• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Enlist the various disorder associated with severe insulin resistance.

  • Defect in insulin receptor gene
    • Leperchunism- most severe
    • Rabson Mendenhall syndrome – Moderate
    • Type A IR syndrome – mildest- HAIR- AN syndrome
  • 2. Antibodies against insulin receptor
    • Type B insulin receptor syndrome
    • Ataxia telegectasia
• 3. Lipodystrophic syndromes
  • Congenital generalized Lipodystrophy – Bernerdenelli Seip syndrome
  • Familial partial lipodystrophy – Donnigan syndrome, Koberling syndrome
  • Acquired generalized lipodystrophy- Lawrence syndrome
  • Acquired partial lipodystrophy- Barraqurer- Simmons syndrome
  • HIV lipodystrophy

• **Leperchaunism **

• Q. What is the other name of this syndrome?

  • Donohue syndrome

• Q. What is the main defect in this disorder?

  • There is a defect in the gene coding for insulin receptor
  • Hence these patients have an absence of insulin receptor – INSR gene

• Q. What are the clinical features?

  • Short stature
  • Severe insulin resistance
  • Fasting Hypoglycemia and post-prandial hyperglycemia
  • Growth retardation starting from intrauterine life
  • Autosomal recessive
  • Death by 1 year of age
  • A very rare disorder

• Q. What is the treatment?

  • IGF1

• **Rabson mendenhall syndrome **

• Q. Tell me something about this syndrome.

  • It is similar to Leperchaunism but milder
  • They survive till adolescence

• Q. What are the Clinical features of this syndrome?

  • Diabetes by 5-6 years requiring high dose of insulin
  • Coarse senile facies
  • Dysplastic dentition
  • Pineal gland hyperplasia

• **Type A insulin resistance syndrome **

• Q. What is Type A insulin resistance syndrome?

  • This is a mutation in the insulin receptor
  • Patients generally present in adolescence with features of insulin resistance and hyperandrogenism

• Q. What is the other name of this syndrome?

  • This is the one called HAIR-AN syndrome
    • H- hyperandrogenism
    • Insulin resistance
    • Acanthosis nigricans
  • Pearl
  • Insulin receptor disorder
    • Mildest- Type A IR syndrome
    • Moderate- Rabson Mendenhall syndrome
    • Severe – Leperchaunism

• **Type B insulin resistance syndrome **

• Q. What is the pathogenesis of this syndrome?

  • This is due to antibodies against insulin receptors- this is called AIRA - anti-insulin receptor antibody

• Q. What are the clinical features of this syndrome?

  • Typically present in middle age females
  • May have associated with other autoimmune disorders

• Q. Will this always lead to hyperglycemia?

  • No
  • It can lead to hypoglycemia or hyperglycemia depending on whether the antibody is activating or blocking

• Q. Of the two, which presentation is more common?

  • Hyperglycemia is more common than hypoglycemia

• Q. Which other syndrome is associated with antibodies against insulin receptors?

  • Ataxia telegectasia

• Q. What is the typical age of presentation?

  • 30-50 years

• Q. Is it associated with other autoimmune diseases?

  • Yes
  • Has been reported with SLE and other autoimmune disorders

• Q. When is the antibody stimulatory and when is it blocking?

  • At low titers the antibody tends to be stimulatory - leading to hypoglycemia
  • In high titers, it tends to be blocking- leading to hyperglycemia

• Q. Does it follow a consistent pattern?

  • No
  • It waxes and wanes
  • Sometimes the antibody disappears leading to periods of euglycemia

• Q. What is the characteristic biochemical signature of this disorder?

  • They have insulin resistance but Triglyceride is NOT elevated
  • This is the sin-quo-non of this condition

• Q. Apart from this what are the other markers of this condition?

  • Fasting insulin levels >20 mIU/l
  • Lean patient requiring >3 units/kg/day

• Q. Is the antibody available commercially?

  • No
  • It is done only in selected research labs

• Q. What are the clinical features?

  • 1. Weight loss is typical
    • They are severely catabolic during the hyperglycemic phase
  • 2. Acanthosis nigricans
    • which improves with improvement in the disease state
  • 3. Hyperandrogenism

• Q. When do they develop hypoglycemia?

  • So they have a hypoglycemic phase and a hyperglycemic phase
  • During the hyperglycemic phase- they need massive amounts of insulin- but they don't develop hypoglycemia because of that
  • Hypoglycemia develops when the hyperglycemia phase resolves and it is often spontaneous
  • So basically these two states are often separate- and though they can both exist in the same person- they exist at different times
  • Hypoglycemia can be severe enough to cause mortality

• Q. What are the aspects of managing this disorder?

  • 

• Q. How is the hyperglycemia phase managed?

  • U500 or other concentrated insulin is the treatment of choice
  • Try to target normal fasting glucose levels
  • OAD doesn't seem to work
  • Please note- achieving fasting glucose in a normal range is a sign of reducing antibodies- in this stage, they can have partial agonist action of antibodies - this can lead to hypoglycemia in the future hence it is a good time to reduce insulin doses
  • IGF-1 is found to be useful for correcting hyperglycemia in anecdotal reports

• Q. How is hypoglycemia treated?

  • With glucocorticoids

• Q. What immunomodulation therapy is recommended?

  • A combination of Rituximab + high dose pulse glucocorticoids + cyclophosphamide is found to be effective
  • Azathioprine is given during the maintenance phase
  • Be careful when giving immunomodulation during the hyperglycemia phase- because it can reduce antibodies which can make it stimulating and produce hypoglycemia- this can be fatal