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Publications and Talks
RXR agonist CNX-013-B2 has a potential to reduce Aß deposition, increases clearance, along with reduced neuronal death in both N2a cells and astrocytes
12th International Conference on Alzheimer's & Parkinson's Diseases, March 18-22, 2015, Nice, France
Somesh BP, Anil TM, Satish Kumar V, Anup O, Jagannath MR
OBJECTIVES: Alzheimer’s disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Aβ accumulation leads to the deposition into plaques and is believed to play a role in initiating the pathologic cascade leading to neuronal death. Cholesterol transport protein Apolipoprotein E along with ATP-binding cassette transporter A1 (ABCA1) plays an important role in the clearance of Aβ from the brain. It is known that RXR/LXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing transcription of key cholesterol shuffling vehicles, ABCA1 and ApoE. In this study, we report impact of a potent and selective RXR agonist CNX-013-B2 on Aβ deposition, clearance, neuroinflammation/stress and neuroprotection in both neuronal cells and astrocytes.
METHODS: N2a cells and mouse astrocytes were used to study the impact on the expression of markers of different mechanisms that regulate Aβ deposition, clearance, neuroinflammation/stress and neuroprotection after treating the cells with high cholesterol.
RESULTS: Treatment with CNX-013-B2, a selective small molecule rexinoid with an EC50 of 48 nM towards human RXRa resulted in a significant increase in cholesterol efflux along with 3-5 fold increase in both ABCA1 and ABCG1 gene expression. CNX-013-B2 increases mitochondrial biogenesis and activity along with increased expression of NMDR, PGC1a and FOXO1 which are known as neuroprotective markers. CNX-013-B2 reduces ROS levels, MCP1 and IL1b expression along with decrease in caspase3 levels. CONCLUSIONS: RXR activation with CNX-013-B2 can reduce Aβ deposition and neuroinflammation/stress, can increase clearance and can act as a neuroprotective agent.
Therapeutic action of CNX-013-B2: similarity and synergy with exercise training in C57BL6/j mice on high fat diet
Keystone Symposia - Diabetes and Metabolic Dysfunction (J6), January 27 - February 1, 2015, Santa Fe, New Mexico USA
MR.Jagannath, MO.Anup, MV.Venkataranganna, BP.Somesh, M.Yogananda, M.Onkaramurthy, GR.Gowtham, R.Anoopraj, HA.Patil, TM.Anil, MK.Verma, K.Harsha, MN.Lakshmi, PM.Pallavi, S.Yogeshwari, V.Satishkumar
Physiological adaptation induced by endurance exercise training has been proven to be protective against obesity and associated metabolic dysfunction as well as maintenance of oxidative muscle mass. Hence an orally active agent with ability to mimic or potentiate the genetic effects of exercise endurance is considered superlative in the space of medical therapy.
We have previously reported that CNX-013-B2 (B2), a novel rexinoid modulates activity of multiple nuclear receptors, provides excellent control of metabolic parameters and also enhances treadmill running capacity of untrained C57BL6/j mice on high fat diet (DIO). To assess if B2 possessed exercise mimetic properties, metabolic parameters (including body weight) were monitored in DIO mice that were either subjected to treadmill running (10 min/day for 5 days/week; n=10) or treated with B2 (10mg/kg qd; n=10) or both treadmill training and B2 (n=10).
After 4 weeks fasting glucose was significantly reduced only in the exercise plus B2 treatment group (138.75 mg/dl vs 169.33mg/dl DIO control; p<0.05). By 5th week body weight increased in the DIO control animals (41.15 g vs 27.61g lean control; p<001) while it decreased to 35.0g (p<0.01) in treadmill exercised group, 34.53g (p<0.01) in B2 treated group and to 32.01g (p<0.001) in the exercise and B2 treated group. Treadmill exercise alone could not improve glucose while treatment with either B2 alone or treadmill exercise plus B2 treatment significantly reduced glucose excursions as measured by oGTT performed during 4th week of study in DIO mice.
B2 treatment alone shows similar significant reduction in adiposity, ectopic fat content and body weight as compared to exercise training and an additive effect in reducing whole body weight when combined with exercise training. Targeted gene expression studies shows very significant synergistic effect in modulation of several fat oxidation genes along with oxidative stress and angiogenic growth factors in gastrocnemius muscle of B2 treated exercise trained mice.
A systems biology approach highlights the role of GSK3-beta in the regulation of PDX1 by IL1-beta in pancreatic beta cell
RECOMB/ISCB Conference on Regulatory and Systems Genomics, Seventh Annual Conference, November 10-14, 2014, San Diego, USA
Jisha Vijayan, Yogeshwari Sivakumaran, Rajagopal Rangarajan, Mahesh Verma, Anup Oommen, Krishnamurthy Sheshadri
A network model describing the response of proliferation (PDX1) to inflammation (IL1-Beta) in beta cell is described. The model is automatically extracted using an automated path-tracing algorithm from a large beta cell network based on integration of extensive literature. A mathematical model based on mass action kinetics is formulated for this network model. A steady-state simulation of the mathematical model shows that PDX1 decreases as IL1-beta is increased, saturating at high IL1-beta levels. Measurements on mouse pancreatic beta cell line (NIT-1) confirmed this behavior. Further simulations showed that under conditions of GSK3-beta inhibition, the response of PDX1 to IL1-beta reverses to increasing behavior, again saturating at high IL1-beta levels; further, the PDX1 levels were lower in this case. The saturation levels in both of these cases are comparable. Again this behavior was confirmed by measurements. This study highlights the role of GSK3-beta in the switching of PDX1 response to IL1-beta.
CNX-013-B2, a PPAR Pan-Activator Rexinoid, Provides Robust Control of Glucose, HbA1c, Triglyceride, and LDL Cholesterol in db/db Mice and Does Not Cause Hemodilution and Edema in Rodents
American Diabetes Association (ADA), 74th Scientific Sessions, June 13-17, 2014, San Francisco, USA
MR Jagannath, Singh Jaideep, R Madhusudhan, MN Lakshmi, TL Pooja, S Yogeshwari, C Suni, MK Verma, AN Yateesh, TM Anil, M Omkaramurthy, C Harish, Y Moolemath, BS Naveen Kumar, D Prashant, TK Chheda, O Patil, AM Oommen, MK Govind, MV Venkataranganna, BP Somesh
Treatment of 6 weeks old db/db mice orally with 2.5, 5.0 and 10 mg/kg CNX-013-B2 qd (9am) for 8 weeks resulted in a reduction of 20 - 28% in fasting plasma glucose, 11 - 30% in fed plasma glucose, 3 - 24% in Glucose AUC24hrs, 1.4 - 2.4% in HbA1c, 14 - 21% in serum triglyceride and 33 - 42% in LDL-C levels. Though decreases in fasting and fed serum insulin levels did not reach statistical significance HOMA-IR showed a significant 25 - 35% reduction indicating improvement in whole body insulin sensitivity. CNX-013-B2 did not either change food intake or increase body weight. There was no change in the relative or absolute weight of liver, kidney, heart, and the different adipose depots and in liver and muscle triglyceride content. CNX-013-B2 significantly increased Succinate Dehydrogenase activity of gastrocnemius muscle by ~40% over db/db control and also significantly reduced CDK5 mediated phosphorylation of PPARγ at Ser-273 in mesentric adipocytes. At 10 mg/kg dose of CNX-013-B2 genes whose mRNA expression increased included Sterol Response Element Binding Protein 1c (SREBP1c), Thyroid Hormone Receptor β (THRB), Aceyl-CoA oxidase 1 (ACOX) and MDR2 in liver, SREBP1c and Myocyte enhanced factor 2c (Mef2c) in muscle, PPARγ and UCP2 in inguinal adipose tissue. Interestingly mRNA expression of Uncoupling Protein 3 (UCP3) and Pyruvate Dehydrogenase 4 (PDK4) in muscle was reduced. At 10 and 30 mg/kg dose levels rosiglitazone caused edema and hemodilution, including a reduction in RBC number and hemoglobin, while CNX-013-B2 did not cause any change in the parameters compared to untreated control Wistar rats. Long term treatment of Wistar rats with 25, 50 and 100 mg/kg of CNX-013-B2, po, for 28 days did not cause any test compound-related adverse effect on clinical chemistry, gross pathology, physiological behavior, body weight, organ weights, micropathology and urinary parameters.
CNX-013-B2, A selective PPAR PAN Activator Rexinoid regulates glucose and lipid metabolism in various animal models of disease and has potential to function as an exercise mimetic and enhance exercise endurance in mice
Keystone Symposia - Challenges and Opportunities in Diabetes Research and Treatment (J1), January 12-17, 2014, Vancouver, British Columbia Canada
M Venkataranganna, Y Moolemath, C Harish, S Yogeshwari, M Onkaramurthy, L Pooja, K Verma, K Sadasivuni, K Govind, R Jagannath, N Lakshmi, M Anil, Pallavi, K Satish, B Somesh, J Singh, B Madhusudhan, S Chako, S Baggavalli, A Oommen
Retinoid X Receptor α (RXRα) regulates intracellular receptor signaling pathways involved in, among others, glucose and lipid metabolism and has potential to impact multiple risk factors associated with the metabolic syndrome.We report the pharmacological activity of CNX-013-B2, a potent and selective RXRα agonist with pan-PPAR activity, upon qd dosing of C57BL/6j DIO mice (2.5-10mg/kg for 10 weeks) and Syrian Golden Hamsters (10mg/kg for 12 weeks) on high cholesterol diet. In comparison with control DIO animals treatment with CNX-013-B2 resulted in a 10-12% reduction in fasting glucose (196.30±3.16 Vs 153±3.83 mg/dl), 20% in fasting serum triglycerides, 25% free fatty acids, 20% fasting glycerol, 25% total cholesterol and 43% LDLc.Similarly in comparison with control animals treated hamsters displayed a significant 20% and 45% decrease in serum total cholesterol and LDLc, respectively, and a reduction in fatty streaks in thoracic aorta. In DIO animals treatment with CNX-013-B2 resulted in significant reduction in body weight gain without any impact on food intake. Weight of different adipose depots was significantly reduced and an enhanced insulin sensitivity leading to a significant 40-50% reduction in both fasting and fed insulin levels and a 10% reduction in glucose AUC during OGTT was observed.Enhanced locomotor activity, (in Actimeter), and an increase in endurance capacity, as determined by treadmill running, were associated with 25% increase in succinate dehydrogenase activity in muscle treated with CNX-013-B2. CNX-013-B2, administered at 10 mg/kg b.wt for 7 days, did not reduce serum levels of T3, T4 and TSH in Wistar rats indicating minimal impact on the Hypothalamus Pituitary Thyroid axis. The reduction in serum TSH levels will likely be dependent on time of dosing of animals owing to the circadian nature of TSH secretion in rodents. CNX-013-B2 is a highly active and selective RXR agonist with good potential to provide glycemic and lipid control. Due to its potential to function as an exercise mimetic CNX-013-B2 can promote favorable metabolic adaptations, especially in the skeletal muscle, to boost endurance and cardiovascular health.
CNX-012-CPD, A direct AMPK activator provides strong glycemic and lipid control in both in vitro and in vivo animal models
11th Annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDC), November 7-9, 2013, LA, USA
Somesh BP, Venkataranganna MV, Jagannath MR, Anup O, Anil TM, Anilkumar D, Yoganand Moolemath, Lakshmi MN, Jaideep Singh, Sunil V, Satish Kumar V, Nitya Shree, Balamurali GV
AMPK Kinase regulates the coordination of anabolic and catabolic processes and can be an attractive therapeutic target to treat T2DM. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-CPD, orally bioavailable small molecule direct activator of AMPK in multiple disease animal models.
Male C57BL/6 mice fed with high fat diet (HFD) were assigned to either vehicle or CNX-012-125 (2.5mg/kg, p.o OD) for 6 weeks. Male golden Syrian hamsters fed with either high cholesterol diet (HCD) alone or with CNX-012-CPD (10mg/kg, p.o. OD) for 8 weeks.
CNX-012-CPD is a highly potent and orally bioavailable compound. It significantly inhibits adipose lipolysis by ~40% and gluconeogenesis by ~60% in rat hepatocytes. CNX-012-CPD reduced fasting blood glucose levels by ~15% (170±6 in HFD Vs 152±9 mg/dl in treatment) and body weight by ~13% (31.85±0.64 in HFD Vs 27±1.16 g in treatment). CNX-012-CPD significantly reduced fasting serum triglycerides by ~27% (189±9 in HFD Vs 134±18 mg/dl in treatment) and a 22% reduction in glucose excursion after the oral glucose challenge (OGTT). CNX-012-CPD showed a 27% reduction in serum cholesterol levels (176±13.28 in HCD Vs 139± 9.78 mg/dl in treatment), 25% reduction in LDL (54 ± 6.46 in HCD Vs 40 ± 4.2 mg/dl in treatment) and 48% reduction in TG (153± 20.68 in HCD Vs 79± 10.25 mg/dl in treatment).
CNX-012-CPD has a potential to provide glycemic and lipid control and also reduce body weight gain and can be good therapeutic agent for the treatment of type 2 Diabetes and dyslipidemia.
Developing a novel screening platform for liver fibrosis using integrative network biology approach
64th Annual Meeting of American Association for the Study of Liver Diseases (AASLD), November 1-5, 2013, Washington DC, USA
Satish KS, Nethra S, Yateesh AN, Pallavi PM, Jisha V, Verma MK, Rao RP, Anup MO, Jagannath MR
Liver injury mediated by various etiologies can cause liver fibrosis. Despite extensive research efforts to identify and understand causal mechanisms underlying the disease pathology, a reliable model system that represents an agglomeration of disease mechanisms is lacking. Using our network biology approach we identified key signaling pathways that drive liver fibrosis and established a liver slice model that captures the fibrotic phenotype induced by these signaling pathways.
Precision cut liver slices (PCLS) of 200?m thickness were obtained from C57B6/J mice aged about 8 weeks. PCLS were cultured in Williams E media containing 25mM glucose and 10% fetal calf serum. We used a cocktail comprising of inflammation mediators, growth factors and lipid derivatives (hereafter referred to as IGL cocktail) to induce fibrotic phenotype associated with inflammation and steatosis. After 24 hours of culture, expression levels of key markers of inflammation, stellate cell activation and fibrosis were measured using Q-PCR. ATP, ROS and triglyceride levels were measured in the liver slices using commercially available kits.
Liver slices when cultured with IGL cocktail remained viable during the treatment period as measured by ATP levels. IGL cocktail treatment resulted in significant increase in expression of key markers of inflammation [IL-6(1.6+/-0.092), TNF-a(2.7+/-0.113), CRP(2.57+/-0.13)], stellate cell activation [aB-Crystallin(1.9+/-0.06), a-SMA(1.9+/-0.14)] and fibrosis [fibulin2(10+/-0.24), Col1a1(3+/-0.26), Col3a1(1.74+/-0.26)] and also showed increase in triglyceride (38%) and ROS levels (50%) and total collagen level (30%) compared to control conditions.
The existing in vitro platforms for studying anti-fibrotic targets relies on non-physiological inducers like CCL4 and this approach might not capture multiple aspects of disease pathology. In our study we have used a unique cocktail activating several signaling pathways, to establish a platform capturing multiple aspects of NASH, such as steatosis, steatohepatitis and fibrosis. This provides a reliable platform for evaluating anti-fibrotic targets and for screening NCEs.
A Novel HSD11B1 inhibitor provides glycemic and lipid control along with significant reduction in weight in C57Bl6/j mice on HFD
4th International Congress on Abdominal Obesity (ICAO 2013), September 12-14, 2013, Seoul, South Korea
Somesh BP, Jagannath MR, Venkataranganna MV, Anil TM, Anup O, Yoganand Moolemath, Harsha K, Jaideep Singh, Sunil V, Nitya Shree, Balamurali GV. Gopal AS
Increased 11β-hydroxysteroid dehydrogenase type 1 (HSD11β1) activity has been associated with metabolic syndrome including hyperglycemia. In this regard, selective inhibitors of HSD11β1have considerable potential for treating type 2 diabetes mellitus and other co-morbidities associated with the metabolic syndrome. In the present study, we investigated in vitro and in diet-induced obese (DIO) mice the anti-hyperglycemic effects of CNX-10-49: a novel and selective HSD11β1 inhibitor.
ChoK1 cells stably expressing human HSD11β1gene and differentiated C2C12 were used for determination of IC50 for both human and mouse isoform. 3T3-L1 preadipocytes were used to evaluate adipocytes differentiation and lipolysis. Fully differentiated C2C12 cells and primary mouse hepatocytes were used to study the impact on glucose metabolism and hepatic glucose output respectively. Male C57BL/6 mice fed with chow diet (10% fat diet) or high fat diet (HFD) (60% fat diet) for 11 weeks. HFD fed animals were assigned to either vehicle or CNX-01-49 (30 mg/kg, po BID) treatment groups (n=8) for 9 weeks.
CNX-10-49 has an IC50 of 5nM and 66nM towards human and mouse HSD11β1 isoforms respectively. CNX-10-49 suppressed cortisone-induced triglyceride accumulation in 3T3-L1 cells. CNX-10-49 also significantly inhibited cortisone and Isoproterenol mediated lipolysis by ~30% in 3T3L1 adipocytes. In C2C12 cells, CNX-10-49 reduced mRNA expression of PDK4 and TRIM63. In primary mouse hepatocytes CNX-10-49 inhibited gluconeogenesis significantly by 15%. Treatment of C57BL/6 DIO mice on HFD with CNX-10-49 significantly reduced fasting glucose by ~12% (196±4.31 in HFD Vs 173±5.35 mg/dl in treatment), fasting insulin by 3 folds and fasting plasma glycerol level by 15%. Compared to HFD mice control animals plasma triglycerides were significantly reduced in mice trated with CNX-10-49 (217±9.34 in HFD Vs 175±9.06 mg/dl CNX-10-49 treated). Even though there was no change in the feed intake body weight was reduced significantly by ~15% (39.3±0.64 in HFD Vs 32.83±1.24 g in treatment). Glucose excursion, during OGTT, was significantly reduced by ~13%; (glucose AUC 57376±1382 in HFD Vs 49680±734 in treatment).
Taken together, our data suggests that CNX-10-49, a selective HSD11β1 inhibitor, may provide significant glycemic and lipid control in type 2 diabetic patients with additional impact on body weight.
Safe and Selective small molecule RXRa agonist modulates glucose and lipid metabolism in ob/ob mice
American Diabetes Association (ADA), 73rd Scientific Sessions, June 21-25, 2013, Chicago, Illinois USA
Jagannath MR, Somesh BP, Venkataranganna MV, Anup O, Manojkumar S, Anilkumar D, Yoganand Moolemath, Anil TM, Madhusudan R, Jaideep Singh, Sunil V, Lakshmi MN, Pooja TL, Suni K Chacko, Yogeshwari S. Nitya Shree
As a ubiquitous heterodimerization partner of many nuclear receptors Retinoid X Receptor α (RXRα) regulates intracellular receptor signaling pathways involved in, among others, glucose and lipid metabolism and has potential to impact multiple risk factors associated with the metabolic syndrome. In the present study we investigated the effect of a potent and selective RXRα agonist CNX-013-B2 (30 mg/kg, p.o., BID for 4 weeks) in obese-hyperglycemic ob/ob mice. Treatment with CNX-013-B2 did not increase either food intake or body weight. In comparison with control ob/ob animals treatment with CNX-013-B2 resulted in a 22% reduction in fed glucose (196.30±3.16 Vs 153±3.83 mg/dl), 16% in fasting serum triglycerides (141.85±8 Vs 119±3 mg/dl), 20% free fatty acids, 14% fasting glycerol, 14% cholesterol and 26% LDL (low-density lipoprotein). In an oral glucose tolerance test a 19% decrease in glucose AUC was observed in the agonist treated animals indicating improvement in insulin sensitivity. After 4 weeks there was no significant change in weight of different depots of fat, kidney and pancreas. A non-significant increase in liver weight was observed in treated animals. In muscle expression of PDK4, SREBP1c, UCP3 and ABCA1 was significantly increased suggesting enhanced glucose and fat metabolism. In liver increased expression of SREBP1c, FASN and SCD1 suggested enhanced de novo lipogenesis. However the increase in liver triglyceride accumulation was non-significant (7%). Expression levels of Cyp7A1, bile acid transporters like MDR3, MRP4 and NTCP and cholesterol transport genes like ABCG5 suggest a robust modulation of cholesterol metabolism in treated animals. Gene expression profile in inguinal fat (PPARγ, UCP2, SREBP1c) indicates increased insulin sensitivity. Treatment of C57BL6/j DIO mice on HFD with 100mg/kg for 5 weeks with CNX_013_B2 did not reduce serum levels of T3, T4 and TSH which indicates minimal impact on the HPT axis. CNX-013-B2 is a highly active and selective RXR agonist with good potential to provide glycemic and lipid control.
A direct activator of AMPK provides strong glycemic and lipid control with potential to reduce body weight in type 2 diabetes patients
2nd International Congress on Prehypertension and Cardiometabolic Syndrome, January 31-February 3, 2013, Barcelona, Spain
Somesh BP, Venkataranganna MV, Jagannath MR, Anup O, Anilkumar D, Anil TM, Yoganand Moolemath, Lakshmi MN, Jaideep Singh, Sunil V, Nagesh Gowda,Vasudha Kadam, Satish Kumar V, Geetha V, Deepashri KM, Balamurali GV
Type 2 Diabetes (T2DM) is characterized by the abnormal glucose and lipid metabolism due in part to resistance to the actions of insulin in different tissues. AMPK, a serine/threonine kinase, a cellular energy sensor that regulates the coordination of anabolic and catabolic processes and can be an attractive therapeutic target to treat T2DM. We report the anti-hyperglycemic effects of CNX-12-59 (a direct AMPK activator) in in vitro cell systems and diet-induced obese (DIO) mice. CNX-012-59 has an EC50 of 80nM in the SAMS peptide phosphorylation assay. AMPK activation by CNX-012-59 is both dose and time dependent in liver and adipose. It significantly inhibits Isoproterenol mediated lipolysis in mature 3T3L1 adipocytes by ~40%. In the study in B6 DIO mice on high fat diet, CNX-12-59 (25mg/kg, BID, po for 8 weeks) reduced fasting blood glucose levels by ~15% (181.57±6.16 in HFD Vs 164±3.83 mg/dl in treatment) and body weight by ~7% (36.85±1.69 in HFD Vs 33±1.24 g in treatment). CNX-012-59 significantly reduced both liver (5.65±0.25 in HFD Vs 4.03±0.16 mg/dl in treatment) and plasma (207±10 in HFD Vs 152±13 mg/dl in treatment) triglycerides by ~30%. Moderate reduction in adipocytes size along with significant reduction in plasma Leptin levels (37.17±7.87 in HFD Vs 12.92±3.6 ng/ml in treatment) were observed along with reduced macrophage infiltration in adipocytes.These findings indicate that direct activators of AMPK have potential to provide glycemic and lipid control and also reduce body weight and can be good therapeutic agents for the treatment of type 2 Diabetes.
Novel 11beta-hydroxysteroid dehydrogenase type 1 inhibitor provides glycemic and lipid control along with significant reduction in weight gain in C57Bl6/j mice on HFD
Keystone Symposia - Diabetes - New Insights into Mechanism of Disease and its Treatment (J6), January 27-February 1, 2013, Colorado, USA
Jagannath MR, Somesh BP, Venkataranganna MV, Anup O, Anilkumar D, Anil TM, Yoganand Moolemath, Manojkumar S, Harsha K, Jaideep Singh, Sunil V, Nagesh Gowda, Nitya Shree, Balamurali GV, Deepashri KM, Vasudha Kadam, Ashok Kumar Reddy, Lakshmi MN, Pereira MM
Increased 11β-hydroxysteroid dehydrogenase type 1 (HSD11β1) activity has been associated with symptoms of the metabolic syndrome including hyperglycemia. In this regard, selective inhibitors of HSD11B1 have considerable potential for treating type 2 diabetes mellitus and other co-morbidities associated with the metabolic syndrome. In the present study, we investigated in vitro and in diet-induced obese (DIO) mice the anti-hyperglycemic effects of CNX-10-49 a novel and selective 11β-HSD1 inhibitor.CNX-10-49 is a highly potent inhibitor of HSD11β1 with an IC50 of 5nM and 66nM towards human and mouse isoforms respectively. CNX-10-49 suppressed cortisone-induced triglyceride accumulation in 3T3-L1 cells. CNX-10-49 also significantly inhibited cortisone and Isoproterenol mediated lipolysis by ~30% in mature 3T3L1 adipocytes. In fully differentiated mouse myotubes (C2C12 cells) CNX-10-49 reduced mRNA expression of PDK4 (Pyruvate Dehydogenase Kinase 4) and TRIM63 (tripartite motif containing 63). In primary mouse hepatocytes CNX-10-49 also inhibited hepatic glucose output significantly by 15%. Treatment of B6 DIO mice on high fat diet with CNX-10-49 (30mg/kg, BID, po for 9 weeks) significantly reduced fasting glucose by ~12% (196±4.31 in HFD Vs 173±5.35 mg/dl in treatment), fasting insulin by 3 fold and fasting plasma glycerol level by 15%. Compared to high fat fed mice control animals plasma triglycerides were significantly reduced in mice trated with CNX-10-49 (217±9.34 in HFD Vs 175±9.06 mg/dl CNX-10-49 treated). Even though there was no change in the feed intake body weight was reduced significantly by ~15% (39.3±0.64 in HFD Vs 32.83±1.24 g in treatment). Glucose excursion, during OGTT, was significantly reduced by ~13%; (glucose AUC 57376±1382 in HFD Vs 49680±734 in treatment).
Taken together, our data suggests that CNX-10-49, a selective HSD11β1 inhibitor, may provide significant glycemic and lipid control in type 2 diabetic patients with additional impact on body weight.
CNX-011-67, A Novel Orally Available GPR40 Agonist Enhances Glucose Dependent Insulin Secretion, Significantly Reduces Fed and Fasting Glucose and HbA1c Levels and Improves Pancreatic Insulin Content in Female ZDF Rats on a High Fat Diet
American Diabetes Association (ADA), 72nd Scientific Sessions, June 8-12, 2012, Philadelphia, USA
Jagannath . M R, Venkataranganna M V, Somesh B P, Anikkumar Dandu, Yoganand Moolemath, Anup Mammen Oommen, Verma M K, Aparna K, Govind M K, Nagesh Gowda, Sanghamitra B, Jaideep Singh, Raveendra Ghodke, Sunil V, Shilpa P C, Niketa P, Vijayaraghav DN, Vasadha Kadam, Dhananjaya D
We previously reported that CNX-011-67 delayed onset of diabetes in male ZDF rats. We now extend our observations to demonstrate that chronic treatment of diabetic female ZDF rats (n = 9) on high fat diet for 8 weeks with CNX-011-67 leads to a 18% reduction in fasting (230±37 (treated) Vs 272±39 (Zdf) mg/dl, n=9) and 20% reduction in random blood glucose levels (285±34 (treated) Vs 361±52 (Zdf) mg/dl, n=9). There was a significant reduction in post-OGTT glucose excursion with a prolonged control of (24h) post meal glucose levels. Treatment with CNX-011-67 enhanced phasic insulin secretion, improved insulinogenic index (0.5±0.1 (treated) Vs (0.3±0.1 (ZDF) and improved islet insulin content (as demonstrated by IFC staining) suggesting enhanced glucose responsiveness of beta cells. Treatment for 8 wks led to 1.1% reduction in HbA1c (p<0.05) and a concomitant 32% reduction in TBARS and 15% in HNE indicating better control of glucose excursion. Enhanced AKT phosphorylation (~20%, n=6) suggested improved peripheral insulin action in adipose, liver and muscle in rats treated with CNX-011-67. Immunohistochemistry studies revealed enhanced insulin content in islets from CNX-011-67 treated rats. In parallel studies, treatment of cultured Wistar rat islets with CNX-011-67 exposed to severe glucolipotoxic conditions (16.7mM glucose and 500µM Palmitate) showed increased IP3 generation (~25%), cytoplasmic and mitochondrial [Ca2+] in NIT-1 cells (~20%). Thapsigargin-triggered endoplasmic reticulum stress-mediated inhibition of glucose stimulated insulin secretion in rat islets was significantly overcome by chronic treatment with CNX-011-67. In summary, these data suggest that long- term oral therapy with CNX-011-67 could be of clinical value to improve islet function by multiple mechanisms to maintain normoglycemia in T2D patients.
CNX-011-67, A Novel Orally Available GPR40 Agonist, Enhances Glucose Stimulated Insulin Secretion (GSIS) and Significantly Reduces Fasting and Non-Fasting Hyperglycemia- Studies In Vitro And In a Preclinical Model of T2DM
American Diabetes Association (ADA), 71st Scientific Sessions, June 24-28, 2011, San Diego, California
MR Jagannath, BP Somesh, MR Venkataranganna, O Anup, D Anilkumar, MK Verma, B Sanghamitra, C Bhawna, S Manoj Kumar, R Sowmya, S Jayalakshmi, V Sunil
While the role of GPR-40 (highly expressed in pancreatic beta cells) has been studied extensively in the amelioration of beta cell dysfunction, its potential as a therapeutic target has not been fully explored. We report the development and application of a highly selective potent and safe GPR40 agonist, CNX-011-67, which exhibits unique properties to improve beta cell function with potential for further development as an oral antidiabetic agent for treating type 2 diabetes mellitus (T2D). In cultured rat islets subjected to severe glucolipotoxic conditions (11mM glucose + 0.5mM palmitate for 72 hrs) chronic treatment with CNX-011-67 (1µM) as a GPR40 agonist (n=3) restored normal expression levels of GCK, PDX1 and PC mRNA, improved intracellular ATP content leading to enhanced glucose stimulated insulin secretion (GSIS) and intracellular insulin content. Treatment with CNX-011-67 also reduced expression of IL-1β, TXNIP and CHOP and significantly reduced beta cell apoptosis (decrease of 25+/-3%, n=3). Acute treatment of human T2DM islets with CNX-011-67 also enhanced GSIS by >30%. Chronic treatment of male prediabetic ZDF rats (n=8) with CNX-011-67 for 7 wks significantly enhanced insulin secretion in response to oral glucose load and delayed onset of fasting glycemia (194.7±26.5 (untreated) v s 107.8±3.8 (treated) mg/dl) by 3 weeks, reduced non-fasting glucose excursions (312.7±35.19 (untreated) vs 260.2±36.2 (treated) mg/dl), reduced fasting free fatty acid [(1.25±0.02 (untreated) Vs 0.82±0.06 (treated) mmol/l) and triglyceride levels (236.09±11.8 (untreated) vs 139.49±11.89 (treated) mg/dl). Treatment with CNX-011-67 reduced HbA1c [5.5± 0.3 (untreated) vs 5.18± 0.11 (treated)], significantly reduced plasma fructosamine levels [236.7 ± 19.1 (untreated) vs 111.25 ± 25.98 (treated)] and HOMA-IR [64.26 ± 6.2 (untreated) vs 41.82± 2.59 (treated)]. These data suggest that long-term oral therapy with CNX-011-67 could be of clinical value to improve islet function by multiple mechanisms and provide good glycemic control.
Association of Visceral Fat with Red Blood Cell Count and Bone Mineral Density in a Diabetic South Indian population
3rd International Conference on Advanced Technologies and Treatments for Diabetes (ATTD), February 10-13, 2010, Basel, Switzerland
S.Sidgiddi, T.S.Sridhar, M.R.Jagannath, D.Ganapathy
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