According to a 1999 paper about murder cases involving insulin overdose, an 83-y

Question

According to a 1999 paper about murder cases involving insulin overdose, an 83-year old lady in a nursing home showed signs of extremely low blood glucose level (0.1 mmol/L, healthy range= 4-8 mmol/L). At first, kidney failure was suspected as the cause of hypoglycemia, but blood analysis showed that insulin level was extremely high (83,360 pmol/L, healthy range= 60-120 pmol/L during fasting, Up to 2,000 pmol/L after glucose intake) while C-peptide level was low (170 pmol/L, healthy range= 260- 1,000 pmol/L). Elevated insulin level coupled with suppressed C-peptide level is virtually diagnostic of an exogenous insulin administration (insulin overdose). (Unfortunately, the lady died 11 months later and the perpetrator was not identified.)

1. What is C-peptide and how is it related to insulin production and secretion?

2. With your answer to question 1, explain how elevated insulin level and suppressed C-peptide level strongly supports exogenous insulin administration, as opposed to overproduction of insulin in such cases of endogenous insulin overproduction as insulinoma or treatment with sulphonylurea.

Explanation / Answer

Answers:

1) The C-peptide, also known as connecting peptide is a 31 amino acid containing polypeptide. It connects or bridges A chain and B chain in the proinsulin molecule. During insulin production in pancreatic beta cells, transcription and translation of insulin gene produce preproinsulin in the endoplasmic reticulum. Preproinsulin contains A chain, C-peptide, B chain and a signal sequence at N terminus. Microsomal enzyme, signal peptidase, cleaves the signal sequence and converts preproinsulin in to proinsulin, which contains A chain and B chain linked by the C-peptide. Proinsulin is then transported to the Golgi complex where it is packaged in secretory vesicles. C-peptide is required for the correct folding and assambly of proinsulin. It helps in forming two disulphide linkages between the A and B chain and one intrachain disulphide linkage in the A chain. The proinsulin then undergoes proteolytic cleavage and forms mature insulin and C-peptide, which are co-secreted in equimolar amounts in the blood. After removal of the C-peptide, end of the B chain becomes free to bind insulin receptor. C-peptide is metabolize in kidneys and a small fraction is excreted unchanged in the urine.

2) As mentioned in the above answer that the C-peptide is secreted in equimolar amounts to insulin, measuring C-peptide level along with insulin level can give idea about person's own insulin secretion (endogenous insulin) and exogenous insulin administration. Exogenous administratuon of insuline suppresses endogenous secretion of insuline and C-peptide. Thus, if insulin is administered exogenously C-peptide level will be relatively lower (due to suppression) than the insulin level. However, if insulin is overproduced, as in the case of insulinoma or treatment with sulphonylurea, the C-peptide levels will also be high because the C-peptide will be co-secreted with the endogenous insulin. C-peptide suppression test is used for the diagnosis of insulinoma, and the test is based on the fact that exogenous administration of insulin suppresses endogenous insulin and C-peptide secretion. So the test involves infusion of exogenous insulin and measurement of glucose and C-peptide during the infusion. Lack of suppression of C-peptide secretion is indicative of insulinoma.

Also, C-peptide level is a better measure of endogenous insulin secretion because the secreted insulin is largely metabolized by liver but C-peptide does not. C-peptide measurement has role in discrimination of diabetes subtypes.

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