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Recent Trends In Diabetic Neuropathy Research

Guided by Dr. Ashutosh Kumar

Presented by J. Vishnu RT/2016/604

Contents

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Introduction

Epidemiology

Etiology

Pathophysiology

Summary

Introduction • Diabetic Neuropathy is a family of nerve disorders caused by diabetes.

• People with diabetes can, over time, develop nerve damage throughout the body.

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Epidemiology

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According to the latest 2014 data from the World Health Organization (WHO),

Globally an estimated 422 million adults are living with diabetes

Expected to rise to 592 million by 2035

Neuropathy affects up to 50% of people with diabetes

Etiology

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Hyperglycemia

Polyol pathway

Hexosamine pathway

Activation of protein kinase C (PKC)

Advanced glycation end - product

Increased oxidative stress

Endoplasmic reticulum stress

Mitochondrial dysfunction

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Mitochondrial Dysfunction in Diabetes Neuropathy

AMPK Signaling

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Impaired AMPK signaling under hyperglycemic conditions is cause mitochondrial dysfunction

Reduced Thr172 phosphorylation of AMPK resulted in decreased

mitochondrial biogenesis and autophagosome formation in diabetic

Activation of AMPK enhances SIRT1

It is further enhances the PGC-1α-mediated mitochondrial biogenesis

AMPK decreases the Nuclear Factor kappa B (NF-κB)-directed neuro inflammation

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Glucose uptake is insulin-independent in neurons via GLUT 3 glucose transporters

During hyperglycemia, glucose overloads in the neuronal cells

This excess metabolic load increases the oxidative phosphorylation of glucose via

Glycolysis and Krebs cycle which increases the production of reducing equivalents; NAD+/

NADPH ratio

Increased reducing equivalents enhances the excess leakage of electrons across the ETC

That transfers to oxygen molecule to generate superoxides so called ROS.

Further , ROS damages proteins, lipids and nucleic acids

Mitochondrial dysfunction

Veera ganesh yerra ,ashutosh kumar, Mol Neurobiol, Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy,2016,2-12

Cont…

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Mitochondria is a semi autonomous cell organelle

Which synthesize 13 important proteins which composes for ETC components.

Damage to mitochondrial DNA aggravates into abnormal ETC

That alters the mitochondrial potential gradient and decrease ATP production

Further the bio-energetic sensor ; AMPK sensitize towards depleted ATP

And compensate the decreased ATP by generating new mitochondria and removing

damaged cell organelles

Via regulating proteins involved in mitochondrial biogenesis and autophagy respectively

Cont…

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Mitochondrial dysfunction in diabetes neuropathy is associated with

1. Abnormal autophagic reflex

2. Inadequate mitochondrial biogenesis

Autophagy :

Definition :

Autophagy is a cellular catabolic process meant for recycling of damaged cellular components through lysosomal digestion

• Autophagy is a neuroprotective measure

• Reduce the accumulation of damaged cellular components and protein Aggregates in

neurological disorders

Yerra VG, Gundu C, et al ;Autophagy: the missing link in diabetic neuropathy? Med Hypotheses 86: 2015,120–126

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• Reduced formation of autophagosomes under hyperglycaemic conditions

• Due to the reduced expression of LC3B-II and Beclin1.

• Beclin1 with class III PI3K enzyme is helps to formation of phagophore

• And recruitment of other autophagy related proteins

• Such as LC3B-II to the phagophore which leads to formation of autophagosomes

• Autophagy is initiated by the formation of a phagophore around cellular cargo

• The process is called nucleation

Veera Ganesh Yerra, Chayanika Gundu, Pragna Bachewal, Ashutosh Kumar, autophagy the missing link of diabetic neuropathy,Elsevier ,2015,212-125

Cont…

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•The phagophore may be derived from Golgi apparatus or endoplasmic reticulum

•It is formed by the association of Atg 13 and Atg 17 with the help of Atg1

•This step is controlled by mammalian target of rapamycin (mTOR) kinase making the

autophagy susceptible for nutrient availability and stress signals

•The mTOR causes phosphorylation of Atg13, prevents its association with Atg1

•It leads to the Abnormal autophagic reflex and mitochondrial dysfunction

•Thus, autophagy plays a vital role in removal of damaged mitochondrial subunits (mitophagy)

and give a new scope for mitochondrial biogenesis

Cont…

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Mitochondrial Biogenesis :

Definition:-

The process by which cells increase their individual mitochondrial mass and copy number

• Advanced research have been shown decreased mitochondrial biogenesis in Experimental DPN

• Majorly mitochondrial biogenesis was shown regulated via AMPK-SIRT 1- PGC 1 α axis

• Two weeks Treatment with A769662; a selective AMPK activator to STZ induced diabetic animals

• Shown increased mitochondrial biogenesis via enhancing AMPK-SIRT 1- PGC 1 α axis

Cont…

Paul Fernyhough et al, Curr Diab Rep 15, Mitochondrial Dysfunction in Diabetic Neuropathy: a Series of Unfortunate Metabolic Events 2015, 2-10

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• PGC 1 α is a transcription co activator of peroxisome proliferator activated receptor (PPAR-γ )

• Which translocalizes into nucleus and binds with respective DNA transcription element

• And regulates the expressions of nuclear respiratory factor (NRF-1) and Tfam

• NRF-1 and Tfam are transcription factors that encodes for mitochondrial subunits

• Together by adopting all important proteins from nucleus into mitochondria and mitochondrial

encoded proteins contributes for formation of new mitochondria- (mitochondrial biogenesis)

Cont…

Sunil Kumar Kota ,International Journal of Clinical Cases and Investigations of diabetes neuropathy , 2012. Volume 4 ,2012, 44:59,

Mitochondrial Dysfunction; Possible Involvement of Mitophagy and Mitochondrial Biogenesis

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Veera ganesh yerra ,ashutosh kumar, Mol Neurobiol, Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury,2016,2-12

Summary

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Impaired AMPK signaling under hyper glycemic conditions is known to cause

Mitochondrial dysfunction in diabetic sensory neurons.

AMPK activation facilitated the clearance of damaged mitochondria and also enhances the

biogenesis of healthy mitochondria.

By Normalizing the mitochondrial superoxide production, we can reduce the mitochondrial

dysfunction in diabetic neuropathy.

Increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed

mitochondrial biogenesis

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Thank you