Diabetic Neuropathy; Diabetes mellitus

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DIABETES: NEUROPATHIES & NEUROMUSCULAR DISORDERS

Neuromuscular disorders

Symmetric neuropathies
Chronic
Distal sensory/autonomic
Autonomic
Sensory-motor
Acute
Painful
Reversible
Asymmetric neuropathies
Lumbosacral plexopathy
Mononeuropathies
Mononeuritis multiplex
Predisposition to immune PN
CIDP
? Diabetic amyotrophy
Perineuritis
Muscle infarction

Overview: Diabetes

Diabetes Classification
Type 1: IDDM
Type 2: NIDDM
Other
Mitochondrial disorders
Neuromuscular disorders
Screening
Metabolic syndrome

Neuropathy: General

From NLM

Drs. Banting and Best In The Laboratory

CLASSIFICATION OF DIABETES MELLITUS

Type 1: Insulin-Dependent Diabetes Mellitus (IDDM)

Clinical
- Onset
  - Usual: 1st 2 decades
  - Most <: 45 years
  - Abrupt
- Body weight: Usually lean
- Insulin deficiency: Absolute
- Genetics
  - 15-fold risk
  - 6% of 1st degree relatives affected
  - 0.4% of unrelated individuals affected
- Immune
  - Immune-mediated destruction of pancreatic beta cells
  - Increased incidence of associated autoimmune phenomena
- Metabolism
  - Ketosis prone
  - Lethal if not treated
- Treatment: Insulin
Pathology
- β cell destruction
- Usually leads to absolute insulin deficiency

Etiologies

Immune-mediated: Associated with antibodies to
- Insulin: 50% to 90%; Higher titers in young children
- Glutamate decarboxylase₆₅ : 80%; Adult onset type IA
- Tyrosine phosphatase-like molecules
  - PTPRN (IA2) : 74%
  - PTPRN2 (IA2-β; Phogrin) : 61%
- Glycolipids: GT3 ganglioside; ? Sulfatide; ? GM2-I
- Cytoplasmic islet cell antigens (ICA)
- Carboxypeptidase H: 10%

Genetic

HLA Class II DR-DQ Linkage Patterns and IDDM Susceptibility in Whites
- Main susceptibility haplotypes in Caucasians (95%)
  - HLA-DR2: With 0102, 0502 and 1601
  - HLA-DR3: Also associated with Xp11 locus
  - HLA-DR4: With 0301, 0302 and 0401 or 0402
- Protective haplotype
  - HLA-DR2: With 0102,0602,1501

Genetic predisposition chromosome loci: IDDM#

1: 6p21.3

2: 11p15.5

3: 15q26

4: 11q13

5: 6q24-q27

6: 18q12-q21

7: 2q31

8: 6q25-q27

9: 3q21-q25
10: 10p11-q11

11: 14q24.3-q31

12: 2q33

13: 2q34

15: 6q21

17: 10q25

18: 5q31.1-q33.1

External link: Colorado

Type 2: Non Insulin-Dependent Diabetes Mellitus (NIDDM)
- Clinical
  - Onset: Usually > 30 years
  - Genetics: > 20% of 1st degree relatives affected
  - Immune: No increase in associated autoimmune phenomena
  - Body weight: Usually obese
  - Metabolism
    - Ketosis resistant
    - Primary metabolic disorder
  - Treatment: Weight loss ± Oral agent or Insulin
- Subtype spectrum
  - Predominantly insulin resistant with relative deficiency
  - Predominant insulin secretory defect with insulin resistance
- Predisposing factors: General
  - Age > 45 years
  - Positive family history
  - Race: Native American; Hispanic; Asian, African American
  - Personal features
    - Obesity
    - Hypertension
    - Dyslipidemia
    - h/o Gestational diabetes
  - Genetic
    - TCF7L2 gene
      - Genetic marker: Microsatellite in intron 3
      - Risk: Homozygote (2.4x) > Heterozygote (1.5x) > Control
      - Gene function: Transcription factor
    - Calpain 10 cysteine protease
      - Polymorphisms in intron 3
    - Peroxisome proliferator-activated receptor γ (PPARG)
      - Transcriptional partner of PGC-1α : Regulator of mitochondrial biogenesis
      - Pro115Gln mutation: Severe obesity
      - Pro12Ala mutation: 15% decreased risk of type 2 diabetes
      - Other mutations: Familial partial lipodystrophy, type 3
    - Adiponectin (APM1; ACDC)
    - WNT5B
      - Mechanism: ? Regulation of adipocyte function
      - Population: Japanese
    - Monozygotic twins: Concordance 3.5x higher than dizygotic
    - Icelandic population: Locus on 5q
- Specific genetic subtypes: 5% of NIDDM
  - Maturity-onset diabetes of the young (MODY) 1
    l Hepatocyte nuclear factor-4-α ; Chromosome 20q12-q13.1; Dominant
    - Clinical
      - Mechanism: Insulin secretory defect; 2^o insulin resistance
      - DM type: MODY
      - Severe diabetes
      - Onset: Post pubertal
      - Complications: Frequent
      - Frequency: 1 American family of Prussian descent
  - MODY 2
    l Glucokinase ; Chromosome 7p15-p13; Dominant
    - Clinical
      - Mechanisms:
        
        Pancreas: Impaired insulin secretion
        
        Liver: Reduced processing of glucose to glycogen
      - DM types: MODY; NIDDM; Gestational
      - Mild diabetes
      - Onset: Childhood
      - Complications: Rare
      - Frequency: Common; Worldwide
  - NIDDM II & MODY3
    l Hepatic transcription factor 1 (TCF1) ; Chromosome 12q24.2; Dominant
    - Clinical
      - Mechanism: Insulin secretory defect; No insulin resistance
      - Severe diabetes
      - Onset: Post-pubertal
      - Complications: Frequent
      - Frequency: Common; U.S., Europe, Japan
  - MODY4
    l Insulin promoter factor (IPF1); Chromosome 13q12.1; Dominant
    - Homozygosity: Pancreatic agenesis & Neonatal diabetes mellitus
  - MODY5
    l Hepatic transcription factor-2 (TCF2) Chromosome 17cen-q21.3; Dominant
    - Clinical
      - Mild diabetes
      - Renal disease: Non-diabetic
      - Mullerian aplasia (50%): Vaginal aplasia; Rudimentary uterus
  - MODY 6: Noninsulin dependent diabetes mellitus (NIDDM)
    l Neurogenic differentiation factor (NEUROD1) ; Chromosome 2q32; Dominant
    - Onset: 30 to 59 years
  - MODY 7: Noninsulin dependent diabetes mellitus (NIDDM)
    l Kruppel-like factor 11 (KLF11) ; Chromosome 2p25; Dominant
    - Diabetes & Glucose intolerance
  - MODY 8: Noninsulin dependent diabetes mellitus (NIDDM)
    l Carboxyl-ester lipase; (CEL) ; Chromosome 9q34.3; Dominant
    - Diabetes & Primary pancreatic beta-cell dysfunction
  - MODY 9: Noninsulin dependent diabetes mellitus (NIDDM)
    l Paired box gene 4 (PAX4) ; Chromosome 7q32; Dominant
    - Mutations also in: Diabetes, type 2 & Susceptibility to Diabetes mellitus, ketosis-prone
  - Noninsulin dependent diabetes mellitus (NIDDM)
    l Mitogen-activated protein kinase 8-interacting protein 1 (MAPK8IP1) ;
    Chromosome 11p12-p11.2; Dominant
  - Noninsulin dependent diabetes mellitus (NIDDM) I: Predisposition factors in ethnic groups
    - Mexican Americans from Starr County, Texas: Chromosomes 2q37 (Calpain 10 ); 15q21.1; 10q26
    - Pima Indians: Chromosomes 1q21-1q23; 11q23-q25 (DM & Obesity)
    - Whites: Chromosomes 1q21-1q23; 12q24
    - French whites: 1q21-1q24; 3q27-qter (Early onset < 45 years)
  - Insulin receptor substrate (IRS) 1
    l Chromosome 2q36
    - IRS protein
      - Mediates insulin action
      - Prominent role in skeletal muscle
    - Single patient identified
    - Clinical DM type: NIDDM
  - Solute carrier family 2, member 2 (SLC2A2): Glucose transporter 2 (GLUT2)
    l Chromosome 3q26.1-q26.3
    - Genetics
      - Mutation: Val197Ile
      - Other mutations produce: Fanconi-Bickel syndrome
        
        Hepatorenal glycogenosis
        Renal Fanconi syndrome
        Galactose intolerance
        Malabsorption
        Psychomotor retardation
    - GLUT2 Protein
      - Function: Low-affinity glucose transporter present in the plasma membrane
      - Location
        
        Insulin-producing β cells of pancreatic islets: Highest in microvilli facing adjacent endocrine cells
        Not in other islet endocrine cells
  - Noninsulin dependent diabetes mellitus (NIDDM)
    l Solute carrier family 2, member 4 (SLC2A4) ; Chromosome 17p13; Dominant
    - Mutation: Val383Ile
    - 1 patient identified
  - Mitochondrial
    - Clinical DM type: NIDDM & Deafness
  - Hyperproinsulinemia
    l Chromosome 11p15.1-p15.5; Dominant
    - Clinical DM type: NIDDM; MODY
Other types of DM
- Genetic defects
  - β cell function
  - Insulin action
  - Insulin receptor
    - Diabetes mellitus: Insulin resistant or NIDDM
    - Other associations: ± Acanthosis Nigricans ; Leprechaunism ; Rabson-Mendenhall syndrome
  - Peroxisome proliferator-activated receptor γ (PPARG)
    - Diabetes mellitus, insulin-resistant
    - Acanthosis nigricans
    - Hypertension
  - Diabetes, transient neonatal
    l Chromosome 6q24; Recessive
  - Diabetes, permanent neonatal
    l Glucokinase ; Chromosome 7p15-p13; Recessive
  - Diabetes, permanent neonatal or relapsing
    l KCNJ11 (Kir6.2) ; Chromosome 11p15.1; Recessive
  - Immunodeficiency, Polyendocrinopathy & Enteropathy, X-linked (IPEX)
    l Forkhead Box P3 (FOXP3) ; Chromosome Xp11.23-q21.1; Recessive
    - Diabetes mellitus: Insulin-dependent
    - GI: Enteropathy; Peritonitis
    - Hypothyroidism
    - Anemia; Thrombocytopenia
    - Skin: Dermatitis; Eczema
  - Other genetic syndromes associated with diabetes
- Pancreas: Exocrine disease
  - Pancreatic agenesis: Insulin promoter factor 1
- Endocrinopathy
- Mitochondrial
- Toxic: Drug or chemical induced
- Infection related
- Immune-related DM: Autoantibodies
  - Glutamic acid decarboxylase (GAD): 65 kD
    - Occur in: 25% of presymptomatic DM patients; Adult onset DM type IA
    - Also associated with: Stiffman syndrome
    - Sensitivity: Occur in 69% of IDDM sibs who develop DM
    - Specificity: 42% of positives developed DM over 7.7 years
  - Islet cells (ICA)
    - Sensitivity: Occur in 81% of IDDM sibs who develop DM
    - Specificity: 43% of positives developed DM over 7.7 years
  - Tyrosine phosphatase-like molecules
    - ICA512 (IA-2)
      - Sensitivity: Occur in 69% of IDDM sibs who develop DM
      - Specificity: 55% of positives developed DM over 7.7 years
    - IA2-β : 61% sensitivity
  - Insulin
    - Sensitivity: Occur in 29% of IDDM sibs who develop DM
    - Specificity: 25% of positives developed DM over 7.7 years
    - Higher titers in young children
  - Glycolipids: GT3 ganglioside; ? Sulfatide; ? GM2-I
  - Antibodies: Clinical correlations⁴
    - Multiple antibodies: Higher risk for developing diabetes; Lower C-peptide
    - ICA + GAD65 antibodies: Less neuropathy, nephropathy or hypertension in adult type I DM
    - Single antibody positivity & low Ab titers: Phenotype similar to NIDDM (type 2 DM) patients
    - Antibody negative patients: More DM complications in adult type I DM
Gestational DM

OVERVIEW: DIABETES & NEUROPATHY

Prevalence of diabetes mellitus: 6% of US population
Prevalence of neuropathy in diabetes mellitus
- Disease onset: 7.5%
- 25 years after onset: 50%
- Overall: 30%
- Similar or slightly higher in NIDDM (Type 2) vs. IDDM (Type 1)
Risk factors for developing diabetic neuropathy⁹
- Glycemic control: Higher glycosylated hemoglobin
- Cardiovascular risk factors: Metabolic syndrome
  - Hypertension
  - Smoking
  - Obesity
  - Triglyceride levels: High
- Presence of cardiovascular disease
- Type 2 diabetes: α2B adrenoceptor gene (ADRA2B)¹³
  - Gene has Insertion (I)/Deletion(D) polymorphism: I/D of 3 glutamic acid residues
  - 2x greater frequency of D allele in Type 2 patients with peripheral neuropathy
  - More severe neuropathy in patients with D allele
  - Polymorphism also associated with
    - Obesity
    - Impaired insulin secretion
    - Earlier onset of diabetes
    - Increased risk of acute coronary ischaemia
    - Autonomic dysfunction: Increased sympathetic nervous system activity
Screening test for diabetes mellitus: Fasting plasma glucose
- After 8 hour fast
- Level: > 126
- Repeated on 2 separate occasions
- Glycosylated hemoglobin may be used but is less standardized
Neuromuscular & other disorders with associated diabetes
- Genetic
- Other
Pathological mechanisms in DM: Hyperglycemia results in⁵
- Protein glycation
  - Example is Hemoglobin A1C
  - Associated with increased permeability of proteins across blood-nerve barrier: Accumulation in nerve
- Advanced glycosylation endproducts (AGEs)
  - Supply free radicals: Autoxidative glycation, or Glycoxidation
  - AGE receptors: Trigger cellular oxidant stress by inducing cytokines
- Oxidative stress
CNS: Spinal cord atrophy reported with diabetes

DIABETIC NEUROPATHIES: SYMMETRIC

Chronic

Distal: Sensory ± Autonomic
- Most common type of diabetic neuropathy
- Clinical features
  - Sensory loss: Usually pansensory
    - Occasionally with selective involvement of fiber types
      - Small fiber: Pain; Often involved early
      - Large fiber: Paresthesias; Absent ankle reflexes
    - Associated with foot ulcers in chronic DM
      - 7x increase
      - Middle-aged & elderly diabetic patients
      - Location: Soles of the feet
      - Frequent neuropathic osteoarthropathy
  - Weakness
    - Severity: Mild
    - Distribution: Legs; Distal
    - Association: Chronic DM
  - Autonomic involvement: Some patients
    - Sympathetic denervation: Increased peripheral blood flow
    - Cardiac denervation
  - Charcot's joints (Neurogenic osteoarthropathy)
    - Onset
      - Age: 50 to 65 years
      - Course: Usually gradual, Ocasionally acute
      - Location: Navicular bone
    - Locations: Foot 60%; Ankle 10%
    - Associations
      - Poorly controlled insulin-dependent diabetes
      - Osteopenia (100%)
      - Calcification: Vascular smooth muscle cells (78% to 90%)
      - ? Regional increased blood flow (Hyperemia)
      - ? Related to disorders of OPG/RANK-L pathway
    - X-rays: Bone & Joint destruction; Calcific deposits around joint
- Temporal risk of neuropathy after onset of DM
  - Symptomatic evidence
    - 5 years: 4% to 10%
    - 25 years: 13% to 15%
    - Mean time after DM onset: 8 years
    - Increased Frequency: Women; Increased Age
  - Objective evidence (Clinical or electrophysiologic): 65% to 80% of all diabetics
- Risk factors & associations
  - Clinical features
    - General: Increased
      - Age
      - Body weight
      - Height
      - Disease duration
    - Diabetes
      - Duration
      - Hemoglobin A1C
      - Arterial stiffening & thickness: Type 2 diabetes
    - Systemic disorders
      - Hypertension (Diastolic)
      - Retinopathy
      - Metabolic syndrome
    - Smoking
  - Laboratory features
    - Lipids: Increased risk
      - HDL-cholesterol: Reduced
      - Triglycerides: Increased
    - Albuminuria
  - Hyperglycemia: Degree & duration
    - ? Related to polyol pathway
      - Aldose reductase & sorbitol dehydrogenase convert glucose to fructose
      - Poorly controlled diabetes ® More Sorbitol & fructose in cell
      - More Sorbitol ® Hypoxia & ischemia
      - ? Myoinositol: Reduced ® Slowing of nerve conduction velocity
      - Mice transgenic for Aldose reductase ® Galactosemic neuropathy
    - Protein glycosylation
    - Intensive insulin therapy reduces risk of developing neuropathy by 60%
  - Aldose reductase 2 gene polymorphism
    - Dinucleotide repeat 2.1 kb upstream (5' end) of transcription start site
      - Near osmoregulatory element for aldose reductase gene transcription
    - Z+2 allele: 14% risk of DM neuropathy after 20 years
    - Other alleles: 38% risk
  - T-cell Receptor β chain
    - Associated with susceptibility to microvascular complications in IDDM
  - Other possible pathogenic factors
    - Metabolic compromise
    - Ischemia
    - Oxidative stress
    - Neurotrophic support: Reduced
- Progression
  - Neuropathy may be asymptomatic for long periods
  - Longer latency: After onset of Type I, than Type II, diabetes
  - Slow over 5 to 20 years
  - Effects of glycemic control¹¹
    - Progression of neuropathy occurs despite good efforts at control
    - Least progression: Aggressive blood sugar control
    - Control benefits other associated features: Triglyceride and high-density lipoprotein cholesterol levels
- Electrodiagnostic testing
  - SNAP amplitudes: Reduced
  - Conduction velocities: Normal or Mildly reduced
  - Refractory periods: Shorter in diabetic nerves, ? related to reduced nodal Na⁺ currents
- Pathology
  - Axonal loss
    - Axon loss: Large & small axons in motor-sensory neuropathies
    - Younger patients with IDDM: Loss is unform among fascicles
    - Older patients with NIDDM: May have multifocal axonal loss
  - Axonal regeneration
  - Capillary walls: Thickened; Hyalinization (Reduplication of basement membranes)
  - Axonal swellings in distal axons
  - Collagen: Increased around vessels¹
    - Collagen I & III increase: A common change in many neuropathies
    - Collagen IV, V, VI increase
      - Around endoneurial vessels
      - Collagen, Type VI increase relatively specific for diabetes
  - Basal lamina: Tubes often persist after axonal degeneration
Autonomic neuropathy, Diabetic⁷
- General
  - Most common cause of autonomic neuropathy in developed contries
  - Clinical symptoms: General
    - Multiple autonomic systems involved: Sympathetic & Parasympathetic
    - Usually only occur long after onset of diabetes
    - Often associated with: Distal sensory-motor neuropathy
  - Subclinical autonomic dysfunction can occur within
    - One year of diagnosis in type 2 diabetes
    - Two years of diagnosis in type 1 diabetes
  - Patterns of involvement
    - Sympathetic & Parasympathetic involvement: Common in type 1 & type 2 diabetes
    - Type 1 diabetes: Sympathetic & Parasympathetic functions correlate
    - Type 2 diabetes: Parasympathetic function more affected
  - Increased risk with
    - Duration of diabetes
      - Subclinical manifestations: 30% after 10 to 15 years
      - Clinical symptoms: 1% to 5%
    - Severity of hypoglycemia
    - Hemoglobin A1C: High
    - Age: Increased
    - Body weight: High
    - Systemic disorders: Albuminuria; Retinopathy
    - Presence of associated polyneuropathy
    - Insulin-dependent diabetes
    - Hypertriglyceridemia
  - Long term
    - Overall mortality & Sudden death: Increased
    - Mortality rates with cardiovascular autonomic neuropathy: 27% to 56% over 5�10 years
- Genito-urinary
  - Erectile dysfunction
    - Frequency
      - Most common symptom of diabetic autonomic neuropathy
      - 30�75% of diabetic men
    - Clinical syndromes
      - Ejaculatory failure: Sympathetic nervous system dysfunction
      - Erectile dysfunction with preserved ejaculation & orgasm
        
        Impaired nitric-oxide mediated relaxation of smooth muscle in corpus cavernosum
        
        Locations: Autonomic nerves; Endothelium
    - Course
      - Initially partial
      - Progression to complete over 1 to 2 years
      - Usually irreversible
    - Increased frequency with
      - Age
      - Duration of diabetes
      - Vascular disease
    - Pathogenic factors
      - Autonomic neuropathy
      - Atherosclerotic involvement of the internal pudendal artery
      - Impaired endothelium-dependent relaxation of penile smooth muscle
      - Metabolic control impaired
      - Somatic sensory impairment
  - Retrograde ejaculation: Uncommon; Occurs in diabetics with selective sympathetic failure
  - Voiding dysfunction: Dysfuncton of bladder emptying
    - Frequency: Symptomatic in up to 50% of patients with diabetes, and there is
    - Physiological evidence of bladder dysfunction: 43�87% of insulin-dependent diabetes
    - Earliest manifestation of autonomic bladder dysfunction
      - Impaired sensation
      - Increases the threshold for initiating micturition reflex
    - Intermediate features: Reduced detrusor activity causes
      - Incomplete bladder emptying
      - Increased postvoid residual
      - Reduced peak urinary flow rate
      - Bladder overdistension
    - Late features
      - Urinary retention
      - Overflow incontinence
  - Females: Reduced vaginal lubrication
- Cardiovascular
  - Dysfunction present in 20% of asymptomatic diabetics
    - Longitudinal testing: R-R variation; Valsalva maneuver; Postural blood pressure testing
    - Vagal denervation: High resting heart rate
    - Cardiovascular reflexes: Impaired
  - Postural hypotension
    - Pathophysiology: Efferent sympathetic vasomotor denervation; Reduced vasoconstriction
    - Subclinical changes: 17% to 43%
    - Symptomatic involvement
      - Symptoms: Lightheadedness, Weakness, Cognitive impairment, Blurred vision
      - Cognitive impairment without lightheadedness: Common in patients > 60 years
      - Less than 1% of diabetic neuropathy
      - Symptoms may be reduced with more chronic involvement
    - Prominent involvement associated with: Multisystem autonomic failure
    - Exacerbation: Postprandial; Early morning; Increased ambient temperature
  - Cardiac disorders
    - Sympathetic denervation
      - Abnormal vasoconstriction
      - Impaired myocardial coronary blood flow & myocardial contractility
    - Parasympathetic denervation
      - Reduced R-R interval variation
      - Vagus involvement: Increased heart rate
      - Increased cardiovascular mortality after myocardial infarction
    - Sympathetic + Parasympathetic
      - Heart rate fixed
      - Inadequate capacity to increase rate with physiological demands
    - Cardiovascular autonomic function: Reduced
      - Associated with increased risk of silent myocardial ischemia & mortality
- Gastrointestinal
  - May involve all parts of GI tract
  - Gastroparesis
    - Gastric motor disorders are relatively common: Occur in up to 50% of brittle diabetics
    - Symptoms
      - Discomfort: Nausea, Vomiting, Early satiety, Postprandial bloating, Diffuse epigastric pain
      - Early satiety
      - Weight loss: Variable; May be profound
      - Some patients asymptomatic
      - Laboratory: Food residue retained in stomach
    - Other associations
      - Poor correlation between symptoms and laboratory-demonstrated gastroparesis
      - Reversible component: Asociated with hyperglycemia
  - Constipation
    - Most common lower-GI symptom: Up to 60%
    - Can alternate with episodes of diarrhea
  - Nocturnal diarrhea
    - Profuse watery diarrhea
      - May persist for hours to several days
      - Can be accompanied by fecal incontinence
    - Associated with somatic & autonomic neuropathy
    - More common in type 1 diabetes
    - Rule out drug toxicity: Metformin
  - Fecal incontinence
    - Due to: Incompetence of anal sphincter or Reduced rectal sensation
    - Exacerbated by diarrhea
- Sudomotor syndromes
  - Hypohidrosis
    - Loss of thermoregulatory sweating
    - Initially distal: Glove-stocking distribution
    - May become diffuse: With more severe autonomic neuropathies
  - Hyperhidrosis: Feet associated with coldness
  - Gustatory sweating
    - Excessive facial sweating in response to food, especially spicy
    - Associated with cervical sympathetic denervation
- Skin: May be among earliest manifestations of autonomic neuropathy
  - Mechanisms: Changes in microvascular skin blood flow & sudomotor function
  - Clinical features: Dry skin; Hypohidrosis; Development of ulcers, fissures & cracks
- Other
  - "Brittle diabetes"
  - Hypoglycemic autonomic failure
- Differential diagnosis: Autonomic neuropathy
- Laboratory evaluation
  - Cardiovascular heart rate tests: Heart rate response to deep breathing, Valsalva maneuver & standing
  - Sudomotor: QSART to evaluate distal postganglionic axons
  - Adrenergic function: Cardiovascular responses to stimuli
- Prognosis: Moderately increased mortality over 10 years with autonomic neuropathy
Sensory-Motor
- Distal weakness & sensory loss
- Progressive over 1 to 2 years
- May be due to multifocal diabetic neuropathy
- Nerve biopsy: Blood vessels with complement deposition & cellular infiltrates
Chronic immune demyelinating polyneuropathy (CIDP)
- Increased incidence in diabetics

Acute Diabetic Neuropathies

Acute painful
- Pain
  - Burning & hypersensitivity: Feet
  - May be severe
  - Often worse at night
- Signs: Often only mild changes
  - Mild sensory loss: Distal; Symmetric
  - Tendon reflexes: Normal or Reduced
- Associations
  - Poorly controlled diabetes
  - Recent onset of insulin therapy
  - Rapid weight loss
- Improvement: After control of diabetes & weight gain
Rapidly reversible diabetic neuropathies
- Hyperglycemic
  - Newly diagnosed, untreated diabetes
  - Asymptomatic reduction of nerve conduction velocities
- Treatment induced⁸
  - Onset
    - After onset of hypoglycemic treatment
    - May occur in children or adults
    - Months to years after onset of diabetes
  - Clinical
    - Discomfort: Paresthesias; Burning; Leg tenderness
    - Sensory loss: Pan-modal
    - Distribution: Distal; Lower limbs; Symmetric
    - Course: Monophasic; Symptoms disappear with continued control of blood sugar
    - May be associated with retinopathy
  - Nerve conduction: Abnormalities may persist after resolution of symptoms

DIABETIC NEUROPATHIES: ASYMMETRIC

General feature: Often have acute or stepwise onset
Lumbosacral plexopathy
- Nosology: Similar syndromes
- Epidemiology
  - Overall prevalence: 0.08% of diabetics
  - More frequent with type II (1.1%) than type I (0.3%) diabetes
- Clinical features
  - Weakness
    - Asymmetric
    - Proximal weakness: Quadriceps; Thigh adductors; Psoas
    - Distal weakness: Ankles & Toes
    - Localized to lumbosacral plexus or lumbar roots
  - Pain
    - Localized to: Hip, buttock, or thigh
    - May be severe
    - Usuallly lasts months after disease onset
  - Sensory loss: Distal
- Associated factors
  - Poor diabetic control
  - Weight loss
  - Non-insulin dependent diabetes
- Differential diagnosis
  - Lumbosacral plexopathy
  - Cauda equina lesion
- Electrodiagnostic
  - EMG: Multifocal denervation in paraspinous & leg muscles
  - NCV: Axonal loss; Small CMAPS & SNAPs
- Pathology: Probably inflammatory vascular radiculoplexopathy³
  - Inflammation
    - Location: Epineurial; Perivascular related to small vessels
    - Type: Mononuclear ± PMN (Early in disease course)
    - Intermediate cutaneous nerve of the thigh
  - Pipestem capillaries: Endoneurium
  - RBC extravasation or hemosiderin around vessels
  - IgM deposition: Endoneurium & Subperineurial space
  - Activated complement (C5b-9) deposition: Endothelium of small vessels
  - Reduced myelinated ± unmyelinated axons
  - Differential fascicular loss of axons
- Treatment
  - Pain control
  - Diabetic control
  - Corticosteroids: Solumedrol, iv, pulse
  - ? IVIg: Hastens recovery; dose 2g/kg q month x3
- Prognosis
  - Slow recovery over 6 to 24 months after diabetic control
  - Partial or complete
- Variant syndrome: Diabetic amyotrophy
  - Nosology: Proximal diabetic neuropathy
  - Frequency: Rare
  - Onset: Sub-acute
  - Associations: Diabetes, poorly controlled; Weight loss, prominent
  - Clinical features
    - Pain: Severe; Unilateral
    - Weakness: Proximal, especially quadriceps & psoas; Unilateral
    - Sensory loss: Not prominent
    - Disease course: Monophasic; Recovery over months, even without treatment
- Variant syndrome: Multifocal diabetic neuropathy⁶
  - Frequency: Occasional
  - Onset: Sub-acute
  - Clinical
    - Pain
    - Weakness
      - Asymmetric
      - Predominant pattern: Distal; Legs
      - Other: Proximal legs; Thoracic (Radiculopathy); Arms (Ulnar, Radial)
    - Sensory loss
    - Impotence in males
  - Laboratory
    - Electrophysiology: Asymmetric axonal loss
    - CSF: Protein often high
  - Pathology
    - Inflammation: Perivascular inflammation & hemorrhage; Vasculitis in some
    - Axonal degeneration & loss
Mononeuropathies: May involve single nerves or roots
- Cranial nerve
  - Especially in older diabetics
  - Third nerve most common
    - Onset: Late adulthood
    - Sudden onset
    - Retro-orbital pain
    - Sparing of pupil involvement
    - Recovery: No misregeneration; Within weeks to months
  - 7th nerve
    - Probably involved more often than general population
- Limb
  - Vascular lesions: Major limb nerves can be affected
    - Onset: Abrupt & painful
    - Common location: Lumbosacral plexopathy
    - Recovery: Best with distal lesions, acute onset
  - Damage at common compression sites
    - Carpal tunnel syndrome: 25% asymptomatic; 8% symptomatic
    - Other: Ulnar; Posterior tibial (Tarsal tunnel)
- Trunk
  - Sensory
    - Acute, unilateral pain
    - Distribution: 1 or multiple thoracic nerves
    - Pain is non-radicular & difficult to manage
    - Hypersensitive skin region
  - Motor: Weak abdominal wall muscles; May lead to heriation
  - Associations
    - Especially in patients > 50 years
    - Some patients with weight loss: r/o malignancy
  - Course: Spontaneous improvement over 1 to 2 years
Mononeuritis multiplex
- Multiple mononeuropathies with polyneuropathy
- Coexisting focal compression neuropathies
  - Ulnar compression at elbow: More common in diabetes
  - Median at wrist: Often asymptomatic
- See: Lumbar plexopathy; Diabetic amyoptrophy

DIABETIC MUSCLE INFARCTION (Myonecrosis)²

Swelling of left distal leg

Associated features
- Diabetes
  - Chronic
  - Insulin-dependent
  - Poorly controlled (22%)
  - Type I (80%) or II (20%)
  - Duration: Mean 16 years; Range 1 to 50 years
- Renal (90%): Most with nephropathy; 25% failure
- Retinopathy (65%)
- Neuropathy (80%)
- Hypertension
- Female (66%) > Male
Onset
- Acute
- Pain, tenderness & swelling
- Age: Mean 40 years
- Male = Female
Clinical
- 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
  - 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: Normal or mildly elevated
- Sedimentation rate: Often elevated > 100 mm/h
- X-ray: Vascular mineralization
- MRI: Edema
  - High & asymmetric signal on T2 images
  - Location: Muscle; Perifascial space; Subcutaneous
  - Fluid in tissue planes
  - Gadolinium: Minimal enhancement
- Muscle biopsy
  - Necrotic & regenerating muscle fibers
  - Hyaline thickening of arterioles
  - Perivascular inflammation
  - Hemorrhage
  - Edema
- Serum CK: High in 45%; Mean 2x
Cause: ? Diabetic microangiopathy
- Thickening of small artery walls
- Vascular occlusion
Treatment: Symptomatic
- Rest
- Analgesics
- Gradual mobilization

MRI: Diabetic myonecrosis of L leg

ANIMAL MODELS

Streptozotocin

Model of type I diabetes
Mechanisms
1. ? ADP-Ribosyltransferase (PARP) activation ®
2. Reduced substrates NAD(+) & ATP ®
3. Cellular death 2° energy depletion
Effects: Destroys insulin-producing β islet cells of the pancreas

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

METABOLIC SYNDROME¹⁰

Criteria
- Abdominal obesity (Waist circumference high)
  - Males: ≥102 cm (≥ 40")
  - Females: ≥88 cm (≥ 35")
- Atherogenic dyslipidemia
  - Triglycerides: ≥ 1.7 mmol/l
  - HDL cholesterol
    - Males: <1.03 mmol/l
    - Females: <1.29 mmol/l
- Elevated blood pressure
  - 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)
Diabetes Associations
- Diabetes
  - Control: Worse
  - Disease duration: Longer
- Complications
  - Type 1: Nephropathy; Neuropathy
  - Type 2: Nephropathy; Neuropathy; Cardiovascular disease; Retinopathy
Other features: Non-alcoholic steatohepatitis
Epidemiology
- Occurs in 50% of severely obese children
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

TRIGLYCERIDES: Increased

Triglyceride level >300 mg/dl: Frequent asymptomatic sensory-motor axonal neuropathy
- Sensory nerves: Prolonged distal latencies
- Motor & Sensory nerves
  - Conduction velocities: Mildly slowed
  - Amplitudes: Normal
- Anatomy: Legs more involved than arms
Triglyceride level: High
- Increased risk of neuropathy in diabetes
- Higher levels in patients with idiopathic sensory neuropathy
Triglyceride level: Very High
- Epidemiology: 6 patients described
- Clinical: Polyneuropathy
  - Painful
  - Distal: Feet
  - No weakness or autonomic changes
  - Tendon reflexes: Reduced at ankles (50%)
- Treatment: Improvement in 1 patient with reduction of triglycerides
Other disorders

Further information
American Diabetes Association

Return to Polyneuropathy differential diagnosis
Return to Neuromuscular home page

References
1. Acta Neuropathol 2000;99:539-546
2. Am J Kidney Dis 2000;35:1212-1216, J Clin Neuromusc Dis 2003;5:96�102
3. Neurology 2000;55:83-88
4. Diabetologia 2001;44:1005-1010
5. Diabetes Metab Res Rev 2002;18:260�272
6. Brain 2003;126:376-385
7. Diabetes Care 2003;26:1553�1579
8. J Pediatr 2004;144:281-283
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;115:327�330

4/3/2008