Type 1 diabetes is one of the most common chronic childhood illnesses, affecting 18 to 20 per 100 000 children a year in the United Kingdom. The term type 1A diabetes for immune mediated diabetes with its destruction of the islet β cells of the pancreas.2 Non-immune mediated diabetes with severe insulin deficiency is termed type 1B. At present, the development of type 1 diabetes is a life sentence to a difficult therapeutic regimen that is only partially effective in preventing acute and chronic complications.

However, because hormone replacement with insulin therapy is sub-optimal,

acute and long-term complications are endemic despite the implementation of lifestyle and other disease management measures.

Type 1 diabetes is fatal unless treated with insulin. Injection is the most common method of administering insulin; insulin pumps and inhaled insulin have been available at various times. Pancreas and islet transplants have been used to treat type 1 diabetes; however, islet transplants are currently still at the experimental trial stage.[4]

Background

Type-1 Diabetes has been conventionally managed by twice daily insulin. While this is convenient from administration point of view, the level of insulin achieved was not physiological, owing to the characteristics of the types of insulin used, and sometimes pose difficulty in food habit and exercise pattern especially in a young child. Rapid-acting analogue insulin, on the other hand, is more physiological, and can be better suited for the patient’s needs as well as food habits.

Current practice:

Children and young people with suspected type 1 diabetes should be offered immediate (same day) referral to a multidisciplinary paediatric diabetes care team that has the competencies needed to confirm diagnosis and to provide immediate care.

At the time of diagnosis, children and young people with type 1 diabetes should be offered home-based or inpatient management according to clinical need, family circumstances and wishes, and residential proximity to inpatient services. Home-based care with support from the local paediatric diabetes care team (including 24-hour telephone access to advice) is safe and as effective as

inpatient initial management1

Insulin regimens

While the insulin regimen should be individualised for each patient, three basic types of insulin regimen can be considered2.

One, two or three insulin injections per day: these are usually injections of short-acting insulin or rapid-acting insulin analogue mixed with intermediate-acting insulin.

Multiple daily injection regimen: the person has injections of short-acting insulin or rapid-acting insulin analogue before meals, together with one or more separate daily injections of intermediate-acting insulin or long-acting insulin analogue.

Continuous subcutaneous insulin infusion (insulin pump therapy): a programmable pump and insulin storage reservoir that gives a regular or continuous amount of insulin (usually in the form of a rapid-acting insulin analogue or short-acting insulin) by a

subcutaneous needle or cannula3.

Insulin preparations

Different types of insulin are available for use in the insulin regimens for type 1 diabetes. They work for different lengths of time when injected subcutaneously. The appropriate insulin with its particular absorption profile should be matched to the person’s needs in an attempt to obtain normal to near-normal blood glucose control.

The main categories of insulin are:

• rapid-acting insulin analogues: these aim to work like the insulin normally produced to cope with a meal; they have an onset of action of approximately 15 minutes and a duration of action of 2-5 hours.

• short-acting insulins: these work more slowly than rapid-acting insulin analogues; they have an onset of action of 30-60 minutes and a duration of action of up to 8 hours

• intermediate-acting insulins: these have an onset of action of approximately 1-2 hours, maximal effects between 4 and 12 hours and a duration of action of 16-35 hours

• long-acting insulin analogues: these can last for a longer period than intermediate-acting insulins; they are normally used once a day and achieve a steady-state level after 2-4 days to produce a constant level of insulin3.

Methods of delivering insulin:

Children and young people with type 1 diabetes should be offered a choice of insulin delivery systems that takes account of their insulin requirements and personal preferences.

Monitoring glycaemic control:

Children and young people with type 1 diabetes and their families should be informed that the target for long-term glycaemic control is an HbA1c level of less than 7.5% without frequent disabling hypoglycaemia and that their care package should be designed to attempt to achieve this.

Children and young people with type 1 diabetes and their families should be encouraged to perform frequent blood glucose monitoring as part of a continuing package of care

that includes dietary management, continued education and regular contact with their diabetes care teams.

In our own trust, we have 58 children diagnosed with type 1 diabetes. 46 of them are on multi dose regime and 12 on twice a day insulin. An retrospective audit was conducted looking at the HbA1C control over a period of 12 months and associated complications. The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6. Complications with hyper cholestrenemia and microalbuminuria was noted in 3 children on twice daily insulin as compare with 2 on multi dose regime. Diabetic retinopathy changes in 2 children and necrobiosis lipodica in one child on twice daily insulin.

We are now encouraging all newly diagnosed diabetic children to start on multi dose regeime from the begining. Have developed proforma for the diabetic clinic to emphasise the importance of regular investigations and scrrening procedures in the prevention of compications. We would try to reaudit in a years time to complete the audit cycle and to improve the HbA1C levels in our children.

Review of literature

Target glucose levels

The fact that chronic hyperglycemia is associated with an increased risk of microvascular complications of type 1 diabetes was demonstrated in the Diabetes Control and Complications Trial (DCCT)4.

In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, micro-albuminuria, proteinuria, and neuropathy, as assessed over the period of 7 years.

The subsequent Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993.5  Not only do benefits include continued reductions in the rates of microvascular complications, additionally significant differences in cardiovascular events and overall mortality emerged. These benefits occurred in spite of the fact that subjects in the intensively treated group and those in the standard treatment group maintained similar A1C levels (approximately 8%) starting one year after the formal trial ended. Therefore, it is postulated that a “metabolic memory” exists, and that better early glycemic control sets the stage for outcomes many years in the future.

Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. For many, the A1C target should be <7%, with premeal blood glucose level of 80-130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, CVD, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an A1c of <8% and preprandial glucose levels of 100-150 mg/dL.

Self-monitoring of glucose levels

Optimal diabetic control requires frequent self-monitoring of blood glucose levels. Frequent monitoring allows for rational adjustments in insulin doses. Most patients with type 1 diabetes require 2 or more injections of insulin daily with doses adjusted based on self-monitoring of blood glucose levels. In general, individuals with type 1 diabetes should test a minimum of 4 times per day-before each meal and at bedtime.

Subcutaneous continuous glucose sensors are now available, making the continuous glucose monitor (CGM) possible. These devices measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling.

CGM transmits to a receiver, which is either a pager like device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia.

Several drawbacks exist:

first, there is a lag between glucose levels in the interstitial space and capillary blood, so the levels recorded by the CGM may differ from a finger stick glucose.

For that reason, the trends tend to be more helpful. Second, patients may over treat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough-a phenomenon known as stacking) as well as over treat lows (the glucose levels rise slowly with ingestion of carbohydrate).

Patients using CGM and/or insulin pumps can often provide very detailed information as to their insulin regimens as well as recent alterations in blood glucose levels.

Types of insulin

By definition, patients with type 1 diabetes require lifelong treatment with insulin to promote glucose utilization. Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Although pork, beef, and beef-pork insulins were previously used, recombinant human insulin is used almost exclusively in the United States. Commercially prepared mixtures of insulin are also available.

Insulin is sensitive to heat and exposure to oxygen. Once a bottle of insulin is open, it should be used for no more than 28 days and then discarded, even if insulin remains in the bottle. Use of old insulin can result in a lack of clinical effectiveness. Insulin in a pump reservoir for longer than 3 days may lose its clinical effectiveness (although insulin aspart has now been approved for use for up to 6 days in a pump). Sometimes, insulin distributed from the pharmacy has been exposed to heat or other environmental factors and may be less active. If a patient is experiencing unexplained high blood sugar levels, new insulin vials should be opened and used.

Common insulin regimens

Although emergency physicians rarely start new therapy for patients with diabetes, being acquainted with the various forms of insulin and the common regimens is useful.

When treating patients with type 1 diabetes, the goal is to provide insulin in a manner that is as physiologic as possible. Insulin replacement is given as a basal insulin (either long-acting [glargine or detemir] or intermediate-acting [NPH]) and preprandial (premeal) insulin (either rapid-acting [lispro, aspart, or glulisine] or short-acting [regular]). For patients on intensive insulin regimens (multiple daily injections or insulin pumps), the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg, 2 additional units of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and attention to the control of their diabetes.

Common insulin regimens include the following: (1) split or mixed, such as NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper; (2) split or mixed variant: NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, NPH before bedtime (designed to reduce fasting hypoglycemia by giving the NPH latter in the evening); (3) multiple daily injections (MDI), a long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients), and a rapid-acting insulin before meals or snacks (dose adjusted based on the carbohydrate intake and the blood glucose level); and (4) continuous subcutaneous insulin infusion (CSII), rapid-acting insulin infused continuously 24 hours a day through an insulin pump at one or more basal rates, with additional boluses given before each meal, and correction doses administered if blood glucose levels exceed target levels.

Rapid-acting injectable insulins

With the most rapid onset of action, these insulins are used whenever a rapid onset and short duration is appropriate (eg, before meals or when the blood glucose level exceeds target and a correction dose is needed). Rapid-acting insulins are associated with less hypoglycemia than regular insulin.

Insulin aspart (NovoLog)

Onset of action is 5-15 min, peak effect is in 30-90 min, and usual duration of action is 4 h. Has FDA approval for use in insulin pumps

Doses vary; adjust dose according to patient’s metabolic needs; adjust to achieve premeal and bedtime blood glucose levels of 80-140 mg/dL (children <5 y, 100-200 mg/dL)

Insulin glulisine (Apidra)

Onset of action is 5-15 min, peak effect is in 30-90 min, and usual duration of action is 4 h. Has FDA approval for use in insulin pumps.

Individualize dose; intended for intermittent SC injection with meals or use by external infusion pump

Insulin lispro (Humalog)

Onset of action is 5-15 minutes, and usual duration of action is 4h.

Doses vary; adjust dose according to patient’s metabolic needs; titrate to maintain a premeal and bedtime glucose of 80-140 mg/dL

Short-acting injectable insulins

Currently, short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 diabetes. They are used when a slightly slower onset of action or greater duration of action is desired.

Intermediate-acting injectable insulins

With their relatively slow onset of action and relatively long duration of action, these insulins usually are combined with faster-acting insulins to maximize benefits of a single injection.

Insulin NPH (Humulin N, Novolin N)

Onset of action 3-4 h, peak effect in 8-14 h; usual duration of action 16-24 h. Appears cloudy. Must be gently mixed and checked for clumping; if clumping occurs, the insulin should be discarded.

Long-acting injectable insulins

These insulins offer a long duration of action and are effective basal insulins. In patients with type 1 diabetes, they must be used in conjunction with a rapid-acting or short-acting insulin given before meals.

The US Food and Drug Administration (FDA) has issued an early communication to health care practitioners regarding 4 recently published observational studies that describe the possible association of insulin glargine (Lantus) with an increased risk of cancer.28 Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than what is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the risk that actually exists and therefore warrants further evaluation.

The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

Insulin detemir (Levemir)

The package insert states the duration of action ranges from 5.7 h (low dose) to 23.2 h (high dose), but, in clinical practice, the duration of action is similar to insulin glargine.29

Insulin glargine (Lantus)

Onset of action 4-6 h, generally no discernible peak effect, but an increased effect may occur at 10-20 h; usual duration of action 24-28 h.

Genes

Alleles or genetic variants associated with type 1 diabetes provide either susceptibility to or protection from the disease. An interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for disease and provides potential targets for both prediction and prevention of disease6 . The concordance for type 1 diabetes is approximately 50% for monozygotic twins, and the risk to a first degree relative is approximately 5%7 . The major genetic determinant of susceptibility to diabetes lies within the major histocompatibility complex (termed IDDM 1). More than 90% of patients who develop type 1 diabetes have either DR3, DQ2 or DR4, DQ8 haplotypes, whereas fewer than 40% of normal controls have these haplotypes.6 DR3-DR4 heterozygosity is highest in children who develop diabetes before age 5 (50%) and lowest in adults presenting with type 1 diabetes (20-30%), compared with a US population prevalence of 2.4%. Only one non-HLA gene has been identified with certainty-IDDM 2 on chromosome 11p5.5-and this contributes about 10% of the familial aggregation of type 1 diabetes. This locus is a polymorphic region that maps to a variable number of tandem nucleotide repeats (VNTR) 5′ of the insulin gene. Studies in man indicate that different sizes of this VNTR 5′ of the insulin gene are associated with risk for type 1 diabetes. The long form of the VNTR (> 100 repeats, class III) is associated with protection from diabetes. This influence of the insulin gene locus may relate to variation in expression of insulin within the thymus (greater thymic insulin message with protective VNTR). 1 shows a summary of the susceptibility loci for type 1 diabetes.

Epidemiology

Although most attention has focused on the increase in type 2 diabetes, a parallel rise in type 1 diabetes has occurred8 .

Type 1 diabetes has always been known as a disease of childhood, but more recent epidemiological studies have indicated that the incidence is comparable in adults9. The enormous international variation in incidence is now recognised. A child in Finland is almost 40 times more likely to develop type 1 diabetes than a child in Japan and almost 100 times more likely to get the disease than a child in the Zunyi region of China10 . The EURODIAB collaborative study, a registry involving 44 countries in Europe, indicates an annual rate of increase in incidence of type 1 diabetes of 3-4%, with a larger increase in some central and eastern European countries 11. The largest rate of increase is seen in children aged 0-4 years. Type 1 diabetes is associated with other autoimmune conditions; the most common association is with thyroid disease12. The Belgian Diabetes Registry indicated that the prevalence of thyroid peroxidase autoantibodies is 22% in patients with type 1 diabetes. Approximately 1 in 10 patients with type 1 diabetes express transglutaminase IgA autoantibodies, and more than half of these patients have coeliac disease on intestinal biopsy. Approximately 1 in 50 people with type 1 diabetes have 21-hydroxylase autoantibodies, and approximately 25% of these patients progress to Addison’s disease

Prevention and new treatments

To date no treatment has been shown to prevent type 1 diabetes in humans. More than 100 different treatments prevent type 1 diabetes in the NOD mouse model, and this may indicate that disease prevention in this model is “too” easy.28 Two major trials have been conducted to try to prevent type 1 diabetes. In the United States, the diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high and moderate risk) would prevent or delay diabetes. These treatments did not overall slow the progression to diabetes. The European nicotinamide diabetes intervention trial (ENDIT) also found no difference in protection from diabetes when participants were assigned to either oral nicotinamide or placebo treatment (P Bingley, European Association of the Study of Diabetes, Budapest, September 2002). Many challenges remain in this field; in particular assays for pathogenic human T cells are not yet available. Such assays have the potential to provide surrogate markers to guide evaluation of immunotherapy; in the absence of such markers, the primary outcome of trials today is the preservation of insulin secretion (for example, measurement of C peptide secretion). TrialNet and the Immune Tolerance Network created by the US National Institutes of Health will be focusing not only on the prevention of diabetes but also on preventing further loss of islet βcells in patients with new onset type 1 diabetes.

Insulin remains the main treatment in type 1 diabetes. The diabetes control and complications trial (DCCT) showed the importance of strict metabolic control in delaying and preventing complications.29 The risk of hypoglycaemia is still the major limiting factor in achieving euglycaemia with insulin treatment. The introduction of rapidly absorbed insulin analogues has reduced variability of insulin absorption and allows insulin administration in young children after meals.30 Another recent introduction to the insulin market has been insulin glargine, which functions as a very long acting insulin (peakless basal insulin).31Combinations of engineered very long acting insulins and rapid acting insulins can provide control and convenience similar to that obtained with insulin pumps.

The use of metformin treatment alongside insulin has increased in patients with type 1 diabetes. Recent studies have suggested that metformin might benefit type 1 diabetes patients who are overweight, are receiving large doses of insulin, or have an HbA1c > 8%.32 The coexistence of insulin resistance in patients with type 1 diabetes is a new area of interest. Islet transplantation with modified immunosuppressive regimens can cure type 1 diabetes. Islet transplantation is a consideration for the limited but important subset of patients with recurrent severe hypoglycaemic episodes not responsive to medical management.33 Inability to control autoimmunity and alloimmunity and a lack of donor organs limit the application of islet transplantation.

Summary & conclusion:

DCCT trial was a landmark trial based on 1441 volunteers over a period of 10 years( 1983-1993). The study showed the importance of keeping glucose levels as close to normal ( physiological levels). This study was conducted over 29 medical centres based in USA and Canada.

Multicentre studies over the last two decades have shown that MDI are better than twice a day insulin regimes. The main issues with twice daily insulin injections were having high HbA1C levels, which in turn led to long term complications:

There was early development of hyper cholestrenemia, diabetic retinopathy, micro vascular renal disorder and peripheral neuropathy.

The second main issue with twice a day insulin regime was children’s lifestyle had to be quite rigid since they had to wake up every morning to have their insulin, have their breakfast, then have a mid day snack, later lunch, post lunch snack, tea with their evening insulin and later another snack before going to bed. This also led to obesity, over weight and other complications associated with it.

Given the need for sticking to a rigid diet, which often was not possible, lead to fluctuating intake, leading to a fluctuating glucose levels.

With multiple daily regime, the child is noted to have better quality of flexible lifestyle, the insulin and glucose control is more physiological. Their diet can be more variable, no need to snack in-between meals, less long term complications and better control of HbA1C noted.

The only drawback of multidose regime is the need for constant monitoring of glucose level and the need for giving multiple injections per day.

With twice daily regime the child has to run behind the insulin, whereas in multiple daily dosing the insulin runs behind the child.

Majority of the European countries have since then, joined the bandwagon of multi dose regime, and have demonstrated fall in HbA1C and hence reduced number of complications. This has also lead to increased quality of life. Most of the European countries have been able to achieve the target HbA1C of around 7.5.

UK has not been able to switch over to multi dose regime from twice a day. There are multiple causes for this, and lack of resources being the main cause. The uptake of multidose regime has been patchy throughout the UK.

Parents and education of parents regarding the need of multidose regime is a key factor in achieving successful implementation of multi-dose regime.

In our own trust, we have a shifted from the traditional twice a day approach to multidose regime. Over the last 18 months, overwhelming majority of our patients have been shifted to this regime( 46 out of 58). In the remainder, we have not been successful, owing wide range of causes, one of the main being patient choice.

The average HbA1C of children on multi dose regime was 8.2 while that on twice a day was 9.6.

3 of those 12 children have shown at least one complication- including; hyper cholestrenemia and microalbuminuria in 3, Diabetic retinopathy changes in 2 and necrobiosis lipodica in one child.

Diabetes