Treatment – Insulin 2017-04-02T08:22:19+00:00

Treatment for IDDM Patients (Insulin Dependent Diabetes Mellitus)

A Treatment Regime Requiring Careful Management
by Derek C. Beatty, BSc DipM.

The author, a Type 1 insulin dependent diabetic patient since 1979 who was originally prescribed animal insulin was switched from animal to human insulin in 1985 and suffered from hypoglycaemia unawareness for 9 years. Personal tragedy motivated him to research the management of IDDM by reviewing 18 clinical papers published worldwide based upon over 1,300 references dating from 1890 – 1993.

The History of Insulin

Insulin received its name before it was discovered. In 1889 in Germany Oskar Minkowski and Joseph von Mering observed that total pancreatectomy in experimental animals led to the development of severe diabetes mellitus, and began the speculation that a mysterious substance produced by the pancreas is responsible for metabolic control.

Supporting evidence for the hypothesis gradually mounted and by around 1910 it was widely hypothesised that an internal secretion of the pancreas controls carbohydrate metabolism. In 1920 Fredrick Grant Banting, a physician and surgeon from London Ontario became interested in carbohydrate metabolism and in May 1921 began research using dogs into diabetes based on a hypothesis that internal secretion from the pancreas was somehow being nullified in pancreatic extracts by the action of externally secreted digestive ferments. Banting, assisted by a research student Best, began research in May 1921 by injecting depancreatized dogs with intravenous injections of saline extracts of chilled atrophied pancreas. A pattern of hypoglycaemic effects were noted. In late 1921 Banting and Best had accumulated evidence which showed that their extract often reduced the blood glucose in diabetic dogs.

On 11 January 1922 clinicians at Toronto General Hospital injected a 14 year old severely diabetic boy with 15ml of pancreatic extract made by Banting and Best. The first clinical test was a failure however on January 23 1922 a new series of injections began on the boy who responded immediately. His glycosuria almost disappeared and his ketonuria did disappear. His blood glucose dropped to normal. This was the demonstration of the isolation of the internal secretion of the pancreas that the world had awaited for 30 years for. JB Collip, a biochemist, had produced the extract supported by JJR Macleod, professor of physiology at Toronto University.

On 3rd May 1922 Macleod delivered a complete summary of the Toronto work to a meeting of the Association of American Physicians in Washington and 18 months later in 1923 Macleod and Banting were awarded the Nobel Prize in physiology and medicine for which haad become one of the fastest recognitions of a medical discovery. By the end of 1923 insulin was being used commercially and safely to treat people with diabetes in most Western countries with two major producers emerging, one in the USA and one in Denmark.

In the UK on 24 July 1925 at Guy’s Hospital, London, the first UK patient to be treated with insulin was a 6 year old young girl. New generations of insulin prepared from animals were introduced in the 1930’s, the 1940’s and the 1950’s. In the 1970’s another generation of animal insulins was introduced aimed at eliminating proinsulin and other immunogenic peptides. These monocomponent insulins took the purification of animal insulin almost as far as it could go. By the late 1950’s chemists understood the exact structure of the insulin molecule in the context of the knowledge of DNA and the process of life. With the advent of molecular biology this led to genetic engineering techniques leading to the biosynthesis of real human insulin. (2)

Human Insulin

The first symposium on human insulin as a treatment for diabetic patients was in March-April 1981, just 8 months after the first injections of human beings insulin of recombinant DNA origin into humans and only 6 months after the first conference on the subject. Papers presented at the symposium provided the scientific basis for the performance of large scale clinical studies of recombinant human insulin. The results were presented in June 1882 at a conference of the American Diabetes Association in San Francisco. At the same time another conference was held on human insulin produced semi synthetically by the enzymatic conversion of pork insulin.

The availability of human insulin stimulated an explosion of research in insulin biochemistry and action, insulin physiology and pharmacology. Human insulin was the first product of biotechnology to enter the clinical arena and served as the stalking horse for the explosion of biotechnology worldwide.

Recombinant human insulin played a role in making the regulatory process easier for all recombinant DNA products. The US Food and Drug Administration (FDA) took up the challenge and performed the regulatory task with due diligence and speed. One company submitted an application to the FDA in spring 1982 and was granted approval in October 1982.

Human insulin offers the advantages of favourable immunogenicity in comparison to animal insulins and today local insulin allergy and injection site lipotrophy are virtually unheard of in the USA. Insulin purification and human insulin introduction have ensured this. Likewise immunological insulin resistance has been virtually eliminated. Advances in recombinant DNA technology has permitted the development of other insulin related molecules. (1)

Drug Development, Mixtures, Analogues and Modelling

New directions in drug development, mixtures, analogues and modelling have resulted in intensified regimes in the treatment of diabetes. Evidence suggests that the lowering of blood glucose levels will forestall the development of chronic complications of diabetes. The importance of glycaemic control in preventing the progression of retinopathy, nephropathy and neuropathy in patients with IDDM is well known. Those who choose to self-monitor their blood glucose are in a constant state of vigilance with respect to their well-being in general and the possibility of hypoglycaemia.

The peak effects of neutral regular human insulin, 0.2 U/kg subcutaneously, do not occur until 3-4 hours after injection and are present for as long as 8 hours. The administration of regular insulin would seem to be an ideal method for mimicking normal insulin secretion. Patients with basal-bolus programmes have higher than normal serum insulin concentrations throughout their day and night probably as a result of the long acting nature of the pre meal bolus infusions of neutral regular insulin. Deficiencies of conventional insulins led to the development of improved insulins or insulin analogues and the first analogue of human insulin was beef insulin.

The development of insulin mixtures, especially 70% NPH and 30% regular insulin has provided patients with a convenient method for taking two insulins and has obviated errors inherent in the multiple-step procedure of self-mixing thus enhancing quality of life for many, but not all, patients. (3)

Insulin Therapy in Type 2 Diabetes

In patients with type 11 diabetes the morbidity and mortality attributable to microvascular complications is increased by two to four times and the microvascular complications is several fold greater than in an unmatched non diabetic population. In addition to hyperglycaemia, diabetic type 2 patients are characterised by a variety of abnormalities such as obesity, hyperlipidaemia, hypertension, insulin resistance, and diabetic retinopathy. In Sweden for example insulin is currently used 3.7 times more frequently per 1000 inhabitants than in neighbouring Finland, although the incidence of diabetes in Sweden is only 70% that of in Finland.

The beneficial effects of insulin treatment for type 2 diabetic patients include: –

  • Reduces fasting and postprandial hyperglycaemia
  • Reduces gluconeogenesis and heptic glucose production
  • Enhances insulin secretion in response to a mixed meal or glucose stimulus
  • Improves oxidative and nonoxidative glucose disposal – Induces antiatherogenic changes in serum lipid and lipoproteins

The adverse effects are however: –

  • Risk of hypoglycaemia and severe hypoglycaemia
  • Increases body weight, primarily fat mass
  • Hunger
  • Sodium and fluid retention
  • Hyperinsulinemia – Hyperinsulinemia could be an innocent bystander with respect insulin treatment of diabetic patients. (6)

Hypoglycaemia Unawareness

Hypoglycaemia Unawareness in IDDM is a disturbing area in the treatment and management of IDDM in which a threefold increase in incidence has been seen in the UK in the last decade. Syndromes include severe iatrogenic hypoglycaemia and pathogenesis is unknown but is multi factorial creating a vicious circle. Many patients suffer 1-2 episodes of hypoglycaemia per week and in a year 10-25% of patients suffer one severe disabling episode of hypoglycaemia resulting in coma or seizure which can result in disturbing neurological activity including in some instances leading to aggression and possibly violence. 4% of deaths of IDDM patients are from hypoglycaemia.

Physiological and behavioural defences against hyperinsulinemia sometimes occur. Behavioural changes of neuroglycopenia (glucose deprivation) include seizures, coma and the ultimate result of prolonged neuroglycopenia is death. Patients with cervical chord transections (interrupt brain to sympathochromaffin neural outflow) do not recognise hypoglycaemia. Thresholds in patients vary from 3.8mM to 2.8mM glucose. 7% of patients have reported hypoglycaemia unawareness and up to 16% of patients have reported partial unawareness. It is believed there is a need to deliver insulin in a more physiological fashion in order to avoid the problems of hypoglycaemia. (7)

Insulin Regimes and Strategies for IDDM

Insulin regimens and strategies for IDDM have been based upon insulin research over the last 80 years resulting in improved purity, an availability of human insulin, the development of insulin analogues using recombinant DNA technology to improve pharmacokinetics. Despite these advances however attempts at physiological insulin replacement for IDDM continue to be disappointing.

Numerous variables affect insulin absorption and as a consequence may cause circulating insulinemia. Variables which affect absorption include site of injection, depth of injection, insulin species, insulin mixtures, insulin dose, exercise and local heat. The rate of insulin absorption decreases progressively when comparing abdomen to arm to leg. These differences can be large and it has been shown that I125 labelled regular insulin disappears 86% faster from the abdomen than from the leg. If an attempt is made to maintain consistency in nutrient intake in relationship to insulin dose for a specific meal it appears evident that the site of insulin injection be consistent. This is contrary to the traditional advice given to patients several years ago to avoid lipodystrophy. The depth of insulin injection and ambient temperature can affect insulin absorption. This may mean that if a patient is used to the temperate climate of the UK then take a summer vacation in the Mediterranean then hypoglycaemia may occur one to three hours after intake of morning insulin as experienced in the form of hypoglycaemia unawareness by the author. The effect of exercise on subcutaneous insulin absorption has been well documented in animal and human studies and if insulin is injected into a limb, and that limb is exercised, marked acceleration in insulin absorption can occur. A typical example can be if insulin is injected into the leg, then grass is cut using a motor lawnmower, in a reasonable sized garden, glucose level elevated to say 15.5mM by carbohydrate intake prior to exercise, can reduce to as low as 4.2mM after exercise which is dangerously close to the threshold level for some patients.

The pharmacokinetics of insulin absorption are influenced by the insulin species, the dose, and the interaction of various modified insulin preparations. Human insulin is absorbed more rapidly than animal insulins, however when considering basal insulin requirements, beef and pork insulins have a longer duration of action and for most purposes can be considered peak less when compared with human insulin. Many reports have indicated an increased frequency of hypoglycaemia unawareness with human insulin when patients are switched from beef/pork insulins.

The most significant and well documented risk of intensive insulin therapy is the increased frequency and risk of severe hypoglycaemia resulting in confusion, coma and seizure leading in some instances to violence. Insulin treatment depends on patients motivation, benefits, self-management, goals of therapy, social support and financial implications. In this state of severe hypoglycaemia a patient is likely to require immediate assistance from family, friends, colleagues, and in some instances a doctor or the emergency services. There is an urgent need in the UK to provide information and training to members of the public, family, friends and colleagues of diabetics, diabetic clinic staff and clinicians, GPs and the emergency services to address the problem. (5)

Physiological Responses to Hypoglycaemia

Physiological responses to hypoglycaemia depend upon the availability of glucose as a fuel for cerebral metabolism. Blood glucose must be maintained above a critical level to preserve adequate brain function. To deny the brain of glucose leads to loss of neurological and motor control. This can lead to a change in P300 responses and cerebral function change.

Since 1987 there has been an issue of public concern with the loss of awareness of hypoglycaemia in human insulin treated patients as changes to the brain function occur during hypoglycaemia. This issue appears not to have been correctly addressed by the NHS in the UK since its discovery. (8)

Nocturnal Blood Glucose Control in Type 1 Diabetes

A major problem in replacing insulin in type 1 diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. All available intermediate or long acting insulin preparations have a peak period profile, excess insulin action at midnight, and insulin waning at dawn occur whenever insulin is given at supper time. This easily results in hypoglycaemia in the early evening hours and in the fasting state. The dawn phenomenon is the combination of an initial decrease in insulin requirements between 2400 and 0300 hours followed by an increase in insulin needs between 0500 and 0800 hours.

Nocturnal hypoglycaemia is a fearful condition for three reasons.

1) During sleep the autonomic symptoms may not be potent enough to awaken the patient thus mild hypoglycaemia may progress to severe hypoglycaemia at a time when external assistance to the patient may not be available.

2) The excessive correction of hypoglycaemia at night by spontaneous counter regulation and food ingestion may cause subsequent hyperglycaemia.

3) Frequent episodes of unrecognised nocturnal hypoglycaemia may induce hypoglycaemia unawareness which may lead to severe hypoglycaemia at any time day or night. Furthermore for a given plasma insulin concentration hypoglycaemia may induce subsequent hyperglycaemia at any time.

Strict control of blood glucose levels is therefore essential to avoid these side effects. (10)

Clinical Pharmacology of Human Insulin

Human insulin is used daily by millions of diabetic patients. The biological effect of human insulin is comparable to that of porcine insulin. After subcutaneous injection, pharmacological and clinical studies have showed pharmacokinetic and pharmacodynamic differences between human and animal insulins. These differences can be more pronounced and can be of clinical relevance with intermediate and long acting insulin preparations. Optimal metabolic control can be achieved with either human or highly purified animal insulin preparations provided appropriate insulin replacement strategies are adopted.

Human insulin has made it possible to treat IDDM patients with a hormone that has an amino acid sequence identical to endogenous insulin. After characterization of the biological activity of human insulin in vitro and in animal studies a series of efficacy and safety trials was performed in humans. Several studies in early years compared the potency of human insulin and animal insulin preparations with respect to their pharmacological properties. Later studies compared human insulin preparations manufactured using different methods.

Most of the literature on human insulin, including proceedings of commercial sponsored symposia, was published 15 – 20 years ago, all non-peer reviewed, and very few papers have passed a peer review system. This disturbing fact may be relevant since pharmacological differences between human insulin and animal insulin may have practical implications for the daily therapy for millions of patients worldwide and possibly up to 80,000 IDDM patients in the UK.

The structure of animal insulin has minor but potentially important differences from human insulin. Porcine insulin differs by one amino acid (alanine instead of threonine at the carboxy-terminal of the beta chain at position B30), and beef insulin differs by two additional alterations of the sequence of the A-chain (threonine and isoleucine on positions A8 and A10 are alanine and valine). There is thus nearly a complete homology between human insulin and porcine insulin in the amino acid sequence. Biosynthetic production of human insulin has been made possible by advances in genetic engineering especially in recombinant DNA technology. In the drug model human insulin shows a more rapid onset and shorter duration of action, along with a lower potency, compared to bovine insulin. When using the intravenous route investigators have come to the conclusion that there is little or no difference in the biological potency of human insulin and animal insulin. This does not appear to apply however to the subcutaneously injected route where clinical studies have shown a difference in absorption properties between human and animal insulin.

It has been suggested that the daily dose of insulin should be reduced by 10-25% when switching from animal insulin to human insulin. Furthermore it has also been suggested that it may be necessary to change the insulin dosage depending on activity. For example an office worker may have to reduce insulin dosage at weekends if undertaking exercise and children may have to alter insulin dosage when participating in summer sporting and camping activities. Furthermore it has also been suggested that an overlapping interaction exists between the metabolic activity of the insulin of the current injection and that of the previous day’s injections. This unpredictable accumulation of insulin action can result in prolonged and severe hypoglycaemia. (11)

Child Growth and Diabetes Mellitus

Prior to the discovery of insulin linear growth failure was common among children with IDDM. Today significant growth failure is unusual in paediatric diabetes clinical populations. However significant abnormalities in the hypothalamic pituitary-GH axis exist even in normally growing children with IDDM. What happens postpubertally when GH secretion declines is unknown but studies in adults with IDDM suggest that growth hormone levels may remain elevated and insulin like growth factor levels may be reduced. (12)

Insulin Therapy and Glycaemic Control in Pregnancy

Dietary therapy is the keystone of diabetes management. In 1922 Priscilla White, an American physician, devoted her time to the care of children and women with diabetes of juvenile onset. Before the availability of insulin good treatment of diabetes was important with patients seen weekly by both an obstetrician and physician. With the advent of insulin patients were given enough insulin to prevent glycosuria and ketosis with a basic dose of long acting insulin before breakfast supplemented by 3-4 doses of short acting regular insulin before meals and evening snack. Patients were taught to weigh out amounts of food based on a diet plan of 30 kcal/kg body weight. The average 2 hour postprandial blood glucose was found to be 8.3 mM. Close attention to detail resulted in low frequencies of diabetic ketoacidosis in 2% of pregnancies and hypoglycaemic coma resulted in 1% with no foetal deaths.

The most important limiting factor in intensified insulin therapy of diabetic women is the maternal CNS danger from hypoglycaemic coma which appears to come on more quickly and often without warning signs during gestation. In pregnancy the foetal-placental unit continues to consume glucose and alanine in post absorptive periods, and exogenous insulin may limit alternative fuel sources by restraining lipolysis. Fortunately the foetus seems to be protected from maternal hypoglycaemia.

A challenge for the future is to determine the level of diabetic control necessary to produce normally developing offspring, assuming congenital malformations can be prevented. Older controversial data on childhood intellectual function requires renewed attention. In 1969 it was reported by Farquhar of Edinburgh that follow up of 210 children of insulin treated diabetic women 5 children had educational sub normality; 20 had congenital abnormalities and 10% were less than the third percentile for height and greater than 20% had excessive weight by adolescence. (13)

Insulin Delivery Systems and DCCT

The DCCT (Diabetes Control and Complications Trial) has changed the question from whether to how by definitively proving that improved control reduces the occurrence of long term complications. The trial also highlighted major adverse side effects of current approaches to severe hypoglycaemia.

In the DCCT 1422 patients were followed for a mean of 6.5 years. The results showed that intensive therapy reduced the risk of complications by the following: Retinopathy 76% Neuropathy 60% Nephropathy 35-56% Cardiac and macro vascular events 44%

Hypoglycaemia worsened by increasing threefold.

Intensive therapy for IDDM patients is a total behavioural and education package, one element of which is the insulin, its administration and regimen. Follow ups and education demonstrated in the DCCT, with weekly telephone calls and monthly visits, is probably impracticable in a clinical setting and too expensive to implement in the UK. The DCCT cost $168 million (£100+ million) which would result in an annual cost per patient of $18,000 (£10,000).

The DCCT recommends that the UK needs bigger diabetes care teams and more contact time for patient education. It is important that treatment plans be fitted into the patient’s life and not vice versa.

New developments include external insulin pumps which are available. On the horizon are implanted pumps, nasal insulin and inhaled insulin. Still others for the future include hybrid artificial pancreases and closed loop implanted pumps. In the USA pancreas transplants are done primarily in patients in need of coexisting kidney transplantation. (14)

Biosynthetic Human Insulin

The daily treatment of more than 2 million patients worldwide with one brand of rDNA human insulin demonstrates the value of rDNA technology in providing an important medical product and an assurance that diabetic patients will have a guaranteed supply of this vital hormone. The classical structural work performed by Watson and Crick in the 1950’s and on insulin by Sanger led to the introduction of the first human healthcare product to be derived from rDNA technology being introduced in 1982. The first rDNA human insulin was in fact administered to a normal volunteer at Guy’s Hospital, London, in July 1980. Approvals to market human insulin were given in August 1982 in the UK; and in October 1982 in Germany and the USA. By 1992 registration had been achieved in 65 countries worldwide.

In the UK in 1985 5% of the insulin market was human insulin however by 1989 the share had risen to over 80% mainly as a result of campaigning by insulin manufacturers. In 2014 in the UK around 20,000 patients are still treated with animal insulin.(15)

Insulin Therapy in Paediatrics

The introduction of human insulin and daily self-monitoring of blood glucose instead of urine monitoring for those diabetics not affected by blood phobia has changed the therapy for the treatment of IDDM. With the introduction of more purified insulins in the late 1970’s localised skin reactions and allergic reactions decreased.

During the first few weeks after diagnosis insulin requirements often decrease in children as endogenous insulin secretory capacity is restored during the honeymoon phase of IDDM. During puberty it is not uncommon to have to increase insulin doses by 20-30%. The relative insulin resistance which accompanies puberty is closely correlated with increased concentrations of sex hormones and growth factors. These changes occur about two years earlier in girls than in boys.

Dramatic decreases in insulin intake are often required in periods of marked physical activity, and for example during summer camps doses often have to be reduced by 25-50% despite a marked increase in food uptake. These reductions are attributable to increased levels in physical activity and at such times close glucose monitoring is usually required.

Generally human insulins are absorbed more rapidly than animal insulins and have a slightly shorter duration of action. Common scenarios are an increase in pre-lunch hypoglycaemia due to rapid absorption of human insulin injected before breakfast and is often noted if no mid-morning snack is taken.

Symptoms of hypoglycaemia frequently change with time, sometimes in subtle ways. Hypoglycaemia unawareness and severe hypoglycaemia in Europe in the 1980’s may have resulted from overzealous treatment by well-meaning physicians. Increasing the dose of pre-supper insulin can increase the risk of pre-dawn hypoglycaemia and dawn hyperglycaemia, sometimes resulting in nocturnal seizures.

Pen injectors are widely used in Europe however in the USA they have not become so popular. This may be because currently available pen injectors do not readily allow dose-to-dose modification of rapidly and long acting insulins.

Insulins can go bad prior to expiry date especially in the summer months. This is possibly due to the reduced zinc content of many formulations leading to instability at higher temperatures.

The main reason for bedtime and 01.00-03.00 glucose monitoring is safety to prevent severe hypoglycaemia.

In the event of irrational behaviour treatment with glucose should be implemented immediately and blood glucose tests can be performed immediately afterwards when the situation has settled. Hypoglycaemia unawareness is common with younger children and in children with a longer duration of diabetes. It is important that family, teachers, friends are aware what to do in the event of hypoglycaemia as recurrent hypoglycaemia may be associated with defects in neurobehavioral function in later life.

Treatment for IDDM children has improved over the last decade however hypoglycaemia and inconvenience remain major problems and it appears that no real cure is just around the corner. (16)

Immunogenicity and Allergenic Effects of Insulin

Immunological complications of insulin therapy have been evident since animal insulins became available in 1922. Today patients exposed to intermittent treatment by insulin appear to be at higher risk to more severe and persistent allergic reactions. Factors which appear to influence immune response to insulin can be divided into three categories:

a) Insulin factors – purity; species (bovine>pork>human); physical properties (pH); retarding agents (zinc, protamine, surfen).

b) Individual factors – age; immunological background; presence of insulin autoantibodies.

c) Mode of insulin administration – subcutaneous>intravenous; insulin pumps; interrupted insulin therapy.

It has been found that transfer from highly purified porcine insulin to human insulin decreases the insulin binding to IgG in already sensitised patients in some cases. Human insulin has very low immunogenicity and allergenecity. Human insulin is therefore suitable for patients with insulin allergy, immunological insulin resistance or lipoatrophy.

The National Health Service Patients Charter and IDDM in the UK

Under the terms of the Patients Charter in the UK the NHS has a responsibility to advise patients of any side effects of treatment regimes. In the area of insulin dependent diabetes treatment in the UK the dissemination of knowledge of the side effects associated with the use of human and animal insulin appears to be sadly lacking and has led to a significant number of tragic circumstances.

To provide this information to patients, their relatives, friends and colleagues, would enable the side effects of insulin treatment to be discussed and acute episodes of hypoglycaemia may be avoided as corrective action can be taken and glucose or glucogen administered. If not recognised and corrected hypoglycaemia may lead to behavioural problems and neurological disorder or worse.

Diabetic patients never wish to be diabetic – it simply happens for a number of reasons and diabetics have to make the best of life. A stabilised diabetic can, like other normal people, make a major contribution to enhancing the wealth, prosperity, happiness and welfare of our country, the European Community and the rest of the world. The National Health Service has a duty under the terms of the Patiens Charter to ensure that diabetics receive acceptable treatment and are notified of the possible side effects of the treatment. The diabetic patient and his or her medical team and carers need to work together as a team to ensure that this happens.

From the patient’s point of view hypoglycaemia and hypoglycaemia unawareness are the most feared complication of insulin treatment. Its management requires sensitive discussion and preventative strategies. Fatal outcome as a result of hypoglycaemia has led to a number of unexplained sudden deaths amongst insulin dependent diabetics in the UK along with tragic car accidents and mobility accidents.

These are worrying factors if insulin dependent diabetic management is to rely on the use of human and animal insulin in the UK for IDDM patient treatment without the incorporation of an urgently required education programme within the NHS to advise IDDM patients and their families of the side effects of prescribed treatment regimes so that diabetics can live more comfortable and confident lives.

HUMAN INSULIN v ANIMAL INSULIN

Porcine insulin has one amino acid difference from human insulin, alanine instead of threonine at the carboxy terminus of the B chain (position B30) and beef insulin differs by two additional alterations of the sequence of the A-chain (threonine and isoleucine at positions A8 and A10 are alanine and valine).

In 1991, Egger et al published information indicating more severe episodes of hypoglycaemia with human insulin. Seventeen patients (33% of the study) were admitted to hospital with coma complicated by seizure or pyramidal signs compared with 17% (10 patients) treated with animal insulin.

Animal insulin resulted in no deaths, one patient treated with human insulin died.

The researchers concluded that human insulin has no advantages over highly purified animal insulins. Costs and benefits should be seriously considered as well as availability and method of production.

Hypoglycaemia results when blood glucose levels fall to < 2.8 – 3.8 mmol/l leading to sweating, tremor, restlessness, lack of concentration, visual disturbance, aggressiveness, and sometimes violence. At glucose concentration of 2.0 mmol/l cognitive dysfunction occurs, EEG stimulus becomes incorrect, and third party support is required. At glucose concentration of 1.0 mmol/l diabetic coma, but not necessarily unconsciousness occurs, requiring support from a third party.

Fast acting insulin peaks at 1-2 hours after injection and moderate insulin at 6-8 hours. Long acting insulin’s act in 12-18 hours. Snacks are important to avoid hypoglycaemic attacks. Women tend to be reluctant to snack whereas men are comfortable snacking. Exercise can cause low glucose levels for up to 18 hours and may have to be compensated for by reducing insulin intake at night. Excessive alcohol intake can also cause low or disturbed glucose levels for up to 18 hours. The location of the insulin injection site can play an important role when exercise is taken.

Blood glucose must be maintained above a critical level to preserve adequate brain function. To deny the brain glucose leads to loss of neurological and motor control. This can lead to a change in motor responses and cerebral functions.

A diabetic patient, when treated with animal insulin, is likely to perceive the warning signs of hypoglycaemia as being physiological such as tingling, sweating, tremor and hunger. When treated with human insulin a diabetic is likely to experience warning signs of hypoglycaemia or neuroglycaemia in the form of neurological disturbances such as mental disturbance, unrest, behaviour change, aggression, irritability, appearance of drunkenness and sometimes violence. This was clinically reported in the late 1980’s and has led to reports that in a group of 100 patients studied, hypoglycaemia increase was reported by 60%; depression was reported by 26%; memory loss was reported by 14%; muscular weakness was reported by 6%; joint cramp pain was reported by 7%; personality change was reported by 19%. Since the introduction of human insulin in the mid 1980’s an increase in violence, suicide, impotence, and untimely death, has been reported to have increased. Tight glucose control can in some instances lead to very low glucose levels occurring during the night leading to the potentially fatal risk of acute hypoglycaemia being encountered during sleep.

The difference in treatment by human insulin, or porcine and beef insulin, may be of particular concern in patients encountering recurrent hypoglycaemia in whom a change from animal to human insulin could exacerbate a worrying tendency to neuroglycaemia.