1. Presented By
Sasmita Saha
2nd Year, M. Pharm.
Roll-550
Under guidance of
Prof. P.D. Mali
SINHGAD COLLEGE OF PHARMACY, VADGAON, PUNE-41

2. Diabetes? Insulin-dependent diabetes mellitus (IDDM)/ Juvenile.
 Noninsulin-dependent diabetes mellitus (NIDDM).
 Secondary diabetes.
 Gestational diabetes
 Impaired glucose tolerance/ Asymptomatic/ chemical/ subclinical/
borderline
 latent diabetes (prediabetes be abandoned).

3. Neuropath
y ??
 Diabetes
 Mechanical injuries
 B12 or folate vitamin
 Cancers Alcohol excess
 Chronic kidney disease
 Chronic liver disease.
 Injuries Infections
 Guillain- Barré
syndrome
 Certain inflammation
 Hereditary diseases
 Idiopathic
 Problem with the nerve, arising from injury or abnormal activity.
 Might be central/ peripheral.
 Mono, Multiple-mono & Poly- Neuropathies
Dr. Helen Webberley, Neuropathy: Symptoms & diagonosis,18 March
2016.(http://www.medicalnewstoday.com/articles/147963.php?page=2)

4. Diabetic
Neuropathy ?? Neuropathic disorder due to diabetes mellitus, nerve damage
occurs by high blood sugar level.
 Macrovascular complication's, & small blood vessels that supply
nerves (Vasa Nervorum).
 Characterized by:
1.Gradually increasing urinary albumin
excretion (UAE).
2.High blood pressure (BP).
3. Declining glomerular filtration rate.
4. Absence of other renal/renal tract diseases
5. Diabetic retinopathy
• Krista Davies, Diabetic neuropathy, Ohio northern university
• Unger J, Cole BE. Recognition and Management of Diabetic
Neuropathy. Prim Care Clin Office Pract 2007; 34: 887-913.

6. Types
J gareth llewelyn, The diabetic neuropathies: types, diagnosis and management, J Neurol Neurosurg Psychiatry 2003; 74(Suppl II):ii15–ii19
• Sensorimotor- Distal Symmetric/ Peripheral Neuropathy
Diffuse
Sensorimotor Polyneuropathy
Asymmetric lower limb motor neuropathy/ Amyotrophy
Symmetric Proximal lower limb motor neuropathy
• Autonomic neuropathy- Vasomotor
Sudomotor
CVD
GI
Genitourinary
• Central neuropathy- Stroke, Seizures, Schizophrenia, Dementia, & Cognitive
impairment
• Focal neuropathy- Focal-limb, Truncal
Thoracolumbar radiculoneuropathy
Cranial, & Entrapment
• Proximal neuropathy-lumbosacral radiculoplexus (Bruns-Garland
syndrome) / femoral neuropathy/ diabetic amyotrophy

7. Pathogenesis
MICRO-&-MACROVASCULAR COMPLICATIONS.
• Metabolic Pathways- 1. Polyol pathway
2. Hexosamine pathway
3. Prostaglandin Pathway
4. L-Carnitine Pathway.
5. Neurotrophic factors
• Inflammatory Mechanism- 1. NO degradation
2. A.G.E.
3. Oxidative stress.

8. Reddemma Sandireddy, Veera Ganesh Yerra, Aparna Areti,Prashanth Komirishetty, and Ashutosh Kumar, Neuroinflammation and Oxidative
Stress in Diabetic Neuropathy, International Journal of Endocrinology, 2014, 1-11.
Pathophysiology of diabetic
neuropathy

9. Neurovascular effects of altered
metabolism in diabetes
Sean O’Brien,Margaret Schwedler, Morris D. Kerstein, Peripheral Neuropathies In diabetes, Nonoperative management of
Lower extremity arterial disease, part 1, 78(3),1998 June, 393-408.
 Increased polyol
pathway flux, elevated
oxygen free radical
formation, and
advanced glycosylation.
 Impaired W-6 essential
fatty acid and carnitine
metabolism depends on
both hyperglycemia and
hypoinsulinemia or
impaired insulin action

10. Polyol Pathway
• Sorbitol induced osmotic distress
• Decreased GSH & increase in ratio of NADPH/NAD+, inhibits the activity
of glyceraldehyde-3-phosphate dehydrogenase
. (Vikramadithyan RK, Hu Y, Noh HL, et al. Human aldose reductase expression in transgenic mice. J Clin Invest. 2005 Sep;115:2434-2443.)

11. Increased flux through the first half
of the POLYOL PATHWAY can reduce
the effectiveness of the glutathione
redox cycle in scavenging oxygen
free radicals,& leading to
neurovascular dysfunction.
Causal relationship
between metabolic
changes and
peripheral nerve
blood flow &
function.

13. • Increased AGE
precursors and
pathology.
James L. Edwards, Andrea Vincent, Thomas Cheng, and Eva L. Feldman*, Diabetic Neuropyath: Mechanisms to Management, Pharmacol Ther. 2008 October ; 120(1): 1–34.
AGE
Pathway

14. PKC Pathway
• Consequences of Hyperglycemia induced PKC(β- and δ-isoforms)
activation, from DAG.
Michael Brownlee, Biochemistry and molecular cell biology of diabetic complications, Nature,2001 December, 414: 813-820.
James L. Edwards, Andrea Vincent, Thomas Cheng, and Eva L. Feldman*, Diabetic Neuropathy: Mechanisms to Management, Pharmacol Ther. 2008 October ; 120(1): 1–34.

15. Hexosamine
Pathway
Michael Brownlee, Biochemistry and molecular cell biology of diabetic complications, Nature,2001 December, 414: 813-820.
Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964-969..
O-linked N-Acetyl glucosamine ,
reducing expression of insulin
responsive genes, leading to
selective insulin resistance in
vascular endothelial cells.

16. L-Carnitine Pathway
• L-carnitine Can prevent type 2 diabetes by improving fat metabolism
Tina Kaczor, The Therapeutic Effects of Acetyl-L-Carnitine on Peripheral Neuropathy: A Review of the Literature, Natural Medicine Journal,2010 August, 2(8).

17. How does hyperglycemia increase
superoxide production by the
mitochondria ?From the overview of glucose metabolism-
• Electron flow through ETC by 4 inner membrane-
associated enzyme Complexes, & cytochrome c and
mobile electron carrier ubiquinone.
Electron donors from the
TCA (NADH and FADH2)
generate a high
mitochondrial membrane
potential (DmH+).
Inhibits electron transport at
complex III, & increases free-
radicals half life.
Coenzyme Q intermediates
reduces Oxygen to
superoxide.

18. Mitochondrial
superoxide
activates 4 major
pathways.
Each of the
4 different
pathogenic
mechanisms
reflects a single
hyperglycemia-
induced process:
overproduction
of superoxide by
the
mitochondrial
electron-
transport chain.
Michael Brownlee, The Pathobiology of Diabetic Complications A Unifying Mechanism, Diabetes:54, June 2005, 1615-1626

19. PARP Pathway
PARP found in Schwann,
endothelial cells, and
sensory neurons. A nuclear
enzyme closely associated
with oxidative-nitrosative
stress, implicated in
glucotoxicity.
ROS-induced DNA damage activates
PARP and modifies GAPDH.
Unifying mechanism of hyperglycemia
induced cellular damage.

20. Oxidative stress &
apoptosis
-Role in Neuronal Dysfunction
 Insulin resistance causes
mitochondrial
overproduction of ROS in
macrovascular endothelial
cells by increasing FFA flux
and oxidation.
o Not a microvascular effect
Hofmann S, Brownlee M: Biochemistry and molecular cell biology of diabetic complications: a unifying mechanism. In Diabetes Mellitus: A Fundamental and Clinical Text. 3rd ed.
LeRoith D, Taylor SI, Olefsky JM, Eds. Philadelphia, Lippincott Williams & Wilkins, p. 1441–1457, 2004.

21. Neuroinflammation & Role in
Peripheral Nerve Damage-
Inflammatory mediators
 Cytokines
o Chemokines
o TNFs
 Toll like
receptors
 NF-κB
Sean O’Brien,Margaret Schwedler, Morris D. Kerstein, Peripheral Neuropathies In diabetes, Nonoperative management of
Lower extremity arterial disease, part 1, 78(3),1998 June, 393-408.

22. Fig: Cytokine network in the pathogenesis
Of streptozotocin-induced neuropathic pain.

23. Neuroinflammation and neuropathic pain: Hyperglycemia induced Followed by a peripheral injury

24. Pro inflammatory
cytokines
Intracellular cytokine-associated signaling pathways.
Juan F. Navarro-González, and Carmen Mora-Fernández,J. Am Soc Nephrol, 2008;19:433-442.

25. The roles of TNF-α as recognized at different levels of the nervous system in Diabetic
neuropathy: (1) At Site Of Nerve Injury; (2) At Dorsal Root Ganglion; (3) At Dorsal Horn Of
The Spinal Cord; and (4) At The Brain And Higher Centers.

26. Natalie M. Wilson and Douglas E. Wright*,Inflammatory Mediators in Diabetic Neuropathy, J Diabetes Metabolism 2011,S5-004, 1-6

27. Crosstalk between oxidative
stress and inflammation

29. Central
Complications
D.J. Robinson et al., Diabetes and Mental Health, Canadian Journal of Diabetes(37),2013, S87-S92

30.  Diabetes mellitus/Hyperglycemia and stroke damage
 Acidotoxic brain damage and pannecrosis.
 Excitotoxic brain damage




31. Small Nerve Fibers Defy Neuropathy Conventions-
- Peripheral neuropathy research study suggests even prediabetes could
cause nerve damage.(JULY 11, 2016).
(https://www.foundationforpn.org/2016/07/11/small-nerve-defy-neuropathy-
conventions/ )
Neuropathy Pain Strongest Predictor of Depression in Diabetes
-Conflicting results from studies examining the use of duloxetine or
pregabalin, an antidepressant can be added to analgesics.(August 02, 2016),
(http://dvr.sagepub.com/content/early/2016/06/21/1479164116653240.full.pdf+html )
Underlying Cause of Diabetic Peripheral Neuropathy Targeted in
Gene Therapy Trial(July27,2016)
-VM BioPharma Announces First Patient Dosed in Phase 3 Study of Gene
Therapy Candidate, VM202, in Painful Diabetic Peripheral Neuropathy, First
Pivotal Gene Therapy Trial to Target Underlying Cause of Diabetic
Peripheral Neuropathy,( https://www.foundationforpn.org/2016/07/11/gene-therapy-
trial-target-underlying-cause-diabetic-peripheral-neuropathy/ )
 Recent
Approches

32. Central nervous system role in painful diabetic peripheral nerve
disease (January 27, 2016). (http://medicalxpress.com/news/2016-01-central-
nervous-role-painful-diabetic.html) .
 Invokana: The “Cure” That is as Bad As The Disease- (August 23,
2016)
-Invokana is part of a class of drugs known as “gliflozins.
(http://trofire.com/2016/08/23/invokana-cure-bad-disease/ )
Vitamin D be Linked to Carpal Tunnel Syndrome-
-Lower levels correlated with earlier age for disease development.
(http://www.medpagetoday.com/MeetingCoverage/ASBMR/54044 )
 Recent
Approches

33. Refere
nces1. Dr. Helen Webberley, Neuropathy: Symptoms & diagonosis,18
March 2016.
2. D.J. Robinson et al., Diabetes and Mental Health, Canadian Journal
of Diabetes(37),2013, S87-S92.
3. Natalie M. Wilson and Douglas E. Wright*,Inflammatory Mediators
in Diabetic Neuropathy, J Diabetes Metabolism 2011,S5-004, 1-6.
4. Sean O’Brien,Margaret Schwedler, Morris D. Kerstein, Peripheral
Neuropathies In diabetes, Nonoperative management of Lower
extremity arterial disease, part 1, 78(3),1998 June, 393-408.
5. Hofmann S, Brownlee M: Biochemistry and molecular cell biology
of diabetic complications: a unifying mechanism. In Diabetes
Mellitus: A Fundamental and Clinical Text. 3rd ed. LeRoith D,
Taylor SI, Olefsky JM, Eds. Philadelphia, Lippincott Williams &
Wilkins, p. 1441–1457, 2004.

34. 6. Michael Brownlee, The Pathobiology of Diabetic Complications A
Unifying Mechanism, Diabetes:54, June 2005, 1615-1626.
7. Tina Kaczor, The Therapeutic Effects of Acetyl-L-Carnitine on
Peripheral Neuropathy: A Review of the Literature, Natural
Medicine Journal,2010 August, 2(8).
8. Michael Brownlee, Biochemistry and molecular cell biology of
diabetic complications, Nature,2001 December, 414: 813-820.
9. Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signalling
links O-GlcNAc transferase to insulin resistance. Nature.
2008;451:964-969.
10.James L. Edwards, Andrea Vincent, Thomas Cheng, and Eva L.
Feldman*, Diabetic Neuropathy: Mechanisms to Management,
Pharmacol Ther. 2008 October ; 120(1): 1–34.
References

35. 11. Anders A.F. Simaa,b,c, Hideke Kamiyaa,c, Zhen Guo Li, Insulin, C-
peptide, Hyeperglycemia & Central Nervous System Complications in
Diabetes Mellitus, European Journal of Pharmacology (490),
2004,187– 197.
12. Ursula Stockhorsta, Detlev de Friesa, Hans-Joachim,,
Steingruebera, Werner A. Scherbaum, Insulin and the CNS: effects on
food intake, memory, and endocrine parameters and the role of
intranasal insulin administration in humans, Physiology & Behavior
(83),2004, 47–54.
13. Bingmei Yang, Andrea Hodgkinson, Beverley A. Millward,
Andrew G. Demaine, High glucose-induced DNA-binding activities of
nuclear factor of activated T cells 5 and carbohydrate response
element binding protein to the myo-inositol oxygenase gene are
inhibited by sorbinil in peripheral blood mononuclear cells from
patients with type 1 diabetes mellitus and nephropathy,
International Journal of Diabetes Mellitus 2, 2010, 169–174.
References