Late Complications of Diabetes

• Circulatory Abnormalities:
  • Atherosclerosis: more extensive and occurs earlier (accelerated course)
    • Lesions initiated by oxidized LDL
  • Increased platelet adhesiveness
  • Increase secretion of endothelin-1
    • Endothelin-1:powerful vasoconstrictor; vascular smooth muscle mitogen
  • Decreased nitric oxide production:
    • Nitric oxide: vasodilator; anti-mitogenic in vascular smooth muscle
  • Diabetes: procoagulant state--
    • increased levels of tissue factor
    • deficiency of tissue factor pathway inhibitor type 1
    • factor VIII elevated
    • impaired fibrolysis: (probably as a result of increased tPA inhibitor, type 1)
  •  Symptoms:
    • Intermittent claudication, gangrene, impotence (vascular)
    • Coronary artery disease; stroke:common
    • Silent myocardial infarction

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• Retinopathy:
  •  Diabetic retinopathy: leading cause of blindness in the U.S.
  • Retinopathic lesions:
    1. simple (background)
    2. proliferative
  • Progression:
    • Increased capillary permeability
    • Retinal capillary occlusion (saccular and fusiform aneurysms)
  • Vascular lesions associated with:
    • Proliferation of lining endothelial cells
    • Pericyte loss around vessels
  • Proliferative retinopathy: new vessel formation and scarring.

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• Diabetic Nephropathy
  •  Renal disease: leading cause of death and disability due to diabetes.
  • 50% of end-stage renal disease in United States: diabetic nephropathy
  • Complication rates:
    • 35% of IDDM patients
    • 15 to 60% of NIDDM patients (ethnic background dependent; highest -- Pima Indians;lowest- Europeans)
  • Two pathologic patterns:
    • diffuse-- more common
      • widening of glomerular basement membrane
      • menangial thickening
    • nodular
      • periodic acid-Schiff-positive material: deposited at glomerular tuft periphery
      • hyalinization of afferent and efferent arterioles
      • deposition of albumin and other proteins in tubules and glomeruli

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• Diabetic Neuropathy
  • Major cause of morbidity
  • Peripheral Polyneuropathy: most common
    • bilateral, characterized by:
      1. numbness
      2. paresthesias
      3. severe hyperesthesias
      4. pain (deep-seeded, severe)
  • Mononeuropathy: characterized by --
    • wrist drop
    • foot drop
    • paralysis of third, fourth or sixth cranial nerve
  • Radiculopathy:
    • Sensory syndrome: pain -- distribution of one or more spinal nerves -- usually in chest wall or abdomen
  • Autonomic neuropathy:
    •  Significant target: gastrointestinal tract -- symptoms include:
      • esophageal dysfunction
      • delayed gastric emptying
      • constipation or diarrhea
    •  Orthostatic hypotension
    •  Syncope
    •  Cardiopulmonary arrest; sudden death
    •  Bladder dysfunction (may require chronic catheter drainage)
    •  Impotence/retrograde ejaculation
  • Treatment:
    • Pain: if severe, codeine -- drug of choice -- other options:
      • phenytoin
      • combination treatment with amitriptyline and fluphenazine

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• Diabetic Foot Ulcers:
  • Secondary to diabetic neuropathy: abnormal pressure distribution
  • Vascular disease (decreased perfusion): augments ulcer development
  • Infection: common (multiple organisms)
    • Initial antibiotic treatment (until culture results are available):
      • ampicillin-sulbactam plus gentamycin or aztreonam

• Autonomic Dysfunction:Diabetes Mellitus:
  • initial finding: often asymptomatic abnormal vagal function (reduced heart rate variation with deep breathing)
    • Loss of myelinated and non-myelinated small nerve fibers in splanchnic distribution, carotid sinus, and vagus nerve
  • Enteric neuropathy:
    • disturbances and gut motility
    • nausea/vomiting
    • achlorhydria
    • bowel incontinence
  • Other Symptoms:
    • impotence
    • urinary incontinence
    • pupillary abnormalities
    • postural hypotension
    • symptoms of hypoglycemia -- blunted or detectable because damage to sympathetic adrenal gland innervation prevents epinephrine release
    • Autonomic dysfunction may lengthen Q-T interval -- associated with sudden cardiac death

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