1. Mitochondrial dysfunction plays a key role in the pathogenesis of type 2 diabetes through decreased oxidative capacity, increased reactive oxygen species production, and impaired insulin secretion.
2. Imeglimin is a new antidiabetic drug that targets mitochondrial function through several mechanisms, including improving complex II activity, decreasing oxidative stress, and increasing PGC-1α and mitochondrial biogenesis.
3. Clinical trials have shown imeglimin to be effective at reducing blood glucose levels and to have a good safety profile, suggesting it may be a promising new treatment for type 2 diabetes.
Imeglimin, What is new?
By Dr. Usama Ragab Youssif
Lecturer of Medicine - Zagazig University
Agenda
Mitochondrial function and dysfunction
Mitochondrial (dys)function in diabetes
Diabetes core defects and Imeglimin
Imeglimin drug development and approval
Imeglimin and Heart
Sitagliptin an oral anti-diabetic agentAmruta Vaidya
A concise presentation on the DPP-IV inhibitor Sitagliptin an oral anti-diabetic agent. Its general mechanism of action, pharmacokinetics, safety is included.
Imeglimin, What is new?
By Dr. Usama Ragab Youssif
Lecturer of Medicine - Zagazig University
Agenda
Mitochondrial function and dysfunction
Mitochondrial (dys)function in diabetes
Diabetes core defects and Imeglimin
Imeglimin drug development and approval
Imeglimin and Heart
Sitagliptin an oral anti-diabetic agentAmruta Vaidya
A concise presentation on the DPP-IV inhibitor Sitagliptin an oral anti-diabetic agent. Its general mechanism of action, pharmacokinetics, safety is included.
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
This prsentation explains the use of biomarker with reference to an article: Accelerating Drug Develeopment using Biomarkers-Sitagliptin.
It was presented my my 2 friends and me. Hope it helps you guys.
Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ...magdy elmasry
Cardiologists and diabetes.Target organs and action mechanism of antidiabetic drugs.Cardiovascular Outcome Trials
( CVOTs ) in Diabetes.Completed and ongoing CVOTs in type 2 diabetes.Diabetes Medications
and
Cardiovascular Impact.Recommendations for management of diabetes
Cardiovascular safety of anti-diabetic drugs.
This Presentation Give You A brief Information About DPP4 And New Recommendations .This Presentation Guide You How To Treat Patients With Safety.
For Further Contact:03354999496
Anti-Obesity Pharmacotherapy: Where are we now? Where are we going?InsideScientific
Obesity is a treatable chronic disease. With nearly 2 billion individuals worldwide classified as being overweight and 650 million as having obesity, it is critical to optimize implementation of existing treatment interventions and develop novel therapies to mitigate the obesity pandemic. Anti-obesity medications are one of the essential tools in our medical toolbox to help patients achieve their health and weight goals.
In this webinar, Dr. Jastreboff discusses current use of anti-obesity pharmacotherapy, mechanisms involved, and agents in various stages of development with considerations for next steps. The presentation aims to inspire development of innovative therapeutics while optimizing use of existing agents to address the urgent need to effectively and sustainably treat millions of individuals with obesity around the world.
Key Topics Include:
- Understand the role of anti-obesity pharmacotherapy in the treatment of obesity
- Describe current anti-obesity pharmacotherapy
- Discuss anti-obesity medications under development
Resveratrol, Caloric Restriction and Longevity in Human Mitochondrial Dysfunc...Ayetenew Abita Desa
Caloric restriction and the phytoalexin resveratrol found to increase longevity and decrease aging. This is the summary I have made after extensive review. everybody is invited to comment on it.
SGLT2I The paradigm change in diabetes managementPraveen Nagula
Just like ARNI, SGLT2I have changed the face of diabetes management and they have a good profile in multimodality management because of pleiotropic effects
This prsentation explains the use of biomarker with reference to an article: Accelerating Drug Develeopment using Biomarkers-Sitagliptin.
It was presented my my 2 friends and me. Hope it helps you guys.
Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ...magdy elmasry
Cardiologists and diabetes.Target organs and action mechanism of antidiabetic drugs.Cardiovascular Outcome Trials
( CVOTs ) in Diabetes.Completed and ongoing CVOTs in type 2 diabetes.Diabetes Medications
and
Cardiovascular Impact.Recommendations for management of diabetes
Cardiovascular safety of anti-diabetic drugs.
This Presentation Give You A brief Information About DPP4 And New Recommendations .This Presentation Guide You How To Treat Patients With Safety.
For Further Contact:03354999496
Anti-Obesity Pharmacotherapy: Where are we now? Where are we going?InsideScientific
Obesity is a treatable chronic disease. With nearly 2 billion individuals worldwide classified as being overweight and 650 million as having obesity, it is critical to optimize implementation of existing treatment interventions and develop novel therapies to mitigate the obesity pandemic. Anti-obesity medications are one of the essential tools in our medical toolbox to help patients achieve their health and weight goals.
In this webinar, Dr. Jastreboff discusses current use of anti-obesity pharmacotherapy, mechanisms involved, and agents in various stages of development with considerations for next steps. The presentation aims to inspire development of innovative therapeutics while optimizing use of existing agents to address the urgent need to effectively and sustainably treat millions of individuals with obesity around the world.
Key Topics Include:
- Understand the role of anti-obesity pharmacotherapy in the treatment of obesity
- Describe current anti-obesity pharmacotherapy
- Discuss anti-obesity medications under development
Resveratrol, Caloric Restriction and Longevity in Human Mitochondrial Dysfunc...Ayetenew Abita Desa
Caloric restriction and the phytoalexin resveratrol found to increase longevity and decrease aging. This is the summary I have made after extensive review. everybody is invited to comment on it.
П. Сутерс "Проявления инсулинорезистентности и гликемический контроль в интен...rnw-aspen
Доклад с 15 Межрегиональной научно-практической конференции "Искусственное питание и инфузионная терапия больных в медицине критических состояний" 21-22 мая 2015 г
Alterations of Mitochondrial Functions and DNA in Diabetic Cardiomyopathy of ...CrimsonPublishersIOD
Alterations of Mitochondrial Functions and DNA in Diabetic Cardiomyopathy of CCK1 Receptors-Deficient Rats by Abdelbary Prince, Magdy A Ghoneim, Abdallah M El-Ebidi, Hala A Mousa and Jin Han in Interventions in Obesity & Diabetes
'Lo último en obesidad'. Este es el título del Simposio Internacional que organizamos en la Fundación Ramón Areces los días 1 y 2 de diciembre de 2015. En colaboración con la Fundación General CSIC, reunió a algunos de los mayores expertos en la materia para analizar cómo reducir este grave problema de salud pública.
Diabetes Mellitus - An Integrated Approachpgahalya
This Slide contains information about Cause, Symptoms, Prevalence, Pathophysiology, Diagnosis, Complications and Management of Diabetes mellitus. It includes both Conventional and Naturopathic management.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
NVBDCP.pptx Nation vector borne disease control program
Imeglimin a new class a new approach for diabetes management
1. Approaching Mitochondrial bioenergtics : A new
prospect for type 2 diabetes
Prepared and presented by :
Dr . Yara Eid
Professor of Endocrinology and Metabolism –Ain-Shams
University
2. Key points
• Mitochondrial structure and function
• Mitchondrial dysfunction in diabetes
• Glimins : a targeted therapy for
diabetes ?!
3. Mitochondrial bioenergetics
• Bioenergetic Science started in seventh century with the pioneer
works by Joseph Priestley and Antoine Lavoisier on photosynthesis
and respiration, respectively
• It progressed over the past century till full elucidating the glycolytic
pathway , Kerbs cycle , ETC and identification of UCP and still
progressing
4. The power stations in
human body
key regulator of GSIS
REDOX generator
Regulator of apoptosis
7. Mitochondrial
biogenesis
• Mitochondria can change their number, size and activity within a cell
through dynamic alteration of biogenesis, fusion and fission
• The master switch of mitochondrial biogenesis is the peroxisome
proliferator-activated receptor-c coactivator (PGC)-1a and PGC-1b
• PGC-1a regulates various aspects of mitochondrial function including
biogenesis, adaptive thermogenesis, fatty acid oxidation and peripheral
tissue glucose uptake
8. Mitochondrial dysfunction in diabetes
1. Genetic factors
• mtDNA mutations
• nuclearDNA mutations (MODY , 3 subtypes are associated with
mitochondrial dysfunction and B cell dysfunction)
• Large scale genome studies in type 2 diabetes showed at least two genes
from 18 to have a close relationship with mitochondrial dysfunction
9. Mitochondrial dysfunction in diabetes
2. Environmental factors
• Obesity :
o sedentary life style decrease mitochondrial content and oxidative capacity
o Increased caloric intake and increased intramyocellular and intrahepatic fat
accumulation , increase REDOX generation
• Environmental pollutants
o Persistent organic pollutants (POPs) are the true environmental factor
causing mitochondrial dysfunction leading to T2DM through decreasing
mitochondrial oxidative capacity and thereby ATP production
10. • Mutated and
decreased expression
of mDNA
• Increased Apoptosis
• Decreased
mitochondrial
remodelling
11. Decreased mitochondrial fatty acid oxidation increases cytosolic
LCAC, a potent inhibitor of glycogen synthase and hexokinase, and
leads to insulin resistance through decreased level of AMPK
17. DeFronzo RA, 55th EASD meeting , The role of mitochondrial dysfunction in the pathophysiology of diabetes ;
oral presentation # S22.1 . 18th September 2019
Imeglimin
Lipid oxidation
mDNA
PCG-1 α
18. Summary
• Imeglimin improves Mitochondrial function by:
1. improves Complex II activity leading to increased
mitochondrial oxidation of CII substrate (lipids) and Inhibit
Complex I activity
2. Decrease ROS overproduction and protecting mitochondria
from excessive oxidative stress (Beta cell preservation)
3. Increase PCG-1α , the master regulator of mitochondrial
biogenesis.
4. Increase the number of mitochondria . (increase ATP and
increase GSIS )
DeFronzo RA, 55th EASD meeting , The role of mitochondrial dysfunction in the pathophysiology of diabetes ;
oral presentation # S22.1 . 18th September 2019.
19. TIMES Clinical studies Phase 3 program
Trials of Imeglimin Efficacy and Safety
Spin off in 2009 Diabetes specialist Deal in 2017
Imeglimin the first of five
promising Antidiabetic programs
including AMPK activator
20.
21.
22.
23. Phase 2 trial
DeFronzo RA, 55th EASD meeting , The role of mitochondrial dysfunction in the
pathophysiology of diabetes ; oral presentation # S22.1 . 18th September 2019.
24.
25.
26. TIMES 2 study-DDP4i TIMES 2 study-SGLT2 inhibitors
DeFronzo RA, 55th EASD meeting , The role of mitochondrial
dysfunction in the pathophysiology of diabetes ; oral presentation
# S22.1 . 18th September 2019.
27.
28. Imeglimin in conclusion
• A GAME CHANGER : First OHA with Multiple targeted mechanism of
action
• Addresses core diabetes pathologies : decrease hepatic glucose
production , improves skeletal insulin sensitivity , improves beta cell
function.
• Speculated to be the first effective ttt for NASH.
• Safe in CKD 3A patients (65-45ml/min)
• Ongoing preclinical trials in Heart failure ( HFpF and HFrF).
Editor's Notes
Mitochondria have their own DNA and several copies of mitochondrial DNA (mtDNA) are present per mitochondrion5. The mtDNA is a circular DNA with 16,569 base pairs7. It encodes 37 genes. Thirteen genes are coding for proteins of the electron transport chains and the rest are coding for the two rRNA and the 22
tRNA. In contrast, the majority of proteins regulating mitochondrial
structure, metabolic function and biogenesis are encoded by
the nuclear DNA (nDNA). For example, the transcription and
replication of mtDNA is regulated by the mitochondrial transcription
factor A (TFAM), which is encoded by the nDNA8.
There is complex interplay between the nucleus and the mitochondria
to ensure proper functioning of the mitochondria
Major functions of mitochondria. The three major functions of mitochondria in regard to energy metabolism include: (i) adenosine
triphosphate (ATP) production; (ii) generation of reactive oxygen species (ROS); and (iii) apoptosis. The NADH and FADH2, which are reducing
equivalents yielded from the tricarboxylic acid (TCA) cycle, transfer the electrons to the electron transport chain through complex I and complex II,
respectively. As the electrons are transported to complex III and IV, the protons are accumulated in the intermembranous space generating the
electrochemical gradient. Complex V uses the proton gradient as the driving force to generate ATP. During the process of electron transport, some
of the electrons can be leaked and transferred to O2, which results in ROS generation. When the cellular ATP is depleted or in excess of ROS,
mitochondrial proteins such as cytochrome c, caspases and apoptosis initiating factors are released to cytosol and initiate the process of apoptosis.
ADP, adenosine diphosphate.
A mitochondrion is structurally divided into four compartments: (i) the outer membrane, which is capable of freely transporting
ions and small molecules; (ii) the intermembranous space, where protons are accumulated and generate an electrochemical gradient; (iii) the inner membrane, which allows thetransport of otherwise impermeable adenosine diphosphate (ADP), phosphate and ATP, and anchors subunit complexes of the electron transport chains; and (iv) the matrix where oxidation of pyruvate and fatty acids occur (Figure 1). The inner membrane has numerous invaginations called the cristae, which gives mitochondria its characteristic morphology. By increasing the surface area, mitochondria can increase the ATP generating capacity.
When calorie intake is in
excess or the capacity of oxidative phosphorylation is limited,
the electron transport is impaired in the electron transport chain
and has higher chance of being converted to ROS. These ROScan damage proteins, lipids and mtDNA of mitochondria and
further increase the production of ROS. The mtDNA has no
introns and has a poorly equipped repair mechanism, rendering
it susceptible to oxidative damage and mutations. The mtDNA
mutations accumulate with age, and these mutations might play
an important role in the process of senescence and diabetes
Mitochondria are also the prime regulators of apoptosis6.
When confronted with cellular stress, mitochondria open the
mitochondrial permeability transition pore (mtPTP)18. Opening
of the mtPTP allows the release of mitochondrial proteins, such
as cytochrome c, caspases and apoptosis initiating factor (AIF),
to induce apoptosis. Oversupply of calories or physical inactivity
can impair the transfer of electrons through the electron transport
chain, leading to increased production of ROS and consequent
apoptosis in various cells and tissues6
MODY 1, 3, 4
HNF-4a, the gene mutated
in MODY1, is a transcription factor of the nuclear hormone
receptor superfamily and plays a role in hepatocyte differentiation36.
It has been shown that genetic alteration of HNF-4a
could result in decreased mitochondrial function, such as
reduced pyruvate oxidation, decreased ATP generation and
blunted glucose-stimulated insulin secretion in pancreatic
b-cells37.
Disuse of mitochondria and ATP decrease content
are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes.[1] Because of their persistence, POPs bioaccumulate with potential adverse impacts on human health and the environment. The effect of POPs on human and environmental health was discussed, with intention to eliminate or severely restrict their production, by the international community at the Stockholm Convention on Persistent Organic Pollutants in 2001.
Many POPs are currently or were in the past used as pesticides, solvents, pharmaceuticals, and industrial chemicals.[1] Although some POPs arise naturally, for example volcanoes and various biosynthetic pathways, most are man-made[2] via total synthesis.
Patients with diabetes who have mutations in mtDNA or mitochondria related nuclear DNA, largely show impaired pancreatic
b-cell insulin secretory function. This is because ATP generated from mitochondria is the key factor that couples the blood
glucose level with insulin secretion. When blood glucose enters the pancreatic b-cell, increased ATP/ADP ratio depolarizes the
plasma membrane by closing the ATP-sensitive K channel. This leads to a calcium influx by the opening of the voltagesensitive
calcium channel. Increased calcium concentration stimulates the fusion of insulin containing granules with the plasma membrane and consequently leads to insulin secretion88. A defective mitochondrial function in any of the above
processes can lead to impaired insulin secretion and T2DM.
AMPK is a cellular energy gauge that senses the AMP/ATP
ratio77. Its activation inhibits acetyl-CoA carboxylase78, therefore
decreasing fatty acid synthesis in the liver and increasing fatty
acid oxidation in the muscle. Interestingly, AMPK can increase
the expression of PGC-1a and the consequent pathway of
mitochondrial biogenesis79, 80. In contrast to obesity, physical
activity and calorie restriction increase AMPK
Obese insulin resistant individuals are characterized by increased plasma free fatty acids (FFA)
concentrations, an elevated basal rate of lipolysis and impaired suppression of lipolysis by insulin
(Koutsari and Jensen 2006 , 1643–50). Increased levels of FFA may directly mediate the development
of insulin resistance since it was shown that plasma FFA concentration correlates with the degree of
insulin resistance and experimental elevation of plasma FFA in young healthy individuals induces
insulin resistance (Belfort et al. 2005 , 1640–48). How increased FFA cause insulin resistance has not
been completely elucidated. A growing body of evidence shows that nutrient overload causes accumulation
of specifi c intramyocellular FFA metabolites. These metabolites interfere with the insulin
signalling cascade and the glucose transporter GLUT 4 resulting in decreased insulin-mediated glucose
uptake