Hypoglycaemia, Cognitive Function, Aggressive Behaviour and Violence
INSULIN – A Voice for Choice by Professor Arthur Teuscher
A thorough discussion of the controversy surrounding animal and ‘human’ insulin
In the early 1980s synthetic ‘human’ insulin produced by recombinant DNA technology came onto the market. Despite an acknowledgment by the manufacturers regarding the potential dangers of ‘human’ insulin they soon began to withdraw bovine and porcine insulin from markets all over the world, and promoted more expensive ‘human’ insulins as a superior replacement. Diabetics had no option but to effectively switch to the new synthetic insulins and often they received little or no information about their potentially life-threatening side effects.
In the first part of this book the author provides fundamental information about insulin therapy and its history. A detailed discussion of the hazards confronting some diabetic patients when using ‘human’ insulin follows. Due to more pronounced hypoglycemia symptoms animal insulin can be regarded as safer than ‘human’ insulin for 10–20% of diabetic patients. The last part of this publication looks at the pharmaceutical industry’s decision to withdraw animal insulin from the market and describes the struggles of a new global movement to secure its continued availability.
This book not only provides potentially vital background information for those who depend on insulin, but also deserves the attention of professionals who prescribe or distribute this medication. It can also serve as a reference for patient advocates, relevant government departments and pharmaceutical companies.
30 YEARS OF SYNTHETIC INSULIN, ARE PEOPLE WITH DIABETES GETTING THE BEST DEAL?
A report of patient’s concerns 2007
Recent increased forecasts in the incidence of diabetes worldwide leads to concerns amongst patients and their carers who are susceptible to suffering from hypoglycaemia or low blood glucose. Some manufacturers of insulin state in product information that if severe hypoglycaemia is not treated it can cause temporary or permanent brain damage and death.
Hypoglycaemia is a severe medical condition which can cause temporary and sometimes permanent brain damage if severe acute episodes are not corrected promptly. Occasionally family members and members of the public are incapable of differentiating between ‘domestic violence’, ‘violence and aggressive behaviour associated with alcohol’ and ‘acute diabetic hypoglycaemia with violent convulsions and seizure’. This can be very distressing for patients treated for diabetes with insulin, their carers, families and nursing staff in hospitals when treating hypoglycaemia with seizure and violent convulsions.
Evidence is now accumulating on impairments in cognitive functioning during hypoglycaemia and of the direct effects of insulin on brain receptors in certain neuroanatomical regions. Both areas of research may be indirectly relevant to the question of whether synthetic human insulin can cause violence either through a direct action on brain receptors or through the rapid induction of hypoglycaemia or the development of hypoglycaemic unawareness.
The Psychobiology of Hypoglycaemia was presented at the Royal College of Psychiatrists/Diabetes UK conference on Psychological Wellbeing and Diabetes in London in December 2005 by Professor Stephanie Amiel of King’s College, London. In this paper the evidence, including neuroimaging evidence, that cognitive impairment occurs during hypoglycaemia was covered. Hypoglycaemia stimulates the anterior cingulate gyrus. It also leads to increased insulin uptake in the ventral striatum and orbitofrontal cortex. These areas are interconnected and are not only involved in monitoring bodily sensations and emotions, stimulating the appetite centre, food-seeking centre and reward centres; but are also involved in emotional processing including precipitating anger and an emotional reaction to the restraint of physical aggression (Ref: review of the Neurobiology of Emotion Perception by Phillips, M et al (2003) Society of Biological Psychiatry).
Research by Rotte, M and colleagues at the Magdeburg University Medical School in Germany (see Rotte et al (2005) Insulin affects the neuronal response in the medial temporal lobe in humans, Neuroendocrinology 81 (1) 49-55) showed insulin activation of the medio-temporal lobe and fusiform gyrus. Again, these are brain areas involved in emotional regulation, learning and memory.
This information is helpful in elucidating the link between synthetic insulin, hypoglycaemia, violence and other distressing emotional states. Other studies in this delicate area include:
Hypoglycaemia and the brain
BM Frier Royal Infirmary of Edinburgh, Edinburgh, UK.
The brain is dependent on a continuous supply of glucose as its source of energy, the rate-limiting step being the rate of transport across the blood-brain barrier. Glucose deprivation of the brain causes neuroglycopenia and rapid malfunction. This is demonstrated by the development of abnormal neurophysiological function with slowing of neural transmission and electroencephalographic changes, and by the progressive impairment of cognitive function, affecting several domains. The cognitive dysfunction is manifested as neuroglycopenic symptoms of hypoglycaemia, while autonomic (principally sympatho-adrenal) activation generates classical autonomic symptoms. The glycaemic threshold for onset of these symptoms can be modified in people with insulin-treated diabetes, with cerebral adaptation underlying the syndrome of impaired awareness of hypoglycaemia. Regional cerebral blood flow is also altered acutely during acute hypoglycaemia, with blood flow increased in the frontal cortex, so protecting the most vulnerable part of the brain. These regional vascular changes become permanent in people exposed to recurrent severe hypoglycaemia and in those with impaired awareness of hypoglycaemia. Severe brain damage during hypoglycaemia is rare.
Very young children are most susceptible to cognitive impairment resulting from severe episodic hypoglycaemia. Recurrent exposure to severe hypoglycaemia in middle-aged adults with type 1 diabetes appears to have a modest adverse effect on intellectual function, and neuroimaging with MRI has suggested an association with cortical atrophy. Further studies that examined cognitive function and neuroimaging in people who had developed type 1 diabetes in childhood or adolescence, found no correlation between hypoglycaemia exposure and cognitive performance, but revealed a relationship between poorer cognitive ability and the presence of microvascular disease (as retinopathy), implying that chronic hyperglycaemia may affect the brain. These diabetic subjects had a higher incidence of small punctate white matter lesions demonstrable on neuroimaging, which may represent premature ageing of the brain. © Society for Endocrinology (2005). Reproduced by permission.
Study Using New Imaging Technology Detects Subtle Brain Changes In Patients With Type 1 Diabetes – February 2006
Although people with diabetes are twice as likely as the general population to develop depression, the cause of this increased risk is not well understood. Now, a Joslin Diabetes Center-led collaboration has documented for the first time subtle changes in the grey matter of the brain of type 1 diabetes patients compared to control subjects who did not have diabetes. They made these observations using voxel-based morphometry (VBM), a relatively new magnetic resonance imaging (MRI) technology that allows researchers to take very sensitive measurements of small regions in the brain. For the first time, doctors have reason to ask if the increased risk of depression could in fact be due to changes in brain.
“We have known for a long time that diabetes can damage the nerves that control the extremities and those that control internal organs like the heart and the intestine,” says the study’s principal investigator, Alan M. Jacobson, M.D., head of Behavioral and Mental Health Research at Joslin Diabetes Center. “This research helps document diabetes-related changes to the central nervous system. People tended to assume that the stress of dealing with a severe chronic illness and its complications was the sole source of depression. That still is an important issue, but now we have evidence that something else might be at work.”
Equally important, by showing the effectiveness of VBM for observing and evaluating changes in brain structure that appear to be related to diabetes, the study opens up whole new approaches to understanding the central nervous system in diabetes. This technology creates three-dimensional images of magnetic resonance imaging data, which researchers can then use to observe and evaluate structural changes, in this case, in the brain.
“We’ve used this technology to look at patients with bipolar disorder or with classic neurodegenerative disorders, but this is the first study to use VBM to investigate brain changes in patients with diabetes,” says co-investigator Perry Renshaw, M.D., Ph.D., who directs the Brain Imaging Center at McLean Hospital in Belmont, Mass.
For the study, the researchers measured grey matter densities in areas of the brain responsible for memory, language processing and attention. When they compared the images of 82 patients who had type 1 diabetes for 15 to 25 years with minimal complications to those of 36 age-matched control subjects who did not have diabetes, they discovered lower levels of grey matter density in the group with diabetes. Among that group, they also found that these lower levels in density were associated with poorer glycaemic control and higher frequency of hypoglycaemic events that led to unconsciousness.
“This study definitely does not mean that everyone who gets type 1 diabetes will suffer from clinically significant brain damage,” Dr. Jacobson emphasizes. Indeed, he explains that in fact they observed little difference in cognitive function when patients with diabetes were compared to the participants in the control group. What is important, however, is the new tool researchers now have to examine what changes do occur, what drives them, and how they may affect brain functions, including those that lead to depression.
Understanding changes in brain structure becomes particularly critical as more and more people with type 1 diabetes are living longer lives, explains co-investigator Gail Musen, Ph.D., also of Joslin. “We want to be able to understand how the metabolic changes of diabetes affect the risks these patients face so we can find ways to minimize them as they go on to live 50 or more years with this disease.”
Dr. Jacobson and his colleagues will continue now to follow the patients in the study to observe if and how the changes progress over time and whether high or low blood glucose influences that progression. Because they can also use MRI to measure the brain’s response to stimuli like cognitive or emotional tests, they will also start looking at functional changes.
“Now that we’ve identified unexpected structural changes in the brains of people with diabetes, we need to understand more about how these relate to changes in brain function,” says Dr. Renshaw. “The more we understand the problem, the better solutions we can find.”
Other researchers participating in the study include Caitlin Sparks and Katie Weinger, Ed.D., R.N., of Joslin; In Kyoon Lyoo, M.D., Ph.D., and Jaeuk Hwang, M.D., of Seoul National University College of Medicine and Hospital in Korea; Christopher M. Ryan, Ph.D., of the University of Pittsburgh School of Medicine; David C. Jimerson, M.D., of Beth Israel Deaconess Medical Center in Boston; and the late John Hennen, Ph.D., M.P.H., who was a biostatistician at McLean Hospital. Funding for the study was provided by the National Institutes of Health. Source: © Joslin Diabetes Center
Neuroimaging Studies on Cognitive Dysfunction
Tamara Hershey, Ph.D. Washington University in St Louis, USA Department of Psychiatry
Keywords: cognition, development, diabetes, dopamine, memory, neuroimaging, neuropsychology
Cognitive dysfunction in diseases relevant to dopamine, such as Parkinson’s disease, Tourette syndrome, attention deficit disorders, or schizophrenia, can be limiting and disabling. Currently, when deficits in cognitive skills such as working memory are seen in these patient populations, it is speculated that the impairments are due to dysfunction of the dopaminergic pathways. Using a combination of functional neuroimaging, pharmacological and cognitive techniques, we are trying to differentiate the effects of these very different disease processes on dopaminergic and cognitive systems.
We are also examining the impact of type 1 diabetes on children’s’ cognitive skills, particularly memory. Using neuropsychological and neuroimaging methods, we are studying how memory function and its neural underpinnings are affected by severe hypoglycaemia and severe hyperglycaemia, and how this relationship is altered across development. © Washington University in St Louis
Improving Diabetic Control without Hypoglycaemia
Diabetes management requires to:
a) Promote Good Health
b) Prevent Complications
c) Prevent Disabilities
d) Treatment with correct type and dose of insulin best suited to patient needs
e) Sensible diet
f) Sensible exercise regime
In the DCCT, Diabetes Complications and Control Trial, 1422 patients were monitored over a 9 year period. With conventional treatment 60% of patients developed retinopathy. With DCCT only 15% of patients developed retinopathy. The target measurements were:
Blood glucose before meals 3.9 – 6.7 mml/L
Blood glucose 2 hours after meals 10.0 mm/L
Blood glucose at 3.00am 3.6 mm/L
Target treatment was 3 insulin injections per day to mimic the body requirement for insulin. Target glucose monitoring was 4 blood glucose tests per day.
A 1% drop in HBA1c resulted in a 38% increase in hypoglycaemia.
Actions of Blood Glucose levels are:
4.0 mm/L Body reacts by producing extra adrenalin to compensate for low blood glucose
3.6 mm/L Hypoglycaemia onset
2.0 mm/L Cognitive DIsfunction occurs
2.0 mm/L EEG Stimulus becomes incorrect
1.0 mm/L Coma occurs
66% of patients suffer from hypoglycaemia. Many patients do not notice they are running low blood glucose levels.
Hypoglycaemia without warning leads to brain dIsfunction. At 2.5-3.0 mm/L if not corrected it is then too late and hypoglycaemia occurs. After 15 years on insulin 25% of patients have occasional instances of acute hypoglycemia requiring support from a third party, family, friend, colleague.
Fast acting insulin peaks at 1-2 hours. Moderate insulin peaks at 6-8 hours. Peaks are usually at mid-day before lunch, and at night. Snacks are important to avoid hypoglycaemic peaks. Women are reluctant to snack whereas men are usually comfortable at snacking.
Exercise causes low glucose for 18 hours after the exercise is taken. This can be compensated fro by reducing insulin intake at night.
Human insulin is one molecule different from animal insulin. A substantial number of patients do not feel comfortable when treated by human insulin.
After 15 years problems sometime arise with patients who have switched insulins from animal to human insulin. Human insulin is a reasonable insulin but is not suitable for some patients.
The absorption of insulin, and in fact of any endocrinology replacement therapy seeks to mimic that normally produced by the human body. The administration of insulin requires further development in this area. Some patients find that 2-3 injections per day are better however in the USA until 20 years ago many patients were only having a single insulin injection per day. Location of the insulin injection can also play an important role. For example if injected in the leg of a cyclist this can lead to fast insulin reactions.
Case 1 was a 48 year old factory supervisor. 27 years an insulin dependent diabetic. Experienced in managing his diabetes. Manipulates insulin injection dosage and times according to glucose readings. His wife was concerned about frequent hypos, some with loss of consciousness. Job was on the line. Erratic glucose readings from 1.8-24 mm/L. Active walking between work sites. Driving could be a problem. He needs to know about how much glucose to take to correct hypoglycaemia. His family should be included in discussions. He needs to avoid complex carbohydrate foods. He may need quick acting insulin if blood glucose levels are high. Two injections per day.
Case 2 was a 26 year old ballet dancer on insulin for 9 years. Rehearses from 2.00-6.00pm and perform from 9.00pm – 3.00am. Wakes at mid-day. Encountered regular hypos during performances and high glucose levels of 20 mm/L in the morning. Exercise compensated for some insulin requirement. Acarbose may be of assistance but side effects may be a problem. Insulin dosage should be reduced during exercise.
Case 3 was an obese lady requiring large doses of insulin 56 units 30/70 am and 38 units 30/70 pm. High HbA1c 12%. When hospitalised the patient turned out not to require insulin.
Regular blood glucose monitoring was seen as being of advantage to these patients with at least 4 glucose tests per day.
Bibliography – and Clinical References in the Public Domain
1) A History of recurrent Severe Hypoglycaemia in Adults with Insulin-Dependent Diabetes is associated
with Brian Atrophy, by Perros et al, Edinburgh, November 1996.
’11 patients with a history of 5 or more severe episodes of hypoglycaemia were scanned by MRI. 9 patients
had abnormal scans. Two types of abnormality were observed namely high intensity rounded lesions distributed
in the periventricular white matter and cortical atrophy.’
2) Severe Hypoglycaemia and cognitive impairment in diabetes, by Deary, Frier, Edinburgh, BMJ, 28.9.1996
‘The Average cerebral impact of several episodes of severe hypoglycaemia over a period of between 5 and 15
years is either mild or negligible. For a few individuals, with vulnerability factors which as yet remain obscure,
brain function may be permanently and importantly affected.’
3) Severe deterioration in Cognitive Function and Personality in Five Patients with Long-standing
Diabetes: A Complication of Diabetes or a Consequence of Treatment? By Gold et al, Pittsburgh USA,
Diabetologia 1993, 36
4) Permanent Neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man.
Wredling et al. Sweden and Norway. Diabetologia 1990, 33.
5) Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of
recurrent hypoglycaemia and other chronic complications, by Ryan et al, Pittsburgh USA, Diabetologia 1993, 36.
‘A Single episode of moderate hypoglycaemia can readily produce a transient disruption in cognitive functioning. Studies using the insulin-glucose clamp technique have repeatedly demonstrated that when plasma glucose
levels are experimentally reduced below 2.8mmol/l both diabetic and non-diabetic subjects often show a marked decline in mental efficiency.’
‘Although the excitotoxic hypothesis of neuronal necrosis is based upon animal studies in which a single episode
of very severe hypoglycaemia is maintained for at least 30 minutes it is not inconceivable that repeated episodes
of moderate hypoglycaemia would, over time, have cumulative effect that leads to significant neuronal damage in humans.’
‘Subjects were asked if they ever had an episode of hypoglycaemia so severe that you sought medical help (emergency room doctor). Whenever possible, estimates were corroborated by another family member, and by
review of medical records.’
‘Moreover clinical case reports have indicated that a single episode of severe hypoglycaemia may produce a
variety of transient of permanent neurological disorders including hemiplegia, amnesia and coma while neuropathological studies have demonstrated the presence of hypoglycaemic associated neuronal necrosis
in the cortex, hippocampus, and basal ganglia of humans and animals.’
‘Neurophysiologic and neuro imaging studies have demonstrated that diabetic adults with a history of poor
metabolic control have clear evidence of brain dysfunction. This has been demonstrated most convincingly by Dejgaard et al who studied 20 middle aged diabetic adults, all of whom had evidence of peripheral neuropathy. Abnormal brain stem auditory evoked potentials were found in 40% of these subjects, and abnormal magnetic resonance imaging results (characterised as lesions 2-10mm in size) were found in 69% of the diabetic subjects.’
‘There can be no doubt that a severe episode of hypoglycaemia may result in significant brain dysfunction.’
6) Intensified conventional insulin treatment and neuropsychological impairment, by Reichard et al, Sweden,
BMJ 7.12.1991, 303.
‘Episode hypoglycaemia might cause permanent brain damage.’
7) Severe Hypoglycaemia and intelligence in adult patients with insulin- treated diabetes, by Dreary et al,
Edinburgh and Aberdeen, Diabetes February 1993, 42.
8) Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-
treated diabetes mellitus, by Langan et al, Edinburgh, Diabetologia 1991, 34.
‘A ‘Mild’ episode of hypoglycaemia was defined as one which was self treated during which there had been no alteration in conscious level, while a ‘severe’ episode required external assistance for recovery, whether or not
loss of consciousness had occurred.’
9) Effect of Long-Term Glycaemia Control on Cognitive Dysfunction, by Lincoln et al, Nottingham, Diabetes
Care, June 1996, 19.6.
10) Complications in IDDM are caused by elevated blood glucose level: The Stockholm Diabetes Intervention
Study (SDIS) at 10-year Follow up, by Reichard et al, Stockholm, Upsala, Sweden, Diabetologia 1996, 39.
‘All Patients were followed up with regard to mortality, ketoacidosis, body mass index and severe hypoglycaemia (requiring help from someone else). The effects of severe hypoglycaemia on cognitive function were followed
with a battery of computerised tests.’
‘During the last 2.5 years of the study eight patients from each group needed emergency hospital care and
intravenous glucose. Five patients in the ICT group and two patients from the ST group received subcutaneous
or intramuscular injections of glucogen outside of hospital during the same period.’
11) Recurrent Severe Hypoglycaemia and Cognitive Function in Type 1 Diabetes, by Gold et al, Edinburgh,
Diabetes Medicine 1993, 10.
12) Neurobehavioural Complications of Type 1 Diabetes, Examination of Possible Risk Factors, by Ryan,
Pittsburgh, USA, Diabetes Care, January 1988, 11.’
‘A very different set of risk factors has been identified in diabetic adults. Perhaps the most potent of these is
profound hypoglycaemia. After a hypoglycaemia episode, the diabetic patient may develop intellectual
impairments that range from merely a slight decrease in learning efficiency or eye hand coordination to severe impairment in virtually all cognitive domains.’
13) Effects of Intensive Diabetes Therapy on Neuropsychological Function in Adults in the Diabetes Control and Complications Trial by the DCCT Research Group, Bethesda, USA, Annals of Internal Medicine, 5.2.1996, 124.
‘Although animal studies have provided the most compelling evidence for hypoglycaemia induced brain
dysfunction, investigators of several recent cross sectional studies have concluded that five or more episodes
of severe hypoglycaemia may be associated with mild cognitive impairment, as measured by performance on neuropsychological test.’
‘Severe hypoglycaemic episodes were defined as those in which the patient had incapacity sufficient to require
the assistance of another person.’
‘Approximately one third of severe hypoglycaemic episodes involved coma seizure, or suspected seizure.’
‘in the intensive treatment group, 16 severe hypoglycaemic episodes involving coma, seizure or suspected
seizure occurred per 100 patients – years compared with 5 such episodes in the conventional treatment group.’
14) Post hypoglycaemic Encephalopathy, case reports, by George M Jones, M.D. American Journal of Medical Services, 1947, 213.
‘The Clinical entity post hypoglycaemic encephalopathy, has been previously reported under headings of
synonyms such as fatal hypoglycaemia, mental deterioration associated with convulsions and hypoglycaemia,
cerebral damage from insulin shock, irreversible or hypoglycaemic insulin coma, fatal hyper insulinism with
cerebral lesions due to pancreatic adenoma, and post hypoglycaemic coma or syndrome, and psychiatric complications of hypoglycaemia in children. Even before the introduction of insulin, Joslin recognised that hypoglycaemia was a very serious factor in the treatment of diabetes.’
In 1932′ Terplan reported the case of a 16 year old boy who did not regain consciousness for 3 days after
insulin shock, the blood sugar levels being normal for these 3 days. Post-mortem examination showed
extreme oedema of the brain and destruction of ganglion cells.’ Wilder wrote:’ a feature of this type of coma (hypoglycaemia) that is very characteristic is its rapid termination when glucose is administered.’
Case 1 – 26 year old white man, diabetic for 4 years, September 8 1943, found unconscious, perspiring
profusely and unresponsive, transferred to hospital. ‘The patient became quite unruly and violent, struggling constantly, having to be restrained, and pulled out the intravenous needle after only 300cc of 5% glucose had
been administered.’ There was no change in the clinical course during the interval except that the patient
screamed irrationally at times.’ ‘Thereafter the Patient improved and apparently had an uneventful course
after proper regulation of his diabetes.’
Case 2 – 55 year old white male, diabetic since 1938, was admitted to st Paul’s Hospital in diabetic coma on
February 13th 1945 at 12 noon having been found unresponsive at 10.00 am, but was alright at 7am. 10%
glucose solution was started intravenously immediately upon his arrival and was continued until the patient had received 4000cc by 10.45pm. The Patient remained semi comatose on March 1st until 9.00pm at which time he appeared very restless, got out of bed, struggled with the nurses, and had alternating intervals of crying out
irrationally and of being quiet. The patient remained about the same until the 16th March when he became
weaker, his temperature began rising, and signs of pneumonia appeared in the lungs. He died on March 18th at 8.20pm.
Case 3 – 7 year old white male, diabetic since January 1943, admitted to Baylor university hospital at 4.30pm
on September 27 1945 following convulsions. As the patient continued to have convulsions and was comatose
it was decided to bring the child to Dallas. The patient was admitted to hospital upon arrival.’ The patient was
given 70cc of 50% glucose and 1000cc of 10% glucose intravenously. At 6.00pm on September 28th,
respirations ceased permanently.’ The patient died.
Clinically cases of post hypoglycaemia encephalopathy have been reported in every age group, as frequent
in children as in adults.
‘Darrow had 2 cases of convulsions and mental deficiency in children following hypoglycaemia.’
Another similar case with coma for 17 days terminating in death reported by Lawrence et al.
It is recommended that the term post hypoglycaemic encephalopathy be used for this very definite clinical
entity. Members of the medical profession should be aware of this very serious complication of hypoglycaemia
and combat any prolonged low blood glucose level vigorously.
15) Patients who carefully Manage Diabetes May Face Hidden Risks, By James s Hirsch, Wall Street Journal 29.6.1996. This describes a 26 year old insulin dependent diabetic nurse, two months pregnant, who following diabetic coma, lost control of her car which battered off the road and crashed into a tree, killing her. Authorities estimate she was travelling at 73 miles per hour and there was no skid marks. She passed out and her foot hit
the accelerator. Research studies estimate that between 4% and 13% of the insulin dependent diabetic patients
who die each year perish in hypoglycaemia related accidents.
16) Human Insulin – A Decade of Experience and Future Developments – Diabetes Care Dec 1993
17) Report to BDA Low Task Force – 1992
18) Human Insulin Advice – Forest & Evans 1992
19) Hypoglycaemia Unawareness in Diabetics Transferred from Beef / Porcine Insulin to Human Insulin – A. Teuscher; W D Berger, The Lancet August 15 1987
20) Human insulin and unawareness of hypoglycaemia: need for a large randomised trial – Egger, Smith,
Teuscher, BMJ August 1992
21) The Diabetes Handbook – Day, BDA 1986
22) DCCT Diabetes Control and Complications Trial – 1993
23) Bellagio Report – 1996
24) Diabetes & cognitive function: the evidence so far – A British Diabetic Association Report November 1996
25) Hypoglycaemia in insulin requiring diabetes – A patient and carer perspective – IDDT 1997
26) Cochrane Review – ‘Human’ insulin versus animal insulin in people with diabetes mellitus – Richter, Neises 2002
27) INSULIN – A Voice for Choice by Professor Arthur Teuscher , Karger 2007
28)30 YEARS OF SYNTHETIC INSULIN, ARE PEOPLE WITH DIABETES GETTING THE BEST DEAL?
A report of patient’s concerns IDDT 2007