Wolfram's Syndrome and secondary causes of diabetes

Today we had an interesting discussion of a patient with Wolfram's Syndrome or DIDMOAD, this generated an interesting discussion on secondary causes of insulin resistance:

1) What the heck is DIDMOAD?

• Wolfram syndrome has three genetic forms one of them being DIDMOAD
• It is an autosomal recessive disorder with incomplete penetrance, affecting 1/770 000
• DI - Diabetes insipidis: due to loss of vasopressin secreting cells, anterior pituitary dysfunction has also been described
• DM - Diabetes Mellitus: Patient typically develop diabetes in childhood requiring insulin (due to an inability to convert pro-insulin to insulin)
• OA - Optic atrophy occurs early in childhood 
• D - Deafness: sensorineural deafness

2) What are other causes of insulin resistance?

• Primary pancreatic: Infiltrative (hemochromatosis, amyloidosis), cystic fibrosis, pancreatic cancer, chronic pancreatitis, surgical removal/trauma
• Endocrine: Cushings (secondary to elevated cortisol), acromegaly, pheochromocytoma (secondary to adrenergic stimulation), Conn's (secondary to hypokalemia)
• Drugs: Steroids (increases gluconeogenesis and decreases peripheral glucose transporter), thiazide diuretics, atypical anti-psychotics, nicotinic acid, HAART therapy, ocreotide infusion, inotropes
• Unusual causes: muscular dystrophy, friedrich's ataxia, Wolfram's syndrome etc.

3) Work up and Management of hyperglycemia:

• Confirm: Repeat the accucheck
• Look for causes: 
• Known diabetes? HHS/DKA (look for precipitating factors: infarction, infection, insulin non-compliance, new diagnosis of diabetes) 
• Secondary causes of insulin resistance: i.e. medications
• Look for perpetuating factors:
• Severe hypovolemia results in both hemoconcentration and decreased GFR leading to decreased filtration of glucose
• Increased adrenergic/stress state drives gluconeogensis and insulin resistence
• Investigations:
• Physical exam to look for precipitating factors and degree of volume depletion
• Laboratory work to look for DKA/HHS and precipitating factors:
• ABG, anion gap, serum ketones, serum osmolarity, electrolytes (esp. K+), creatinine
• Septic w/u, ecg, troponin/ck, amylase/lipase
• Treatment:
• Fluids for the hyperglycemia
• IV Insulin to close the anion gap and decrease fat metabolism and the generation of ketones. Continue until the anion gap is closed
• potassium replacement
• Treat the underlying cause
• Transition to SC insulin once patient's B.G. is stable and insulin requirements have been minimal and stable and patient is eating... and in the daytime! Ensure at least 1-2 hrs of overlap.
• Please see the following article for treatment of Diabetic ketoacidosis: CMAJ 2003 Treatment of DKA/HHS