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Diabetic Polyneuropathy

Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) ↑ Glycolysis (breakdown of glucose) ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, polyols (sorbitol & fructose), NADH) Protein Kinase C Pathway activated & ↑ inflammation in endothelium, vascular smooth muscle, fibroblasts of blood vessels Prothrombotic state with ↑ vascular fibrosis, ↑ smooth muscle proliferation, ↑ chance of blood clots, ↑ impaired endothelial- mediated vasodilation Arterial stiffening & ischemia Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind AGE receptors on endothelium & white blood cells ↑ Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system Polyol pathway activated in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ NADH (reducing agent) overloads the electron transport chain ↑ Leakage of electrons in the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 28, 2014; updated Nov 16, 2024 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Raafi Ali Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia (↓ Intracellular insulin levels) ↓ Insulin induces expression of neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, insulin-like growth factor (IGF), & vascular endothelial growth factor (VEGF)) ↓ Stimulus for peripheral nerve maintenance & repair Impaired peripheral nerve repair Hyperglycemia (↑ Intracellular glucose levels) Protein Kinase C Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ Inflammation Prothrombotic state with ↑ chance of blood clots, ↑ vasoconstriction & ↑ arterial stiffening Ischemia ↑ Glycolysis (breakdown of glucose) Advanced Glycation End Products (AGEs): end products of glycolysis that have carbohydrates attached AGEs bind cellular receptors Inflammation, vascular permeability, procoagulant activity & monocyte influx Immune cells generate toxic reactive oxygen species as part of their defense system ↑ Intermediates & products of glycolysis (i.e. Protein Kinase C, AGE, sorbitol & fructose, NADH) Polyol Pathway in kidney, retina, nerves Excess glucose converted to sorbitol & fructose Metabolism of sorbitol & fructose produces intermediates that undergo auto-oxidation ↑ Reactive oxygen species ↑ Leakage of electrons when NADH (reducing agent) overloads the electron transport chain ↑ Free radical formation (type of reactive oxygen species that is toxic to cells & tissues when in excess) ↑ Oxidative stress Diabetic Polyneuropathy (damage to & loss of peripheral nerve function due to nerve hypoxia & impaired repair mechanisms) Sensory axonal loss Damage to small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesia (pins & needles feeling), dysthesia (burning, tingling, itching) X-ray: destruction of weight-bearing foot joints Damage to large myelinated fibers Loss of vibratory sensation in glove & stocking pattern distribution; altered proprioception Claw toe deformity Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Distal motor axonal loss ↓ Ability of axons to transmit signals to central nervous system to foot muscles ↓ Foot muscle strength, ↓ Coordination & imbalance between toe extensors & flexors Weight shift creates pressure points Fissures in skin of weight-bearing areas Infection & chronic ulceration Damage to nerves that control contractions of stomach muscles Gastroparesis: stomach muscles weakened, ↓ motility & delayed transit of contents Autonomic neuropathy Damage to nerves that control heart blood flow, contractions & contractility Damage to nerves that control blood flow and arousal responses for sexual function Erectile dysfunction Orthostatic or postural hypotension Exercise intolerance Resting tachycardia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Gurreet Bhandal Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ intracellular insulin levels ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias or tingling and numbness, dysthesias where sense of touch is distorted Hyperglycemia ↑ Intracellular glucose levels This produces an excess of glycolysis intermediates & products of glycolysis (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway in endothelium, vascular smooth muscle, fibroblasts of blood vessels ↑ inflammation Prothrombotic state with ↑ chance of blood clots; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them Polyol Pathway in kidney, retina, nerves Excess glucose is converted to sorbitol and fructose, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Large myelinated fibers Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Imbalance between toe extensors & flexors Weight shift results in pressure points Infection & chronic ulceration Gastroparesis: stomach muscles weakened with ↓ motility Claw toe deformity Erectile dysfunction Altered proprioception X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot: weakening of bones, joints, soft tissues causes pain insensitivity Cardiac: Resting tachycardia, exercise intolerance, orthostatic or postural hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Diabetic Polyneuropathy: Pathogenesis and clinical findings Authors: Amanda Eslinger Reviewers: Mark Elliott Jaye Platnich Alexander Arnold Haotian Wang Hanan Bassyouni* * MD at time of publication Hypoinsulinemia ↓ Neurotrophic factors (i.e. nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, IGF, & VEGF) ↓ stimulus for peripheral nerve maintenance and repair Impaired peripheral nerve repair Sensory axonal loss Small myelinated fibers Impaired pain, light touch & temperature sensation Pain, paresthesias, dysthesias Hyperglycemia ↑ Intracellular glucose levels This produces of glycolysis an excess of glycolysis intermediates & products (i.e. sorbitol & fructose; AGE; Protein Kinase C) PKC Pathway PKC pathway activation results in ↑ inflammation Prothrombotic state; vasoconstriction & arterial stiffening Ischemia Advanced Glycation End Products: The body “glycates” end products of glycolysis, which means that some end products have a carbohydrate added to them AGE’s bind cellular receptors inducing inflammation, vascular permeability, procoagulant activity & monocyte influx Polyol Pathway (i.e. sorbitol & fructose) Excess glucose is converted to sorbitol, which accumulates in cells ↑ Oxidative stress ↑ Free Radical Formation Nerve hypoxia & impaired repair mechanisms leading to dysfunction & loss of peripheral nerves Distal motor axonal loss Abbreviations: AGE – Advanced Glycation End Products IGF - Insulin-like Growth Factor VEGF - Vascular Endothelial Growth Factor PKC – Protein Kinase C Autonomic neuropathy Large myelinated fibers Altered proprioception Atrophy of intrinsic foot muscles Fissures in skin of weight-bearing areas Infection & chronic ulceration Imbalance between toe extensors & flexors Weight shift results in pressure points Gastroparesis Claw toe deformity Erectile dysfunction X-ray: destruction of weight-bearing foot joints Loss of vibratory sensation in glove & stocking pattern distribution Charcot Foot Cardiac: Resting tachycardia, exercise intolerance, orthostatic hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com