Presented By

Sasmita Saha

2nd Year, M. Pharm.Roll-550

Under guidance of

Prof. P.D. Mali

SINHGAD COLLEGE OF PHARMACY, VADGAON, PUNE-41

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).

Neuropathy ??

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)

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 diseases5. 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.

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 NeuropathyDiffuseSensorimotor PolyneuropathyAsymmetric lower limb motor neuropathy/ AmyotrophySymmetric Proximal lower limb motor neuropathy

• Autonomic neuropathy- VasomotorSudomotorCVDGIGenitourinary

• Central neuropathy- Stroke, Seizures, Schizophrenia, Dementia, & Cognitive impairment

• Focal neuropathy- Focal-limb, TruncalThoracolumbar radiculoneuropathy Cranial, & Entrapment

• Proximal neuropathy-lumbosacral radiculoplexus (Bruns-Garland syndrome) / femoral neuropathy/ diabetic amyotrophy

Pathogenesis

MICRO-&-MACROVASCULAR COMPLICATIONS.

• Metabolic Pathways- 1. Polyol pathway2. Hexosamine pathway3. Prostaglandin Pathway4. L-Carnitine Pathway.5. Neurotrophic factors

• Inflammatory Mechanism- 1. NO degradation2. A.G.E.3. Oxidative stress.

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

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

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.)

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.

• 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

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.

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.

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).

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 atcomplex III, & increases free-

radicals half life.

Coenzyme Q intermediates reduces Oxygen to

superoxide.

Mitochondrial superoxide

activates 4 major pathways.

Each of the4 different pathogenic

mechanisms reflects a single hyperglycemia-

induced process: overproduction of superoxide by

themitochondrial

electron-transport chain.

Michael Brownlee, The Pathobiology of Diabetic Complications A Unifying Mechanism, Diabetes:54, June 2005, 1615-1626

PARP Pathway

PARP found in Schwann,endothelial cells, andsensory neurons. A nuclearenzyme closely associatedwith oxidative-nitrosativestress, implicated inglucotoxicity.

ROS-induced DNA damage activates PARP and modifies GAPDH.

Unifying mechanism of hyperglycemia induced cellular damage.

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.

Neuroinflammation & Role in Peripheral Nerve Damage-

Inflammatory mediators

Cytokineso Chemokineso 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.

Fig: Cytokine network in the pathogenesisOf streptozotocin-induced neuropathic pain.

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

Pro inflammatorycytokines

Intracellular cytokine-associated signaling pathways.

Juan F. Navarro-González, and Carmen Mora-Fernández,J. Am Soc Nephrol, 2008;19:433-442.

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.

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

Crosstalk between oxidative stress and inflammation

Central Complications

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

Diabetes mellitus/Hyperglycemia and stroke damage Acidotoxic brain damage and pannecrosis.

Excitotoxic brain damage

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

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

References1. 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.

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 signallinglinks 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

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