The Potential of Carnosine Supplementation in Optimising Cardiometabolic Health

• ClinicalTrials.gov Identifier: NCT02917928
• Recruitment Status: Recruiting
• First Posted: September 28, 2016
• Last Update Posted: June 28, 2022
• Sponsor: Monash University
• Information provided by (Responsible Party): Barbora de Courten, Monash University

Study Description

Brief Summary:

The investigators hypothesise that carnosine supplementation will improve:

1. glycaemic control
2. cardiovascular risk factors
3. cognitive outcomes

in patients with prediabetes and type 2 diabetes, and this will be modulated by reduction in chronic low grade inflammation, oxidative stress and circulating advanced glycation end products levels.

3. Aims

To determine the potential of carnosine supplementation for 14 weeks to improve glycaemic control in type 2 diabetes, reduce risk factors for cardiovascular disease and improve cognitive function as well as identify metabolic pathways involved, specifically by:

1. Improving glycaemic control (HBA1c, fasting and 2 hour glucose and glucose area under the curve after oral glucose tolerance test)
2. Reducing cardiovascular risk factors (lipids; arterial (aortic) stiffness; central blood pressure (cBP); endothelial function).
3. Improve cognitive function (global cognitive score formed by a composite of 4 cognitive tests)
4. Decrease the chronic low grade inflammation, oxidative stress, advanced glycation end products, and advanced lipoxidation end products, and increase detoxification of reactive carbonyl species (RCSs).

Condition or disease	Intervention/treatment	Phase
Poor Glycemic Control; Cardiovascular Risk Factors; Cognitive Function 1, Social	Dietary Supplement: carnosine; Drug: Placebo	Phase 2

Detailed Description:

Type 2 diabetes is a major public health problem worldwide. Obesity itself markedly increases the risk of type 2 diabetes (DM2), which now affects every second obese person. With 60% of adult Australians overweight or obese and 25% of Australians aged over 25 years having prediabetes or diabetes, the quality-of-life and cost impact is inescapable. In Australia, direct healthcare costs for DM2 are currently estimated as $1.1 billion annually, with the prospect of doubling by 2025. Obesity and DM2 dramatically increase the risk of cardiovascular disease (CVD) with ~80% of individuals with both obesity and DM2 develop CVD. The annual healthcare costs for CVD in Australia now amount to $7.7 billion; and the total aggregated costs, including loss of income, are much higher again. Treating DM2 and CVD is expensive and often unsatisfactory. Weight loss and exercise are the mainstay of prevention and therapy but they are difficult and costly to achieve on a large scale; hence the DM2 epidemic continues unabated. Therefore, interventions at low cost and easy to implement at the population level is urgently required.

Neurodegenerative diseases often occurs in people with DM2, and DM2 is in turn associated with increased risk of cognitive decline. Neurodegenerative diseases such as Alzheimer's disease are also associated with metabolic impairment. They share many common pathogenic features with DM2 such as insulin resistance, chronic low-grade inflammation, vascular disease, oxidative stress and accumulation of advanced glycation endproducts (AGEs). Progression of these diseases over years-decades is also worsened by a sedentary life-style. Therefore not surprisingly, regular physical activity is beneficial in those patients, likely due to improvement of neurological, motor and cardiometabolic profile. However, it is difficult and costly to achieve on a large scale, and thus, safe and low-cost strategies are needed.

Type 2 diabetes is associated with increased amounts of ectopic fat depots in muscle including intramyocellular lipids (IMCL), and adipocytes located between muscle groups (inter-muscular) and also between muscle fascicles (intramuscular). Both IMCL and intra- and inter-muscular adipose tissue (IMAT) may deleteriously effect muscle metabolism and insulin sensitivity through increased local secretion of pro-inflammatory adipokines, and inter-muscular fat may additionally impair insulin action through reductions in blood flow to muscle.

Could carnosine be that strategy? Strong molecular and animal data (>2000 papers) suggests that it has great potential, with all the relevant properties. Carnosine, is present in several tissues including muscle and brain, easily crosses the blood-brain barrier, and extensive animal data show that carnosine has chelating properties and modulates glucose metabolism, advanced glycation, pro-inflammatory and pro-oxidative states, as well as motor functions and neurotransmission. A promising further use may derive from its effect on cardiometabolic health and neuroprotection. Current research, confined to animal studies, supports carnosine supple¬ment¬ation for preventing and treating obesity, DM2, CVD, and neurodegenerative diseases - by virtue of its anti-inflammatory, antioxidative, anti-glycating and chelating effects. Our team's novel pilot studies provide the first human cross-sectional and interventional metabolic data, and demonstrate relationships among carnosine, obesity, insulin resistance, and dyslipidaemia. Previous clinical trials also showed that supplementation of carnosine for 2-3 months improved cognitive performance in healthy individuals and patients with neurodegenerative diseases. However, none of them showed its effect in patient with type 2 diabetes and explored the effects of change in cardiometabolic outcomes on cognitive function.

Apart from its excellent side-effect profile, carnosine is cheap and safe (it is an over-the-counter dietary supplement), making it prima facie ideal for widespread, low cost use. Robust human research is now urgently needed to test the therapeutic potential of carnosine in improving cardiometabolic profile and cognitive function, and study the mechanisms involved.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Potential of Carnosine Supplementation in Optimising Cardiometabolic Health in Patients With Prediabetes and Type 2 Diabetes: a Randomsied, Double-blinded, Placebo-controlled Trial
• Study Start Date: October 2016
• Estimated Primary Completion Date: January 2023
• Estimated Study Completion Date: July 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Intervention; Each participant will be given a daily oral dose 2 g of carnosine (4 tablets of 500mg each) for 14 weeks	Dietary Supplement: carnosine; Each participant will be given a daily oral dose 2 g of carnosine (4 tablets of 500mg each) for 14 weeks; Other Name: Pure Carnosine
Placebo Comparator: Control; Each participant will be given a daily oral dose 2 g of placebo (4 tablets of 500mg each) for 14 weeks	Drug: Placebo; Each participant will be given a daily oral dose 2 g of placebo (4 tablets of 500mg each) for 14 weeks; Other Name: Methylcellulose

Outcome Measures

Primary Outcome Measures :

1. Change in Oral Glucose Tolerance Test [ Time Frame: baseline and 14 weeks ]
   After a 10-12 h overnight fast, participants will ingest 75g of glucose over 2 mins. Blood samples will be drawn at 0, 30, 60, 90 and 120 min for plasma glucose and insulin concentrations. We will evaluate the area under the curve.

Secondary Outcome Measures :

1. Change in HbA1c [ Time Frame: baseline and 14 weeks ]
   Blood samples will be measured using High Performance Liquid Chromatography.
2. Change in lipid profile [ Time Frame: baseline and 14 weeks ]
   Blood samples will be analysed using High Performance Liquid Chromatography
3. Change in systolic and diastolic blood pressure [ Time Frame: baseline and 14 weeks ]
   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.
4. Change in arterial stiffness and central blood pressure [ Time Frame: baseline and 14 weeks ]
   Aortic (carotid-femoral) pulse wave velocity (aPWV) will be measured using the non-invasive Complior device (Alam Medical, French).
5. Change in markers of endothelial dysfunction [ Time Frame: baseline and 14 weeks ]
   This is done using non-invasive peripheral arterial tomography (PAT; endothelium-dependent digital pulse amplitude testing (EndoPAT), Itamar Medical Ltd, Israel), which records continuous plethysmographic signals of the finger arterial pulse wave. Finger plethysmographic probes are placed on each index finger; and after a 5 min equilibration 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).
6. Change in heart rate variability [ Time Frame: baseline and 14 weeks ]
   The Zephyr Biomodule BH3 (Black Sensor, produced by Zephyr Technology) will be used to measure heart rate and heart rate variability for three consecutive days.
7. Change in interleukins [ Time Frame: baseline and 14 weeks ]
   Interleukins will be measured by quantitative sandwich enzyme immunoassays (R & D Systems Inc, USA).
8. Change in tumour necrosis factor α [ Time Frame: baseline and 14 weeks ]
   Tumour necrosis factor α (TNFα) will be measured by quantitative sandwich enzyme immunoassays (R & D Systems Inc, USA).
9. Change in macrophage migration inhibitory factor [ Time Frame: baseline and 14 weeks ]
   Macrophage migration inhibitory factor will be measured by quantitative sandwich enzyme immunoassays (R & D Systems Inc, USA).
10. Change in plasma C- reactive protein [ Time Frame: baseline and 14 weeks ]
    Plasma C- reactive protein (hsCRP) will be measured using high sensitivity assay (BN-II nephelometer; Dade Behring Diagnostics, NSW).
11. Change in plasma and urinary advanced glycation end products [ Time Frame: baseline and 14 weeks ]
    Measured by liquid chromatography-tandem mass spectrometry and ELISA tests. Circulating receptor for AGEs will be measured by ELISA. Protein modifications and the effect of carnosine supplementation will be determined by proteomic approaches.
12. Change in plasma and urinary advanced lipoxidation end products [ Time Frame: baseline and 14 weeks ]
    This will be determined by measuring the advanced oxidation protein products and by measuring the cysteinate form of albumin by mass spectrometry. Mercapturic acid adducts with the main reactive carbonyls species will also be quantitatively determined by liquid chromatography electrospray ionization mass spectrometry/mass spectrometry analysis (LC-MS/MS).
13. Change in general cognitive function [ Time Frame: baseline and 14 weeks ]
    Participants' cognitive function will be assessed using Cambridge Neuropsychological Test Automated Battery (CANTAB) battery for Prodromal Alzheimer's disease, Victoria Stroop test, Trail Making Test and Digit Symbol Substitution Test.

Other Outcome Measures:

1. Change in liver stiffness and fat [ Time Frame: baseline and 14 weeks ]
   A non-invasive transient elastography (Fibroscan, EchoSens, Paris) will be used to assess liver fibrosis based on the measurement of liver fat and stiffness
2. Change in Serum and urine carnosine [ Time Frame: baseline and 14 weeks ]
   This will be measured by ELISA for human carnosinase 1 (CN1) with a monoclonal antibody (clone ATLAS, Abcam plc) and peroxidase substrate .
3. Change in skeletal muscle fat and density [ Time Frame: baseline and 14 weeks ]
   We will also measure the change in muscle and fat tissue density of participants' non-dominant leg using Quantitative Computed Tomography (pQCT). Participants will be seated in their non-dominant leg positioned inside the machine gantry. Muscle cross sectional area (mm2) and muscle density (mg/cm3) will be determined using the manufacturer's algorithms.
4. Change in body composition [ Time Frame: baseline and 14 weeks ]
   body composition by dual energy x-ray absorptiometry (DEXA), which is a non-invasive assessment of soft tissue composition by region with a precision of 4-5%; central adiposity assessed in duplicate using a constant-tension tape for taking waist, and hip circumference. Bioimpedance measurement will be also collected for validation purposes.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Age >=18 or <=70 years
• Weight change < 5 kg in last 6 months
• HbA1c level <= 8%
• Patients with prediabetes (Impaired glucose tolerance and impaired fasting glycaemia) or type 2 diabetes (diet controlled or on oral therapy)
• Patients will have to be on oral therapy for diabetes (without changes in treatment) at least for 3 months.
• Patients will be advised not to change their pre-existing therapy for diabetes and cardiovascular risk factors for the duration of the study if HbA1c is not above 8%
• No recent blood transfusion (3 months)
• No current intake of anti-inflammatory medications and supplements
• No significant kidney, cardiovascular, haematological, respiratory, gastrointestinal, 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)
• Pregnant or lactating

Exclusion Criteria:

• Age <18 or > 70 years
• HbA1c level of >= 8%
• Weight change > 5 kg in last 6 months
• Morbid obesity (body mass index >40 kg/m2)
• Current smoking habit and high alcohol use
• Patients on insulin
• Taking anti-inflammatory medications or supplements
• Recent blood transfusion history
• Kidney (estimated glomerular filtration rate < 30 ml/min), cardiovascular, haematological, respiratory, gastrointestinal, 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

Contacts and Locations

Contacts

Contact: Barbora de Courten, MD,PHD,MPH; +61 385722651; barbora.decourten@monash.edu

Locations

Australia, Victoria

Monash Centre for Health Research and Implementation; Recruiting

Melbourne, Victoria, Australia, 3168

Contact: Barbora de Courten, MD,PHD,MPH +61 3 857 22651 barbora.decourten@monash.edu

Principal Investigator: Barbora de Courten, MD,PHD,MPH

Sub-Investigator: Helena Teede, MBBS,PhD

Sub-Investigator: James Cameron, MBBS,MD

Sub-Investigator: Alexander Hodge, BSc,MBBS,PHD

Sub-Investigator: David Scott, BSc,MBBS,PHD

Sponsors and Collaborators

Monash University

Investigators

• Principal Investigator: Barbora de courten, MD,PHD,MPH; Monash University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Baye E, Menon K, de Courten MP, Earnest A, Cameron J, de Courten B. Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2017 Sep 1;7(9):e017691. doi: 10.1136/bmjopen-2017-017691.

• Responsible Party: Barbora de Courten, Professor, Monash University
• ClinicalTrials.gov Identifier: NCT02917928
• Other Study ID Numbers: 16061AI
• First Posted: September 28, 2016
• Last Update Posted: June 28, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Barbora de Courten, Monash University:

carnosine, type 2 diabetes, cardiovascular factors