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DIABETES: NEUROPATHIES & NEUROMUSCULAR DISORDERS

Neuropathy
  General
  Symmetric
    Chronic
      Distal sensory/autonomic
      Autonomic
      Sensory-motor
    Acute
      Painful
      Reversible
  Asymmetric
    Lumbosacral plexopathy
    Mononeuropathies
    Mononeuritis multiplex
    HIEM
  Immune PN: Predisposition
    CIDP
    Diabetic amyotrophy
    HIEM
    Perineuritis
Muscle
  Infarction
Overview: Diabetes
  Classification
    Type 1: IDDM
    Type 2: NIDDM
    Other
  Mitochondrial disorders
  Neuromuscular disorders
  Screening
  Metabolic syndrome


Banting & Best



CLASSIFICATION OF DIABETES MELLITUS
DIABETES & NEUROPATHY: OVERVIEW 22

DIABETIC NEUROPATHIES: SYMMETRIC

  General
  Symmetric
    Chronic
      Distal sensory/autonomic
      Autonomic
      Sensory-motor
      Gustatory
    Acute
      Painful
      Reversible

Chronic Acute Diabetic Neuropathies


DIABETIC NEUROPATHIES: ASYMMETRIC

General
Amyotrophy
Lumbosacral plexopathy
Mononeuropathy
Mononeuritis multiplex
Multifocal
Diabetic neuropathy, Ongoing: Wallerian degeneration

Auche MB; Arch Med Exp Anat Pathol 1890;2:635676


DIABETIC MUSCLE INFARCTION (Myonecrosis) 2
  • Associated features
    • Diabetes
      • Chronic
      • Insulin-dependent
      • Poorly controlled (22%)
      • Type I (80%) or II (20%)
      • Duration: Long; Mean 16 years; Range 1 to 50 years
      • Other microvascular complications: Common (97%)
        • Renal (90%): Most with nephropathy; 25% failure
        • Retinopathy (65%)
        • Neuropathy (80%)
    • Hypertension
    • Female (61%) ≥ Male
  • Clinical
    • Onset
      • Acute
      • Pain & tenderness
      • Swelling
      • Age: Mean 40 years
    • Location
      • Thigh
        • Anterior (65%)
          • Gracilis; Rectus femoris; Vastus medialis
        • Medial (21%)
        • Posterior (14%)
      • Other muscles
        • Distal leg: Anterior or Posterior
        • Arms (3%)
        • Multiple (27%)
    • Pain: At rest; Increased with movement
    • Examination: Mass in thigh; Tenderness
    • Course
      • Self limited
      • Resolution: Over weeks to months; Mean 2 months
      • Recurrence common
        • Frequency: 37% to 62%
        • May recur several times
        • May be Contralateral
        • Median time: 2 months
      • Long term
        • High 5 year mortality with cardiovascular complications
  • Laboratory
    • Serum CK: High in 45%; Mean 2x
    • Sedimentation rate: Often elevated > 100 mm/h
    • X-ray: Vascular mineralization
    • MRI: Best diagnostic modality
      • Muscle: Enlargement & "Edema"
      • Signal
        • High & Asymmetric: T2 & Inversion-recovery images
        • Gadolinium: Minimal enhancement
        • T1: Isointense or hypointense
      • Location of damage: Muscle; Perifascial space; Subcutaneous
      • Tissue planes: Fluid
    • Muscle biopsy
      • Necrotic & regenerating muscle fibers
      • Hyaline thickening of arterioles
      • Perivascular inflammation
      • Hemorrhage
      • Edema
    • Ultrasound
      • Internal linear echogenic structures
      • No internal motion under transducer pressure
      • No predominantly anechoic areas
  • Cause: ? Diabetic microangiopathy
    • Thickening of small artery walls
    • Vascular occlusion
  • Treatment: Symptomatic
    • Rest
    • Analgesics
    • Gradual mobilization
Swelling of left distal leg
MRI: Diabetic myonecrosis of L leg

MRI: Diabetic myonecrosis of L thigh (Quadriceps)

ANIMAL MODELS

Streptozotocin
METABOLIC SYNDROME 10
  • Criteria
    • Abdominal obesity (Waist circumference high)
      • Males: ≥102 cm (≥ 40")
      • Females: ≥88 cm (≥ 35")
    • Atherogenic dyslipidemia
      • Triglycerides: High; ≥ 1.7 mmol/l
      • HDL cholesterol: Low
        • Males: <1.03 mmol/l
        • Females: <1.29 mmol/l
    • Blood pressure: High
      • Systolic: ≥130 mmHg
      • Diastolic: ≥85 mmHg
    • Insulin resistance
      • Abnormal glucose testing: May occur as Type 2 diabetes
      • May be associated with
        • Dysregulation of fatty acid oxidation
        • Increased myocellular lipid
          • In untrained persons (non-athletes)
  • Epidemiology
    • Adult populations: 20% to 36%
      • More with: Increased age (> 65 years)
      • Females > Males
      • Death ratio: Higher in males
    • Children, Severely obese: 50%
  • Associations
    • Diabetes
      • Control: Worse
      • Disease duration: Longer
      • Complications
        • General: Nephropathy; Neuropathy
        • Type 2: Cardiovascular Δ; Retinopathy
    • Other
      • Cardiovascular events
      • Steatohepatitis, Non-alcoholic
      • Deaths, Premature
      • Non-essential amino acid (NEAA) metabolism: Disorders
        • Serine & Glycine levels: Reduced 25
        • L-serine deficiency in metabolic syndrome & diabetes
          • Related to
            • Impaired glycolysis
            • Reduced synthesis of precursor: 3-phosphoglycerate
          • Effects
            • Phospholipid synthesis: Reduced and increased synthesis
            • Deoxysphinganine synthesis: Increased
            • Homocysteine disposal: Impaired
            • Glycine: Deficiency
        • Serine & Disorders
      • Branched-chain amino acid (BCAA; valine, leucine, isoleucine) levels: High 25
        • Contribute to
          • Increased levels of aromatic amino acids (phenylalanine, tyrosine, tryptophan)
          • Insulin resistance
      • Adipokines: Leptin, Adiponectin, Resistin
    • Predisposing factors
      • Physical inactivity
      • Diet, unhealthy
      • Smoking
      • Heritability (10% to 30%)
      • Lamin AC mutations
  • Metabolic Syndrome in Obesity: Mitochondrial Dysfunction
    • Subsarcolemmal mitochondria
      • Generate ATP for energy requiring processes at cell surface
    • Mitochondria may play role in propagation of insulin signaling
    • Reduced oxidative enzyme capacity correlates with
      • Severity of insulin resistance
      • Reduced capacity for lipid oxidation
      • Increased risk for obesity
    • Subsarcolemmal mitochondrial electron transport chain activity is reduced in
      • Obesity: 3.5 fold
      • Type 2 diabetes: 7 fold
INTERPRETATION OF GLUCOSE TESTING
Glucose Pattern Fasting Glucose Glucose Load
(2 Hours after)
Normal < 100 mg/dl < 139 mg/dl
Impaired fasting 100-125 mg/dl < 139 mg/dl
Impaired tolerance ≤ 125 mg/dl 140-199 mg/dl
Diabetes ≥ 126 mg/dl ≥ 200 mg/dl
Fasting glucose: Overnight fast + Level drawn before 8:30 AM
Glucose tolerance: 75-g oral anhydrous dextrose load after fasting

TRIGLYCERIDES: Increased
Further information
American Diabetes Association


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References
1. Acta Neuropathol 2000;99:539-546
2. Am J Kidney Dis 2000;35:1212-1216, J Clin Neuromusc Dis 2003;5:96102, Indian J Endocrinol Metab 2011;15(Suppl 1):S58-61
3. Neurology 2000;55:83-88
4. Diabetologia 2001;44:1005-1010
5. Diabetes Metab Res Rev 2002;18:260272
6. Brain 2003;126:376-385
7. Diabetes Care 2003;26:15531579
8. J Pediatr 2004;144:281-283, Ann Neurol 2010;67:534541
9. NEJM 2005;352:341-350
10. Diabetes Care 2006;29:2701-2707, Nat Clin Pract Neurol 2006;2:276-282
11. Diabet Med 2006;23:1016-1020
12. Neuro Endocrinol Lett 2005;26:775-779
13. Exp Clin Endocrinol Diabetes 2007;115:327330
14. Diabetes 2009;58:1634-1640
15. Diabetes Care 2009; Oct 21
16. Diabetes Metab 2012; Apr 12
17. Nature Medicine 2012; Online May
18. Acta Neuropathol 2000;99:539-546
19. Brain 2012;135:3074-3088
20. J Diabetes Investig 2019 Jun 20
21. J Peripher Nerv Syst 2020 Nov 24
22. Nat Rev Endocrinol 2021 May 28
23. Drugs Real World Outcomes 2022 Jun 20
24. Nutrients 2022 Dec 30;15(1)
25. Int J Mol Sci 2023;24:1724, Nature 2023;614:118-124

2/6/2023