation and in pathophysiology of diabetic nephropathy. Specifically, TGF beta is a key mediator in development of diabetic nephropathy. This study was performed to evaluate the relationship between PKC activation and TGF f3 production in mesangial cells under high glucose condition. METHODS: The expression of the TGF beta mRNA was evaluated in cultured human mesangial cells by semiquantitive RT-PCR, under varying degree of glucose concentrations (5 mM, 10 mM, 30 mM) with and without treatment of PKC inhibitors (calphostin C, Vitamin-E). RESULT: In control group (no treatment), ratio of TGF beta/beta-aetin mRNA in 5mM, 10mM, 30mM glucose were 1.694+/-0.223, 3.383+/-2.089, 5,474+/-1.74S, respectively. In calphostin C treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10mM, 30mM glucose were 1.457+/-0,322, 1.379+/-0.138, 1.205+/-0.050, respectively. In vitamin E treated group, ratio of TGF beta/beta-actin mRNA in 5mM, 10rnM, 30mM glucose were 1.198+/-0.081, 1.995+/-1.625, O.S04+/-0.570, respectively. In 10mM glucose concentration, ratios of TGF beta/beta-actin mRNA were reduced in calphostin C and vitamin E treated groups, compared with those in control group. But, there were no statistical significancies (p=0.191, 0.208). In high glucose concentration (30mM), ratios of TGF /3/f3-actin mRNA were significantly reduced in calphostin C and vitamin E treated groups compared with those in control group (p<0.05), respectively. CONCLUSIONS: These results indicate that high glucose concentration induce TGF beta expression in eultured mesangial cells through PKC activation. This suggests that selective PKC beta isoform inhibitors may be useful for treatment and prevention of diabetie nephropathy.
Effect of Hyperglycemia on Internalization of Insulin-receptor Complexes in Human Umbilical Vein Endothelial Cells.
Ki Ho Song, Yu Bae Ahn, Je Ho Han, Soon Jip Yoo, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 1999;23(2):131-141.   Published online January 1, 2001
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AbstractAbstract PDF
BACKGROUND
It is well known that hyperglycemia activates protein kinase C (PKC) in vascular endothelial cells. However, the effect of hyperglycemia on internalization and recycling of insulin receptors by insulin in endothelial cells has not been examined thus far. METHODS: Human umbilical vein endothelial cells (HUVECs) were isolated from healthy, pregnant women. Confluent HUVECs were incubated in a culture media containing either 5 (NG group) or 25 mM glucose (HG group) for 4 days. Then, we measured the insulin binding, internalization and recycling of the insulin receptor and release of internalized insulin into the media. RESULTS: There was no difference in binding of 0.17 nM 125I-insulin between the two groups. However, the amount of internalized 125I-insulin, determined by the aeid washing method, was significantly greater in the HG group compared to the NG group. The addition of 10 pM 1-(5-isoquino-linesulfonyl)-2-methyl-piperazine (H7), a PKC inhibitor, to the HG group prevented the increase of internalization in 125I-insulin. In addition, preincubation with unlabeled insulin resulted in a decrease of 125I-insulin binding to a greater extent in the HG group compared with the NG group, indicating that high glucose levels increased internalizntion of insulin receptors. The high glucose-induced increase in internalization of insulin receptors was prevented by an addition of H7. Recycling of insulin receptors to the cell surface was not affected by high glucose. Internalized 125I-insulin released into media with time. The released amount of I-insulin in the HC group tended to be greater compared to the NG group. CONCLUSION: These results suggest that hyperglycemia may increase internalization of the insulin-receptor complexes in vascular endothelial cells through PKC activation.

Diabetes Metab J : Diabetes & Metabolism Journal