Category: Hypoglycaemia

Insulin as a murder weapon: the case of Colin Norris

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Adapted from Journal of Forensic and Legal Medicine Feb 2023 Insulin murder and the case of Colin Norris by Alan Wayne Jones University of Linkoping, Sweden.

Although insulin is an essential medicine and a life saving drug, it has been used in many poisonings. These can be accidental, suicidal or to deliberately cause harm. An insulin overdose causes severe low blood sugars, and if untreated can lead to coma, irreversible brain damage and death.

Normally, in non- diabetic individuals, the beta cells in the pancreas secrete the same amounts of insulin and C peptide into the portal venous system. In the liver, the insulin is broken down faster than the C peptide, so normally there is more C peptide in the general circulation than insulin. When there is more insulin in the system than C peptide, that is a very strong indicator that insulin from a non- pancreatic source has been administered.

Sophisticated biochemical measuring systems can identify insulin analogues. This provided part of the evidence that convicted Colin Norris, a nurse, of injecting insulin into five of his patients, four of whom died as a result.

Clinical symptoms of low blood sugars occur when the blood sugars drop below 2.5 (UK) or 45 (USA), although the exact threshold can vary between individuals. If this is prolonged for up to 6 hours or more then the brain damage can be irreversible and death can occur. The hormonal response to correct low blood sugars also prolongs the QT interval in the heart electrical pacing mechanism leading to an increase in cardiac arrhythmias and sudden death.

Proof of insulin poisoning requires positive identification of the causative agent in plasma or serum samples taken from the victim before the low blood sugar is corrected.

The first proven case of murder by insulin occurred in the mid 1950s and forensic evidence was obtained from analysing tissue samples from around injection marks on the victim’s buttocks.

During an investigation into suspicious deaths caused by insulin, the entire case scenario and totality of the evidence must be carefully considered. Tissue samples around any injection marks need to be kept for later analysis of insulin and C peptide levels.

In a Leeds hospital, in September 2002, a Mrs Hall was recovering from a hip joint operation and seemed to be making good progress. In the early hours she was found unresponsive. A bedside test showed that her blood sugar was only 1.5. Although intravenous dextrose was given, she never regained consciousness and later died. She did not have diabetes. Assays showed that the insulin level was far higher than the C peptide level indicating that pharmaceutical insulin had been injected. It was believed that she may have been mistakenly injected with insulin which was kept for patients in an unlocked fridge.

Nurse Colin Norris became the prime suspect. As part of the investigation a retrospective review of other unexpected deaths and incidents which could have been due to insulin administration were found. Four incidents had occurred in the previous year when Colin Norris was on duty. Three earlier deaths had been attributed to natural causes at the time and there was no toxicological evidence that any of them had been injected with insulin. Colin Norris maintained his innocence throughout the investigation.

In October 2005 Colin Norris was charged with murdering four patients and attempting to murder a fifth by the injection of insulin. The trial started at Newcastle Crown Court in October 2007. In March 2008 he was found guilty and was sentenced to life imprisonment. He was described by the judge as a “thoroughly evil and dangerous man…arrogant and manipulative….with a real dislike of elderly patients. There cannot be any suggestion that you were motivated to hasten their ends to spare them suffering”.

After the first appeal against Norris’s conviction failed in 2009, clinical evidence emerged that spontaneous attacks of hypoglycaemia in elderly and frail patients are not as rare as the jury had been led to believe. Indeed, a literature review showed that 2-10% of elderly frail patients, who can be malnourished, with co-morbidities such as sepsis, liver disease, or kidney failure are vulnerable to attacks of hypoglycaemia.

Other weaknesses in the case were:

The insulin vials on the ward were not subject to any inventory.

No insulin or needles were found near Mrs Hall.

The fingertip blood sample showing low blood sugar was not verified with a venous blood sample.

The very high insulin level was found on an NHS assay machine, not a more accurate forensic one. Rigour in following chain of custody procedures were not done. A confirmatory sample had also not been done.

The low blood sugar had been corrected before the low C peptide versus high insulin was found.

Spontaneous hypos can indeed occur in the elderly and frail.

Another hypoglycaemia related death had occurred at the hospital but it had not been mentioned as Norris had not been on duty. Thus the police were suspected of cherry picking cases to incriminate Norris.

Toxicological evidence of hypoglycaemia was only found for Mrs Hall. Death certificates for the other suspected hypoglycaemia deaths had been attributed to old age and other natural causes.

The cause of death of Mrs Hall was brain damage due to insulin induced hypoglycaemia but it was not known if the pathologist had looked for any insulin secreting tumours.

One of the senior police officers had been involved in the Dr Harold Shipman case two years previously and he may have been primed to find another serial killer in the health profession.

The Criminal Case Review Committee, which is the official authority in the UK charged with looking into miscarriages of justice, have examined the evidence and recommended that the court of appeal have a fresh look at the case.

My comment: It will be interesting to find out what happens and what their reasoning regarding this case will be. Meanwhile, look after yourself, look after your diabetes, keep up a healthy lifestyle and keep out of hospital!

The optimal HbA1C for non low carbing type ones could be 6.5-7%

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Adapted from Lind M et al. BMJ 28 August 2019

In type one diabetes in adults and children there could be a sweet spot for blood sugar control.

Under 6.5% severe hypoglycaemia rates increase. Retinopathy and nephropathy risks are not lower however below 6.5% compared to 6.9%. My comment:  In low carbers however, they have considerable protection against severe hypoglycaemia due to more precise meal/insulin matching, although they do experience more episodes of mild hypoglycaemia.

Risks for mild complications begin at levels over 7.0% and severe complications rise with levels over 8.6%.

Current guidelines vary in their HbA1C recommendations, anywhere from 6.5% to 7.5%.

The complication rates were based on 10,398 adults and children with type one diabetes on the Swedish National Diabetes Registry who were diagnosed between 1998 and 2017.

 

 

 

Type Ones get near normal blood sugars on very low carb diets

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Adapted from Management of Type One Diabetes with a very low carbohydrate diet by Belinda S Lennerz et al. Pediatrics Volume 1 number 6, June 2018.

Exceptional glycaemic control of type one diabetes mellitus with low rates of adverse events was reported by a community of children and adults who consumed a very low carb diet. This study was done by recruiting patients via an online survey. Their medical records were then used to confirm their results.

Of the 316 respondents, just over a third were parents of diabetic children. The mean age of diagnosis was 16 years and the duration of diabetes was a mean of 11 years. The mean time of following a VLCD was just over 2 years. The mean daily carb intake was 36g. The mean HbA1c was 5.67%. Only 2% of the respondents reported diabetic hospitalisations. 4 admissions were for DKA and 2 for hypoglycaemia.

In the USA the average HbA1C for type one diabetics is 8.2%.  The ADA target to reduce complications is set at under 7.5% for children and under 7% for adults. Only 20% of children and 30% of adults reach these targets.

A major difficulty is achieving post meal blood sugar targets. The carbohydrate load has the greatest influence on this. A VLCD is regarded as between 20 and 50g of carb at each meal or between 5-10% of total meal calories from carbohydrate. Some practitioners worry about advising diabetics about VLCD because of concerns about DKA, hypos, lipid problems, nutrient deficiency, growth failure and sustainability.

The study was approved by the Boston Children’s Hospital.  The recruitment group were people who were following Dr Bernstein’s Diabetes Solution. They came from the USA, Canada, Europe and Australia. They were all confirmed as having type one diabetes from their medical records.

Symptomatic hypoglycaemia was reported by 69% of the participants but severe hypos were rare. Most people had 1-5 episodes of mild hypos a month.

Most people had the characteristic low triglycerides, high HDL, high total cholesterol and high LDL pattern.  The average trig/hdl ratio was 1:1 indicating excellent cardiometabolic health. BMI was also lower than population averages for age. The DCCT covered 1441 adolescents and young adults and the factors that showed the greatest effect on cardiovascular risk were: HbA1c, then trigs, then LDLc.

The commonly reported growth deceleration noted with type one diabetes is generally thought to be due to poor blood sugar control.  In this study group however the children’s height were modestly above averages for age and gender.

A few participants deliberately did not disclose their low carb diets to their health care providers due to concerns about being criticised, pressured to change behaviour or accused of child abuse. Although 49% of participants thought that their health care provider approved of VLCDs, a robust 82% of the health care providers said they did.

We don’t know how generalisable the findings in this study could be. This group may be particularly well motivated and may be pursuing other health related behaviours such as physical activity. None the less,  the level of glycaemic control and low rates of DKA and severe hypos revealed by this study break new ground in research into diabetes management for type one diabetes.

 

 

 

RCGP: Adapting diabetes medication for a low carb diet

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Adapted from RCGP July 19 Adapting diabetes medication for low carbohydrate management of type two diabetes by C Murdoch et al.

This topic has been well covered in our book but has been reviewed in this article. 

Type two diabetes can be reversed by a low carb diet. Changes in medication need to keep pace with lowered blood sugar levels that result. A low carb diet can range from under 30g to 130g of carb a day.  Blood pressure medication also often needs to be reduced or stopped as lower blood pressure results from a reduction in insulin resistance.

Sulphonylureas, meglitinides and insulin all reduce blood sugar and if not reduced appropriately can result in hypoglycaemia.  It is reasonable to cut the dose of these by 50% when a low carb diet is started. Once the diet is stabilised the levels can be increased if this is necessary. If a patient has very high blood sugars eg HbA1C of 10% or more then a reduction of 30% can be considered initially. As more weight is lost or more carb is cut from the diet, further reductions can then be made. Some patients will be able to stop insulin and oral hypoglycaemics entirely as progress is made.

Some patients have latent autoimmune diabetes and although they can reduce their doses, their insulin must be maintained at some level. These patients can often be identified because they developed type two diabetes when they were thin.

Some patients who may need to stay on some insulin have had type two diabetes for many years and have ceased to make any pancreatic insulin. (Secondary beta cell failure).  My comment:  Users of sulphonylureas eg Gliclazide over five years are prone to this problem.

It is important to provide plenty of blood glucose testing strips to patients over the transition so they can let you know if they are experiencing hypos.

GPs can refer to endocrinologists for advice over patients who are giving concern.

Flozins also known as SGLT2 inhibitors increase the risk of ketoacidosis in patients who have significant pancreatic insufficiency.  The ketoacidosis is hard to recognise because the blood sugar is often normal or only very slightly raised. The person just feels ill and may vomit. My comment: in my experience this effect is difficult to predict but usually occurs in the first week or two of treatment. Low carb diets of below 30g-50g of carb a day also produce dietary ketones so can muddy the waters even more. Therefore is someone is on a flozin and starts a low carb diet it is best to suspend the flozin. They may not require it after a while on a low carb diet in any event.

Commonly used drugs that do not give any risk of hypoglycaemia include Metformin, Glutides, Glitazones, Gliptins and Acarbose.

About a quarter of people on metformin get diarrhea and need to go on the long acting version or stop it altogether.  Because acarbose is meant to help block starch and this is eliminated on a low carb diet, this drug can be stopped.  Glutides, Glitazones, Gliptins can be stopped when blood sugars are at a satisfactory level.  My comment: The target blood sugar will vary from patient to patient. You can see more about this in my PHC talk on you tube or in our book.

 

 

 

BMJ: Flozin effects in type one diabetes

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 Adapted from BMJ 13 April19 Efficacy and safety of dual SGLT 1/2 inhibitor sotagliflozin in type one diabetes Musso G, Gambino R. Cassader M, Pascheta E. BMJ 2019:365:1328

Flozins are increasingly used for patients with “double diabetes” in practice. The authors of this study searched for randomised controlled trials for the drug Sotagliflozin to find out how effective they were and what safety issues were apparent. Over three thousand patient responses were studied. There were six trials that were of moderate to good quality and they ran between four weeks and a year. The relative pluses and minus are listed.

lowered HbA1c by  0.34% (small)

reduced fasting and post meal blood sugars

reduced daily total, basal and meal insulins

reduced time in target blood sugar range

reduced body weight by 3%

reduced systolic blood pressure by 3 mmHg

reduced protein in the urine

reduced the number of hypoglycaemic events

reduced the number of severe hypoglycaemic events

On the other hand these factors were increased:

Ketoacidosis increased by a factor of x 2 to x 8 depending on the study looked at

genital tract infections increased by a factor of x 2 to x 4.5

diarrhea increased up to x 2

volume depletion events increased by up to x 4

Patients got better blood sugar results from the higher dose of 400mg Sotagliflozin compared to the 200mg dose without increasing the risk of adverse events.

Most DKA episodes occurred as the drug was being started and patients cut their insulin dose too much, in anticipation of reduced blood sugars.

My comment: The risk of DKA in type twos is not very common but is a known effect of flozins, so it is not that surprising that this is increased in type ones too. The reduction in hypoglycaemia events and severity is a new finding and suggests an increasing role for flozins in type one management.

 

 

 

Type ones on low carb diets experience less hypoglycaemia

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Adapted from Why low carb diets for type one patients? Jun1 2019 by Emma Kammerer Pharmacy Doctorate Candidate Bradenton School of Pharmacy originally published in Diabetes in Control.

Both Dr Jorgen Neillsen and Dr Richard Bernstein have shown that insulin users have fewer attacks of hypoglycaemia and that the attacks are less severe.  A new randomised controlled study by Schmidt et al confirms this finding.

Studies have shown that when a high carb diet is consumed there 20% greater error in carbohydrate estimation compared to when a low carb diet is chosen. This then affects the insulin dose administered, and thus the resulting blood sugars.

Schmidt wanted to look at the long term effects on glycaemic control and cardiovascular risk in type one patients on a low carb diet compared to a high carb diet.

The study was a randomised open label crossover study involving 14 adults who had had diabetes for more than 3 years, to eliminate the honeymoon effect. The patients went on one diet for 12 weeks, had a washout period of another 12 weeks, and then took up the other diet.  This was done so that the glycated haemoglobin levels would not be carried over from one diet to the next.

A low carb diet was defined as less than 100g carb a day and a high carb diet as over 250g per day.

Patients were given individualised meal plans and education on how to eat healthy carbs, fats and proteins. They all were experienced insulin pump users. They were asked to record total carbohydrate eaten but not the food eaten. Measurements were taken on fasting days on the first and last day of the study periods.

Blood glucose levels were downloaded from continuous glucose monitoring devices.

Four patients dropped out of the study so ten completed the test which was considered satisfactory by the statistician involved.

Results showed that the time spent in normal blood sugar range 3.9 to 10 mmol/L ( USA 56-180) was not significantly different for each diet.

The time spent in hypoglycaemia, below 3.9 (USA 70) was 25 minutes less a day on the low carb diet, and six minutes less a day below 3.0 (USA 56).

On the low carb diet glycaemic variability was lower and  there were no reports of severe hypoglycaemia.

On the high carb diet, significantly more insulin was used, systolic blood pressure was higher and weight gain was more.

There was no relevant changes in factors for cardiac risk between the two study arms.

The study showed that a low carb diet can confer real advantages to type one patients but education on how to conduct a low carb diet and manage the lower doses of insulin is required.

Schmidt, Signe et al. Low versus high carbohydrate diet in type 1 diabetes: A 12 week randomised open label crossover study. Diabetes, Obesity and Metabolism. 2019 March 26.

 

 

Hypoglycaemia: the neglected complication

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Adapted from Hypoglycaemia: the neglected complication by Sanay Kalra et al.

Indian J Endocrinol Metab. 2013 Sep-Oct; 17(5): 819-834

Hypoglycaemia is an important complication of glucose lowering therapy in patients with diabetes mellitus. Attempts made at intensive glycaemic control invariably increases the risk of hypoglycaemia. A six fold increase in deaths due to diabetes has been found in patients with severe hypoglycaemia compared to those not experiencing severe hypoglycaemia.

Repeated episodes can lead to hypoglycaemia unawareness. Complications  of hypoglycaemia include stroke, heart attacks, cognitive dysfunction, retinal cell death and loss of vision. Apart from this there are the effects on quality of life regarding sleep, driving, employment, exercise and travel.

To maintain good glycaemic control, minimize the risk of hypoglycaemia and thereby prevent complications, there are steps that need to be taken: recognise risk factors for hypoglycaemia, use appropriate self monitoring of blood sugar, select treatment regimens that have little or no risk of incurring hypoglycaemia and teach health care professionals and patients how to avoid hypoglycaemia.

Although the DCCT showed that complications were reduced when blood sugars were brought under a HbA1C of 7%, other trials have noted a three fold risk of hypoglycaemia when the level is reduced under 6.5%. This tends to negate any improvements in long term complications.

Insulin users are most at risk. Those who have had diabetes for more than 15 years are particularly at risk. The DARTS study showed that the risk of severe hypoglycaemia was 7.1% for type one patients, 7.3% for type two patients and 0.8% for type twos on sulphonylureas. This causes increased cost for their healthcare as hospitalisation for around a week is needed in the average case.

The majority of hypos are due to medications but there are other potential causes such as: pancreatic or islet cell tumours, dietary toxins, alcohol, stress, infections, sepsis, starvation and excessive exercise.

In diabetics not eating enough food was the most common cause. Others were physical exercise, insulin miscalculation, stress, overtreating a high blood sugar, and impaired glycaemic awareness.

Nocturnal hypoglycaemia is seen in half of diabetic children, particularly under the age of 7. Dead in bed syndrome causes 5-6% of all deaths in type one youngsters.  Contributory factors are increased exercise that day or delayed meals.

In type two patients additional causative factors are alcohol ingestion and liver disease and duration of insulin over ten years. As in type ones there tends to be more hypoglycaemic unawareness as the person ages. In type twos  there is a 9 fold increase in deaths in those with hypoglycaemic unawareness.

Severe hypos in elderly patients increase the risk of dementia, functional brain failure and cerebellar ataxia. There are clear signs of neuronal death in specific brain areas at post mortem in these patients and a history of fits make these more extensive.

Hypos in elderly patients promote cardiac ischaemia. Arrhythmias are more likely due to catecholamine release during hypos. Prolonged QT intervals lead to increased heart rate, fibrillation and sudden cardiac death.  Inflammatory cytokines are released during hypos, abnormalities of platelet function and the fibrinolytic system occur.

Hypos can cause double vision, blurred vision and dimness of vision.  Blindness can occur due to retinal cell death.

Recurrent hypos make people feel powerless, anxious and depressed. Acute hypos cause mood swings, irritability, stubbornness and depression.  Quality of life scores are worse in patients with recurrent hypos.

Driving ability is affected by hypos. The affected driver can inadvertently cross lanes and speed and generally drive worse.

Hypos at night may be recognised by sleep disturbance, morning headaches, chronic fatigue and mood changes. In young children fits and bed wetting may occur.

Hypos at work can be awkward, embarrassing and frightening. Hypos are particularly dangerous for those who work at heights, underwater, on railway tracks, oil rigs, coal mines, handling hot metals or heavy machines.

Expert medical advice and planned action counselling can help workers. So can self blood glucose testing, healthy food options in canteens, flexible meal times, arrangements to carry and use emergency glucose/sugar, storage and disposal sites for medications and sharps, and time off for medical appointments. Work time and productivity due to hypos can be reduced and nocturnal hypos can also have a knock on effect the next day.

Hypos in children tend to be increased in summer months when they are more active. In adults, intense prolonged exercise following an episode of recent severe hypoglycaemia can damage skeletal muscle and the liver and can cause severe neurological symptoms.

Travelling long distances, particularly over times zones can cause insomnia, tiredness, stress, reduced appetite, nocturia,  gastric disturbance, muscle aching and headaches. Psychological symptoms include low mood, irritability, apathy, malaise, poor concentration. These deficits in both physical and mental performance can profoundly affect decision making.

The fear of hypos can affect patients more profoundly than the fear of long term complications.  Withholding of insulin can occur. Sometimes patients refuse to start it when they need it and sometimes they miss out their doses.

About 30% of type one patients are affected by hypoglycaemia unawareness and under 10% of type two patients are thus affected. Duration of insulin use is the main common factor.

Educating patients about how to detect, treat and prevent hypoglycaemia must be understandable to the patient and their family.

In 2013 the ADA recommended that insulin users test their blood sugars 6-8 times a day.

Basal insulin needs to be matched to the patients needs. If hypos persist, particularly overnight, switching to pump therapy may help.

Newer diabetic medications, which do not cause low blood sugars such as the gliptans and gliflozins, may be preferable in type two patients who have multiple co-morbidities, are elderly,  who live alone, are at high risk of falls, and who have hypoglycaemia unawareness or who otherwise could not effectively deal with a hypo.