The Safety of Insulin Analogues – should patients be concerned?

As a patient-centred, independent charity the Trust has a responsibility to provide people with diabetes with information. The global insulin manufacturers are withdrawing some of the most widely used GM ‘human’ insulins and recommending treatment with insulin analogues. After very careful consideration, this Supplement has been produced to help inform people with diabetes about the risks and benefits of following this recommendation.

Insulin analogues are new biotechnology products and as such, are likely to have different patterns of toxicity with unknown consequences. The long-term effects and safety of insulin analogues have not been established.

The clinical benefits of insulin analogues have been extensively studied and have proved to be negligible in terms of glycaemic control but the biological effects have not been systematically studied despite their carcinogenic potential being recognised by the scientific community.

People with diabetes are no exception to the principle that they should have an informed choice of treatment including risks and benefits but the majority of them are not aware of the carcinogenic potential of insulin analogues or that their long-term safety has yet to be established.

Some patients may consider even a minimal carcinogenic risk with insulin analogues is unacceptable when there is little or no benefit in day to day blood glucose control.

"The carcinogenic potential of insulins is recognised by the scientific community."

Gupta K, et al
Am J Med Sci. 2002; 323(3)

"Recent publications concerning the assessment of carcinogenic potential of specific human insulin analogues are scarce"

Stammberger I, et al
Int J Toxico. 2002;21(3)

"People are being prescribed too many drugs, before the full consequences of adverse side effects are known."

"Tighter controls on the promotion of new drugs should be introduced until more is known of their potential side effects."

"Post-marketing surveillance in the UK is inadequate. This has several causes: lack of investigation of a drug’s benefits and harms in real life situations and institutional indifference to the experience and reports of medicines users."

House of Commons
Health Committee Report, April 5th 2005
The Influence of the Pharmaceutical Industry

What are insulin analogues?
Insulin analogues are artificial derivatives of the natural hormone insulin and are designed to have different absorption profiles compared to GM ‘human’ insulins.

Short-acting insulin analogues [eg Humalog and NovoRapid] are absorbed more quickly and are of shorter duration than GM ‘human’ insulin and long-acting analogues [Lantus, Levemir] are designed to have a longer action with a more consistent release during the day.

National Institute of Clinical Excellence [NICE] Guidance on the use of long-acting insulin analogues – insulin glargine [Lantus] December 2002

1. Insulin glargine [Lantus] is recommended as a treatment option for people with Type 1 diabetes
2. Insulin glargine is not recommended for routine use for people with Type 2 diabetes who require insulin therapy. It should be considered only for those people with Type 2 diabetes who require insulin therapy and who fall into the following categories:
3. Those who require assistance from a carer or healthcare professional to administer their insulin.
4. Those whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemic episodes.
5. Those who would otherwise need twice daily basal insulin injections in combination with oral anti-diabetic drugs.

Cost
NICE estimates that 137,000 people in the UK would be eligible for insulin glargine treatment. The extra cost of glargine per annum for Type 1 diabetes is £101 compared to NPH [long-acting human insulin] and £162 for Type 2 diabetes compared to NPH. If all the potentially eligible people were changed to glargine, then this would cost the NHS around £16million per annum. These costs are based on vial costs and so would be increased with use of the more expensive cartridges.

Note: Determir [Levemir] is a similar cost to glargine.

Glossary of Terms

Apoptosis – Normal self-induced termination of a cell’s life, to become replaced by a new one.

Carcinogenic – A substance that has cancer forming properties.

Carcinoma – A type of cancer.

Co-morbidity – The presence of several diseases/conditions.

Endpoints – A research term that defines what is being measured in the study to show the outcomes of a treatment.

Hexamers – The bonding together of insulin molecules forms a six-pack [hexamer] but only individual insulin molecules are biologically active so the body must first break the six-pack.

IGF-1 or insulin-like growth factor – A hormone which has a broad range of effects including promotion of cell survival, cell proliferation of cells, inhibition of apoptosis, stimulation of metabolism.

Insulin receptors – Insulin receptors are the chemical structures on cells, where insulin binds to the cell and where insulin can get its messages inside the cell.

In-vitro testing – Literally means ‘in glass’ and is a research term for observations made outside the body eg the action of drugs on bacteria, in-vitro fertilisation means the fertilisation of the egg outside the body.

In-vivo testing – Studying something in living creatures [human beings and animals]

Monomers – Single insulin molecules

Mitogenicity – Promotion of the division and proliferation of any cell, including malignant and non-malignant tumour cells.

Neoplasm – Another word for a tumour that literally means ‘new formation’

Sprague-Dawley rats – A type of rat used in research into the possible development of breast tumours because of its high spontaneous incidence rate of breast cancer ie the type of rat used is the one that is most likely to produce breast tumours if this risk is present.

Subcutaneous injection – Injection into the tissue beneath the skin.

Thrombocytes – Blood platelets involved in coagulation to stop bleeding

Toxicity – The poisonous effects of a substance.

Use of terminology when referring to insulins
Genetically engineered, genetically modified and GM are used interchangeably throughout this document. The same applies to the names of insulin and their brand names:

Name of insulin	Brand Name
Insulin glargine	Lantus
Insulin aspart	NovoRapid [NovoLog in the US]
Insulin lispro	Humalog
Insulin determir	Levermir

 

NPH – Neutral Protamine Hagedorn also referred to as isophane insulin and is the most commonly used long-acting insulin in the UK.

This Supplement contains our concerns in two versions. This first version uses layman’s language and is less technical but it is based on the more technical version that follows which provides more detail and the supporting references.

Version One – using layman’s language
Regulatory requirements for insulin analogues: weighing therapeutic benefits against potential carcinogenicity

Authors:

Prof. Dr. med. Ernst Chantelau
Department of Endocrinology, Diabetes and Rheumatology
Diabetesambulanz MNR-Klinik
PO Box 10 10 07
D- 40001 Dusseldorf
Germany

Mrs Jenny Hirst
Co-Chairman
InDependent Diabetes Trust
PO Box 294
Northampton
UK

Background
In September 2004, the commonly used arthritis drug Vioxx was withdrawn from the market after it became publicly known that patients taking it were at twice the relative risk of heart attack and stroke as those taking a placebo or dummy pill. During the five years that it was on the market, it is likely that many people suffered heart attack, even death, and stroke. Questions have been raised about the effectiveness of the regulatory system and how long this information was known prior to drug’s subsequent withdrawal.

Adverse events associated with the effects of the anti-depressant, paroxetine [Seroxat] highlighted in the BBC programme, Panorama, resulted in the Committee on Safety of Medicines [CSM] issuing a safety statement about the recommended dose. However, this statement was not based on new evidence but "on a review of the original dose finding studies carried out for the licensing of paroxetine". In other words, information the CSM had before the drug reached to market and once again lives were unnecessarily harmed or lost as a result of this system failure.

These situations necessarily raise questions about the effectiveness of drug regulatory authorities, their speed of response and their vigilance. They demonstrate the need for more effective research prior to a drug reaching the market and of equal importance, the need for improved post-marketing surveillance when new drugs are used on the wider population. Patients are rightly concerned about the safety of the drugs they take and the systems in place to ensure their short and long-term safety and effectiveness. These needs are especially important with the introduction of new biotechnology products, such as insulin analogues, which can have unpredictable adverse effects.

Drug toxicity

There is a now a wide range of drugs available and the pattern of drug toxicity is likely to change with the introduction of new biotechnology products.

Drug Toxicity:

• May vary
• May affect and organ system
• The different genetic make up leads to different drug responses between people
• The clinical consequences of individual drug response can be great
• New biotechnology products are likely to have different patterns of toxicity compared to the more predictable ones of chemically produced drugs.

An early example of this was genetically engineered tryptophan introduced in 1988 and withdrawn within months because it was associated with 37 deaths and 1500 people being permanently disabled. Genetic engineering was implicated because the toxin responsible has never been shown to be present in the non-genetically engineered tryptophan that was used for many years without these adverse effects.

Adverse reactions
Adverse reactions can occur immediately or within weeks, months or years after starting to take a drug. Reporting suspected adverse reactions [ADRs] is not a mandatory requirement for physicians and health professionals. So spontaneous reporting schemes of suspected ADRs, such as the Yellow Card Scheme in the UK, are the cornerstone of post-marketing surveillance and are still the only way of monitoring the safety of a drug throughout its life. The problem with spontaneous reporting is that less than 10% of all serious and only 2-4% of non-serious suspected ADRs are actually reported.

Thus with 90% of serious adverse drug reactions going unreported, it is unsurprising that patients are concerned about the safety of drugs and the systems in place for monitoring them.

Introduction of genetically engineered insulin
In 1982, genetically engineered insulin, misleadingly named ‘human’ insulin, was the first drug genetically engineered drug to be marketed. In common with tryptophan, there was a failure to recognise that drugs produced by biotechnology could have different patterns of toxicity and it appears that when giving marketing approval, the regulatory authorities considered the method of manufacture to be unimportant. It is possible that assumptions about the safety of GM ‘human’ insulin could have been made because its predecessor, natural animal insulin, had an excellent and long history of safety.

During the 1980s in the UK over 80% of people with insulin-requiring diabetes were changed to genetically engineered ‘human’ insulin for no clinical reasons but on assumptions of its superiority, and not on evidence of its superiority, over natural animal insulin previously used. An estimated 10% of people reported, and continue to report, adverse effects when using GM insulin but patients’ reports of adverse reaction reports were largely ignored and GM ‘human’ insulin became first line treatment for people with insulin requiring diabetes.

No long-term, large-scale studies to compare GM ‘human’ and animal insulin have ever been carried out and in 2002 a Cochrane Review showed that the vast majority of the studies that have been carried out are of methodologically poor quality. It also showed that many of the important issues for patients such rates of diabetes complications and mortality and quality of life issues were never investigated in high quality randomised clinical trials. So ‘human’ insulin was given marketing authorisation:

• without consideration of the method of manufacture and possible unexpected adverse reactions
• with little attention paid to the quality of the post-marketing studies
• without any long-term studies to compare complication and mortality rates or long-term safety.

However patients were not made aware of these facts or their rights to a choice of insulin treatment, so they are understandably concerned about the quality and validity of information they receive and the drug monitoring systems in place, supposedly for their protection.

Introduction of insulin analogues
Insulin analogues are the most recent biotechnology products used in the treatment of diabetes. They are artificial derivatives of the natural hormone human insulin. They were designed to have absorption profiles that more nearly mimic the action of normal insulin production by the body compared to artificial ‘human’ insulin. In short-acting ‘human’ insulin the individual insulin molecules clump together [aggregate], six at a time, to form a hexamer. Only individual insulin molecules are biologically active, so the body must first break the six pack into individual molecules [monomers]. But in analogues the hexamers bind together so weakly that they break apart much faster making the insulin molecules biologically active immediately.

However analogues also differ in their biological effects with unknown consequences, such as their effects on:

• mitogenicity [promotion of division and proliferation of any cell, including tumour cells
• apoptosis [see glossary]
• glucose and lipid metabolism
• thrombocyte function
• protein degradation

The therapeutic effects of analogues have been extensively investigated and have shown negligible clinical benefit for patients but the biological effects have not been systematically studied. It is of special concern that the carcinogenic potential of insulin analogues remains to be determined on human carcinoma tissue in accordance with the recommendations issued by the European Agency for the Evaluation of Medical Products [EMEA] in their document, Points to consider CPMP/SWP/372/01.

While scientists have used analogues to study the insulin molecule, insulin manufacturers were more interested in their commercial potential and in 1988 Novo Nordisk announced the development of their prototype analogue, B10Asp. By virtue of a slight modification of the human insulin molecule B10Asp did not aggregate as much as regular ‘human’ insulin and was absorbed from the subcutaneous tissue 15minutes earlier. B10Asp was absorbed into the circulation significantly faster and with higher peak concentrations than ‘human’ insulin but a controlled trial failed to show that B10Asp had any benefit in terms of glycaemic control when compared to ‘human’ insulin.

From this study it was obvious by 1995 that manipulations of the subcutaneous absorption of rapid-acting [regular] insulin have only very little clinical impact on HbA1c and may explain why analogue insulin produces only less than 5% of the total variations in HbA1c. Much greater percentages of the total variation in HbA1c is accounted for by:

• the size of the insulin dose
• the amount and timing of carbohydrate intake
• the timing of exercise in relation to carbohydrate intake and/or insulin administration
• the effects of stress or intercurrent illness
• psychosocial aspects
• residual beta cell function [the amount of insulin that is still produced by the body’s own cells].

All clinical trials with B10Asp were stopped in 1992 when it was shown to promote breast cancer in rats. Nevertheless, in 1996 the first rapidly absorbed insulin analogue, lispro [Humalog], reached the market amidst warnings from Professor Stephanie Amiel [Diabetic Medicine, 1998;15;537-538] that "there remains a risk of unexpected problems with any new agent and we should remember that the structure of the new insulin is a little closer to IGF than the old insulin". The closeness to IGF-1 is important because it has broad range of effects including promotion of cell survival, cell proliferation of cells, inhibition of apoptosis, stimulation of metabolism.

In 2000 the first slowly absorbed long-acting insulin analogue, glargine [Lantus] was introduced. It has a flat, apparently peakless activity, and a duration of 24hours. This was followed in 2004 by the introduction of determir [Levemir], a once or twice daily long-acting insulin analogue.

Treatment Goals
Good control is not only the avoidance of high blood glucose levels [hyperglycaemia] but also the avoidance of low blood glucose levels [hypoglycaemia]. Hypoglycaemia is a daily fear of people with diabetes so a reduction in hypoglycaemic events can improve quality of life. It is therefore important to look at the effects of insulin analogues on hyper- and hypoglycaemia.

Short-acting insulin analogues
As could have been expected from the B10Asp study, Humalog and NovoRapid have barely shown any clinical benefits over GM ‘human’ insulin in terms of blood glucose levels as measured by HbA1c and daily blood glucose tests.

Studies comparing control of hypoglycaemia for Humalog and NovoRapid with GM ‘human’ insulin showed the following:

Type of hypoglycaemia	Number of studies analysed	Effects of using Humalog or Novolog/NovoRapid
Frequency of mild hypoglycaemia	22 studies	Reduction in 5 studies
Frequency of severe hypoglycaemia	12 studies	No change in 10 studies
Frequency of nocturnal hypoglycaemia	24 studies	Reductions in 6 studies (19)

A Cochrane Review [2004] of short-acting analogues supported all the above findings and concluded that:

• short-acting insulin analogues have only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin
• until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues
• due to fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications
• for safety purposes, a long-term follow-up study of large numbers of patients who use short acting insulin analogues is needed.

Long-acting insulin analogues
The clinical benefits of glargine [Lantus] as measured by HbA1c were small in comparison to GM ‘human’ insulin and when compared to twice daily long-acting [NPH] ‘human’ insulin there was no difference in hypoglycaemia.

At the time of writing, detemir [Levemir] has only been on the market a short time but manufacturers information shows little, if any, improvement in HbA1c and it is claimed that there is less weight gain when compared to ‘human’ insulin.

Studies carried out on selected patient groups
It is important to note that all clinical studies with insulin analogues have been conducted on carefully selected patient groups that have excluded all those with diabetic complications and any other conditions. So the effects of insulin analogues on people with these conditions is not known. Equally unknown are the effects of insulin analogues on mortality and other hard endpoints like blindness, amputation and end stage renal disease.

It is worth noting that the Drugs and Therapeutics Bulletin [Oct 2004 Vol 41;No10] reported on the use of insulin analogues as first line treatment: "In our view, this approach is not justified given that what still needs to established about the analogues – long-term benefits and safety. Also there is no convincing evidence to justify switching patients from existing conventional therapy to analogues if they have appropriate glycaemic control without troublesome hypoglycaemia."

Safety issues – the potential for carcinogenic effects
As discussed, the rapid acting analogues B10Asp was shown to induce or promote breast cancer in Sprague-Dawley rats [type of rat used because it is most likely to produce breast cancer if a risk is present]. B10Asp was called the ‘super-mitogen’ and subsequent analogues reaching the market have been measured against this for their carcinogenic potential.

It was increasingly recognised that changing the physico-chemical properties of the GM ‘human’ insulin molecule will inevitably change its biological properties although manufacturers tried to play down the potential risks. Long before the European Medicines Evaluation Agency [EMEA] was asked to approve long-acting insulin analogue, glargine, it was found to be highly mitogenic [caused cell proliferation] on in-vitro testing with human osteosarcoma cells [cancerous cells from tissue surrounding bone]. On February 17, 2000 this information, still unpublished, was presented to the EMEA by the manufacturers, Aventis, in an oral explanation. The EMEA accepted the company’s claim that this information was irrelevant and subsequently approved the drug. In June 2000, a paper publicly disclosed the mitogenicity of insulin glargine [Lantus] on osteosarcoma cells and in June 2001 Aventis publicly confirmed this information in an abstract presented to the American Diabetes Association.

Recently even more abnormal biological actions of insulin analogues as compared to ‘human’ insulin have been identified by various researchers:

• Humalog and NovoRapid /NovoLog inhibit thrombocyte function
• Humalog inhibits apoptosis in tumour (insulinoma) cells and protein degradation.
• A new insulin analogue, insulin Glusilin (Aventis) inhibits apoptosis in tumour (insulinoma) cells.
• Lantus, but not Humalog, increases serum IGF-1 concentrations in diabetic patients.
• On the receptor level eg of osteosarcoma cells, rat cardiomyocytes, human skeletal muscle cells, Lantus binds less to the insulin receptor and more to the IGF-1 receptor than does human insulin, and causes abnormal post-receptor signalling compared to human insulin.

[Published data on NovoRapid/Novolog are scarce].

In most instances, the animal toxicology experiments presented to the drug regulatory boards [the EMEA and the FDA] for the approval of insulin analogues were flawed. The experiments were not in accordance with the EMEA 2001 recommendations and are not suitable to rule out clinically relevant carcinogenicity of these insulins.

• Humalog was studied in rats which do not develop breast cancer (Fischer 344 rats
• Lantus was studied in dosages much lower than those of B10 Asp that induced breast cancer in cancer-prone rats
• The exposure time of the rats against Lantus was too short, as many rats died from hypoglycaemia before the end of planned 24-months observation period.
• Standard 2-year carcinogenicity studies in animals have not been performed or published to evaluate the carcinogenic potential of Humalog and NovoRapid/NovoLog.

Toxicology studies

Insulin analogue	Experimental design	Dosage	Duration	Outcome
B10 Asp	Sprague-Dawley rats	20-200 U/kg	12 months	breast cancer+++, dose-related
Humalog	344 Fischer rats	20-200 U7kg	12 months	no breast cancer
Lantus	Sprague-Dawley rats	5-12.5 U/kg	<24 months	malignant fibrohisticytoma++ malignant lymphoma (+)
NovoLog NovoRapid	Sprague-Dawley rats	10-200U/kg	12 months	breast cancer with 200 U/kg, significant difference to untreated controls, no significant difference to regular human insulin

Conclusions
Insulin analogues are new biotechnological products with unknown biological effects.

The actions of natural insulin in humans and animals has been brought about by evolution over millions of years and the delicate balance between its metabolic and mitogenic efficacy functions very well in every species in order to maintain survival. This cannot be said of artificial insulin analogues that interfere with this balance in unpredictable and unknown ways.

This lack of information prompted the EMEA [2001] to call for better pre-clinical testing of insulin analogues in order to definitely rule out any relevant carcinogenicity of these compounds. The ‘Points to consider document CPMP/SWP/372/01 on the non-clinical assessment of the carcinogenic potential of insulin analogues states:

"Native human insulin has, in addition to its metabolic actions, a weak mitogenic effect. This effect has become important for the safety of insulin analogues,……since structural modifications of the insulin molecule could increase the mitogenic potency, possibly resulting in growth stimulation of pre-existing neoplasms…"

"Although enhanced insulin-like growth factor 1(IGF-1) receptor activation and/or aberrant signalling through the insulin receptor have been implicated, the mechanism(s) responsible for the mitogenic activity of insulin analogues remain to be clarified…"

According to this same EMEA document, insulin analogues should be investigated on neoplastic [tumour] tissue rather than on non-neoplastic [normal] tissue, including in-vivo studies with tumour tissues transplanted on immunodeficient animals:

"Since there is evidence that receptor in neoplastic [tumour] tissues may react differently from those in normal tissues, it is desirable that the choice of test systems will cover testing of mitogenicity in non-neoplastic as well as neoplastic tissues."

"Due to substantial background data on spontaneous tumour incidence, the rat may be considered a suitable species and in view of the responsiveness to AspB10….at present the Sprague-Dawley rat may be thought of as first-hand choice. … other species or models, like the promotion of established human tumour cell lines grafted on immunodeficient animals might be considered."

As evidence that IGF-1 promotes colonic-, breast-, prostatic-, and lung cancer growth is accumulating, it is mandatory that insulin analogues should be studied preferably on these neoplastic tissues. However, none of these investigations have so far been carried out or published.

In a public meeting on May 5, 2004 Professor Jürgen Eckel, Germany, announced that he is to carry out a systematic investigation of the mitogenic potency of insulin analogues. However, it will take years for the results of this investigation to be completed and published. Unless cancer growth promotion is properly excluded, the safety of insulin analogues will remain unknown and patients will be unable to assess their risks and benefits in order to make an informed choice of treatment. If patients safety is to be protected and their rights to an informed choice is to be respected, it is essential that patients are provided with the facts as they stand. When the clinical benefits of insulin analogues have proved to be negligible in terms of diabetes control, even a minimal carcinogenic risk could be classed as unacceptable by some patients.

 

Version two – the more technical version that follows which provides more detail and the supporting references.
Regulatory requirements for insulin analogues: weighing therapeutic benefits against potential carcinogenicity

Summary
Recent events with Cox-2 inhibitors have demonstrated that there is a need for greater effort into research before a new drug reaches the market and for improved post-marketing surveillance. There is a wide range of drugs available and the pattern of toxicity is likely to change with the introduction of new biotechnology products.

Insulin analogues are just such a product as they are artificial derivatives of the natural hormone insulin, designed to improve the absorption profiles compared to human insulins after subcutaneous injection. However, analogues also differ from human insulin in their biological effects such as, effects on mitogenicity, apoptosis, glucose and lipid metabolism, thrombocyte function and protein degradation, with unknown consequences. While the therapeutic effects have been investigated extensively and found to be negligible, the biological effects of insulin analogues remain to be systematically studied. Of special concern is that the carcinogenic potential of insulin analogues remains to be determined on human carcinoma tissue, according to the recommendations issued by the European Agency for the Evaluation of Medicinal Products (EMEA Points to consider document CPMP/SWP/372/01).

Introduction
Spontaneous adverse drug reactions reporting schemes, such as the Yellow Card Scheme in the United Kingdom, are the cornerstone of post-marketing drug safety surveillance and remain the only way of monitoring the safety of a drug throughout its life on the market. A problem with spontaneous reporting is that less than 10% of all serious and 2-4% of non-serious adverse reactions are reported (1). It must be hoped that the recent introduction in the United Kingdom of patients being able to report adverse drug reactions (2) will improve the number of reports and the post-marketing surveillance system, assuming that patients’ reports carry the same weight as those from doctors and healthcare professionals.

Adverse events associated with the effects of the anti-depressant. paroxetine [Seroxat] highlighted in the BBC programme, Panorama, resulted in the Committee on Safety of Medicines [CSM] issuing a safety statement about the recommended dose (3) in March 2003. However, this statement was not based on new evidence but "on a review of the original dose finding studies carried out for the licensing of paroxetine". In other words, information the CSM hadthe information before the drug reached the market and once again lives were unnecessarily harmed or lost as a result of this system failure.

Pirmohamed et all point out (1) that there is a wide range of drugs available and the manifestations of drug toxicity may vary, may affect any organ system and that the pattern of toxicity is likely to change with the introduction of new biotechnology products. An early example of this was the introduction of genetically engineered tryptophan in 1988, withdrawn within months because it caused 37 deaths and 1500 people to be permanently disabled (4). Genetic engineering was implicated because the toxin responsible had never been shown to be present in non-genetically engineered tryptophan that had been used for many years without these adverse effects.

Human insulin was the first genetically engineered drug to be marketed in 1982. In common with tryptophan, regulatory authorities considered the method of production to be immaterial because natural animal insulin had one of the best safety profiles on the market with the only major side-effect being hypoglycaemia, technically caused by overdose (5). In effect regulatory authorities considered the new laboratory produced human insulin to be substantially equivalent to natural animal insulin used for more than 60 years. Patients were changed to the new ‘human’ insulin not for clinical reasons but on the assumption of superiority and not evidence of its superiority over its animal insulin predecessors.

An estimated 10% of patients reported, and continue to report, adverse effects when using genetically engineered human insulin. Despite awareness that genetic variability leads to differences in drug response between individuals (6) and that the clinical consequences of individual variation in drug response can be great, the adverse reactions with genetically engineered insulins have been largely ignored and they have become first-line treatment for people requiring insulin. However, there have been no large-scale studies to compare human and animal insulins and the vast majority of studies that have been carried out are classed as being of ‘poor methodological quality’ in a Cochrane Review (7). Not only was human insulin given marketing authorisation without consideration of the method of manufacture but post marketing studies have been of poor quality.

With this background for such a widely prescribed, and therefore highly profitable product as insulin, it is unsurprising that the rofecoxib and paroxetine situations have arisen. If patients are to be protected, regulatory bodies need to reconsider drugs that have already received marketing approval and this is particularly applicable to the more recently developed insulin analogues.

Hundreds of human insulin derivatives, nowadays called analogues have been designed by chemists since the molecular structure of human insulin became known in the 1960s (8,9). While scientists were using these compounds to study structure-function relationships of the insulin molecule, insulin manufacturers were interested in their commercial potential after recombinant DNA biotechnology had opened the way for industrial production. Novo Nordisk announced the production of insulin analogues for therapeutic purposes in 1988 (10). Their prototype analogue, B10Asp, was designed to aggregate less than regular human insulin in pharmaceutical preparations. Pharmaceutical regular human insulin molecules aggregate in the vial to hexamers which, after subcutaneous injection, must disintegrate to insulin monomers before they can enter the circulation. This process of hexamer disintegration takes about 10-15 minutes inside the subcutaneous fat tissue. There is no such time lag after intramuscular injection, perhaps due to the better vascularisation of muscular tissue, and hence faster wash-out of injected insulin. The analogue B10 Asp, by virtue of a slight modification of the native human insulin molecular structure, did not aggregate as much as regular human insulin and was absorbed from the subcutaneous tissue about 15 minutes earlier than human regular insulin.

However, a controlled trial failed to show any benefit in terms of blood glucose regulation of B10Asp versus regular human insulin, although B10Asp was absorbed into the circulation significantly faster and with higher peak concentrations than human insulin (11). From this study it was obvious in 1995 that manipulations of the subcutaneous absorption of rapid acting (regular) insulin have only very little clinical impact on HbA1c, and may explain only less than 5% of total variation in HbA1c. Much greater percentages of the total variation in HbA1c are accounted for by the size of the insulin dose, the amount and timing of carbohydrate intake, the timing of exercise in relation to the carbohydrate intake and/or the insulin application, effects from stress or intercurrent illness on insulin sensitivity, psychosocial aspects and residual ß-cell function (12).

All clinical trials with B10Asp were suspended in 1992, when this compound was shown to promote breast cancer in rats (13). Nevertheless, rapidly absorbed ‘monomeric‘ regular insulin analogue Lispro (Humalog®) was launched in 1996 and reached the UK market in 1998 when Amiel (5) warned that there remains a risk of unexpected problems with any new agent and "we should remember that the structure of the new insulin is a little closer to IGF structure than the old insulin".

Therapeutic potentials
Clinical superiority of Humalog® over human insulin in terms of blood glucose regulation with HbA1c and blood glucose daily profiles was barely detectable (14), as could have been expected from the B10Asp study (11). The same holds true for another insulin analogue, Aspart (Novolog®/ NovoRapid®) as despite its faster subcutaneous absorption, the effects on blood glucose regulation were very similar to those of regular human insulin. In 2000, Aventis launched a slowly absorbed insulin analogue, Glargine (Lantus®); again, the clinical benefits in comparison to human insulin were small (Table 1).
Table 1: Effect of insulin analogues on controlling hyperglycaemia

Aspart (NovoRapid® NovoNordisk) + NPH human insulin versus regular human insulin + NPH human insulin

Number of patients in studies	Changes in HbA1c measurements
1070 Type 1 diabetic patients in Europe:	HbA1c – 0.12% within 6 months
884 Type 1 diabetic patients in USA:	HbA1c – 0.15% within 6 months, – 0.14% within 12 months

 

(NovoNordisk, scientific information on NovoRapid®/NovoLog 1999, 2000 (15))

Glargine (Lantus®,Aventis) + regular human insulin versus NPH human insulin + regular human insulin

Number of patients in study	Changes in HbA1c measurement
333 Type 1 diabetic patients	HbA1c – 0.14% versus NPH human insulin (15,16)

 

Glargine (Lantus®, Aventis) + insulin Lispro (Humalog®, Lilly) versus NPH human insulin + insulin lispro

Number of patients in study	Changes in HbA1c measurement
619 Type 1 diabetic patients	HbA1c no statistically significant difference (17)

 

Note: note that a -0.15% change in HbA1c translates into 5mg/dl (0.27mmol/l) change in blood glucose (18)

Table 2: Effect of insulin analogues on controlling hypoglycaemia

Humalog® or Novolog®/NovoRapid®, versus regular human insulin

Type of hypoglycaemia	Number of studies analysed	Effects of using Humalog® or Novolog/NovoRapid®
Frequency of mild hypoglycemia	22 studies	Reduction in 5 studies
Frequency of severe hypoglycaemia	12 studies	No change in 10 studies
Frequency of nocturnal hypoglycaemia	24 studies	Reductions in 6 studies (19)

 

 

Glargine (Lantus®) once per day versus NPH human insulin twice per day

No difference in hypoglycaemia (16)

In summary, the beneficial effects of insulin analogues on control of hyper- and hypoglycaemia in diabetic patients were nearly nil. A previous review article (20), and a most recent Cochrane review have come to the same result (21). All clinical studies with insulin analogues had been performed in carefully selected patient groups, excluding those with diabetic complications and co-morbidity. Hence the effects of analogues on these conditions are not known, nor the effects on mortality and other hard endpoints like blindness, amputation, end stage renal disease.

Safety issues: carcinogenic potential
After B10Asp was shown to induce or promote breast cancer (13) in Sprague-Dawley rats, which have a high spontaneous incidence rate of breast cancer and this insulin analogue was called "super-mitogen" (22), it was increasingly recognised that changing the physico-chemical properties of the human insulin molecule will inevitably change its biological properties:

"Mutation of the insulin molecule through recombinant DNA technology has produced ‘monomeric’ insulin, which does not form hexamers and is therefore more readily absorbed following subcutaneous injection. The pharmacokinetics and biological actions are thus altered… " (23)

However, the manufacturers tried to play down potential risks with the manufacturers claiming that the biological differences of Humalog® to human insulin were not harmful:

"Insulin receptor binding: equipotent to insulin IGF-1 receptor binding: approx.160% as potent as insulin DNA synthesis: marginally more potent than insulin(approx.1-4x); possibly explained by enhanced IGF-1 receptor affinity" (24).

Insulin Glargine (Lantus®) was found to be highly mitogenic on in-vitro testing with human osteosarcoma cells long before the EMEA had been asked for approval of the compound (25). On February 17, 2000 this information, still unpublished, was reported to the EMEA in an oral explanation by Aventis. The EMEA accepted the company’s claim that the finding was irrelevant, and subsequently approved the drug (24). A paper (26) in June 2000 publicly disclosed the mitogenicity of insulin Glargine on osteosarcoma cells and in June 2001, Aventis publicly confirmed this information in an abstract presented to the ADA (27):

"Lantus® binds more actively to IGF-1 receptors: In human hepatoma cells (Hep G2), Lantus® affinity for the IGF-1 receptor was 5-7 fold relative to human insulin…In human osteosarcoma cells, IGF-1 receptor affinity of Lantus® was 3.5-7.6 fold relative to human insulin….in a second study on osteosarcoma cells, IGF-1 receptor affinity of Lantus® was 14 fold relative to human insulin….and thymidine uptake (i.e. incorporation into DNA) in response to Lantus® was 6.1 fold higher compared with human insulin.. "(27)

Recently, even more abnormal biological actions of insulin analogues (as compared to human insulin) have been identified by occasional investigations of various researchers. Humalog® and NovoRapid®/NovoLog® inhibit thrombocyte function (28,29); Humalog® inhibits apoptosis in tumour (insulinoma) cells (30), and protein degradation(31). A new insulin analogue, insulin Glusilin (Aventis) inhibits apoptosis in tumour (insulinoma) cells (30). Lantus®, but not Humalog®, increases serum IGF-1 concentrations in diabetic patients (32,33). On the receptor level e.g. of osteosarcoma cells, rat cardiomyocytes, human skeletal muscle cells, Lantus® binds less to the insulin receptor and more to the IGF-1 receptor than does human insulin, and causes abnormal post-receptor signalling compared to human insulin (21,29,34). Published data on NovoRapid®/Novolog® are scarce (26,35,36).

The animal toxicology experiments, presented to the drug regulation boards, such as the FDA or EMEA, for approval of the insulin analogues (Table 3), in most instances were flawed, and not in accordance with the recommendations issued by the EMEA 2001. These experiments are not suitable to rule out clinically relevant carcinogenicity of these compounds. Humalog® was studied in rats which do not develop breast cancer (Fischer 344 rats (37)), while Lantus® was studied in dosages much lower than those of B10 Asp (13) that had induced breast cancer in cancer-prone rats(38). Furthermore, the exposure time of the rats against Lantus® was too short, as many rats died from hypoglycaemia before the end of planned 24-months observation period.

Table 3: Toxicology studies

Insulin analogue	Experimental design	Dosage	Duration	Outcome
B10 Asp (6)	Sprague-Dawley rats	20-200 U/kg	12 months	breast cancer+++, dose-related
Humalog® (29)	344 Fischer rats	20-200 U7kg	12 months	no breast cancer
Lantus® (30)	Sprague-Dawley rats	5-12.5 U/kg	<24 months	malignant fibrohisticytoma++ malignant lymphoma (+)
NovoLog® (31)	Sprague-Dawley rats	10-200U/kg	12 months	breast cancer with 200 U/kg, significant difference to untreated controls, no significant difference to regular human insulin

 

Standard 2-year carcinogenicity studies in animals have not been performed or published to evaluate the carcinogenic potential of Humalog® and NovoLog ®(39).

Conclusion
Insulin analogues are new biotechnological pharmaceuticals with unknown biological effects. Natural insulin, be it human or animal insulin, has been brought about by evolution over millions of years; its delicate balance between metabolic and mitogenic efficacy is very well functioning in every species to maintain survival. This cannot be said of artificial insulin analogues, which interfere with this balance in an unpredictable way. This lack of information prompted the EMEA in 2001 to call for better pre-clinical testing of insulin analogues in order to definitely rule out relevant carcinogenicity of these compounds (40).

"Native human insulin has, in addition to its metabolic actions, a weak mitogenic effect. This effect has become important for the safety of insulin analogues, i.e. compounds derived from insulin with a molecular composition and/or structure that has been modified as compared to native human insulin, since structural modifications of the insulin molecule could increase the mitogenic potency, possibly resulting in growth stimulation of pre-existing neoplasms…"

"Although enhanced insulin-like growth factor 1(IGF-1) receptor activation and/or aberrant signalling through the insulin receptor have been implicated, the mechanism(s) responsible for the mitogenic activity of insulin analogues remain to be clarified…"(40)

According to the EMEA document (40), insulin analogues should be investigated on neoplastic rather than on non-neoplastic tissues, including in-vivo studies with tumour tissues transplanted on immunodeficient animals.

"Since there is evidence that receptor in neoplastic tissues may react differently from those in normal tissues, it is desirable that the choice of test systems will cover testing of mitogenicity in non-neoplastic as well as neoplastic tissues."

"Due to substantial background data on spontaneous tumour incidence, the rat may be considered a suitable species and in view of the responsiveness to AspB10….at present the Sprague-Dawley rat may be thought of as first-hand choice. … other species or models, like the promotion of established human tumour cell lines grafted on immunodeficient animals might be considered." (39)

Since evidence is accumulating that IGF-1 promotes colonic-, breast-, prostatic-, and lung cancer growth (41) it is mandatory that insulin analogues should be studied preferably on these neoplastic tissues. However, neither of these investigations have so far been carried out or published. In a public meeting on May 5,2004 Professor Jürgen Eckel, Germany (22,30) announced that he is about to start a systematic investigation of the mitogenic potency of insulin analogues. It will take years for the results of this investigation to be completed and published.

Unless cancer growth promotion is properly excluded, the safety of insulin analogues will remain unknown and patients will be unable to assess their risks and benefits in order to make an informed choice of treatment. If patients safety is to be protected and their rights to an informed choice is to be respected, it is essential that they are provided with the facts as they stand. As the clinical benefits of insulin analogues have proved to be negligible in terms of diabetes control, some patients may consider that even a minimal carcinogenic risk of insulin analogues may be unacceptable.

The long and short-term health of patients must be protected by greater effort being put into researching the safety of new drugs and by greater vigilance on the part of regulators before they reach the market. For physicians prescribing drugs and for patients’ exercising their rights to an informed choice of treatment, decisions are made on the basis of weighing up the risks and benefits of the various therapies that are available to them. In order to truly achieve this, there needs to be greater transparency and more effort put into good quality clinical research before new drugs reach the market accompanied by more effective and more vigilant post-marketing surveillance.

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Introduction – For Parents of Children and Young People with Diabetes

Parents of children and teenagers who have diabetes are very special sorts of carers. They are suddenly faced with the diagnosis of their child and at the same time, the loss of their healthy child. They are bombarded with information about insulin, diet, blood tests, blood glucose control, hyper- and hypoglycaemia and the future health of their child. It is a difficult time for the whole family and there are many worries, fears and concerns. We hope that this section will provide information, help and support. Knowing that you are not alone with the experiences of living with diabetes in your child can be a help and a comfort.

One message that we all need to remember is:

Whatever the cause of your child’s diabetes and however you may feel, it is not your fault that it has happened and there is nothing you could have done to prevent it.

Child diagnosis

The role of parents and their involvement in day to day living with diabetes is very different according to the age of their child when diagnosed. If your child is diagnosed when young, then clearly, as a parent, you are taking full responsibility for your child’s diabetes everyday and for 24 hours a day. If your child is a teenager when diagnosed then very often the teenager takes immediate responsibility for injections, blood testing, diet etc and the parents role is one of watching over with less direct involvement. This may sound easier but in many ways it isn’t, especially if your teenager’s diabetes clinic has given you only minimal involvement in the diabetes educational programme.

However, whatever the age of your child when diabetes is diagnosed, it is a difficult, often traumatic time and most parents go through similar feelings. We care deeply for our children and it would not be natural if we did not go through a period of grief. These feelings are:

Shock – That this can happen to our child.

Denial – ‘This can’t be happening to my child’. ‘I’ll wake up in the morning and it will have been a bad dream.’

Anger – ‘Why my child?’ ‘Why not someone else’s child?’

Sadness and grief – A sense of loss for the healthy child you had and for the expectations you had for your once healthy child.

Guilt – ‘Is it something that I have done?’ ‘Could I have prevented it?’ Guilt is not a rational feeling because it is certainly not anyone’s fault when a child has diabetes. But Mums especially seem to feel guilt when their child is diagnosed and probably for a long time afterwards. But there is a very important message for ALL parents: Whatever you may feel or think and whatever the cause of diabetes, it is NEVER YOUR fault that your child has diabetes and there is nothing that you could have done to prevent it.

The need to know – Many parents go through the stage of wanting to know why their child has diabetes and where it came from. This seems to be part of the process, a need to blame someone or something, perhaps this helps to ease the burden of ‘guilt’.

Responsibility – It seems that the whole future health of your child rests on your shoulders and this is a huge weight to carry around.

A Personal Experience of Diagnosis
My daughter was diagnosed soon after her fifth birthday, one Friday evening, a Friday evening that I shall never forget! She was admitted to hospital – this was the first time either of my children had been away from me, so that alone was difficult. During her stay we were given masses of information about diabetes by innumerable different people – hypers, hypos, diet, exercise and shown how to inject. No one seemed to understand that I could not take all this in, the shock of diagnosis and accepting this was all my mind could deal with. So when we left hospital, along with all the other feelings of shock and grief, I felt alone, frightened and very ignorant about diabetes.

We were also given some of the hard facts of diabetes:

• It was here forever and my little girl would have insulin injections for the rest of her life.
• We needed to keep ‘good control’ of her diabetes to avoid the complications in later life.
• It was a simple matter of injecting the right amount of insulin to balance with the food – I learnt that this was rubbish, there is nothing simple about achieving ‘good’ control!
• She could live a perfectly normal life with diabetes.

I think that these last two statements were most confusing and unrealistic. They also had a long lasting and damaging effect. No doubt they were said to cheer me up! But actually they had just the opposite effect.

Initially diabetes seemed to take over our whole lives – injections, tests, snacks, meals. It was just like having a new baby in the house. On top of all these practical things there was still the worry of my daughter’s reaction to her diabetes; how she would cope; my son’s reactions to the changes and would he feel left out and finally the turmoil of my own emotions.

I waited for the normal life I had been promised to appear. It didn’t seem to arrive and I felt that this was my fault – I must be doing something wrong. I felt as if it was my inability to manage that was preventing us from having this ‘normal life’ the doctor had promised. I felt a failure. That one statement led me to expect that life would go back to how it had been before diabetes – normal. Had this not been said to me, my expectations would have been different and I would not have felt such a failure, nor so much guilt for not achieving this ‘normal’ life we had been promised.

Life has been normal now for many years – diabetes just became part of our lives, a part that does affect the whole family and a part that cannot be ignored. We all have feelings about diabetes, especially the child with it. We found that it was important to talk about these feelings within the family or within a parent support group because this way they seem normal and are normal when living with diabetes. Once I realised that our experiences were similar to those of many other people in the same position, that I was not the only one who could not always achieve the standards set by the clinic and that I was not a failure, life became much better for us all.

Looking back now over the 34 years my daughter has had diabetes, I know that some of my feelings that I had at diagnosis are still there – the guilt and the sadness. They only really loom if there are problems, which do occur from time to time, but I also now know that I have always done my personal best. This ‘best’ may not seem as good as someone else’s best, but it was my best and none of us can be expected to do anymore than our best.

A quote from my daughter when she was 25 and had diabetes for 20 years. “Nobody wants diabetes but if I had to have it, I’m glad I got it when I was young and can’t remember life without it. Being diabetic is just part of me and not something that suddenly hit me. I didn’t have to get used to any great changes in my life or adjustments in my lifestyle or self image.”

Diagnosis – hospitalisation or home?
If your child suddenly becomes very ill and this is an emergency then hospitalisation at the time of diagnosis has to take place. If you notice over a matter of weeks or days that your child is unwell, going thin and drinking a lot, you usually see your GP who then diagnoses diabetes. Whether hospitalisation takes place in this case very often is dependent on the local policy. Diagnosis and treatment maybe started at home without a hospital stay or it maybe that a couple of days are spent in hospital. In the past children always stayrd in hospital for several at diagnosis.

There are advantages and disadvantages to both policies

• Going into hospital can be quite traumatic for your child even though visiting in children’s wards has few restrictions nowadays and parents staying overnight is often available. It also means that your child will be away from school longer.
• It has the advantage of giving you, the parents, time to adjust to the diagnosis, time to be sad and angry etc, away from your child. It gives you time have a break where you do not have to keep up the ‘brave face’ all the time for your child.
• A stay in hospital has the advantage of making everyone concerned realise that diabetes is a serious condition that needs care and attention and cannot be treated lightly – this includes the parents, other family members, friends and teachers. Diagnosis at home and back to school in a couple of days has the disadvantage of reducing the importance and effects of diabetes, especially in the eyes of outsiders such as teachers. It may seem to them like any other minor illness for which a child is absent for a few days. This could affect how your child is treated in the future by the school, friends and family. It could also affect how you are treated – you could be seen as a fussing parent if people underestimate the significance of diabetes. [The neurotic mother syndrome that many of us know so well!]
• Diagnosis at home means that life is less disrupted for everyone and diabetes does not seem at this stage to be such a huge infringement on normal life. It also enables you to have the help, advice and support in your own home where you feel more comfortable and are less intimidated by all the white coats of hospital.  

Whatever the circumstances this is not an easy time for anyone and it is important that the seriousness and subsequent changes in lifestyle that diabetes brings, are not underestimated or influenced by whether or not your child is hospitalised at diagnosis. Research has yet to provide evidence of which is better – diagnosis at home or in hospital.

Climbing that Mountain

All too often we read about children, teenagers and adults with diabetes climbing mountains, sailing the seas and doing all sorts of fantastic things. I’m sure these articles are written with the best of intentions – to make us all feel better and let us know that our children can do anything, even with diabetes. Well they probably can, providing they take all the necessary precautions.

Does this actually make us feel better? Do they, in fact, make us feel worse, more inadequate and perhaps even a bit of a failure because we, or our children, don’t achieve these things?

They shouldn’t because the vast majority of people with or without diabetes don’t want to climb a mountain or sail across the Atlantic – they simply want to lead a normal everyday life just like their friends. This is just as great an achievement as climbing a mountain! Your child with diabetes attending its first party on its own, your teenager going to its first disco without going hypo or having blood sugars out of the roof – these are achievements that are just as important as climbing any mountain. These are the things that enable our children with diabetes to be like their friends and this is something that matters greatly to them, especially as they get into the teenage years. We can be justifiably proud of them for this – they don’t have to climb a mountain!

Are we over enthusiastic about their achievements?
I think that sometimes we, as parents, are in danger of this. Quite naturally we want our children with diabetes to achieve their full potential and we don’t want diabetes to interfere with their schoolwork or their hobbies. But we have to be very wary of falling into the trap of encouraging our children to do things just to prove that they can do them and to prove they are just as good, if not better, than their non-diabetic friends. We also have to be wary of our own desires to prove that our children can achieve even though they have diabetes.

We have to ask ourselves about the people in the articles – did they climb the mountain because they wanted to or did they do it to prove that they could as someone with diabetes? Would they have wanted to climb the mountain if they had not had diabetes? Are they going to go through life trying to prove that diabetes does not interfere with their lives? If the answer to this last question is yes, then I think this is sad and I do not believe that any of us, as parents, want that for our children. If they want to climb mountains because that is their hobby, then that’s fine.

The balancing act
Just like the rest of living with diabetes, getting this aspect right is a balancing act. We do not want to pressurise our children with diabetes into being high achievers but at the same time, we do not want to ‘spoil’ them simply because they have diabetes. Finding this balance is not easy – it is probably just as difficult as getting good blood glucose results!

One thing that most of us discover fairly early after diagnosis is that the world does not make allowances for someone with diabetes, whether a child, teenager or an adult and having this in mind when bringing up a child with diabetes, helps to find a balance. The one thing we all want for our children is that they are able to cope in the adult world, they grow up to be independent, healthy and above all, happy. 

The role model
Having said all of this there is a place for role models and Gary Mabbutt who was captain of Spurs and the first person with diabetes to play football for England, is a good example. ‘If Gary Mabbutt can play football for England, then diabetes doesn’t have to stop me doing anything.’

Gary and his family were in a TV programme about his life and his diabetes kept cropping up. Without in any way detracting from Gary’s success, the programme showed that he came from a footballing family and he was well on the way to a football career when he was diagnosed with diabetes in his teens. Gary’s real achievement was that he did not let diabetes interfere with his ambitions to be a professional footballer. This is the role model that children with diabetes need. He was not trying to prove that he could be a footballer and have diabetes – but he was not letting diabetes stop him from doing what he wanted to do. There is a subtle difference. His parents were rightly very proud of him and we can be equally proud of our children when they do what they want to do, while at the same time managing their diabetes.

Life at School with a chronic condition

The NHS Research and Development Programme funded a two-year study to investigate the support needs of young people with special health needs attending mainstream schools. They consulted young people, their parents and teachers. I don’t know whether young people with diabetes are classed as having a ‘chronic physical condition’ but the results of the study certainly apply to them. It showed that:

• Young people were making active efforts to manage their own condition in school.
• They felt they needed support from health and education professionals in dealing with absence from school, including keeping up with school work.
• They also felt they needed support for joining in school activities, relationships with other pupils and having someone to talk to about health-related worries.
• Young people and parents said that support from teachers was variable, depending on the teacher’s awareness and understanding of the child’s condition.
• Teachers felt their need for health information was largely unmet and they did not want to rely solely on parents or school doctors for advice and information.
• Teachers urged the child’s health professional to make contact on a regular basis.
• All participants in the study expressed concern about systems in the education services for passing information between and within schools.  

All these issues can apply to children and young people with diabetes. I think the teachers have probably hit the nail in the head when they say that they would like direct and regular contact with the child’s healthcare professional.

But one has to ask just how realistic this is in terms of time, effort and cost. I am sure that the effort would be worthwhile, especially, for instance, during the teenage years when both parents and the young people themselves are going through a difficult time. There may be behavioural problems related to having to conform to the diabetes regime and when parent / child communications may be difficult. The time has to be given by teachers as well as health professionals, and having had experiences of trying to organise meetings for teachers about diabetes in children, I have to say that these were often poorly attended because they were in after school time. 

If this problem for children with chronic conditions is going to be tackled, then there has to be real commitment on the part of everyone concerned. It has always seemed to me that the organisations representing children and young people with the various conditions should get together and work with the education system to find a way to answer the needs of the children and young people, the parents and the teachers. It is not simply a matter of producing information sheets that never get read or passed on to the relevant teachers.

Information for teachers and for parents

Children and young people with diabetes are a particularly vulnerable group as they grow up with diabetes. We know from parents’ experiences that school can present problems for children with diabetes and additional worries for parents. So we have developed Information Packs to try to help and alleviate some of these problems.

Parents Pack
This contains the following information, which is especially for parents of children and young people with Type 1 diabetes, including the Parents Passport for Schools to give to the teacher.

Teachers Pack
This Pack contains information about diabetes to provide them with a better understanding of diabetes and help to understand the needs of children with the condition. 

All the above are provided FREE of charge from IDDT and with membership of IDDT you can also receive the general quarterly newsletter.

Research of practical help

This section covers just some of the research that has been carried out which may be of practical help in managing your child’s diabetes or which may offer some possible explanations for just some of the mysteries of day to day living with diabetes in your family. However, when looking at research we must always be remember:

• Studies are never the last word on a subject and often more research is necessary before the results should be put into practice.
• Research is often carried out on specific groups of people and therefore the results cannot be extended to assume that the effects will be the same for everybody with a condition or disease.
• Research is often carried out using small numbers of people and this will not necessarily prove a theory or demonstrate all the adverse effects of a treatment or drug. More research with large numbers of participants is necessary.
• Research that is published in reputable journals is peer-reviewed by experts but there is a great deal of research which is not published and not necessarily because it is not good research, therefore we are not receiving the complete picture. In other words there is a publication bias.  

Artificial Sweeteners in drinks for children
Research in children between the ages of 2 and 4 shows that they are close to exceeding the accepted daily intake of saccharin and that the main sources of sweeteners are in concentrated soft drinks like squash.

From July 1996 new legislation came into effect to try to reduce these levels. Sweeteners should no longer be added to normal squashes but only to drinks labelled as ‘sugar free’. There are also rules about dilution so that labels must make it clear how diluted the squash should be. This is particularly important for children with diabetes, and their brothers and sisters, who will all drink sugar-free squash regularly.

Examples of what sort of information should be clearly labelled:

• One part squash to six parts water.
• For toddlers add extra water.
• Labels giving diluting instructions according to the child’s age [obviously this is the best labelling.]

Accuracy of insulin doses in small children
Although most children inject with a pen, for those injecting with  a syringe, the accuracy of the dose is important especially in small children who usually require small doses of insulin. In this case, a small variation on a small amount of insulin could be significant in controlling blood glucose levels and could be the cause of erratic results.

A study published in ‘Diabetes Care’, January 1996 involved ‘caregivers’ of children with diabetes and 10 of these were parents who shared the responsibility of injecting their child. It was found that one person’s estimate of a specific dose was not the same as another and especially with small doses – this varied by about 0.25 units in either direction. This variability occurred in the spouse pairs just as much as the unrelated people and although the study is not recent, the messages still apply.

Clearly this could mean that the child may receive the prescribed dose of insulin but on any given day doses will vary by 0.25 units up or down. This could affect blood sugar levels and account for unexpected results. The researchers offered several possible ways of combating this problem while still enabling parents to share the responsibility of injections:

• One parent always giving the morning injection and the other always giving the evening injection.
• If the parent is going to be away for their usual injection, then pre-fill the syringe or several syringes if necessary.
• If the child goes into hospital then it may be preferable for the parents to give the injections.
• Use a syringe with wider spaces between the markings for greater accuracy – 0.3ml and 0.5ml syringes are available.

Hypoglycaemia in adolescents
A study published in Diabetic Medicine has shown that symptoms of hypoglycaemia vary in adolescents with diabetes compared to adults with diabetes. Hypoglycaemia was induced in 20 adolescents who had diabetes for an average of 5.4 years. All of them had acute autonomic symptoms [classic warnings] although those with tight control had to have lower blood glucose levels before the hypo symptoms occurred. The most common symptoms were hunger, tiredness, feeling weak, feeling warm and trembling. However, the sweating response was absent in the adolescents but not in the adults.

Parental distress affects children with diabetes
Researchers in the US found that behaviour problems in children with Type 1 diabetes are not related to the medical diagnosis of diabetes, but to their mother’s depression and the parental distress at diagnosis. They investigated 114 children with diabetes, 107 children with juvenile arthritis and 88 healthy children. They found that diagnosis of diabetes or arthritis in the children was associated with depression in mothers and distress in both parents. The children did not appear to react to the diagnosis of a serious medical condition but they did react to their parents’ reactions.

Changes in attention with hypo and hyperglycaemia in children with Type 1 diabetes
Researchers in Austria compared the results of a computerised attention test in 38 children with Type 1 in relation to various spontaneously occurring blood glucose levels. The levels used were <3.3mm0l/l, 3.3-8.3mmol/l and 8.3mmol/l. They found that the attention varied significantly with blood glucose levels. The highest number of errors and longest response time was observed during the test run for hypoglycaemia.

The results showed that attention in children with diabetes was significantly reduced compared to the norms for the test. This was especially noticeable during mild hypoglycaemia. These results were not influenced by age, sex, age at diagnosis, metabolic control or the results of the intelligent test. The authors concluded that in children with diabetes a significant reduction in attention was found not only at mild hypoglycaemia but also at low normal blood glucose levels. This shows that attention deficits may occur in children with diabetes even before they are aware of any hypo symptoms.
Eur J Pediatr 1998 Oct; 157[10]: 802-805 

Results from the Yorkshire childhood diabetes register
In June 1999 Diabetes Care published the results of a study that examined the hospital obstetric and neonatal records of 196 children with diabetes who were listed on the Yorkshire Childhood Diabetes Register. Each child with diabetes was matched with two control subjects of the same age and gender. After comparing the 325 control subjects’ hospital records with those of the diabetic children they found that the risk of diabetes is increased in…

• births to older mothers,
• mothers with Type 1 diabetes,
• high blood pressure during pregnancy
• neonatal illnesses.

As in previous studies, they also found that children who are breast fed immediately after birth may develop better defences against Type 1 diabetes.

Family Relationships

As an organisation whose members have the practical experience of living with diabetes, one thing that we are all very aware of is that diabetes affects everyone in the family. This is probably especially so when it is your child who has diabetes and being aware of this may help to prevent some of the pitfalls which make life more difficult. Everyone in the family has their own way of coping with diagnosis and the subsequent changes in the life of the family. We all react differently, so it is impossible to cover all the various dynamics in all families. Here are just a few examples that may help you to realise that your family is not alone with your experiences and concerns.

Mums and Dads
However strong a marriage or relationship is, it is important to recognise that diabetes, like any other chronic condition, can put a strain on that relationship and diabetes in the child that you both care about so much, is no exception. However, it can, and often does, bring couples closer together at time of diagnosis:

Quote from a friend of a family where one of the children had been diagnosed 12 months earlier. "You seemed a very close family. It was as if you had all closed ranks and didn’t want to let anyone else in."

But is that the case when living with diabetes 24 hours a day, 365 days a year every year? Sometimes the day to day stress can affect the parent’s relationship with each other and cause conflicts. 

Responsibility
It is best if the responsibility for your child’s diabetes can be shared but very often, because of circumstances, one parent takes most of the responsibility. This is usually for very practical reasons – work. So, by force of circumstances, it is the often Mum who shoulders most of the responsibility, although the following can apply just as much to Dads who shoulder most of the responsibility. Here are just some of the possible effects, citing Mum as been the main ‘carer’:

• Dad feels excluded and Mum feels he doesn’t do enough or is not interested. Resentment builds up.
• Mum feels that their child’s diabetes has become her sole responsibility and then resents Dad having an opinion on decisions about control or approaches to diabetes within the family.
• The worry and energy spent on ‘getting everything right’ makes Mum tired and irritable and arguments easily develop.  

Visiting the diabetic clinic
This should be seen as helpful but it often feels like the third degree and a test of the competence of the parents. You have been set blood glucose targets for your child and these may well have not have been achieved. [I say this as an old hand at parenthood because I concluded that all too often the targets are unachievable if you want any sort of life that is not totally ruled by diabetes!] However, the fact that you are questioned about these and why the results are not what the health professionals at the clinic would like to see, makes you feel guilty, ashamed, a failure. Worst of all, you feel you are letting your child down and at risk of affecting their future health. You may also feel angry with the health professionals for making you feel this way when you have being trying really hard ‘to get it all right’. The parent who does not attend the clinic does not have to go through all this and they probably cannot understand the effects it can have. It is easy for resentment to grow against the parent who escapes this ritual.

Fear of hypoglycaemia
This is very common and understandably so. It is a time when we have to make decisions and take action and we feel a great weight of responsibility for the outcome. Severe hypos at night are frightening, especially if accompanied by seizures and, whether the fear is rational or not, we sometimes fear that our child will die. All of this can result in:

• Conflicts from one parent wanting to raise blood sugar levels to avoid future night hypos and the other parent not agreeing because of their fears of the long-term complications.
• Both parents not sleeping well and being tired etc. The parent who has to go to work the next day assuming that their sleep should be less disturbed and the other seeing this as a ‘cop out’!
• Because of fears of night hypos, one parent sleeping in the child’s bedroom – not good for the relationship between the parents.

Quote from a Mum: "It seemed at one point every time we had sex Gabby knew and walked into our bedroom in a hypo. I found it difficult to have sex and my husband could not understand why – he thought I was being irrational and that I no longer cared for him."

Not feeling able to go out for an evening together because of the fear that the babysitter will not be able to handle a hypo, gives parents no break and freedom, not even for a few hours. If both parents are not happy with this, it can lead to fewer activities as a couple and doing more things separately. Even worse, it can mean that one partner is always the one to go out.

Quote from one Mum: "We didn’t used to argue very much and then only about one thing – money! Now we argue a lot more and about only  two things – diabetes and money!"

Siblings and their rivalry
It is unavoidable that sometimes your child with diabetes comes first:

• At diagnosis everything centres on the child with diabetes.
• Hypos have to be dealt with immediately, even if you are helping his brother or sister with their homework.
• Mealtimes often are influenced by diabetes and so is the food the family eats.
• Clinic visits have to fit into the family routine.
• At times of illness or emergency, the needs of your child with diabetes do come first.
• Depending on their ages, it is easy to ask the brother or sister to ‘keep an eye out’ without realising that this is a responsibility that they don’t need or want. If the children go to the same school, it is not uncommon for the teachers to ask the brother or sister to help with a hypo.  

The list is almost endless and it is obvious that diabetes in the family is going to affect the brothers and sisters in many different ways. It can, and often does, bring them closer and they show a protective approach if anyone criticises their sibling with diabetes. But at the same time, it is natural that there may be some resentment and jealousy. Families have to work their way around these problems but being aware of them and attempting to meet them before they develop into permanent sources of conflict and sibling rivalry is half the battle. Talking about the problems within the family is important and it is not unreasonable to apologise to the brother or sister for perhaps not spending as much time with them as you would like. They need an explanation, albeit, within the limits of their age and level of understanding. They need to know that you love them just as much as you always have, and as much as your child with diabetes, and that because diabetes is serious, it sometimes has to come before everything else.

Tip from a Mum: "I found that blaming diabetes rather than my daughter [with diabetes] was the best way around problems – we could all hate it together then. It helped to make my son realise that when things were difficult, it was not his sister’s fault but the fault of diabetes."

Quote from a sibling: "Often one of the first signs that my sister was hypo was that she would get bad tempered and argumentative – this often happened before Mum realised that she was hypo and so we would both get into trouble. Then the penny would drop and my sister was given sugary foods. She came around feeling happy again, totally unaware that we had been very angry with each other, but I remember being left still feeling angry with her. Even though I knew she’d been hypo she had still made me angry and a biscuit for me didn’t sort out how I felt!"

But let us not forget that sibling rivalry works both ways!
Just as we can see that the child without diabetes feels jealous and envious, the child with diabetes can feel jealous and envious of their sibling because they are well and don’t have diabetes. They may even feel that you love their brother or sister more, because they don’t have diabetes – perhaps a difficult concept for us as parents because so much more time, energy and worry seems to go into the child with diabetes!

Here is a point worth remembering at times of conflict. What is the first thing we do in the mornings with our child with diabetes – blood test, injection, then breakfast. Essential but not the nicest way to start the morning! If injections and blood tests are difficult and a struggle to achieve [in young children and teenagers, for example] then there may also be a battle! So it is hardly surprising that they feel that you don’t care about them compared to their sibling. The role of a Mum is expected to be loving and caring – the person who protects, supplies comfort and does all the nice things. This image falls down when your child has diabetes – Mum has to do or instigate nasty things, starting straight away in the morning! No wonder they can feel unloved and resentful. 

Grandparents
As parents going through our own grief at the time of diagnosis and having to learn so much, we are perhaps unaware of the effect it can have on our parents [our children’s grandparents].

A personal experience
My daughter was diagnosed when she was 5 and her brother was 6 – they had two grandmothers but no grandfathers. My mother had difficulty believing that Bev had diabetes and she was upset and emotional for a very long tome. Perhaps only now that I am a grandmother myself do I truly understand what she felt like. Grandchildren are very special – we can enjoy them, we can spoil them and we are free from the responsibilities we had with our own children. So I can now understand why my mother felt so upset when Bev was diagnosed. To a grandparent, it also seems so unfair that we are older, but it is someone so young who should have a lifelong condition like diabetes.

I’m quite sure that my mother sometimes felt I was being hard with Bev without realising that I was doing what I had to do and what I thought was best for her. But I was lucky, she never interfered or criticised. But I know of other families where this has not been the case, probably because of the difficulty the grandparents have in accepting diabetes in the family. The grandparents have interfered, have paid more attention to the child with diabetes, so leaving the other grandchildren feeling left out and ignored. However unintentional, they can leave emotional chaos behind them after a visit.

I have to say that my mother-in-law, Bev’s other Grandma, reacted in a very different way. There were similarities in that it was as if she had difficulty accepting it too, but her way of handling this was to ignore it. I don’t think that she ever understood the seriousness of diabetes or the effects it had on our family life. This was her way of coping and we are all different. It later became a family joke because it was tradition that she made the first cup of tea on Christmas morning and she always asked if Bev took sugar, every single year up to adulthood!

Babysitting
One of the most useful roles that grandparents play is as babysitters, especially nowadays when both parents need to work. But this is often difficult for parents and grandparents.

We, as parents, naturally find it difficult to leave our child with diabetes, even with our own parents. But grandparents may also feel that they cannot babysit because the weight of responsibility is too great or they do not feel to know enough about diabetes. These reactions are understandable but it does limit what the parents can do and it denies the grandparents the pleasure of looking after their grandchildren.

Quote from a parent: "My mother learnt about hypos, testing and food and I learned to leave my daughter with her for a couple of hours during the day to start with. Of course, I was always at the end of a phone. I could not leave her for overnight stays because she sometimes had severe night hypos and this would not have been fair on my mother and nor could I have slept!"

Research quote:
Winthrop University Hospital in the US held an educational programme for grandparents of children under 6 with diabetes. They learnt about injections, food, hypos and glucagon. None had provided overnight care but 50% had provided daytime care. There was a 3 month follow up after the programme and none had ‘graduated’ to overnight care – the reasons given were geography and parental fear of allowing others to care for the diabetic child overnight. However, most grandparents felt much more confident and more able to look after their grandchild, especially if an emergency occurred, and they all felt to benefit from meeting and talking with other grandparents.

Teenagers living with Diabetes

Dr Clare Williams, Institute of Education, University of London
Through working as a nurse and a health visitor for 20 years I had become very interested in the different ways in which people incorporate conditions and treatments into their lives. When the chance came to study for a PhD, I decided to look at how teenagers with diabetes live with their condition. Being the mother of a teenage girl, I was also interested in the role that parents play in helping their teenagers to become independent. Instead of sending out questionnaires to lots of people, the type of research I chose to do – qualitative research – aimed to explore the experiences of fewer people in much more depth, to find out their perspectives.

Who did I interview?
I interviewed 20 teenagers between the ages of 15-18 years, ten boys and ten girls. I also interviewed whichever parent the teenager said helped them the most with their diabetes management – in all cases this was the mother. I wanted to interview people from as many different settings as possible, so I contacted various hospitals and GPs in my area. I received a good response when I placed letters in ‘Young Balance’ and ‘Balance’ asking for anyone interested to contact me. I also talked about my research to whoever would listen and made some contacts that way.

What did I find?
Did mothers think that teenage girls and boys had different needs?
Mothers of girls were much more likely to talk about their daughters being in control and responsible than the mothers of sons, both generally and in relation to the way they managed diabetes. Daughters and sons were seen by mothers as having different needs, although this wasn’t because sons were seen as sicker than daughters. In fact, the mothers of boys were much more likely to describe their sons as very fit than the mothers of daughters. Instead, boys were seen as less able to care for themselves than girls of the same age and consequently, as more in need of the help of their mothers. I’m going to use some quotes from the people I interviewed to illustrate the various points, but I have changed the names so they can’t be identified. For example Martin’s mother told me:

"Girls always seem more organised I find, and you know, she’ll take the little blood testing kit or whatever for going away, everything is packed and organised whereas Martin will, as we’re going down the road, say "Oh, did you get my insulin?" (son aged 15 years and daughter aged 12 years, both with diabetes).

Did teenage boys and girls manage diabetes in a different way?
Yes, there did appear to be a marked difference in how the majority of teenage boys and girls I interviewed lived with diabetes.

Boys’ management of diabetes
The boys I interviewed were much more likely than the girls to describe diabetes as only having minimal effect on their lives. They were also much more likely to try and keep diabetes and its treatment hidden in public settings, as far as they could. This meant, for example, that they were much less likely than the girls interviewed to give themselves injections at school. Martin’s mother told me:

"He won’t do them (blood sugars) at school now, he absolutely refuses, he won’t even do an injection at school. He is on three injection a day and the hospital would like him to go on to four but he won’t do it in front of his friends, and he doesn’t like the fact that he is diabetic in that respect, he wants to be normal." 

Mothers often helped their sons to ‘hide’ diabetes in public, and this was one of the reasons that mothers felt boys needed more help than girls. Julian’s mother told me:

"His diabetes is managed purely from here (home) – once he goes out of the door as long as he has got some glucose tablets and his lunch in his bag, he’s no different to anyone else, which is good really".

It seemed that the teenage boys interviewed were worried that any signs of ‘illness’ could be seen as a weakness by others. Consequently, boys tended not to talk about diabetes with friends and often chose not to tell teachers about it, which meant that their mothers sometimes had to do this for them. For example, mothers told me that if they were worried about their son they might ring up the school, but this wouldn’t be discussed with their sons. A lot of the help that mothers gave their sons tended to be ‘invisible’, in that the boys didn’t seem to realise that things were being done on their behalf. In fact, many mothers felt guilty for giving the help they did, as they often felt under pressure from health professionals to encourage their sons to be independent. This is similar to research findings on adults, where women tend to be the family members who take care of health in a variety of subtle ways.

The majority of boys I interviewed had good control of their diabetes. They tended to manage diabetes in a fairly ‘rigid’ way, which meant that they felt in control of it and it was ‘no big deal’. However, there was a small minority of young men with serious problems that I only came into contact with through my letter in Balance. I was contacted by their mothers, but the young men themselves refused to be interviewed. The lives of these mothers were severely affected because of their knowledge about their sons’ non-adherence to treatment. Harry’s mother told me:

"He tells people that he’ll be dead soon anyway so it doesn’t matter what he does, and that seems to be his whole attitude really….so I’ve given up now, I might as well not say anything….he just doesn’t want to do it, he doesn’t want to know….I feel like I’m watching him kill himself, and there’s nothing I can do about it, absolutely nothing".

The results of my study indicate that teenage boys are more likely than teenage girls to move between two extremes, with the majority managing very well and a small minority managing very poorly. As mothers are likely to be involved in helping boys manage, they are usually the first person to detect problems arising. However, some mothers reported that when they alerted health professionals, they were made to feel as if they were ‘fussing’ unnecessarily.

Girls’ management of diabetes
It seemed more acceptable for girls to admit that they had diabetes, and girls were much more likely to tell teachers and their friends about it. In many ways the girls I interviewed appeared – superficially at least- to manage diabetes well. For example, they were much more likely to follow the four injections a day regime often recommended by health professionals, which meant performing insulin injections at school. However, there were other factors which affected their overall control which I think may tie in with the BDA Cohort Study findings, which identified young women with diabetes as at a greater risk of premature death than young men.

Firstly, I found that teenage girls had often felt under pressure from health professionals to take responsibility for their diabetes management and mothers had little control over the situation. Susan’s mother said:

"I have never once given her an injection from the age of eight – she has always refused any help, and I used to think that maybe sometimes this was far, far too much for her. It was (from the medical profession), "it’s your diabetes Susan, you’re in control, you’ve got to handle this, and you’ll be responsible", and I mean, she just sort of took this on board and that was the end of it".

Following publication of my letter in Balance I was contacted by a number of young women in their 20s who wanted to talk to me about their experiences as teenagers with diabetes. One of these, Louise, reflected back on when she was first diagnosed as having diabetes at the age of 11 years:

"My mum told me that the hospital stressed very much that my parents, they needed to let me have control –I was old enough to be able to do this myself….so as soon as I came out of hospital it was all down to me…. I showed I could cope in a way on the outside, but on the inside – the emotional side I couldn’t cope with it all, I didn’t really start coping until I left home".

One of the consequences of this was that the mothers of teenage girls seldom had much knowledge about how their daughters managed diabetes, in contrast to the mothers of boys, who tended to be more involved in the day to day management themselves. The level of control girls chose to achieve was very much up to them, whereas most of the boys were advised and supported by their mothers.

Of the ten girls interviewed, four had intentionally had often lengthy, and potentially harmful periods of non-adherence to treatment, of which their mothers, and others, were usually unaware. This could take the form of injecting themselves with less insulin than they needed, or even skipping injections completely. It was hard for the girls to explain why they did this, because they often made themselves feel ill. Whatever the cause, one of the resulting effects was that many of the girls expressed feelings of guilt and shame which were not expressed by boys. Reena told me:

"I do feel guilty quite a lot, because I’m thinking, "I’ve ruined everything". Like, the doctor said I would have been taller but he said it was because I didn’t control it that well I haven’t grown that much".

Two specific aspects of diabetes management which also led to girls expressing feelings of guilt were diet and exercise, and these were also the two main reasons that girls saw themselves as ‘unhealthy’. Teenage girls are generally more concerned about their body shape and weight than boys, and it seems that the emphasis on food and weight in the management of diabetes can bring additional problems for girls. Jemma told me:

"I’m on a diet now because I’ve been eating too much and I want to lose weight. I’m conscious of how much I weigh, and even though I eat, I know I shouldn’t be eating so I feel terribly guilty and go out and eat some more because I feel guilty, and it’s a vicious circle, so I’m not healthy at all".

Similarly, the value of exercise in controlling diabetes could also disadvantage teenage girls, who often participate in little exercise or sport. This in contrast to most of the boys, who usually played a lot of sport and described themselves as very fit.

I have tried here to present some of the key findings from my research, although it has been very difficult to summarise 90,000 words succinctly! I would be really interested in any thoughts you might have about the issues raised. I have also written articles for health professionals, although I know that many read the IDDT newsletter. I can’t finish without saying a very big thank you to everyone who went out of their way to help me with my research.

Growing up with Diabetes

Growing up is not easy and growing up with diabetes, or any chronic condition, makes life that much more difficult for your child. This is something that we can recognise and try to understand, but unless we have actually had the experience ourselves we don’t know how it really feels. This is perhaps something that our teenagers with diabetes will remind us of on many occasions!

Here are just some of the experiences that our children may have as they grow up:

• Feeling different from other children.
• Being treated differently from other children at home, at school and socially.
• Not feeling as good as their friends or the other children at school – having a low self-esteem.
• Being aggressively determined to be as good, if not better, than everyone else.
• Being frightened of looking foolish if they have a hypo at school or when out socially and being called names.
• Feeling pressurised to achieve and do everything, by messages of being ‘normal’ when they don’t feel normal.
• Being excluded from school activities or parties because they have diabetes.  

The feelings and experiences of our children with diabetes will vary with the age of diagnosis and there will be different effects for them and the family. It is difficult to grow up with diabetes from a young age and perhaps never know what it is like to not have diabetes and be treated normally. But it is equally difficult to be diagnosed in the teenage years – perhaps more difficult. Suddenly being faced with diabetes and all the changes this means in both lifestyle and self-image during the teenage years, are all happening at one of the most difficult stages of growing up.

One mother’s Experiences of the teenage years!
When my daughter was quite young I remember her going through a phase of believing that no one would want to marry her because she had diabetes. When I was young I believed that no one would want to marry me because I wore glasses. The answer to that was relatively easy – you can wear contact lenses! Not so easy to hide diabetes or to give reassurances to a 10 year old.

So when boyfriends started to appear on the scene at 14 or 15 years old there was always the worry of "when do I tell him about diabetes?" At this age she was very reluctant to tell anyone about it – she just wanted to be like her friends. The good text book standard advice of ‘always tell your friends that you have diabetes, just in case’….. really was totally ignored and understandably so. Teenagers are teenagers and with or without diabetes, they do not want to be different from their friends.

So what does a parent do in this situation? Perhaps this question should be " what can you do in this situation?" I think perhaps the answer has to be – nothing. Sit back, keep your fingers crossed, hope and have a bit of faith.

• Hope that in the long run common sense and self-preservation will prevail. Hope that in the short term if she does have a hypo while she is on the date that it won’t be that bad that she can’t handle it before he notices. Hope that if the worst comes to the worst and he discovers she has diabetes before she has told him, he’s a nice lad and is not put off.
• Faith is very important and sometimes very difficult when we see our teenager at home breaking all the rules, being stroppy and from tome to time being fairly objectionable! But having faith is very important to give your teenager the confidence they badly need and to show that even though you would prefer it if they told their new boy or girlfriend about their diabetes, you do understand how they feel.

This all sounds a bit like women’s magazine stuff, but my 30 plus years of experience as a parent has taught me that the one thing young people do not like is looking foolish in front of their friends. So, they make damn sure that they do not go hypo by eating plenty or by drinking normal [not diet] coke. It is called self-preservation – so have a bit of faith in that, if nothing else! 

What are the alternatives?
There is only one and that is conflict, probably a word that can never be over used when discussing teenagers, parents and diabetes. You can insist that they do the right thing, but you cannot make them. You can keep them cosseted at home longer because of their diabetes, but what are you achieving? Conflict, resentment and a breaking down of family relationships probably at a time when your teenager needs you the most [even though they would not admit it]. You are not needed in the way you were – to manage their diabetes for them, but to just be there, to boost their confidence by showing that you trust them [even if you don’t always!] and to pick up the pieces if or when necessary.

I wasn’t a wonderful parent
If I sound as if I was a wonderful parent who got it right, make no mistake, I wasn’t – you only have to ask my daughter! I learnt the hard way and we struggled through. We had conflicts, battles and tears, both hers and mine. Things improved but the change came from me, rather than her. I attended a course on listening skills and it slowly dawned on me that I wasn’t really listening to my daughter, that my own feelings, my emotions and my worries were preventing me from really listening to her, to her fears and to her concerns. She had them despite the bravado that so often appeared.

So I tried to put all my emotions out of the way and truly listen to her. My emotions were largely ones of caring for her but nevertheless, came over to her as being over protective and not letting go of the apron strings. By putting aside my feelings, many of the conflicts disappeared. It enabled us to develop a good relationship that has continued to today, albeit that there have been some ups and downs along the way!

Two adults together looking back over those years
Now that my daughter is 39 we can look back over the years, the difficulties and the conflicts. We can also look at the good times. I think that we understand each other. She understands that I did the best I could and I admit that I did not always get it right and I have apologised for this, although this probably makes me feel better and rather than her!

Why should parents always get it right, even worse, why should we think that we ARE right! If we have not grown up with diabetes then we do not know how it feels – the difficulties, the conflicts and the worries that our children have. Diabetes in the family is a new experience for all of us, we have no previous experience to guide us through it and it is a continual learning curve. We can only do our best but of one thing I am sure, we have to let go of our children. If they make mistakes in the process, then we have to hope that they are not too serious or damaging, but we have to be there for them when they need us. That is a parent’s role, made more difficult by diabetes but even more essential. 

Discovering Alcohol

Like it or not our teenagers discover alcohol. It is all part of growing up and having diabetes does not alter that, nor does it dull their desire to experiment! It is a worrying time for parents of teenagers with diabetes – we cannot just be slightly amused by the first bout of getting a bit drunk because alcohol affects blood sugars. So it is important that our teenagers learn how and what to drink and what precautions they should take.

The effects of alcohol

• It lowers the blood glucose levels and can lead to hypoglycaemia, especially during the night.
• It can lower blood glucose levels for up to 24 – 48 hours afterwards causing unexpected hypos during that time.
• Drinking can mask the warning signs of an impending hypo and lead to a severe attack.
• Friends around can assume that the person with diabetes is drunk when in fact, they are hypo.
• The carbohydrate content of some alcoholic drinks does not counteract the effects of the alcohol in lowering the blood sugar levels and should not be counted as part of the total daily carbohydrate intake.
• The effects of alcohol will vary in different people and it is necessary for each person to discover how to drink alcohol and avoid hypoglycaemia.
• Alcohol should be taken in moderation.
• Low carbohydrate beers are often very high in alcohol and so should be avoided.

Precautions
It is important to remember that alcohol affects people differently and you have to discover the precautions that are necessary for your teenager with diabetes, to avoid severe hypoglycaemia. This process of discovery has to be approached with care to avoid “learning the hard way”! Here are some pointers:

• Where possible eat a meal with your alcohol.
• If it is a drink in the pub with friends, then nibble crisps or other carbohydrates during the evening.
• Have a good meal before going out and monitor your blood glucose. It may be necessary to give a lower dose of insulin to counteract the effect of alcohol.
• Measure blood sugars before going to bed.
• Drink in moderation.
• Always have a good snack, preferably with both fast-acting and slower-acting carbohydrate, before going to bed.
• Monitor blood sugars more frequently for the next couple of days, especially if there is going to be physical exercise.

Eating Disorders

Please see the Eating Disorders page in the Weight and Diets section

Hypoglycaemia in Children

"Good diabetic control is as much about avoidance of hypoglycaemia as it is about avoidance of high blood glucose levels." A quote from Professor Stephanie Amiel.

Hypoglycaemia, the fear and avoidance of it, is probably the most frequent worry for adults and children with diabetes and their families. These concerns have increased with the present recommendations that blood glucose levels should be as near normal as possible because with this ‘tight control’ there is a threefold increase in the risk of severe hypoglycaemia. For this reason we are treating hypoglycaemia as a separate issue.

For more information, please see our section on Hypoglycaemia

Diabetes and Coeliac Disease

Please see our section on Coeliac disease for more information.

Introduction – Carers Corner

IDDT is a charity concerned with listening to the needs of people who live with diabetes, understanding those needs and doing its utmost to offer help and support. We not only try to help those who actually have diabetes, but also their family carers – the husbands, wives, partners and parents. We all live with diabetes and we recognise that when one member of the family has diabetes, it affects all the other family members to a greater or lesser extent. Family carers have views and needs, they may well be different from those of the person with diabetes, but nevertheless, they are valid and important.

Note: Parents of children with diabetes are very special sorts of carers and if you are a parent then you should visit the section ‘Parents and Family‘.

Carers Direct on NHS Choices is a comprehensive, award winning resource for carers of all kinds. To find out more, please visit the NHS Choices website:

NHS Choices: Carers Direct

Some facts about carers in general

• Carers are the people that voluntarily look after the needs of a family member. They are firmly committed to the tasks they do and these can vary from almost any job to simply watching and listening possibly most of the day and night. 
• In the UK there are an estimated 6 million family carers. If the national agencies and statutory bodies had to provide paid workers to provide this care, the cost would be in the region of £87 billion per year.
• Research has shown that most carers report that their own health suffers as a result of their caring responsibilities.
• The role of caring can be very stressful and tiring and it is important that you seek help before you get to the state where you are so exhausted you can’t even make the effort to look for the help you need.

Carers and Diabetes

We are well aware that for many people the effects of living with diabetes do not seem to put a strain on relationships but we are also aware that for others it does, either sometimes or all the time. Just as diabetes is different in everyone, so is the day to day living with it – we all have different ways of coping with it. Many people with diabetes would not consider themselves in need of a ‘carer’ and see themselves as totally independent, but that may not be how their partner sees the situation.

Quote from a carer: “Independence is fine, but who picks up the pieces when they have a bad hypo? Who wakes up in the morning with only a bad headache, knowing nothing about the 3.00am battle with food – certainly not me!”

Partners can feel:

• Excluded from their partner’s diabetes even though this exclusion may be quite unintentional on the part of the partner who may be unaware of how their partner feels. They may also feel that their knowledge of diabetes is very limited because they have not been included by their partner or included in the education sessions at the diabetes clinic.
• They may feel frightened both on a day to day basis and for the future health of their partner. They may feel alone with their worries and fears with no one to talk to about their own feelings. Talking to an ‘outsider’, even a friend, can make them feel guilty and disloyal to their partner.
• They may feel angry. Diabetes has altered everything and the life they expected may no longer seem possible which in turn, can lead to feelings of guilt and selfishness.
• They may feel that diabetes and the welfare of their partner is a huge responsibility for them and feel unable to cope with this responsibility that has suddenly been thrust upon them. 
• They cannot talk to their partner about their concerns because they do not want to upset them.

While people with diabetes live healthy and independent lives, we have to remember they get older just like everyone else. Unfortunately they may also get the complications of diabetes and so the partner can be placed in the role of caring for 24 hours a day with little or no help and support. This can be stressful and tiring!

Research
These studies are not recent but demonstrate the type of feelings that carers may have. If you are a carer and you feel any or all of these things, then don’t worry you are just like the rest of us.

The impact of severe hypoglycaemic episodes in patients with IDDM on spouses psycho social status and marital relationships.

Diab Care 1997; 20: 1543-1546

This study found that spouses of people with frequent severe hypos had more fear of hypos, more marital conflict about diabetes management and more sleep disturbance worrying about night hypos than did spouses whose partners with diabetes had not had recent severe hypoglycaemia.

Spouse’s worries concerning diabetic partner’s possible hypoglycaemia

Diab Med 1998; 619-622

In this study spouses of people who were treated in emergency for severe hypoglycaemia were interviewed and the results showed the following:

When the partner is late home, for nearly 1/5 of their spouses their first concern was the possibility of a severe hypo.

Severe hypoglycaemia was a source of concern for nearly 2/3 of the spouses.

For nearly 10% of the spouses the possibility of severe hypoglycaemia was ‘always’ a burden.

Message for Healthcare professionals

For a long time IDDT has put forward the view that carers should be more involved in their partner’s diabetes either from the beginning of the relationship where there is pre-existing diabetes, or from diagnosis. Yet so often they feel out in the cold, often by healthcare professionals.

Carers are the ones who pick up the pieces, who deal with the bad hypos and who smooth over difficult family situations, but many carers are telling us that they are not even allowed in the consulting rooms with their partners! If the partner with diabetes does not want them there, then this is a matter between the two of them, but if both partners want to be involved, then there should be no question of ‘not being allowed’ into the consulting room. Carers are not ‘interfering busybodies’ as diabetes does not just belong to the person with it, it belongs to the whole family.

Advantages of carer involvement

• The carer can have a valuable input to the visit. Is the doctor really getting a true picture of what’s going on between hospital visits, how many hypos there have really been, how many violent hypos, and perhaps most importantly, how many hypos without warning symptoms? The person without diabetes certainly cannot report on these because he/she doesn’t know they are having them! Involvement of carers in the clinic visits is a two way process!
• Any changes in the health or wellbeing of the person with diabetes are often noticed first by the carer.
• A well-informed carer can save in health costs by being able to deal with some of the problems that can occur at home and preventing hospital admissions
• If healthcare professionals meet the carers it would provide them with a greater understanding of the whole family and so would enable them to better tailor treatment regimes to individual needs.
• Providing carers with more information and support increases their self-confidence and removes some of the fears and the feelings of exclusion.
• A more contented carer may well lead to a happier, less stressful home life which has to be better for everyone. It can even improve the health of the partner with diabetes because stress affects blood glucose control. 

Quote from Helen, who has diabetes: “I have now changed my insulin from ‘human’ to pork and feel much better. My family says that I am back to my old self again. But I am angry that they had no opportunity to talk to my doctor about the changes that they had noticed so that the problems could have been sorted out sooner.” 

Carers and hypoglycaemia

Certainly from the contacts IDDT has had with carers, the greatest problems occur as a result of hypos, the fear of them, the handling of them, the responsibility for dealing with them correctly or being unable to cope with their partner’s behaviour while hypo. We have no magical answers to these problems but it is necessary to acknowledge the difficulties that some carers experience.

Embarrassment
It is well recognised that the people with diabetes hate the embarrassment that hypos can cause, but carers can also suffer from embarrassing hypos too.

Quote from a carer: “I remember going to a function at my son’s school and half way through my husband, who had virtually lost his warning symptoms of hypos, started to behave in a silly fashion, as if he was drunk. I knew he was hypo and had to rescue the situation. But much embarrassment was caused for my son, even though I went to the school and explained. Do not let anyone believe that diabetes does not affect the whole family.”

Violence and Abuse
One of the most common difficulties expressed to IDDT by carers is the violent, aggressive or abusive behaviour of their partner when they are hypo. Many of these carers are women – maybe they feel unable to be physically in control because of the greater size and strength of their partner but it could simply be that women are more ready to talk about this issue than men.

We recognise that a lot of people never have hypos of this type so it is difficult to understand what it is like to live with the fears that violent and/or abusive hypos produce for the carers who have to deal with them. It is understandable that frustration is added to the fears because no one understands how the carer feels – family, friends and the health professionals probably never see their partner in a hypo and so he/she appears OK and very ‘normal’!

Quote from a carer in just this position. She visited her GP to ask for help. His comment was “Oh, he seems a very nice gentle soul.” Undoubtedly true when he was not hypo. This lack of belief of the carer’s position is insulting and adds to the problems. 

Despair
This is another emotion that is frequently expressed to us. Not only do this group of carers have to deal with violent, aggressive or abusive hypos, but they have to live with the fear of the next one. If the hypos are usually nocturnal, then going to bed each night is accompanied by fear and poor sleep. The ongoing nature of these hypos does lead some partners to feelings of despair and the relationship suffers accordingly.

Quote from a carer: “Sometimes I just want to run away and never come back, but I don’t and I can’t.”

Do we have any advice?

• Take action! Doing nothing can make a difficult situation worse, can increase tension and affect your own health.
• If possible, talk to your partner about what happens when they are hypo and about your fears.
• Discuss their diabetic control and if it is possible to avoid hypos by raising the blood sugars a little.
• Ask if you can attend the clinic with your partner so that you can both get advice.
• If your partner is unwilling for you to attend the clinic with him/her, then make an appointment for yourself to see the diabetes specialist nurse. While he/she cannot discuss your partner’s health, start here and express your feelings.
• Try to meet other carers in similar positions – the nurse may be able to help you with this. Talking to someone that understands can be a great help.
• If you feel you can no longer handle the hypos, call the GP or 999 and ask for an ambulance with paramedics aboard. [If this keeps happening somebody may start to take notice of your problems!] 

Respite Care

This is something we all hope will not be necessary for any of us but we have to be realistic – we all get older and people with diabetes can get complications and the care they need increases. This can be tiring and stressful for the carer. 

What is respite care?
It is a break for the carer. It can either be for a few hours a week just to get out of the house and have time to yourself or it may be necessary to have a couple of week’s break from caring. Whichever is the case, the break can only be a rest if you know that your partner is being well cared for by people who have sufficient knowledge of diabetes. 

Is respite care available and how do I find it?
The first step is to actually admit to yourself that you need a break. This is not always easy because it can feel as if you are not coping. You can feel guilty because you are not doing all the caring. But it is important to remember that a break, even for a few hours a week, may well enable you to be a greater help to your partner because you feel better.

Respite care is not easy to obtain because if there is a shortage of funds within Social Services then it is often respite care that is cut back. It is granted on the needs of the person being cared for, not the carer. Equally, suitable residential care is not easy to find because of the needs of people with diabetes – as we all know it is not just a matter of providing a ‘diabetic diet’!

Quote from a carer: “I look after my 90 year old uncle who has diabetes and from time to time I need a break to recharge my batteries. He can be difficult, especially when hypo. My last experience of residential care has made it difficult for me to leave him where I feel he is properly cared for. One morning he was not given his morning injection because he was being violent. The carers in the home would not go near him and did not call a doctor. Needless to say,  he was having what for him, was a typical hypo and they didn’t give him his breakfast either!”

To find out about the availability of respite care in your area contact

• Social Services
• Your GP or district nurse
• Voluntary organisations such as the Carers Association, Age Concern, Cross Roads.

Remember – respite care will only be a break for you if you can leave the person you care for with people you are happy with, so do not accept something that is not satisfactory. Check that they know about diabetic care. If you spend your free time worrying about the care your partner is getting, then your break will be wasted.