Advantages of Liraglutide Mediated Through Its Effect on Clock Gene mRNA Expression
试验速览
- 阶段
- 不适用
- 入组人数
- 14
- 试验地点
- 1
- 主要终点
- Clock Gene expression
研究概览
简要总结
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 (i.e. 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
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 30 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Type 1 diabetes or secondary forms of diabetes.
- •Use of glucose-lowering therapy apart from metformin and SGLT2 inhibitors.
- •Treatment with GLP-1 receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors within the last 3 months.
- •Major illness with life expectancy < 5 years.
- •Serum creatinine level >2mg/d or renal dysfunction: (estimated glomerular filtration rate <45 mL/min/1.73 m2).
- •Hepatic dysfunction: liver disease or transaminase levels >3-fold above normal.
- •History of acute or chronic pancreatitis or high risk for pancreatitis i.e. triglycerides over 400 mg/dl or alcoholism.
- •Family or personal history of Multiple Endocrine Neoplasia type 2 (MEN-2) or familial medullary thyroid carcinoma.
- •Familial or personal history of multiple endocrine neoplasia type 2 (MEN2), familial or non-familial medullary thyroid carcinoma (MTC)
- •Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy within the previous 5 years (with the exception of basal cell skin cancer).
- •Those taking psychotropic, anorectic medication, steroid treatment or with illicit drug abuse or alcoholism within one year prior to study onset.
- •Congestive heart failure and all cardiac arrhythmias i.e. atrial fibrillation.
- •Pregnancy or lactation.
- •Eating disorders and subjects after bariatric surgery or affected by gastroparesis.
- •Night or rotating shift workers or those who crossed more than 2 time zones during the 2-week period prior to study onset.
- •No change in medication or nutrition supplements or physical activity will be made during the study period.
- •Known proliferative retinopathy or maculopathy
研究组 & 干预措施
Liraglutide (LIR)
Type 2 diabetic randomized to start with two 40 days treatment periods starting with Liraglutide ( IR) treatment, and then after 2 weeks of wash-out, will crossover to second treatment period of 40 days with placebo (PLA)
干预措施: Liraglutide (Drug)
Placebo (PLA)
Type 2 diabetic randomized to start with two 40 days treatment periods starting with placebo ( PLA) treatment, and then after 2 weeks of wash-out, will crossover to second treatment period of 40 days with Liraglutide ( LIR)
干预措施: Placebo (Drug)
结局指标
主要结局
Clock Gene expression
时间窗: Up to 95 days
The Clock Genes mRNA expression will be assessed in white blood cells
次要结局
- SIRT1 mRNA expression(Up to 95 days)
- Beta-cell function(Up to 92 days)
- Overall glycemia(Up to 95 days)
- AMPK mRNA expression(Up to 95 days)
研究者
Daniela Jakubowicz
Prof
Tel Aviv University