July 2002
Vol.9 No. 4
Editors: Dr. Karen L Kwong
Drs. Elaine YW Kwan, Sam SP Lau, KY Wong

Recent Advances in the Treatment of Children
with Type I Diabetes

Dr. Elaine YW Kwan
Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital


Editor's Notes

In this article, Dr Kwan has shared with us advances in the management of type I diabetes. Advantages and disadvantages of 'peakless' long-acting insulin, continuous subcutaneous insulin and inhaled insulin are comprehensively reviewed.

Summary:

Introduction

The beneficial effects of good glycaemic control on chronic complications of diabetes have been firmly established in type I diabetes by the results of the Diabetes Control and Complications Trial (DCCT)1 and the Stockholm Diabetes Intervention Study (SDIS).2 However, effective glycaemic control requires multiple daily injections (MDI) of insulin. It is highly inconvenient and poorly accepted by young children. In addition, there is increased risk of hypoglycaemia and weight gain, both are undesirable in children.

Since the publication of the DCCT results, many attempts have been made to improve glycaemic control in patients with type 1 diabetes. These include the production of new insulin analogues with insulin profiles that better mimic the natural insulin secretion. Ultra-short acting insulin lispro was introduced in 1996 and is available in Hong Kong. Another ultra-short acting insulin analog, insulin aspart, will soon be available. The free insulin profiles of aspart and lispro resemble each other, but insulin lispro shows a more rapid uptake, reaches the maximum peak concentration earlier, and shows a more rapid decline than insulin aspart.3 A 'peakless' long-acting insulin, glargine, has also been approved by the FDA in 2000. Continuous subcutaneous insulin infusion has also gained popularity dramatically over the past 5 years. There is also recent breakthrough in the development of alternative route of insulin delivery, especially through inhalation.

Insulin Glargine

All intermediate- and long-acting insulins currently available are far from ideal. They all needed to be re-suspended before injection, giving rise to large within and between subject variability in subcutaneous absorption. In addition, they all have peak action profiles and short duration of action, and therefore cannot provide a constant 'basal insulin profile' as required for basal insulin secretion.

Insulin Glargine (21A-Gly-30Ba-L-Arg-30Bd-L-Arg-human insulin) is a long-acting insulin analogue approved for use in patients with type 1 and type 2 diabetes mellitus by US Food and Drug Administration in April 2000, and by European Agency for the Evaluation of Medicinal Products in June 2000. It is produced by recombinant DNA technology from 2 modifications of human insulin. Two positive charges was added (2 arginine molecules to the C terminus of the B-chain), which shifts the isoelectric point from a pH of 5.4 to 6.7, making the molecule more soluble at a slightly acidic pH and less soluble at the physiological pH of subcutaneous tissue. A second modification is the replacement of A21 asparagine by glycine, which prevents deamidation and dimerisation, resulting in improved stability. When injected into subcutaneous tissue, it forms a microprecipitate in the physiological, neutral pH of the subcutaneous space. Because of its stability, absorption is delayed and lasts a long time, providing a fairly constant basal insulin supply and an essentially 'peak-less' profile of action.4 The onset of action is around 2 to 4 hours and the duration of action lasts for more than 24 hours.4 The insulin profile after subcutaneous injection, as compared to that of protophane and ultralente, is shown in Figure 1. Insulin glargine is a clear solution formulated at an acidic pH of 4.0 (other long acting insulins are turbid). It cannot be mixed with insulin formulated at a neutral pH.

Clinical Efficacy

Preliminary data from both short-term (4 weeks)5 and long-term (16-28 weeks)6,7 early registration type studies in adults showed that glargine resulted in a reduction in fasting plasma glucose levels and a reduction in hypoglycaemia, especially nocturnal and severe episodes. These clinical effects were also demonstrated in a comparative trial between insulin glargine and NPH in children and adolescents with type 1 diabetes treated for 6 months.8 Some studies also showed a decrease in variability of plasma glucose and a reduction in the dose of insulin required. However, there in no change in overall glycaemic control as shown by glycosylated haemoglobin. Further optimization of the insulin regimen may be required to translate the theoretical benefits of this new therapy into clinically significant benefits.

Insulin glargine was well tolerated without evidence of antibody formation and with minimal injection site reactions.6 However, injection site pain was reported more commonly in the glargine group. This effect may be related to the more acidic pH of insulin glargine.

Possible Mitogenic and Angiogenic Effects

Insulin glargine has up to six-fold greater affinity for IGF-I receptors than human insulin.9 This increased affinity for IGF-I receptor may be associated with mitogenic and antiogenic effects.9 However, this theoretical concern is not supported by animal study. Rats and mice treated with glargine for up to 2 years did not have mammary tumours. The mitogenic activities of glargine and human insulin are also similar in a number of in vitro cell lines.10 Long-term data is required to answer this important question.

The other concern is the demonstration of a three-grade progression of retinopathy in some patients with type 2 diabetes treated with glargine for 1 year or less, because IGF-I signaling has been implicated in the regulation of retinal neovascularization.11 However, an independent panel concluded after reviewing the data that the progression was not related to therapy with insulin glargine.

Continuous Subcutaneous Insulin Infusion (CSII)

Continuous subcutaneous insulin infusion (CSII), often called insulin pump therapy, was introduced in the 1970s as an attempt to mimic the 'artificial pancreas'. However, it only gains popularity in recent years after the publication of the DCCT results and with improvement in mechanic aspects of the pump.

Advantages of CSII

Continuous subcutaneous insulin infusion has sound theoretical advantages. It is the most physiologic method of delivering insulin subcutaneously to achieve near-normal glycaemic control, with bolus doses for meals and a constant basal infusion at night. In particular, it avoids the peak and waning effect of intermediate insulin that causes large blood glucose nadirs in the middle of the night and hyperglycaemia in the early morning. Indeed, severe hypoglycaemia is a frequent event, with 50% of the total daily events occurring nocturnally.12

Multiple studies have shown that CSII provides better glycaemic control than conventional therapy and comparable or slightly better control than multiple daily injections (MDI).13,14 Patients on CSII have lower glycosylated haemoglobin, decreased glycaemic variability and lower fasting glucose values.

In a meta-analysis of 12 randomized controlled trials comparing glycaemic control of CSII with intensive insulin injections in adults with type 1 diabetes, the use of CSII was associated with a lower mean blood glucose concentration (1 mmol/L), less variable blood glucose concentrations, a lower percentage of glycated haemoglobin (0.51%) and an average reduction of 14% in insulin dose (7.6 units/day).15 However, most included studies compared glycaemic control of CSII with multiple injections of regular insulin plus isophane. Ultra-short insulin (before meals with twice-daily isophane insulin) was used in only one study.16 In this study, HbA1c was lowered by 0.5%, with lower blood sugar levels, decreased blood sugar variability and lower insulin dose, but no difference in the frequency of hypoglycaemia. It is still unclear how glycaemic control on pump therapy compares with modern optimised insulin injection regimes, using ultra-short insulin (e.g. Lispro and Aspart) and peak-less insulin (e.g. Glargine). There is also inadequate data to show whether the use of insulin lispro was equally efficient on HbA1c in an intensified MDI regimen and in CSII.

Data comparing CSII with MDI in children are lacking. There is only one recent study in 56 children and adolescents, showing a reduction in glycated haemoglobin and hypoglycaemic episodes in those using CSII.17 In another recent study of continuous insulin infusion only at nighttime in children 7 to 10 years, nighttime infusion resulted in a significant decrease in mean nocturnal blood sugar values, an increase in proportion of blood sugar values within the target range, a decrease in fructosamine values and a decrease in mean total insulin dosage; without a change in the body mass index.18 This approach of nighttime continuous infusion is particularly attractive for children. Because of developmental and cognitive issues, young children <10 years of age may not be able to wear the insulin pump safely when they are in school and not under direct parental supervision. Nighttime continuous infusion can avoid this problem but benefits from reduced nocturnal blood sugar variability and hypoglycaemia due to pump use. However, similar effect might be achieved with the use of the newly available 'peak-less' insulin glargine. There is currently no data comparing the clinical efficacy of nighttime continuous insulin infusion with insulin glargine.

Earlier studies suggested that the risk of diabetic ketoacidosis and hypoglycaemia with CSII was slightly greater than that of conventional diabetes management and MDI.19 However, more recent studies demonstrated that CSII is associated with significantly lower or comparable rates of complications such as hypoglycaemia, ketoacidosis, and weight gain than are MDI.20-22 In addition, studies in adult showed that nighttime CSII can improve counter-regulatory responses and warning symptoms in patients with hypoglycaemic unawareness.23 Indeed, severe hypoglycaemia has now become an acceptable indication for initiation of CSII therapy.

The other significant advantage of CSII is the improvement in lifestyle and the increased flexibility in moment-to-moment living.24

Disadvantages of CSII

In the DCCT, adolescent and adult subjects on CSII had slightly higher frequency of diabetic ketoacidosis due to catheter blockage or mechanical failure and a lack of subcutaneous depot of long-acting insulin. With the use of ultra-short insulin analogue, metabolic deterioration occurs 1.5 to 2 hours earlier than regular insulin with catheter blockage. Catheter site infection and contact dermatitis are the most common complications associated with CSII. To minimize the risk of ketoacidosis and hypoglycaemia, patients must check their blood glucose levels at least 4 times a day. The catheter site and the catheter set should also be changed every 2-3 days to minimize the risk of catheter blockage or skin infections.

The insulin pump costs HK$26,000 and the supplies needed cost around HK$1000 per month. In addition to cost, the most important barriers for the successful use of CSII are good family support, good diabetic knowledge and a commitment to self-care and frequent blood glucose monitoring. Patients must be evaluated carefully before consideration for CSII. Possible positive and negative characteristics for the use of CSII are listed in Table 1.25

Table 1. Characteristics to consider when evaluating a potential CSII user
Positive characteristics Negative characteristics
Motivated to perform self-monitoring of blood glucose levels at least 4 times a day Not demonstrated commitment to do frequent blood glucose monitoring
Good understanding of diabetic self-care (including calculations of diet portion, understanding of insulin action, recognizing and treating hypoglycaemia, DKA, infection) Poor understanding of diabetes
Self-motivated to pursue CSII  
Appropriate awareness of the pros and cons of CSII Misconceptions or myths concerning CSII
Financially affordable  
24 hour support from health care team  

Inhaled Insulin

Inhaled intrapulmonary delivery of insulin offers a potential alternative to preprandial insulin injections. The alveolar region offers a large resorptive surface, a long residence time and an extremely thin and vesiculated cell barrier to promote absorption of drugs.

The absorption characteristics of inhaled insulin are similar to a subcutaneous injection of a mixture of ultra-short and short acting insulins.26 It has a rapid-onset and early peak in action but there is also a 'tail' or delayed absorption component giving it a longer duration of action compared with short acting insulin. The average time to peak insulin levels was 24 min with inhalation powder and 50 min for liquid formulation, compared to subcutaneous injection, which averaged between 80-110 minutes. Intra-individual variability of absorption is no greater than that of injected insulin.27 The mouth-to-blood efficiencies range from 15% to 25%. The current generation of delivery devices, which includes conventional jet-type neublizers with or without spacer devices or holding chambers, limits efficient delivery of aerosolized insulin. Dry powder formulations or new formulations of solubilized insulin that can be generated as particles of optimal size for absorption into the alveoli are developed. A variety of devices and systems are in development to improve the efficiency of drug delivery.

Clinical Efficacy

Clinical studies in human volunteers showed that absorption rate and decrease in glucose levels are similar to those achieved with subcutaneous insulin injection during the fasting state.28 Studies in type 2 diabetic patients also showed that inhaled insulin effectively controls postprandial glucose levels.29 It is well-tolerated with no evidence of irritation, hypoglycaemia, or changes in pulmonary function when administered over short periods. In a recent study involving 73 type 1 diabetic adults, preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection for 12 weeks was compared with control treatment of 2 to 3 insulin injections per day.30 In this study, dry powder insulin was dispersed by air-assisted mechanism into aerosol cloud and captured in a holding chamber for inhalation. Changes in HbA1c, fasting and postprandial glucose concentrations, the occurrence and severity of hypoglycaemia were similar in both groups. Inhaled insulin was well tolerated with no effect on pulmonary function (spirometry, lung volumes, diffusion capacity, and oxygen saturation).

Concerns

Although this alternative method of insulin delivery brings fresh hope for diabetic patients, there are still areas for concern. There is concern that inhaled insulin might have a positive impact on lung disease. Various pulmonary abnormalities including reduction in lung volume, pulmonary elastic recoil, and gas transfer have been demonstrated in diabetic patients.31 Insulin has been shown to exert pro-inflammatory effects. Airway inflammation is lessened in the absence of insulin in human and animals. Diabetes also lessened antigen-induced vagally mediated airway hyper-reactivity and eosinophil accumulation.32 These effects are reversed by insulin. Therefore inhalation of insulin might unmask airway inflammation and asthma in some treated individuals. Further studies are therefore needed to assess the possible development of immunogenicity and toxicity from prolonged exposure to the lung in human.

In addition to the long-term pulmonary effect, there is also concern about its direct vascular effects. Insulin is a vasodilator through stimulation of nitric-oxide release from vascular endothelium.33,34 Supra-physiological dose of insulin can potentially lead to pulmonary hypotension and pulmonary oedema,35 especially in patients with cardiac dysfunction from previous myocardial infraction or diabetic cardiomyopathy.

Last but not least, one need to note that inhaled insulin does not totally abolish the need for insulin injections. Long-acting insulins still need to be given by injection in patients with type 1 diabetes.

References

  1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.
  2. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304-9.
  3. Hedman CA, Lindstrom T, Arnqvist HJ. Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes. Diabetes Care 2001;24:1120-1.
  4. Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of long-acting insulin analog insulin glargine (HOE 901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23:644-9.
  5. Rosenstock J, Park G, Zimmerman J. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group. Diabetes Care 2000;23: 1137-42.
  6. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 2000;23:639-43.
  7. Raskin P, Klaff L, Bergenstal R, et al. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care 2000;23:1666-71.
  8. Schober E, Schoenle E, Van Dyk J, et al. Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes. Diabetes Care 2001;24:2005-6.
  9. Kurtzhals P, Schaffer L, Sorensen A, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005.
  10. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356:443-5.
  11. Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999;5:1390-5.
  12. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997; 46:271-86.
  13. Helve E, Koivisto VA, Lehtonen A, et al. A crossover comparison of continuous insulin infusion and conventional injection treatment of type 1 diabetes. Acta Med Scand 1987;221:385-93.
  14. Düsseldorf Study Group. Comparison of continuous subcutaneous insulin infusion and intensified conventional therapy in the treatment of type 1 diabetes: a two-year randomised study. Diabetes Nutr Metab 1990;3:203-13.
  15. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ 2002;324:705.
  16. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, et al. Comparison of continuous subcontaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care 2000;23:1232-5.
  17. Maniatis AK, Klingensmith GJ, Slover RH, et al. Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics 2001;107:351-6.
  18. Kaufman FR, Halvorson M, Kim C, et al. Use of insulin pump therapy at nighttime only for children 7-10 years of age with type 1 diabetes. Diabetes Care 2000;23:579-82.
  19. Implementation of treatment protocols in the Diabetes Control and Complications Trial. Diabetes Care 1995;18:361-76.
  20. Steindel BS, Roe TR, Costin G, et al. Continuous subcutaneous insulin infusion (CSII) in children and adolescents with chronic poorly controlled type 1 diabetes mellitus. Diabetes Res Clin Pract 1995;27: 199-204.
  21. Bode BW, Steed RD, Davidson PC. Reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes Care 1996;19:324-7.
  22. Boland EA, Grey M, Oesterle A, et al. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 1999;22:1779-84.
  23. Kanc K, Janssen MM, Keulen ET, et al. Substitution of night-time continuous subcutaneous insulin infusion therapy for bedtime NPH insulin in a multiple injection regimen improves counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM. Diabetologia 1998;41:322-9.
  24. Marcus AO. Patient selection for insulin pump therapy. Pract Diabetol 1992:12-18.
  25. Lenhard MJ, Reeves GD. Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. Arch Intern Med 2001;161:2293-300.
  26. Heinemann L, Traut T, Heise T. Time-action profile of inhaled insulin. Diabet Med 1997;14:63-72.
  27. Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Deliv Rev 1999;36:235-47.
  28. Laube BL. Treating diabetes with aerosolized insulin. Chest 2001;120(3 Suppl):99S-106S.
  29. Laube BL, Benedict GW, Dobs AS. The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes. Chest 1998;114:1734-9.
  30. Skyler JS, Cefalu WT, Kourides IA, et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet 2001; 357:331-5.
  31. Ramirez LC, Dal Nogare A, Hsia C, et al. Relationship between diabetes control and pulmonary function in insulin-dependent diabetes mellitus. Am J Med 1991; 91:371-6.
  32. Belmonte KE, Fryer AD, Costello RW. Role of insulin in antigen-induced airway eosinophilia and neuronal M2 muscarinic receptor dysfunction. J Appl Physiol 1998;85:1708-18.
  33. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994;94:1172-9.
  34. Scherrer U, Randin D, Vollenweider P, et al. Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 1994;94:2511-5.
  35. Vallance P, Chan NN. Endothelial function and nitric oxide: clinical relevance. Heart 2001;85:342-50.

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