Recent advances in insulin treatment of children

Abstract:  Since the findings of the Diabetes Control and Complications Trial became public in 1993, intensive insulin therapy has been recommended for all children. However, successful implementation remains a challenge because of developmental, physiological and cultural, as well as practical issues specific to the pediatric population. This article reviews the different insulin regimens that are currently available, from the short- and intermediate-acting insulins to the newer insulin analogs, focusing on insulin therapies that attempt to provide a more physiologic basal–bolus approach to treatment. More and more children are on multiple daily injection regimens or using continuous subcutaneous insulin infusion to achieve better metabolic control. The achievement of optimal glycemic control in children is complicated by their variability in eating habits and activity levels and perhaps more importantly by the risk of hypoglycemia. The hope is that new technologies including continuous subcutaneous glucose monitoring and perhaps a closed-loop system in the near future will help us achieve more optimal glycemic targets in children without increased side effects. In addition, continuous glucose monitoring may teach us better ways to use insulin in children who do not have the technology available to them.     

The Wearable Artificial Endocrine Pancreas with a Needle- Type Glucose Sensor: Perfect Glycemic Control in Ambulatory Diabetics

We have succeeded in miniaturizing a glucose monitoring system into a needle type which preserves the characteristics suitable to apply in a wearable closed-loop control system. The wearable artificial endocrine pancreas (12 times 15 times 6 cm, 400 g) consists of the sensor, a microcomputer system which calculates insulin and glucagon infusion rates and a 2-syringe driving system. When glucose monitorings were attempted by a needle-type glucose sensor inserted in subcutaneous tissue of the forearm or abdomen of healthy and diabetic volunteers, these results were around 10% lower than blood glucose concentrations, but high correlation between them was observed in the range of49–388 mg/dl. Perfect glycemic controls were established by infusing insulin intravenously or even subcutaneously in response to measured glucose concentrations on a moment-to-moment basis in diabetics for a period of several days. By comparing the glycemic controls with those obtained in each patient with intensified multiple insulin injection regimes, the superiority of feedback control with the system was clearly demonstrated. These data might indicate the feasibility of long-term glycemic control in ambulatory diabetic patients with a wearable closed-loop glycemic control system.     

Glycaemic control with modified intensive insulin injections (MII) using insulin pens and premixed insulin in children with type-1 diabetes: a randomized controlled trial

The objective of this study was to compare glycemic control and insulin dosage in children with type 1 diabetes treated by a modified intensified insulin therapy MII using insulin pens (and premixed and regular insulin) with those on conventional insulin therapy. This was a longitudinal, randomized controlled trial for 6 months or more. From a cohort of 125 children with previously diagnosed type-1 diabetes (more than a year after diagnosis) two groups were randomly selected Group AI (n=20) and Group B (n=20). Group AI children and 10 children with recently diagnosed type 1 diabetes (Group AII) were allocated to MII using regular insulin and premixed insulin (30/70 and 40/60 and 50/50). Group B patients continued their conventional insulin therapy for the whole period of the trial. The main outcome measures were glycemic control measured by mean blood glucose concentration and percentage of glycated haemoglobin and total daily insulin dose. Mean blood glucose concentrations before the three main meals, and at midnight, (148, 147, 179 and 127 mg/dl, respectively) were lower in children receiving intensified MII compared with those receiving conventional insulin therapy (192, 174, 194 and 179 mg/dl, respectively) (standardized mean difference 34+/-15 mg/dl), equivalent to a difference of 1.9+/-0.8 mmol/l. This improved control during MII was achieved with no change in the average daily insulin dose in group-AI. In group-AII insulin dose decreased significantly during their first 6 moths of treatment (honeymooning). Glycemic control is better during MII using insulin pens and premixed and regular insulin compared with conventional insulin therapy, without any significant change in insulin dose needed to achieve this level of control. The difference in glycemic control between the two methods is significant and could reduce the risk of micro-vascular complications.     

Treatment of insulin-dependent diabetes mellitus by insulin pump in children under 7 years of age]

BACKGROUND. Conventional insulin therapy for diabetes mellitus is sometimes inadequate for controlling metabolic disturbances in young children; the risk of hypoglycemia is particularly high at this age. METHODS. Ten newly-diagnosed insulin-dependent diabetic children aged 1 to 7 years were treated by continuous subcutaneous insulin infusion using a portable pump. The mean duration of treatment was 17 months (4 to 42 months). RESULTS. The mean individual capillary blood glucose calculated over periods of 6 months ranged from 84 +/- 23 to 206 +/- 97 mg/dl. The glycosylated hemoglobin values were 6.5 to 8.9% during the same period. There was no hypoglycemic coma; 7 children experienced a total of 16 episodes of ketonuria. The average daily dose of insulin used by these 10 patients was 0.72 +/- 0.24 units/kg. CONCLUSION. Continuous subcutaneous insulin infusion is a feasible therapy and it was well tolerated even in the youngest children. External insulin infusion devices appear to be an alternative to conventional insulin therapy and a way of overcoming the therapeutic difficulties encountered with these young patients.     

Closing the loop: combining insulin pumps and glucose sensors in children with type 1 diabetes mellitus

Tight glycemic control of diabetic patients is associated with a reduction in the risk of microvascular and macrovascular complications, yet with elevated risk of severe episodes of hypoglycemia. The goal of "closing the loop" is to develop an autonomous insulin delivery system attached to a device capable of continuous glucose sensing, thus mimicking the islet beta cells activity and its capability of maintaining normal blood glucose levels and freeing the patient from the need of constant calculations of daily insulin and carbohydrates. The closed loop will protect patients from experiencing glucose excursions, including life-threatening events of hypoglycemia, thus improving glycemic control, reducing the fear from hypoglycemia and improving patients' quality of life. This review focuses on the steps towards closing the loop in the attempts to develop an artificial pancreas and on recent ongoing research and future directions in this field.     

Closing the loop: combining insulin pumps and glucose sensors in children with type 1 diabetes mellitus

Abstract:  Tight glycemic control of diabetic patients is associated with a reduction in the risk of microvascular and macrovascular complications, yet with elevated risk of severe episodes of hypoglycemia. The goal of "closing the loop" is to develop an autonomous insulin delivery system attached to a device capable of continuous glucose sensing, thus mimicking the islet beta cells activity and its capability of maintaining normal blood glucose levels and freeing the patient from the need of constant calculations of daily insulin and carbohydrates. The closed loop will protect patients from experiencing glucose excursions, including life‐threatening events of hypoglycemia, thus improving glycemic control, reducing the fear from hypoglycemia and improving patients' quality of life. This review focuses on the steps towards closing the loop in the attempts to develop an artificial pancreas and on recent ongoing research and future directions in this field.     

Current practice of insulin pump therapy in children and adolescents – the Hannover recipe

Abstract:  Increasing evidence points to the importance of achieving low blood glucose variability and also a low hemoglobin A1c (HbA1c) to prevent diabetic late complications. Continuous subcutaneous insulin infusion (CSII) is associated with lower blood glucose variability in children. Frequent indications for starting CSII in youth are recurrent hypoglycemia, need for increased flexibility, poor glycemic control, dawn phenomenon, or needle phobia. At our center, about one-third of all patients across all age groups are currently on CSII. Although the average glycemic control is not very different from those on multiple daily injections, fewer patients are seen in the segment of very high and very low HbA1c with CSII. Across centers, the 'recipes' tailoring CSII treatment to individual patients and cultures are based more on experience than on evidence. However, several typical pediatric features have been identified. Patterns of the hourly basal rate and prandial insulin requirements vary with age. While many adolescents have increased requirements at dawn and dusk, young children show increasing needs in the second half of the day. Low insulin requirements, particularly in neonates, may need insulin dilution. The selection of catheters and needles has to be appropriate for the age. The opportunity to have an electronic memory read-out of all entries and alarms offers new possibilities of therapeutic monitoring, particularly in those youth not keeping good logbooks. This feature can be helpful, if a trustful relationship between the diabetes team and the family is established.     

Improved diabetes control by using ''close adjustment algorithms''

BACKGROUND: Intensive insulin therapy increases the frequency of severe hypoglycemia despite markedly improved glycemic control in patients with type 1 diabetes mellitus. To determine the optimal dose of insulin, the authors designed algorithms based on self-monitored blood glucose levels. METHODS: Each dose of insulin was composed of two components: a basal dose determined on the basis of blood glucose levels over the previous two days and an additional dose determined on the basis of blood glucose level just before insulin injection. The patients were instructed to adjust each dose according to the algorithms. The authors investigated the effects of using algorithms on glycemic control, anthropometric data, body composition, and lipid profile in seven females with type 1 diabetes 12-20 years old. RESULTS: After 3 months, the daily dose of insulin increased significantly from 0.93 +/- 0.18 to 1.16 +/- 0.26 units/kg of body weight, and haemoglobin A(1C) decreased significantly from 8.27 +/- 1.33 to 6.50 +/- 0.64%. Severe hypoglycemia, however, did not occur. Body mass index increased significantly from 21.7 +/- 2.7 to 22.7 +/- 2.9 kg/m(2) with no increase in the percentage of body fat. All lipid-profile data showed a decreasing trend. CONCLUSIONS: Algorithms developed on the basis of self-monitored blood glucose levels are useful in determining the optimal dose of insulin and can improve glycemic control and lipid metabolism.     

Parental fear of hypoglycemia: young children treated with continuous subcutaneous insulin infusion

BACKGROUND: The objective of this study was to examine the association between parental fear of hypoglycemia and average daily blood glucose control of young children with type 1 diabetes receiving continuous subcutaneous insulin infusion (CSII). We hypothesized that parental fear of hypoglycemia would correlate positively with children's average daily blood glucose control. METHODS: Twenty-four families of children with type 1 diabetes who were receiving CSII were recruited from a pediatric hospital. Children had a mean age of 5.7 +/- 1.8 yr (range 2-8 yr) and were evenly split on gender. Parents completed a modified version of the Hypoglycemia Fear Survey - Parents of Young Children (HFS-PYC), a measure designed to assess fear and avoidance behaviors associated with hypoglycemia. Blood glucose was assessed for the 2 wk following completion of the HFS-PYC using a standard home blood glucose meter. RESULTS: Parents of young children obtained a mean total HFS-PYC score of 81 +/- 14.1 (possible range 26-130), suggesting a moderate level of fear. The HFS-PYC was found to be internally consistent and had good test-retest reliability. For parents of young children receiving CSII, fear of hypoglycemia correlated positively with children's mean daily blood glucose levels (r = 0.41, p = 0.05). CONCLUSIONS: Parents of young children with type 1 diabetes who are receiving CSII report significant fear of hypoglycemia. Parental fear of hypoglycemia may be a barrier to prevent optimal glycemic control.     

Assessment of an insulin regime and monitoring techniques in juvenile diabetics

Daily profiles of blood glucose values were obtained in hospital and at home from a group of 25 juvenile diabetics utilizing capillary blood samples and a reflectance meter. Most children were treated with twice daily injections of amorphous insulin zinc suspension (Semilente Insulin). Children tolerated the finger pricks well and all families found the procedure at least as easy as urine testing. In the four-day test period there were 26 episodes of hypoglycaemia in 13 children (52%) and 13 episodes overnight in 9 children (35%). The mean insulin dose for children with one or less hypoglycaemic episode was 0.65 u/kg/day and with two or more episodes was 0.96 u/kg/day (p<0.01). Widely fluctuating blood glucose levels and a tendency to nocturnal hypoglycaemia were frequently observed in children on the twice daily semilente insulin regime regardless of dose. Recommendations are made regarding a more suitable regime. The effect on control of residual pancreatic function and presence of insulin antibodies is discussed.     

Continuous subcutaneous insulin infusion in diabetes mellitus. A year's prospective trial.

Thirteen children aged between 8 and 16 years were entered into a 12 month prospective trial comparing continuous subcutaneous insulin infusion with intensified conventional treatment. Two of seven children on insulin infusion withdrew after eight and nine weeks, and three of six children on conventional treatment withdrew after four to eight weeks. Withdrawals in both groups were related to dissatisfaction with the techniques. The group on insulin infusion treatment achieved a mean plasma glucose of 9.8 mmol/l (176.4 mg/100 ml), a median M value of 50 mmol/l (900 mg/100 ml) and a mean glycosylated haemoglobin of 9.1% during the year. This represents a significant improvement compared with the previous values, and also when compared with the conventional treatment group whose trial values of a mean plasma glucose of 15.5 mmol/l (279 mg/100 ml), median M value of 167 mmol/l (3006 mg/100 ml), and glycosylated haemoglobin of 10.4% were not significantly different from those before the trial. Two children on insulin infusion developed subcutaneous abscesses in the early months. There was an increased incidence of diabetic ketoacidosis in this group, but no difference in the incidence of serious hypoglycaemia between the two groups. The children reported improved well-being when using insulin infusion and continued with the technique after the trial finished. Insulin infusion offers an acceptable means of improving glycaemic control for some diabetic children.     

Practical procedures of insulin therapy in diabetic children

This review article deals with the practical aspects of insulin therapy in insulin-dependent diabetic children. The various types of insulin, their mode of injection, the goals of the treatment and the necessary blood glucose and urinalysis are described. Principles of conventional insulin therapy (2 daily injections) and intensive insulin therapy are given, together with the mode of adjustment of insulin dosages. Finally, the indications of these different treatments are summarized.     

Intensive Insulin Therapy—Effects on M-Value and Frequency of Hypoglycemia—

The frequency of hypoglycemia and M-values were measured on 11 intensively treated insulin dependent diabetic children separated into three groups of once-daily, twice-daily and multiple daily insulin injection regimens. Despite a similar quality of blood glucose control (Hb Al (%): 10.0 ± 1.5, 10.4 ± 2.6, 10.6 ± 2.5) in each of the above regimens, the M-values were 26.2 ± 11.7 in the once-daily, 34.9 ± 17.9 in the twice-daily and 47.7 ± 14.7 in the multiple daily injection regimen (M ± SD), respectively. A mild biochemical hypoglycemia was found more often in the patients under treatment with twice-daily and multiple daily injections. Further, though the mean blood glucose profiles in the patients treated with once-daily and multiple daily injections were very good, marked hypoglycemic blood glucose levels were seen prior to meals, especially before lunch.     

Reduction of insulin dose on changing diabetic children from standard to monocomponent insulins.

21 diabetic children requiring greater than 50 units of standard insulin daily were changed to a monocomponent insulin. During the 3 months before the change the insulin dose had risen significantly from a mean of 70 to a mean of 77 units daily. During the 3 months after the change the dose fell significantly to a mean of 53 units daily. This decrease in insulin requirement was associated with a general improvement in diabetic control. This was assessed clinically and measured in 10 children by an analysis of home urine tests and in 8 children by an analysis of 24-hour urine glucose excretion.     

Glucose therapy for glycogenosis type 1 in infants: comparison of intermittent uncooked cornstarch and continuous overnight glucose feedings

This study was undertaken to test the glycemic response of five infants with glycogen storage disease type 1, aged 0.7 to 1.5 years, to uncooked cornstarch under various dietary conditions, and to evaluate the long-term effects of a dietary regimen consisting of uncooked cornstarch in milk every 4 hours, in addition to three meals daily, on biochemical values and physical growth. The results were compared with previous experience in treating six infants with continuous overnight glucose infusion via gastrostomy plus multiple daily feedings containing an adequate source of glucose. A test dose of cornstarch (1.6 to 1.8 gm/kg) providing four times the calculated hourly glucose production rate, when given in water 15 to 30 minutes after a continuous overnight intragastric glucose infusion was stopped, did not maintain normoglycemia. When the same dose was given in 2% cow milk 4 hours later, mean blood glucose levels remained greater than 68 mg/dl (3.8 mmol/L) for up to 4 hours. A regimen of uncooked cornstarch in 2% cow milk at 4-hour intervals in addition to three meals daily prevented hypoglycemia, and maintained blood lactate at nearly normal levels and serum uric acid and cholesterol within the normal range; triglyceride levels were increased only modestly. Overnight blood glucose levels were comparable to those achieved with continuous intragastric glucose infusion. With this regimen the five infants have maintained linear growth rates normal for their age and genetic potential; the mean percentage of ideal body weight for length percentile did not change significantly, although two of the five patients were overweight (123% and 124% of ideal body weight respectively) after 3 years of treatment. We conclude that a trial of uncooked cornstarch in feedings of milk every 4 hours should be attempted as soon as a more frequent feeding schedule with dextrose-containing formulas proves ineffective, because the former has the potential to provide the continuous glucose required by infants with glycogen storage disease type 1 in a safer and less invasive fashion than continuous intragastric glucose infusion.     

Short-term insulin therapy in adolescents with type 2 diabetes mellitus

The optimum pharmacological treatment of type 2 diabetes mellitus (DM2) in youth for those who fail to achieve adequate glycemic control (HbA1c <7%) with lifestyle intervention is unknown. The aim of this pilot study was to observe the effect of short-term insulin therapy (<16 weeks duration) on glycemic control in youth with DM2. A pre-mix 30/70 insulin was given twice daily to 18 youth aged 10-18 years with DM2 for 8.7+/-4.3 weeks with a starting dose of 0.5 U/kg/day. HbA1c, body mass index (BMI) and episodes of hypoglycemia were monitored during the treatment period and for a 12-month period after insulin was stopped. Mean HbA1c decreased from 12.81% to 7.59% (95% CI 6.54, 8.64). This improvement persisted for 12 months without any further drug therapy. There was no significant change in mean BMI and there were no episodes of moderate or severe hypoglycemia. Decreasing beta-cell glucose toxicity with rapid improvement of blood glucose may play an important role in treatment of DM2 in adolescents. Early success in achieving target blood glucose levels is an important aspect of adolescent DM2 care.     

Clinical application of insulin pumps in the management of insulin dependent diabetes.

Seven volunteers aged 12.0 to 17.9 years participated in a trial to compare conventional insulin treatment with continuous open loop (pump) insulin infusion. After 6 weeks of conventional treatment followed by 6 weeks of insulin pump treatment, 4 children chose to manage their diabetes permanently by means of the insulin pump. The mean blood glucose concentration (based on home blood glucose monitoring) while on conventional insulin treatment showed no appreciable change during the 6 weeks'' treatment on an insulin pump. Compared with conventional treatment, however, the mean 24 hour blood glucose profiles of the patients on pump insulin showed less variation in the blood glucose throughout the day, together with an appreciably lower peak after breakfast. These improvements occurred despite increased dietary flexibility while on pump insulin. The insulin pump seems to be an acceptable form of treatment for some children and young adults with diabetes mellitus and gives near physiological control of blood glucose.     

Continuous glucose monitoring in children with type 1 diabetes: before and after insulin pump therapy

Abstract: Objective: The aim of continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus (T1DM) is to mimic as closely as possible the normal physiologic pattern seen in individuals without diabetes. This study was undertaken to determine the specific areas of improved glycemic control in subjects after initiation of insulin pump therapy and times where further improvement is needed. Research design and methods: Eight patients with T1DM (age 7.5–17 yr) wore the Continuous Glucose Monitoring System (CGMS) (Medtronic MiniMed, Northridge, CA, USA) for 3 d before and 3 months after initiation of insulin pump therapy. The CGMS, which measures inter‐ stitial glucose concentrations every 5 min for a 72‐h period, was used to evaluate glucose profiles. Patients entered 4–5 fingerstick blood glucose measurements daily into the sensor for calibration. Detailed logs of food intake, exercise, and hypoglycemic symptoms were also recorded. Results: Hemoglobin A1c (HbA1C) was reduced (p < 0.007) following 3 months of insulin pump therapy. Post‐CSII continuous glucose profiles demonstrated an overall improvement in hourly mean glucose over a 24‐h period (p < 0.001) as well as a reduction in the area under the curve for glucose (27 ± 4 prepump vs. 8.6 ± 1.4 mg/dL/d postpump, p < 0.004). This improvement was a result of an attenuation of the maximal postprandial glycemic excursions. Postbreakfast 349 ± 24 vs. 267 ± 16 mg/dL, p < 0.003; lunch 340 ± 16 vs. 217 ± 20 mg/dL, p < 0.003. Postdinner average similarly decreased after 3 months of CSII by 22%, p < 0.04. Conclusions: Pump therapy specifically improved the postprandial glucose excursions in children.     

Post-hypophysectomy insulin response in patients with advanced breast cancer

Seven postmenopausal women with metastic breast cancer underwent transsphenoidal hypophysectomy. The rate of disappearance, k*, of iv glucose and insulin following iv glucose and 1-arginine infusion was determined before and after the ablation. The k* was estimated with a linear least squares weighted regression method. The insulin secretory capacity of the pancreas before and after the ablation was evaluated with the index of insulinogenic reserve, the index representing the quantity of insulin secreted per unit of glycemic stimulus. Following iv glucose and arginine, there was no significant difference in the mean k* for glucose and insulin, before and after the ablation. The insulinogenic index before was lower than the normal. After hypophysectomy, the index decreased further for the first 30 min following iv glucose. In patients with advanced cancer the index of insulinogenic reserve is lower than normal and is suppressed further by hypophysectomy.     

Insulin detemir improves glycemic control and reduces hypoglycemia in children with type 1 diabetes: findings from the Turkish cohort of the PREDICTIVE™ observational study

Background: Insulin detemir is a basal insulin analog designed to produce a superior pharmacokinetic profile to basal formulations of human insulin. It has shown consistently improved tolerability in comparison to neutral protamine Hagedorn (NPH) insulin in adult cohorts, but there are relatively few publications involving pediatric cohorts. Methods: The efficacy and safety of insulin detemir in children with type 1 diabetes was assessed using data from the Turkish cohort of PREDICTIVE? (a large, multinational, observational) study. The children investigated were using basal–bolus therapy involving NPH insulin or insulin glargine at baseline but were switched to insulin detemir as part of routine clinical care by their physicians. Results: Twelve weeks of treatment with insulin detemir significantly reduced mean hemoglobin A1c (9.7–8.9%, p < 0.001) and mean fasting glucose [185–162 mg/dL (10.3–9 mmol/L), p < 0.01]. Fasting glucose variability was also lower after treatment with insulin detemir than previously (on either NPH or glargine, p < 0.05). The frequencies of total, major and nocturnal hypoglycemic events were significantly reduced with insulin detemir relative to baseline, with an estimated mean of 6.89 fewer events/patient/yr overall (p < 0.001) and 2.6 fewer nocturnal events/patient/yr (p < 0.01). Weight and insulin dose remained relatively unchanged. Conclusions: Twelve weeks of treatment with insulin detemir improved glycemic control and reduced hypoglycemia in children with type 1 diabetes. This improved tolerability might allow further dose titration and therefore additional improvements in glucose control.