Presented by: Meme Phung

Zhi Yuan Quek Alison Wong

Acute Diabetes

• Jill, aged 30 years, has recently experienced hypoglycaemic episodes. She has experienced weakness & dizziness periodically for the last 5 years and a seizure 2 years previously. She does not have a history of drug abuse or organ dysfunction. A fasting plasma glucose was 3.7 mmol/L, with no accompanying symptoms. An insulinoma is suspected.

What is insulinoma?

• A rare form of tumour of the islets of Langerhans in the pancreas

• Commonly derived from beta cells• Produce excessive amounts of

insulin• 80% are benign, small, single• 10% are malignant (metastasis are

present)• 10% are multiple (MEN 1 hereditary

disease)

CT scan

Symptoms

Due to excessive or inapproriate insulin and proinsulin secretion hypoglycaemia occurs such as:

• Diplopia, blurred vision, palpitations, confusion and abnormal behaviour.

• Episodic unconsciousness• Grand-mal seizures

Symptoms

• May be present from 1 week - several decades prior to diagnosis

• Occur during fasting or after alcohol or exercise and treatment with sulphonylureas

• Weight gain

Signs and Diagnosis

Signs• Low blood glucose• High serum insulin• High c-peptide levelDiagnosis is based on :• Inappropriate hyperinsulinaemia• High ratio of proinsulin to insulin in a fasting

blood sample• CT scanning and/or pancreatic arteriography

to identify the site of the lesion

Inappropriate hyperinsulinaemia

• Frequently have increased proinsulin concentrations and an insulin:proinsulin ratio closer to 1:1

• Normal individuals have a 6:1 ratio

Management

Medical treatment with:• Diazoxide• Hydrochlorothiazide• Octreotide acetateSurgery !

• Insulin- polypeptide hormone- islets of Langerhans

• Pro-insulin- precursor molecule- split into two molecules in equimolar amounts

insulin (physiologically active) C-peptide (physiologically inactive)

HOW ARE INSULIN LEVELS MEASURED?

IMMUNOASSAYS

1. Radioimmunoassay (RIA)- non-specific polyclonal antisera cross-reactivity 38% to 100%

- specific monoclonal antibodies competitive

- unlabelled insulin and 125I-labelled

insulin - fixed amount of tracer and

antibody - amount of tracer inversely proportional to concentration of unlabelled ligand

non-competitive - excess of antibodies immobilized on surface of matrix - insulin in serum captured - detected by labelled secondary antibody

2. Enzyme-linked Immunosorbent Assay

(ELISA)

- non-isotopic - competitive and non-competitive - horseradish peroxidase - spectrophotometry measurement - enzyme activity directly proportional

to captured human insulin

INTERFERENCES

• Issue of specificity - cross-reactivity of insulin

precursors

• Anti-insulin antibodies - interfere with results of

immunoassays - overestimation or underestimation

Why do we measure C-peptide?1.Diagnosis of insulin-induced factitious hypoglycemia

2.Contribution of the diagnosis of insulinoma (insulin suppression test)

3.Assessment of residual beta-cell function in diabetes under insulin therapy

4.Adjunct in the differential diagnosis between type 1 (insulin dependent) and type 2 (non insulin dependent) diabetes

5.Evaluation of insulin secretion in liver disease

1.Diagnosis of insulin-induced factitious hypoglycemia

• Elevation in insulin may be the result of excessive insulin administration

• Commercial insulin preparations do not contain C-peptide.

• You’ll expect the C-peptide levels to be low, if it is exogenous insulin administration (factitious hypoglycemia).

2. Contribution of the diagnosis of insulinoma (insulin suppression test)

• If both C-peptide and insulin (which are released in equimolar amounts) are elevated…

suspect insulinoma?

3.  Assessment of residual beta- cell function in diabetes under insulin therapy

• When endogenous insulin cannot be measured.

• Patients who receive exogenous insulin treatment

anti-insulin antibodies interfere with the RIA for insulin

C-peptide measurement will provide an estimate of the patient’s own remaining insulin-secretory capacity and may help in distinction between type 1 and type 2 diabetes.

4. Adjunct in the differential diagnosis between type 1 and type 2 diabetes

       C-peptide and insulin are secreted in equimolar amounts:

   C-peptide levels can serve as a valuable index to insulin secretion.

 Low C-peptide levels are expected where insulin secretion is diminished (insulin dependent diabetes)

Insulin Suppression Test

• Used for the diagnosis for insulinoma.

PRINCIPLE OF TEST

  In the absence of fasting hypoglycaemia, insulin administration will result in a suppression of endogenous insulin production.

  C-peptide levels will also be suppressed as a normal response to exogenous insulin

METHOD

 72-hour fasting test Insulin to be administered to

patients/subjects to check for insulin suppressibility.

 Blood samples are taken 30,60,90 and

120 minutes after the insulin dose.

• Lab results for blood glucose, insulin and C-peptide.

RESULTSNormal subject:

C-peptide usually suppresses to <1.5ug/L and may be undetectable 30-60min after hypoglycemia has been achieved, with insulin being <10mU/L.

  Insulinoma: • C-peptide is not suppressed by insulin

administration.  • Both insulin and C-peptide levels will be elevated• Insulin >10mU/L, despite low blood glucose of

<2.2mmol/L

Jill was hospitalised and an extended fast was conducted yielding the following results:

  

The c-peptide value at 48 hours was 5 ug/L (0.8-1.9ug/L).

 

12h 24h 36h 48h Range

Glucose mmol/L

3.3 3.1 2.7 2.1 3.6-5.8

Insulin mU/L

8 12 17 35 4-10

 Lab results conducted over a 48-hour period Glucose levels very low (hypoglycemia),

outside the reference interval

 Insulin levels increases to very high, of 35mU/L (outside the

reference interval), C-peptide value also raised. Results support diagnosis of insulinoma

Further tests (e.g. detailed CT scan, MRI, octreotide scan, and an endoscopic ultrasound) need to be performed to detect for the tumour in the pancreas.