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Problems for Discussion - 2 - Biguanides, Sulphonylureas and Insulin

Hypoglycaemic problem
Mrs AB died at home on the 5th of January 2000.

AB arrived in this country in 1997. Her medical history was not available, but she was first seen medically on 25/06/97 for a medical examination for an insurance policy and found to be in good health.

In early November 1999, AB first showed signs of ill health. She was dizzy, had slurred speech, fell down stairs and at one stage drove her car into a tree.

On 20/11/99 AB was admitted into hospital with hypoglycaemia. The hypoglycaemia appeared to be quite resistant to reversal. A sulphonylurea screen for tolbutamide, glibenclamide, gliclazide, glipizide and chlorpropamide was performed and all were negative. The time given for this sample was 00:45h on 21/11/99, which is approximately 17 hours after admission.

Following this admission, further episodes of hypoglycaemia occurred on 27/11/99, 28/11/99, 29/11/99, 05/12/99 and 06/12/99, prompting a provisional diagnosis of insulinoma. C-peptide and insulin levels were raised in the presence of hypoglycaemic episodes. She underwent arterial stimulation tests of the pancreas using calcium gluconate to hepatic, superior mesenteric, gastro-duodenal and splenic arteries into the pancreas. During the test her insulin and C-peptide levels rose dramatically and this was associated with a subsequent drop in blood glucose to 1.6 mmol/L. On the findings of this test a possible site of the insulinoma was localised to the tail of the pancreas. On 13/12/99 a surgical intervention was performed during which palpation and intraoperative ultrasound were negative. A 2.7 mm nodule was discovered in the ileum and histologically thought to be a carcinoid/insulinoma. A distal two-thirds pancreatectomy was performed. She was hypoglycaemic in hospital on two occasions, one pre-op and one post-op.

Following the surgery, the blood sugars remained relatively normal until 21/12/99, when over the next two days she experienced some hypoglycaemias with symptoms. AB was discharged on the 24th of December 1999 following a 36-hour fast without hypoglycaemia. She was discharged on pancreatic enzyme replacement and penicillin for post-splenectomy prophylaxis.

On 02/01/00 and 03/01/00, she again became hypoglycaemic corrected by diet. This persisted on 04/01/00, along with more marked symptoms. On 05/01/00 she was found dead by CB at 06:15. Concerns were raised about whether she was poisoned with hypoglycemic agents.

1. AB presented at admission on the 29th of November 1999 with symptoms of polydipsia, polyuria, polyphagia, and loss of weight and strength. These are symptoms of diabetes; but are they symptoms of the administration of oral hypoglycaemics?

2. While in hospital Mrs AB was on diazoxide from the 2nd of December, 1999 to the 13th of December. On the 6th of December she had a hypoglycaemic episode, blood sugar level (BSL) 2.1 mmol/L. Would diazoxide prevent or counter a hypoglycaemic episode arising from an insulinoma? or from administration of oral hypoglycaemics?

3. AB had readings as low as 0.8 mmol/L? Is there a cut off point for the effect of oral hypoglycaemics on BSLs?

Dr CB is arrested for the murder of his wife. The Police case is that Dr CB killed his wife by administering metformin, glibenclamide and glipizide which he obtained by writing false scripts. The defence case is that Dr B was stockpiling hypoglycaemics to commit suicide and the cause of death of AB is unknown.

Postmortem examination revealed a normal pancreas, an acute ischaemic myocardium, some early pneumonia in one lung but no evidence of an insulinoma was found.

Toxicological analysis
Note that all specimens were post-mortem samples unless otherwise stated.

Blood (femoral)Not detected
Ante-mortem serum1.6 millimoles per litre (mmol/L)
Blood (femoral)0.78 milligrams per litre (mg/L)
Stomach contents0.006 milligrams (mg)
Ante-mortem blood (EDTA tube)0.2 mg/L
Blood (femoral)0.15 mg/L
Stomach contents0.004 mg
Ante-mortem blood (FDTA tube)0.30 mg/L
Blood (femoral)16 mg/mL
Blood (femoral)0.14 mg/L
Stomach contents0.03 mg
Ante-mortem blood (EDTA tube)0.06 mg/L
Blood (femoral)7.0 micrograms per litre
Blood (leg veins)60 microgram/L
Ante-mortem blood (EDTA tube)330 microgram/L
Serum (ante-mortem)Not detected
Blood (femoral)770 microgram/L
Blood (leg veins)700 microgram/L
Ante-mortem blood (EDTA tube)180 microgram/L
Serum (ante-mortem)Not detected
Total clonazepam and 7-aminoclonazepam, as clonazepam equivalent
Blood (femoral)860 microgram/L
Blood (leg veins)830 microgram/L
Ante-mortem blood (EDTA tube)530 microgram/L
Blood (femoral)Not detected
Ante-mortem blood (EDTA tube)Not detected
Blood (femoral)Not detected

4. What is your interpretation of these post mortem analysis results?

5. What is the significance of AB only having a third of a pancreas at the time the hypoglycaemic drugs are supposed to have killed her?

6. Why were the sulfonlylureas not detected in hospital? What would the delay of l7 hours post first hypoglycaemic coma before taking the blood sample do for the sensitivity of the sulphonylurea screen? (The time line is as follows: Mrs B was found comatose at 6.30 am. 10% dextrose was commenced at 13.00. BSL 2.1 at 18.30. BSL 3.1 at 2130. Blood taken 00.45 next morning.)

7. What is the effect of hypoglycaemic drugs on a post calcium-stimulation pancreatic venous sampling procedure done to detect the location of an insulinoma? The notes state: ‘Her sampling results are somewhat unusual in that there is apparent response in the splenic artery but also possibly in the gastroduodenal plus or minus the superior mesenteric artery’.

Further Progress
The Police now believe that AB’s death was due to an injection of insulin obtained by Dr CB just prior to her death.

On the 4th of January, the day before AB’s death, Dr B picked up insulin (Humalog) at 3.00 pm. The children went in to say goodnight to their mother at about 11.30 pm.and she was alive AB was found dead at 6.00 am. However circumstantial evidecne suggests if Dr CB had killed AB with an insulin injection he had to have done it before 10.10 pm.

8. How quickly or slowly does insulin kill?

The trial of Dr B for the murder of his wife is into its second week.

The Crown has just advised that further tests have shown that Mrs B’s pancreatic cells show hyperplasia. This is thought helpful to the defence, as it supports an opinion that Mrs B was suffering from endogenous pancreatogenic hyperinsulinaemic hypoglycaemia.

9. The defence needs to know urgently whether the administration of sulphonylurea drugs could or would cause the islet beta cells in the pancreas to show hyperplasia

/home/wikitoxo/public_html/data/pages/wikitox/problems_for_discussion_2_biguanides_sulphonylureas_and_insulin.txt · Last modified: 2018/09/01 09:01 (external edit)