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| ABSTRACTS |
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| Year : 2015 | Volume
: 47
| Issue : 7 | Page : 8-10 |
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Manjeet Singh Prize
| Date of Web Publication | 11-Dec-2015 |
Correspondence Address:
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
. Manjeet Singh Prize. Indian J Pharmacol 2015;47, Suppl S1:8-10 |
MANJEET SINGH PRIZE-1
Effect of SLC47a1 and SLC47a2 Gene Polymorphisms on Glycemic Response to Metformin in Type 2 Diabetes Mellitus Patients of South India
Gerard Marshall Raj 1 , Mukta Wyawahare 2 , Jayanthi Mathaiyan 1
1 Department of Pharmacology, JIPMER, Puducherry, India, 2 Department of General Medicine JIPMER, Puducherry, India
Objectives: To evaluate the effect of single nucleotide polymorphisms (SNPs) in SLC47A1 (rs2289669) and SLC47A2 (rs12943590) genes on the relative change in HbA1c in type 2 diabetes mellitus patients of South India taking metformin. To determine the genotype frequencies of these SNPs in the healthy population of South India. Materials and Methods: Based on the eligibility criteria, 108 type 2 diabetes mellitus patients on metformin monotherapy were recruited in the study. Demographic and baseline characteristics of all the participants were documented. Venous blood was collected for genotyping (five mL) and HbA1c estimation (two mL). Subjects were followed-up every month for the subsequent three months. DNA was extracted by 'phenol-chloroform extraction method' from the peripheral blood leucocytes. Genotyping for SNP rs2289669 in SLC47A1 gene and SNP rs12943590 in SLC47A2 gene was performed with Applied Biosystems 7300 Real-Time PCR System (ABI, Foster City, CA, USA) using validated TaqMan ® SNP genotyping assay method. HbA1c levels were measured using National Glycohemoglobin Standardization Program certified Bio-Rad D-10™ Hemoglobin Analyzer (Bio-Rad, Hercules, CA, USA). DNA samples of healthy volunteers were obtained from the pharmacogenomics laboratory and genotyped. Results: Patients with "GG" genotype (5.5% decrease in HbA1c from baseline) of SLC47A2 gene (SNP rs12943590) had a better glycemic response than patients with "AG/AA" genotypes (0.1% increase) (p = 0.027). The mean change in FBG was also in line with the relative change in HbA1c across the genotype groups. The poor response of patients with homozygous mutant genotypes ("AA") and heterozygous genotypes ("AG") can be attributed to the presence of the minor variant allele "A". The presence of "A" allele would have resulted in a 'gain-of-function' of the SLC47A2 gene coding for the MATE2 transporter. Hence, this could result in an enhanced renal excretion of metformin causing a lower metformin concentration in the organ system and an inferior glycemic response. On the other hand, the SNP rs2289669 in SLC47A1 gene was not found to influence the glycemic response to metformin (p = 0.079) significantly. However, a reduced regression model showed the association of SLC47A1 genotype, SLC47A2 genotype and BMI on the relative change in HbA1c (Adjusted R 2 = 0.061; p = 0.033). In the healthy volunteers, the "A" allele and "G" allele of SNP rs2289669 had a frequency of 53.4% and 46.6%, respectively. Similarly, in SNP rs12943590, the "A" allele and "G" allele had a frequency of 47.5% and 52.5%, respectively. Conclusion: The clinical response to metformin was significantly associated with SNP rs12943590 in SLC47A2 gene coding for MATE2 transporter. The SNP rs2289669 in SLC47A1 gene coding for MATE1 transporter was not found to be significantly associated with the glycemic response to metformin. However, multiple linear regression analysis revealed that both SLC47A1 and SLC47A2 genotypes along with BMI could contribute for 6.1% of the variability in glycemic response to metformin. The allele and genotype distributions of SLC47A1 and SLC47A2 gene polymorphisms were established in South Indian population and were found to be different from the frequencies of other ethnicities.
MANJEET SINGH PRIZE-2
Modulation of Epigenetic Pathways by Targeting Histone Deacetylases Improve Memory Consolidation in Insulin Resistance-induced Cognitive Deficit in Mice
Rajeev Taliyan, Sorabh Sharma
Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, India
Objectives: Epigenetic modifications of DNA represent a key mechanism for regulation of gene expression during brain development and in memory formation. Recent studies indicated that insulin resistance is a strong risk factor for Alzheimer's disease (AD). Therefore, this study has been designed to evaluate the effect of sodium butyrate, a HDAC inhibitor in insulin resistance induced cognitive impairment in mice. Materials and Methods: Swiss albino mice were subjected to high fat diet (HFD) for 8 weeks to induce insulin resistance like condition. Following HFD feeding, sodium butyrate (NaB) was administered (150 mg/kg and 300 mg/kg i.p) once daily for one week. Behaviourally, morris water maze task was used to assess cognitive impairment in mice. Biochemically, levels of oxidative stress markers, antioxidant enzymes were measured in brain homogenates. Further, levels of global histone H3 acetylation and brain derived neurotrophic factor (BDNF) were measured to explore the molecular mechanism involved in HFD-induced neurodegenerative process. Results: After 8 weeks of HFD feeding the mice exhibit characteristic features of insulin resistance. Moreover, HFD fed mice showed memory dysfunction as assessed by morris water maze. Elevated oxidative stress markers such as malondialdehyde and nitrite levels were observed along with significant reduction of histone H3 acetylation and BDNF levels. However, the mice treated with sodium butyrate showed dose dependent improvement in insulin resistance and associated cognitive decline. Moreover, sodium butyrate treatment was able to ameliorate the levels of histone H3 acetylation and BDNF in a dose dependent manner. Conclusion: Based upon these findings it could be suggested that HDAC inhibition could prove to be beneficial in insulin resistance induced cognitive deficits.
MANJEET SINGH PRIZE-3
Role of GSK-3β/Nf-κb in Regulation of Creb and Pick1 in Primary Cortical Neurons Under Hyperglycemic/Insulin Resistant Conditions
Ashok Datusalia K, Jitendra Narain Singh, Shyam Sharma S
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, Punjab, India
Objectives: High concentration of extra-cellular glucose, as under hyperglycaemic conditions or pathological condition in diabetes, may persist for extended periods of time in neurons which trigger cellular damage, but the exact molecular mechanism remains unclear. The present study was aimed to investigate the role of GSK-3β and NF -κb in hyperglycaemias/insulin resistance-induced deregulation of CREB and PICK1. Materials and Methods: The experimental study protocol was duly approved by the Institutional Animal Ethics Committee (IAEC/13/65), NIPER. Primary cortical neurons were obtained from postnatal (P0) pups and cultured for 10 days. After ten days the cells were exposed to the high glucose (50 mM) for 12 and 24 hr in presence and absence of insulin. Neuronal viability was measured using Calcein AM assay after ten days culture of cortical neurons in comparison to control. Cells were lysed using RIPA (radio immuno precipitation assay) buffer at 4°C and protein expression of pGSK-3β, pCREB, PICK1 and GluR2 were measured using SDS-PAGE followed by western blotting after 24 hr. Results: High glucose exposure for 24 hrs showed significant increase in NF-κB activation in primary-cultured cortical neurons without altering the pGSK-3β, pCREB, PICK1 and GluR2 expression. However, 24 hr high insulin exposure produced significant alteration of pGSK-3β, NF-κB, PICK1 expression and glutamate-induced CREB activation. Treatment with GSK-3β inhibitor (SB 216763) and NF-κb inhibitor (BAY 11-7082) attenuated high insulin-induced alterations of protein in cortical neurons. Conclusion: The present data provide evidence for the significant role of GSK-3β and NF-κb in insulin resistance-induced deregulation of PICK1 and CREB. Pharmacological interventions targeting GSK-3β and NF-κB can be further explored in diabetes and diabetes associated cognitive impairment.
MANJEET SINGH PRIZE-4
AMPK Activation Abates Hyperglycaemic Neuronal Injury in Experimental Models of Diabetic Neuropathy Via Induction of Mitochondrial Biogenesis, Autophagy and Inhibition of Neuroinflammation
Ashutosh Kumar, Veera Ganesh Yerra
Department of Pharmacology and Toxicology, NIPER, Balanagar, Hyderabad, Telangana, India
Objectives: Impaired AMPK signalling under hyperglycaemic conditions is previously reported to cause compromised mitochondrial (mt) functioning in diabetic sensory neurons. AMPK activation is known to enhance mt biogenesis and autophagy in several chronic diseases. Materials and Methods: The present study evaluated the role of pharmacological efficacy of small molecule activator of adenosine monophosphate kinase (AMPK) (A769662) in terms of regulation of mt biogenesis and autophagy in Streptozotocin (STZ)-induced diabetic neuropathy (DN) as well as hyperglycaemia (25 mM) insulted neuro2a cells. Results: Motor and sensory nerve conduction velocities (MNCV & SNCV) and Sciatic nerve blood flow (NBF) were found to be significantly impaired in the STZ induced diabetic rats. 8 week duration of diabetes also resulted in development of thermal and mechanical hyperalgesia which in turn leads to intolerance towards painful stimuli. STZ-induced rats also showed reduced peroxisome proliferator activated gamma coactivator (PGC-1α) directed mt biogenesis and aggravated neuroinflammation as evident by immunohistochemical and western blotting analysis. Treatment of STZ-induced rats with A769662 at two doses (15 & 30 mg/kg, i.p.) during the last two weeks of 8 weeks old diabetic rats significantly enhanced MNCV, SNCV and NBF and improved the pain tolerance. A769662 treatment also increased Thr 172 phosphorylation of AMPK and up regulated the expression of downstream mitochondrial biogenetic axis i.e. PGC-1α-nuclear respiratory factor 1 (NRF1) - mt transcription factor A (Tfam). High glucose induced mitochondrial dysfunction in neuro2a cells leads to increased superoxide production, depolarization of mitochondrial membrane. High glucose conditions even cause repression of neurite outgrowth in neuroblastoma cells. AMPK activation by A769662 in the neuro2a cells suppressed ROS generation, normalized the mitochondrial membrane potential and increased neurite outgrowth. Further, AMPK activation also abolished the pathological effect of NF-κB mediated signal transduction effects in both the models of experimental DN. Conclusion: Our results suggest that compromised AMPK signalling directs the defective mitochondrial biogenesis and turnover in the hyperglycaemia-induced neuronal dysfunction. The data also supports the AMPK activation is associated with inhibition of neuroinflammation in the experimental models of DN.
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