The Potential of Carnosine Supplementation in Reducing the Cardiometabolic Risk

Study Overview
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Brief Summary
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The aim of this study is to determine whether carnosine supplementation in overweight/obese individuals can improve insulin secretion and/or insulin resistance by decreasing sub clinical inflammation. The investigators hypothesise that carnosine supplementation will reduce type 2 diabetes and cardiovascular risk factors by lowering chronic low-grade inflammation (CLI), oxidative stress, advanced glycation end products (AGEs), and advanced lipoxidation end products (ALEs). Aim :To determine the capacity of carnosine supplementation to decrease major risk factors for type 2 diabetes and cardiovascular disease and identify metabolic pathways involved, specifically by: Reducing diabetes risk (insulin sensitivity; secretory function and glucose tolerance) Improving cardiovascular risk factors (lipids; arterial (aortic) stiffness; central blood pressure (cBP); endothelial function). Decreasing the CLI, oxidative stress, AGEs, and ALEs, and increase detoxification of reactive carbonyl species (RCSs).

Detailed Description
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Cardiovascular risk factors including type 2 diabetes underpin a major threat to the globe and result in a heavy health and financial burden across the healthcare system. Treating type 2 diabetes and cardiovascular disease is expensive and often unsatisfactory. Current medications bring unwanted side effects, and often merely delay rather than prevent type 2 diabetes complications and cardiovascular disease. As a further concern, the micro- and macrovascular complications of type 2 diabetes often start developing before actual diagnosis. Diabetes prevention and treatment through weight loss and exercise programs is a difficult and costly public health measure, leaving the tidal wave of type 2 diabetes to swell even more. An alternative is urgently needed: a low-cost safe approach, easy to implement at population level. Could carnosine be that alternative? The evidence suggests carnosine has significant metabolic impact and presents such an alternative. A naturally occurring dipeptide, carnosine is already emerging as a human therapy in exercise physiology, heart failure, cataract prevention and treatment, neurology, and psychiatry. A promising further use may derive from its effect on cardiovascular risk factors. Metabolic research, though confined to animal studies, strongly suggests that carnosine supplementation aids the prevention and treatment of obesity, type 2 diabetes, and cardiovascular disease - by virtue of its anti-inflammatory, antioxidative, and anti-glycating effects. The investigators conducted the first pilot data in human and demonstrate relationships among carnosine, obesity, insulin resistance, and dyslipidemia. Put briefly, the pilot weighs strongly in favour of carnosine as a means of reducing cardiovascular risk in humans. Too good to be true? Apart from its excellent side-effect profile, carnosine is inexpensive and seemingly safe (available as an over-the-counter food additive), making it prima facie ideal for population use. In this setting research is now urgently needed - to test the significant metabolic potential of carnosine to address a major health problem. The investigators propose a comprehensive double-blind placebo-controlled human trial to investigate the effects of carnosine supplementation on cardiovascular risk factors. If the investigators demonstrate a role in reducing risk factors for type 2 diabetes and cardiovascular disease in overweight and obese non-diabetic humans, the public health implications will be revolutionary, offering the world a genuine low cost, accessible, intervention to curtail the advance of obesity, type 2 diabetes, and cardiovascular disease.

Official Title
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The Potential of Carnosine Supplementation in Reducing the Cardiometabolic Risk: a Double-blind, Placebo-controlled Trial

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Dietary Supplement: carnosine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 or <60 years, Weight change < 5 kg in last 12 months BMI >25kg/m2 but weight <159kg due to DEXA scan restrictions Non-diabetic, no allergy, non-smoker, no high alcohol use No current intake of medications including vitamin supplements No kidney, cardiovascular, haematological, respiratory, gastrointestinal, endocrine or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination) Not pregnant or lactating Exclusion Criteria: Age <18 or > 60 years Weight change > 5 kg in last 12 months Diabetes (diagnosed or oral glucose tolerance test (OGTT), allergy Current smoking habit, high alcohol use Current intake of medications including vitamin supplements Kidney, cardiovascular, haematological, respiratory, gastrointestinal, endocrine or central nervous system disease, as well as psychiatric disorder, active cancer within the last five years; presence of acute inflammation (by history, physical or laboratory examination) pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention<br>Each participant will be given a daily oral dose 2 g of carnosine (2 tablets twice daily) for 14 weeks | Dietary Supplement: carnosine<br>* Carnosine capsules (2g) twice per day for 14 weeks<br>|
| Placebo Comparator: Control<br>Each participant will be given a daily oral dose 2 g of identical placebo tablets ( 2 tablets twice daily) for 14 weeks | Other: Placebo<br>* Placebo (methylcellulose) capsules for control group identical to intervention capsules and dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in insulin sensitivity measured by euglycaemic glucose clamp | The clamp will be used to measure insulin sensitivity. The clamp is initiated by an intravenous bolus injection of insulin (9milliUnit/kg). Insulin is then constantly infused at a rate of 40 milliUnit.m-2.min-1 for 120 min into an arm vein, whilst glucose is variably infused to maintain euglycaemia. Plasma glucose values will be monitored every 5 minutes during the clamp and the variable infusion rate of glucose is adjusted to maintain blood glucose at a constant value of 5mmol/L. | From baseline to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of endothelial dysfunction | This is done using non-invasive peripheral arterial tomography (PAT; endothelium-dependent digital pulse amplitude testing (EndoPAT), Itamar Medical Ltd, Israel), which records continuous plethysmo¬graphic signals of the finger arterial pulse wave. Finger plethysmographic probes are placed on each index finger; and after a 5 min equilib¬ration period, a blood pressure cuff on the non-dominant arm is inflated to 60 mmHg above systolic for 5 min and then deflated to induce reactive hyperaemia. Measurements of post-occlusion changes (reactive hyperaemia PAT: RH-PAT) are continued for 10 min. Results are normalised to the non-occluded arm, compensating for potential systemic changes (RH-PAT ratio). | From baseline to 14 weeks | 
| Change in Acute Insulin Secretory Response - Intravenous Glucose Tolerance Test | This will be measured in response to 25g intravenous glucose and calculated as the average incremental plasma insulin level from the third to the fifth minute after the glucose bolus. | From baseline to 14 weeks | 
| Change in Resting systolic and diastolic blood pressure | Resting systolic and diastolic blood pressure and pulse rate will be measured using an automated oscillometric measurement system (Dinamap, USA) after a 30 minute rest. | From baseline to 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carnosine, Insulin sensitivity, low grade inflammation, Oxidative stress, Advanced glycation, Type 2 diabetes, Cardiovascular disease