Role of Carnosine in Prevention & Treatment of Obesity

and Type 2 Diabetes

MARKETING AND TRAINING DEPT

Burden and risk factors for obesity and
type 2 diabetes
 Burden of obesity and type 2 diabetes

• 60% of adult Indians are overweight or obese

• 22% of Indians > 25 years have prediabetes or type 2
diabetes
• 80% obese patients with type 2 diabetes develop
cardiovascular disease
• Annual healthcare costs cca 9 billion
 Risk factors for obesity and type 2 diabetes

Multiple risk factors

• shared with other chronic diseases (cardiovascular diseases,
dementia, depression, cancer, ageing)
• long latency

The ideal preventative strategy/intervention:

• prevents multiple risk factors and therefore diseases
• impacts mechanisms of diseases
• lifestyle intervention (diet & exercise)
• synergistic with exercise
 Tree of chronic diseases
Ageing

CVD Dementia Diseases

Diabetes Obesity Cancer

Hypertension Risk factors

Kidney disease
NAFLD/NASH
Dyslipidemia

Insulin resistance

Inflammation
Physical inactivity Unhealthy diet Mechanisms
AGEs
Oxidative stress
Alcohol abuse Smoking Causes
Why L-carnosine ?
 What is carnosine?
Beta- Alanine L - Histidine

Main dietary sources: 50 to 250 mg/dL

Red meat Whale meat Fish

CN1 – plasma
CN2 – gut
 What is carnosine?

• naturally occurring dipeptide (beta-alanine L-histidine) in humans

– cardiac & skeletal muscle, brain tissue
– first described in 1900
– first appeared around a decade ago - food supplements and skin creams
– advertised an elixir of youth
– yet little human research
Carnosine - Magic Bullet for Chronic Diseases
 Mechanism of Action of Carnosine

- Chronic low-grade inflammation

Yan, 2009; Tsai, 2010; Lee, 2005

- Oxidative stress
Hipkiss, 2011; Ma, 2012

- Advanced glycation (AGEs)

Burcham, 2002; Hipkiss, 2002

- Chelating properties
Price, 2001; Arnal, 2011

- Ischemia
Doborota, 2005; Fujii, 2005

- Sympathetic nervous system activity

Nagai, 2012; Horii, 2012
How could it all work?
Evidence from animal studies
 Carnosine, obesity and type 2 diabetes
(rodents)
Carnosine reduced
• weight
• insulin levels
• insulin resistance
• delayed development of diabetes
• glucose levels in animals with diabetes
• inflammation and oxidative stress
 Carnosine and cardiovascular disease
(rodents)

Carnosine supplementation reduced

• cholesterol and triglycerides in plasma and liver

• oxidation and glycation of LDL (foam cell formation)
• atherosclerosis
• ischaemic effects
Evidence from human studies
 Carnosine supplementation
improves exercise performance

 exercise capacity compared to placebo

• Hobson, 2012 (meta-analysis)

 high-intensity anaerobic performance

• Artioli, 2010
Mechanisms
•  muscle buffering capacity,  lactate
• Swietach, 2014
• improvement in calcium handling and antioxidant capacity
• Sale, 2013
• Dutka, 2004
 Health benefits of carnosine supplementation in humans

Baye & de Courten, Amino Acids, 2016

 Carnosine & Diabetes

•  muscle carnosine content in drug-naïve patients

with type 2 diabetes compared to healthy controls
• Srikanthan, 2012

•  muscle carnosine levels in patients with type 2

diabetes (on glucose lowering therapy) compared to
healthy controls
• Gualano, 2012
 Carnosine supplementation & diabetes risk

RCT: 12-week intervention with carnosine vs placebo

Pilot trial
Carnosine supplementation prevents
• decrease in insulin sensitivity
• increase in insulin secretion

de Courten et al, Obesity, 2016

Carnosine improves glucose and insulin levels during OGTT
in patients with impaired glucose tolerance

* P<0.05
 RCT in patients with prediabetes
with carnosine compound

N=52, obese individuals with prediabetes

Intervention: 4 months
Liu et al, Plos One, 2015
Liu et al, Plos One, 2015
 Carnosine effects body composition

44 patients with type 2 diabetes on therapy (Metfromin and Glibeclamide)

Mean age 43 years, duration of diabetes 4.5 years, HBA1c 6-6.5%
Intervention: 12 weeks, 1g Carnosine Houjeghani, Nutr Res, 2018
Carnosine improves glucose and lipid metabolism

Houjeghani, Nutr Res, 2018

Carnosine lowers advanced glycation end-
products

Houjeghani, Nutr Res, 2018

Carnosine lowers inflammation markers

Houjeghani, Nutr Res, 2018

 Carnosine, vit B1 and α-lipoic acid improve obesity
and glucose metabolism

N=82, obese sedentary patients with T2DM, mean age 57 years, baseline HbA1c 8.3%
Intervention: 8 week intervention, 6mg/kg body weight (cca 500mg/day)

Karkabounas, J Med Food, 2018

Carnosine improves HBA1c, lipid profile and renal function patients
with type 1 diabetes and nephropathy

N=85, 9-18 year old patients with type 1 diabetes (> 5 years), HbA1c ≤ 8.5%
Intervention: Carnosine 500mg BD, all patients on ACE inhibitor captopril 25 mg daily

Elbarbary, Pediatric Diabetes, 2017

Carnosine reduced HBA1c and Triglycerides

HbA1c (n=283): MD (95%CI): -0.49% (-0.60, -0.38), p<0.001

Triglycerides (n=265): MD (95%CI): -0.42 mmol/L (-0.57;-0.27), p<0.001

Menon…de Courten, unpublished

 Carnosine - Summary

• food supplement
• safe
• anti-inflammatory, anti-oxidative, anti-AGE, chelating properties
and effects on SNS
• all effects are important for many chronic diseases
• additive effect with exercise
• compelling evidence from animal studies (2000 animal studies)
• evidences of human data
• proven beneficial - potential use for primary prevention many
chronic diseases as well as add-on to standard therapy
Carnosine supplementation in overweight and
obese individuals and patients with IGT and
type 2 diabetes
 Hypothesis

It was hypothesised that carnosine supplementation in overweight

and obese individuals (Study 1) and patients with IGT and T2DM
(Study 2) will improve:

• diabetes risk factors (Study 1) or glycaemic control (Study 2)

• cardiovascular risk factors
• cognitive outcomes

and this will be modulated by reduction in chronic low-grade

inflammation, oxidative stress and circulating AGE levels.
 Participants & Methods

• participants:
• 84 overweight and obese individuals (Study 1)
• 52 adult patients with impaired glucose tolerance and T2DM (Study 2)

• design: double blind placebo randomised controlled trials

• intervention: 1g carnosine or matching placebo

• length of intervention: 14 weeks

• measurements: before and after intervention

 Inclusion criteria

• Study 1:
– Overweight and obese individuals
– Age 18-60 years
• Study 2:
– Patients with IGT or T2DM (diet controlled and on
Metformin only)
– Age 18-70 years
– Stable dose of metformin for least 3 months

• No significant change in weight in last 6 months

• No intention to loose weight during the course of the study
 Exclusion criteria

• HbA1c level > 8% for patients with diabetes

• Morbid obesity (>40 kg/m2) - DEXA limitation

• Taking other glucose lowering medications than

metformin including injectables

• Taking regular anti-inflammatory medications or

supplements potentially effecting glucose metabolism

• current smoker or high alcohol/recreational drug use

 Exclusion criteria

• Significant other chronic diseases and psychiatric

disorders

• Presence of acute inflammation

• Pregnant or lactating

• Not speaking English (need to complete cognitive

function tests - time)
 Outcomes

Obesity Diabetes CVD Cognition

• % body fat • insulin sensitivity • Lipids, lipidomics • CANTAB+

• FFM • insulin secretory function • arterial stiffness • depression
• IMAT • glucose tolerance • blood pressure / cBP • sleep
• Steatosis • ACR • endothelial function
• Diet • HRV
• Exercise

-inflammation in plasma and PBMC, oxidative stress, advanced glycation and lipidoxidation end products
-signalling muscle tissue
-microbiome
-DNA – ageing markers ie telomere length, telomerase
 Tree of chronic diseases
Ageing

CVD Dementia Diseases

Diabetes Obesity Cancer

Hypertension Risk factors

Kidney disease
NAFLD/NASH
Dyslipidemia

Insulin resistance

Inflammation
Physical inactivity Unhealthy diet Mechanisms
AGE’s
Oxidative stress
Alcohol abuse Smoking Causes
SCHIZOPHRENIA/OCD/AUTISM

MARKETING
&
TRAINING DEPARTMENT
AGEs(Advanced Glycation of End Products)

 Glycation is the non enzymatic joining of a sugar compound with a protein or

amino acids

 Glycation is a pathological process, the end result of the process of glycation is

the formation of AGE products that crosslink with other proteins and lipids and
inactive them or make them essential non functional

 When there is a increased AGE receptor formation, proteins modified by

advanced glycation end products( AGE proteins) act as photosensitizers of DNA
damage this leads to damaged microcirculation

 AGE promotes inflammation

 AGE effects fats, DNA and other biological materials.

Schizophrenia

 Schizophrenia is a serious disorder which affects how a person thinks, feels and
acts. Someone with schizophrenia may have difficulty distinguishing between
what is real and what is imaginary,
 May be unresponsive or withdrawn and have difficulty expressing normal
emotions in social situations.

What Causes Schizophrenia?

 The cause of schizophrenia is still unclear. Some theories about the cause of this
disease include: genetics (heredity), biology (abnormalities in the brain’s
chemistry or structure); and/or possible viral infections and immune disorders.

 People with schizophrenia have an imbalance of the brain chemicals or

neurotransmitters: dopamine, glutamate and serotonin.

 The imbalance of these chemicals affects the way a person’s brain reacts to
stimuli

 This problem in processing different sounds, sights, smells and tastes can also
lead to hallucinations or delusions.
 Obsessive-Compulsive Disorder
 Obsessive-compulsive disorder or OCD is one of the most common types of
psychological disorder.

 OCD is most commonly defined, invasive thoughts or repetitive actions that are
understood to be irrational and unnecessary. These recurring, invasive thoughts,
called obsessions, and uncontrollable, repetitive actions, called compulsions.

 Leads significant stress and disruption in daily life, not all people with OCD suffer
from both obsessions and compulsions, even though it is most common together.

OCD can take many forms

 Seeking cleanliness, orderliness or symmetry

 Performing repetitive acts that are thought to be protective, such as counting or

praying
 Repeatedly checking, often for the purpose of safety

 Obsessive-compulsive disorder is a mental illness. It's made up of two parts:

obsessions and compulsions.
 OCD in children
 OCD that begins in childhood is more common in boys than girls with the
usual time of onset of OCD later for females than males.
 The condition might be triggered by a combination of genetic, neurological,
behavioural, cognitive, and environmental factors.
 Neurological causes
 Imbalances in the brain chemicals serotonin and glutamate may play a part
in OCD.
Environmental causes

 Environmental stressors may be a trigger for OCD in people with a

tendency toward developing the condition

Traumatic brain injury (TBI)

 In adolescents and children has also been associated with an increased
risk of onset of obsessive-compulsions.

 30 percent of children aged 6 to 18 years who experienced a TBI

developed symptoms of OCD within 12 months of the injury
 OCD usually develops into a chronic condition if left untreated, with
episodes where symptoms seem to improve. Without treatment,
remission rates are low, at around 20 percent.

 However, around 40 percent of people who develop OCD in childhood or

adolescence experience remission by early adulthood.
 Autism
 Autism is a highly variable neurodevelopmental disorder that first
appears during infancy or childhood, and generally follows a steady
colours without remission.

 Symptoms gradually begin after the age of six months, become

established by age two or three years and tend to continue through
adulthood

 It is distinguished not by a single symptom but by a characteristic

triad of symptoms: Impairments in social interaction;
Impairments in communication; and restricted interests and
repetitive behavior. Other aspects, such as atypical eating

 Autism is associated with a combination

of genetic and environmental factors risk factors during pregnancy
include certain infections, such as rubella, toxins including valproic
acid, alcohol, cocaine, pesticides and air pollution, fetal growth
restriction, and autoimmune diseases other proposed
environmental causes
 Autism

 Autism affects information processing in the brain by altering

connections and organization of nerve cells and their synapses.

 Autism's symptoms result from maturation-related changes in

various systems of the brain. Its mechanism can be divided into two
areas: the pathophysiology of brain structures and processes
associated with autism

 The neuropsychological linkages between brain structures and

behaviors. The behaviors appear to have multiple
pathophysiologies.

 The immune dysregulation, gastrointestinal inflammation,

malfunction of the autonomic nervous system, gut flora alterations,
and food metabolites may cause brain neuroinflammation and
dysfunction.

 Neural connections and the immune system are a pathway that

may allow diseases originated in the intestine to spread to the brain.
ADHD
• ADHD is one of the most
common neurodevelopmental disorders of
childhood. It is usually first diagnosed in childhood
and often lasts into adulthood.
• Children with ADHD may have trouble paying
attention, controlling impulsive behaviors (may act
without thinking about what the result will be), or
be overly active.
SIGNS AND SYMPTOMS OF ADHD
• It is normal for children to have trouble focusing and
behaving at one time or another. The symptoms
continue, can be severe, and can cause difficulty at
school, at home, or with friends.
• A child with ADHD might:
• daydream a lot
• forget or lose things a lot
• squirm or fidget
• talk too much
• make careless mistakes or take unnecessary risks
• have a hard time resisting temptation
• have trouble taking turns
• have difficulty getting along with others
L-Carnosine Improves Metabolic Risk Factors

In Patients with Diabetes

 Advanced glycation end products (AGEs), harmful compounds

consisting of proteins or lipids that are exposed to sugar and high
temperature levels, play a critical role in aging and the worsening
of degenerative diseases like diabetes.

 When AGEs interact with the receptors for advanced glycation

end products (RAGEs), oxidative stress is systemically increased
and alterations in cell structure and function take place.

 The binding of AGEs to RAGE, associated with endothelial

dysfunction, low-grade inflammation, and insulin resistance , are
recognized as playing a role in the complications associated with
diabetes
L-carnosine

 Protect against diabetes due to its ability to neutralize toxic

compounds and influence glycemic control.

 The physiological properties associated with L-carnosine are its

antioxidant and pH buffering activity and its capacity to protect
against the formation of advanced glycation and its end products.

 Patients with metabolic syndrome and those with high fasting

blood sugar, L-carnosine appears to improve glycemic control and
prevent development of Type 2 diabetes
 In ischemic stroke
 Excitotoxicity considered a main cause of neuronal death.
 The excitotoxic mechanism was processed with excessive glutamate
release, calcium influx, uncontrolled membrane depolarization, decline
of cellular ATP and oxidative stress simultaneously.
 In early stage of ischemic stroke, cytoplasmic calcium overload is a
major excitotoxic event which was regulated by mitochondria calcium
homeostasis. And, mitochondrial dysfunction was induced by increase
of free radicals, in turn, diminished the antioxidant activity.
 Oxidative stress could be considered one of those important causes in
apoptotic or necrotic neuronal death with DNA fragmentation, cell
membrane disruption and blood brain barrier broken.
A NEW WELCOMING ADDITION NOW IN SOLIS
Braineed in Autism
• L –Carnosine significantly improves receptive
speech, socialization, sleep and behavior in autistic
children in just 8 weeks
• Coenzyme Q10 dramatically reduces oxidative
stress and and antioxidant enzyme activity
• DHA contributes in reducing irritability symptoms
and hyperactivity in children with Autistic Spectrum
Disorders
• Can be added to risperidone or any other active
treatment for better results in Autism
Braineed in STROKE
• Supports the active treatment of Stroke…
• DHA ameliorates acute ischemic brain injury in a
macrophage dependent manner to reduce central and
peripheral inflammation
• Carnosine demonstrates significant cerebroprotection
against histological and functional damage, with wide
therapeutic and clinically relevant time windows.
• Influences deleterious pathological processes that are
activated after the onset of ischemia
• Coenzyme Q10 supports the treatment by modulating
inflammatory and degenerative pathways.
Braineed in ADHD symptoms

Ideal addition to active treatment of ADHD…

• L-Carnosine as an adjuvant to methylphenidate significantly decreases ADHD scores
• better than monotherapy
• DHA alone significantly decreases attention deficit and hyperactivity components in just 3
months of treatment
• Coenzyme Q10 contributes for improvement in sustained attention, learning efficiency
and cognitive efficiency

ADHD Scores Inattention sub scale scores

 Braineed in schizophrenia
• Significantly greater reduction in their negative subscale and total score of PANSS
• Coenzyme Q10 and DHA further contributes for alleviation of cognitive symptoms

Effects on –ve symptoms measured on PANSS Effects on overall Psychopathology PANSS

Psychiatry Res. 2018 Apr;262:94-101

MARKETING
INDICATIONS :
 DIABETES AND OBESITY

 SCHIZOPHRENIA

 OBSESSIVE-COMPULSIVE DISORDERS(OCD)

 ISCHEMIC STROKE/TRAUMATIC BRAIN INJURY

 AUTISTIC SPECTRUM DISORDERS(ASD)

 NEUROLOGICAL DISORDERS IN DIABETICS

 ADHD(Attention-deficit hyperactivity disorder)

TARGETED DOCTORS :

PSYCHIATRIST

PAEDIATRIC NEUROLOGIST

NEUROLOGIST

DIABETOLOGIST

CONSULTANT PHYSICIAN
 Braineed tab

PACK 10’S

PRICE 369/-

Combination L Carnosine 200 mg

Strategy
• Identify current prescribers of ignicar and carniwel
tablets
• Use LBL’s to promote in different indications across
specialties
 COMPETITORS (Only plain carnosine)

Brand Name Company MRP

IGNICAR tab LINUX 495/-

CARNISTON
GLADSTONE 480/-
tab
INPUTS :

LBLs SPECIALTY WISE

BRAND REMINDERS
PROJECTION

100 strips

PER TERRITORY PER

MONTH