Ignite Creation Date:
2024-05-06 @ 8:39 AM
Last Modification Date:
2024-10-26 @ 12:03 PM
Study NCT ID:
NCT02783196
Status:
UNKNOWN
Last Update Posted:
2016-05-26
First Post:
2016-05-20
Brief Title:
Effect of Liraglutide on Clock Genes
Sponsor:
Tel Aviv University
Organization:
Tel Aviv University
Study Overview
Official Title:
Advantages of Liraglutide Mediated Through Its Effect on Clock Gene mRNA Expression
Status:
UNKNOWN
Status Verified Date:
2016-05
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
LIR-CG
Brief Summary:
This study is undertaken to search whether glucagon-like peptide-1 GLP-1 analogue Liraglutide by enhancing clock gene and AMPK-SIRT-1 mRNA expression may reverse the metabolic abnormalities of type 2 diabetes improving overall glycemic excursion inflammatory cytokines and β-cell function in type 2 diabetes individuals
The investigators aim is to compare the effect of 40 days treatment with Liraglutide LIR vs 40 days with placebo PLA in T2D participants on the following end points
Primary end-points
Change in the oscillation of CG ie CLOCK BMAL1 Per1 Per2 Cry1 Cry2 Rev-erb-alpha Ror-alpha AMPK SIRT1 and inflammatory cytokines mRNA expression in white blood cells WBCs
Secondary end-points
Overall daily glycemic variation assessed with continuous glucose monitoring system CBMS
Serum levels of inflammatory cytokines TNF-α IL-1β IL-6
β-Cell function derived from glucose and insulin response to OGTT
The investigators aim is to compare the effect of 40 days treatment with Liraglutide LIR vs 40 days with placebo PLA in T2D participants on the following end points
Primary end-points
Change in the oscillation of CG ie CLOCK BMAL1 Per1 Per2 Cry1 Cry2 Rev-erb-alpha Ror-alpha AMPK SIRT1 and inflammatory cytokines mRNA expression in white blood cells WBCs
Secondary end-points
Overall daily glycemic variation assessed with continuous glucose monitoring system CBMS
Serum levels of inflammatory cytokines TNF-α IL-1β IL-6
β-Cell function derived from glucose and insulin response to OGTT
Detailed Description:
Background Cumulative evidence strongly implicates that the disruption of clock genes CGs plays a causative role in insulin resistance hyperglycemia and β-cell dysfunction in type 2 diabetes T2D CGs are synchronized by meal timing Indeed in animals and patients with T2D restricting feeding to specific hours such as large meals assigned to breakfast with reduced dinner can reset and restore CG expression resulting in improved glycemic control insulin sensitivity and reduction of HbA1c compared to isocaloric diet with a different meal timing small breakfast and overeating at dinner Since glucagon-like peptide-1 GLP-1 is secreted within a few minutes in response to food ingestion and it influences multiple humoral and neural signaling pathways that may further influence CG expression in many cells it has been suggested that GLP-1 may be a resetting signal for the CGs synchronizing the food entrainment on CGs expression thereby influencing the glucose metabolism In fact several studies in animal models documented that GLP-1 analogs either exenatide or liraglutide via activation of CG expression and AMPK-SIRT-1 pathway improved insulin sensitivity muscular glucose uptake reduced hepatic and cardiac steatosis inflammatory cytokines and oxidative stress and enhanced β-cell insulin secretion and proliferation independently of the GLP-1 analog glucose-lowering effects
To the best of the investigators knowledge no systemic study in humans to date has investigated the changes in the expression of CGs and AMPK-SIRT-1 pathway concomitantly with the effect on glycemic control insulin sensitivity beta cell function and inflammatory cytokines in T2D individuals during treatment with Liraglutide or other GLP-1 analogs
Hypothesis The investigators hypothesize that Liraglutide by enhancing CG and AMPK-SIRT-1 expression may reverse the metabolic abnormalities of T2D improving insulin sensitivity overall glycemic excursion inflammatory cytokines and β-cell function in T2D individuals
Objectives
The investigators aim is to compare the effect of 40 days treatment with Liraglutide LIR vs 40 days with placebo PLA in T2D participants on the following end points
Primary end-points
Change in the oscillation of CG ie CLOCK BMAL1 Per1 Per2 Cry1 Cry2 Rev-erb-alpha Ror-alpha AMPK SIRT1 and inflammatory cytokines mRNA expression in white blood cells WBCs
Secondary end-points
Overall daily glycemic variation assessed with continuous glucose monitoring system CBMS
Serum levels of inflammatory cytokines TNF-α IL-1β IL-6
β-Cell function derived from glucose and insulin response to OGTT
Methods In a randomized double blind crossover-within-subject clinical trial the investigators will study 18 weight- matched obese and overweight participants with known T2D diagnosed 20 years and HbA1c 70 to 10 BMI 26-32 kgm2 treated with diet alone or diet plus metformin and sodiumglucose cotransporter 2 SGLT2 inhibitors gliflozins
All 18 T2D participant will undergo randomization at baseline to two 40 days treatment periods either starting with LIR treatment and then after 2 weeks of wash-out will crossover to second treatment period of 40 days with PLA or vice-versa starting the first period with PLA during 40 days and then crossover to 40 days with LIR The treatment with LIR and PLA will be up-titrated progressively from 01ml to 03ml to avoid the secondary effects of LIR
Expected results The investigators expect that LIR will lead to enhanced expression of the diurnal oscillation of the CGs and AMPK SIRT1 pathway will reduce serum inflammatory cytokines and overall daily glycemic variation while improving insulin sensitivity and β-Cell function
Significance of the study Showing that GLP-1 analog Liraglutide improves β-cell function in type 2 diabetic individuals by enhancing clock genes mRNA expression and the AMPK-SRIT1 pathway may change the approach of Liraglutide treatment from being an excellent anti-diabetic agent with beneficial effect on the diabetic heart to a drug with the ability to synchronize body metabolism and improve glucose homeostasis in health and disease Presently there are many available drugs for the treatment of type 2 diabetes but their mode of action does not make any of them more advantageous If this GLP-1 analog not only reduces glucose body weight and cardiovascular risk but also synchronizes the circadian clock this would make of Liraglutide the drug of choice immediately after metformin for the treatment of obesity early diabetes and for prevention of T2D complications and cardiovascular events in high risk patients moreover Liraglutide by influencing clock genes expression may further prevent several other age related disorders linked to the disruption of clock genes
To the best of the investigators knowledge no systemic study in humans to date has investigated the changes in the expression of CGs and AMPK-SIRT-1 pathway concomitantly with the effect on glycemic control insulin sensitivity beta cell function and inflammatory cytokines in T2D individuals during treatment with Liraglutide or other GLP-1 analogs
Hypothesis The investigators hypothesize that Liraglutide by enhancing CG and AMPK-SIRT-1 expression may reverse the metabolic abnormalities of T2D improving insulin sensitivity overall glycemic excursion inflammatory cytokines and β-cell function in T2D individuals
Objectives
The investigators aim is to compare the effect of 40 days treatment with Liraglutide LIR vs 40 days with placebo PLA in T2D participants on the following end points
Primary end-points
Change in the oscillation of CG ie CLOCK BMAL1 Per1 Per2 Cry1 Cry2 Rev-erb-alpha Ror-alpha AMPK SIRT1 and inflammatory cytokines mRNA expression in white blood cells WBCs
Secondary end-points
Overall daily glycemic variation assessed with continuous glucose monitoring system CBMS
Serum levels of inflammatory cytokines TNF-α IL-1β IL-6
β-Cell function derived from glucose and insulin response to OGTT
Methods In a randomized double blind crossover-within-subject clinical trial the investigators will study 18 weight- matched obese and overweight participants with known T2D diagnosed 20 years and HbA1c 70 to 10 BMI 26-32 kgm2 treated with diet alone or diet plus metformin and sodiumglucose cotransporter 2 SGLT2 inhibitors gliflozins
All 18 T2D participant will undergo randomization at baseline to two 40 days treatment periods either starting with LIR treatment and then after 2 weeks of wash-out will crossover to second treatment period of 40 days with PLA or vice-versa starting the first period with PLA during 40 days and then crossover to 40 days with LIR The treatment with LIR and PLA will be up-titrated progressively from 01ml to 03ml to avoid the secondary effects of LIR
Expected results The investigators expect that LIR will lead to enhanced expression of the diurnal oscillation of the CGs and AMPK SIRT1 pathway will reduce serum inflammatory cytokines and overall daily glycemic variation while improving insulin sensitivity and β-Cell function
Significance of the study Showing that GLP-1 analog Liraglutide improves β-cell function in type 2 diabetic individuals by enhancing clock genes mRNA expression and the AMPK-SRIT1 pathway may change the approach of Liraglutide treatment from being an excellent anti-diabetic agent with beneficial effect on the diabetic heart to a drug with the ability to synchronize body metabolism and improve glucose homeostasis in health and disease Presently there are many available drugs for the treatment of type 2 diabetes but their mode of action does not make any of them more advantageous If this GLP-1 analog not only reduces glucose body weight and cardiovascular risk but also synchronizes the circadian clock this would make of Liraglutide the drug of choice immediately after metformin for the treatment of obesity early diabetes and for prevention of T2D complications and cardiovascular events in high risk patients moreover Liraglutide by influencing clock genes expression may further prevent several other age related disorders linked to the disruption of clock genes
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None