Type 1 Diabetes Mellitus in Children and Adolescents

Etiology references

1. 1. Bakay M, Pandey R, Grant SFA, Hakonarson H. The Genetic Contribution to Type 1 Diabetes. Curr Diab Rep. 2019;19(11):116. doi:10.1007/s11892-019-1235-1

2. 2. Redondo MJ, Gignoux CR, Dabelea D, et al. Type 1 diabetes in diverse ancestries and the use of genetic risk scores. Lancet Diabetes Endocrinol. 2022;10(8):597-608. doi:10.1016/S2213-8587(22)00159-0

3. 3. Hippich M, Beyerlein A, Hagopian WA, et al. Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families. Diabetes. 2019;68(4):847-857. doi:10.2337/db18-0882

4. 4. Harjutsalo V, Podar T, Tuomilehto J. Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. Diabetes. 2005;54(2):563-569. doi:10.2337/diabetes.54.2.563

5. 5. Redondo MJ, Jeffrey J, Fain PR, Eisenbarth GS, Orban T. Concordance for islet autoimmunity among monozygotic twins. N Engl J Med. 2008;359(26):2849-2850. doi:10.1056/NEJMc0805398

Symptoms and signs references

1. 1. Chiang JL, Maahs DM, Garvey KC, et al. Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association. Diabetes Care. 2018;41(9):2026-2044. doi:10.2337/dci18-0023

2. 2. Cherubini V, Grimsmann JM, Åkesson K, et al. Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents. Diabetologia. 2020;63(8):1530-1541. doi:10.1007/s00125-020-05152-1

Insulin regimens

InsulinInsulin is the cornerstone of management of type 1 diabetes. Available insulin formulations are similar to those used in adults (see table Onset, Peak, and Duration of Action of Human Insulin PreparationsOnset, Peak, and Duration of Action of Human Insulin Preparations). Insulin should be given before a meal, except in young children whose consumption at any given meal is difficult to predict.

Dosing requirements vary by age, activity level, pubertal status, and length of time from initial diagnosis. Within a few weeks of initial diagnosis, many patients have a temporary decrease in their insulin requirements because of residual beta-cell function (honeymoon phase). This honeymoon phase can last from a few months up to 2 years, after which insulin requirements typically range from 0.7 to 1 unit/kg/day. During puberty, patients require higher doses (up to 1.5 units/kg/day) to counteract insulin resistance caused by increased pubertal hormone levels.

Types of insulin regimens include:

• Multiple daily injections (MDI) regimen using basal-bolus regimen

• Insulin pump therapy

• Fixed forms of MDI regimen or premixed insulin regimen (less common)

Most patients with type 1 diabetes should be treated with either insulin pump therapy or with basal-bolus MDI regimens (multiple injections per day of basal and prandial insulin), with the goal of improving metabolic control. In general, children should be offered the most advanced insulin delivery system available, with the final choice guided by the needs and preferences of the patient and family (1).

Insulin Injection

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Clinicians should use the most intensive management program children and their family can adhere to in order to maximize glycemic control and thus reduce the risk of long-term vascular complications.

For those using a MDI regimen, a basal-bolus regimen is typically preferred. In this regimen, children are given a daily baseline dose of long-acting insulin that is then supplemented by doses of short-acting insulin before each meal based on anticipated carbohydrate intake and on measured glucose levels. The basal dose can be given as a once-a-day injection (sometimes every 12 hours for younger children) of a long-acting insulin (glargine, detemir, or degludec), with supplemental boluses given as separate injections of rapid-acting insulin (usually aspart or lispro). Glargine, degludec, or detemir injections are typically given at dinner or bedtime and must not be mixed with short-acting insulin.

In insulin pump therapy, the basal insulin is delivered at a fixed or variable rate by a continuous subcutaneous infusion of rapid-acting the basal insulin is delivered at a fixed or variable rate by a continuous subcutaneous infusion of rapid-actinginsulin (CSII) through a catheter placed under the skin. Mealtime and correction boluses also are delivered via the insulin pump. The basal dose helps keep blood glucose levels in range between meals and at night. Using an insulin pump to deliver the basal dose allows for maximal flexibility; the pump can be programmed to give different rates at different times throughout the day and night.

Insulin Pump

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Insulin pump therapy is increasingly being used in children because of the potential benefits of glycemic control, safety, and patient satisfaction compared to MDI regimens (2, 3). This therapy is typically preferred for younger children (toddlers, preschoolers) due to the ability to provide precise and flexible insulin doses throughout the day (microbolus dosing) in response to both unpredictable food intake and variable insulin requirements, and overall offers an added degree of control to many children (4). Others find wearing the pump inconvenient or develop sores or infections at the catheter site. Individuals must rotate their injection and pump sites to avoid developing lipohypertrophy. Lipohypertrophy is an accumulation of lumps of fatty tissue under the skin. The lumps occur at insulin injection sites that have been overused and can cause variation in blood glucose levels because they can prevent insulin from being absorbed consistently.

Insulin pumps can be integrated with continuous glucose monitoring (CGM) systems to provide real-time adjustment of insulin doses based on blood glucose levels. Such systems, known as automated insulin delivery (AID) systems or hybrid closed-loop systems, are recommended for all patients who take multiple daily injections of insulin and have been shown to lower HbA1C levels and decrease hypoglycemia (5, 6, 7). They are commonly used, and some versions do not require daily fingerstick glucose testing to calibrate the glucose monitor. They are especially useful in patients with type 1 diabetes, particularly for patients with hypoglycemia unawareness or nocturnal hypoglycemia. Hybrid closed-loop systems require patients to input carbohydrate intake prior to meals, whereas fully closed-loop systems, not yet widely available, will not. AID systems are recommended for use in children with diabetes of all ages (1).

Fixed forms of MDI regimens are less commonly used. They can be considered if a basal-bolus regimen is not an option (eg, because the family needs a simpler regimen, the child or caregivers have a needle phobia, lunchtime injections cannot be given at school or daycare). In this regimen, children usually receive neutral protamine Hagedorn (NPH) insulin before eating breakfast and dinner and at bedtime and receive rapid-acting insulin before eating breakfast and dinner. Because NPH and rapid-acting insulin can be mixed, this regimen provides fewer injections than the basal-bolus regimen. However, this regimen provides less flexibility, requires a set daily schedule for meals and snack times, and has been largely supplanted by the analog insulins glargine and detemir because of the lower risk of hypoglycemia and greater flexibility.

Premixed insulin regimens use preparations of 70/30 (70% insulin aspart protamine/30% regular insulin) or 75/25 (75% insulin lispro protamine/25% insulin lispro). Premixed regimens are not a good choice but are simpler and may improve adherence because they require fewer injections. Children are given set doses twice daily, with two-thirds of the total daily dose given at breakfast and one-third at dinner. However, premixed regimens provide much less flexibility with respect to timing and amount of meals and are less precise than other regimens because of the fixed ratios. They are commonly used in children who require gastric tube feeding.

Diet

Medical nutrition therapy tailored to the individual patient is recommended for children with type 1 diabetes (8).

In type 1 diabetes, the use of basal–bolus regimens and insulin pumps with carbohydrate counting (patients or caregivers estimate the amount of carbohydrate in an upcoming meal and use that amount to calculate the preprandial insulin dose) allows for a flexible approach, in which food intake is not rigidly specified. Instead, meal plans are based on the child's usual eating patterns rather than on a theoretically optimal diet to which the child is unlikely to adhere, and insulin dose is matched to actual carbohydrate intake. The insulin:carbohydrate ratio is individualized but varies with age, activity level, pubertal status, and length of time from initial diagnosis. Technologic advances have allowed for greater precision and customization of insulin doses. The "500 rule" (500 divided by the total daily dose of insulin) can be used to calculate the initial insulin:carbohydrate ratio dose.

Glycemic control and HbA1C target levels

The purpose of glycemic control and glucose monitoring is to reduce the risk of both short-term and long-term complications (9). Lower HbA1C levels during adolescence and young adulthood are associated with a lower risk of vascular complications (10).

In type 1 diabetes, blood glucose levels should be monitored by self-monitoring using fingersticks and a glucose meter or by using a continuous glucose monitoring (CGM) system to optimize control (11). HbA1C should be monitored periodically as well.

Glycemic control may deteriorate as children with diabetes enter adolescence. Management often involves intensive medical supervision combined with psychosocial interventions (eg, mentoring or support groups), individual or family therapy, and psychopharmacology when indicated.

Plasma glucose targets are established to balance the need to normalize glucose levels with the risk of hypoglycemia. In patients not using a CGM, intermittent self-monitoring should be performed 6 to 10 times daily (8, 9). Typical targets for blood glucose levels are 70 to 180 mg/dL (4 to 10 mmol/L), which are in alignment with continuous glucose monitoring (CGM) targets (9). Treatment goals should be individualized based on patient age, diabetes duration, access to diabetes technology (eg, insulin pumps, CGMs), comorbid conditions, and psychosocial circumstances.

HbA1Clevels should be measured every 3 months in all children with type 1 diabetes. An HbA1C target level of < 7% (< 53 mmol/mol) is appropriate for most children, but many children and adolescents do not meet this target (1). A more stringent target level (< 6.5% [< 48 mmol/mol]) may be considered for selected patients in whom the target can be achieved without significant hypoglycemia and without negative impacts on well-being, particularly with the use of CGM and AID systems (9).

The risk of hypoglycemia in children who have hypoglycemia unawareness or lack the maturity to recognize the symptoms of hypoglycemia can limit aggressive attempts to achieve treatment goals. A less stringent HbA1C target level (< 7.5% [< 58 mmol/mol]) should be considered for such patients.

Use of a continuous glucose monitoring (CGM) system can improve HbA1C levels because patients are better able to adjust insulin for meals, have an improved ability to correct hyperglycemic values, and are potentially able to detect hypoglycemia earlier, which prevents overcorrection (ie, excessive carbohydrate intake as treatment for hypoglycemia, resulting in hyperglycemia). CGM systems should be offered, when available, to children of all ages (12).

CGM metrics, derived from use over the most recent 14 days and reported in a standardized format, are recommended to be used in conjunction with HbA1C level. The ambulatory glucose profile (AGP) is a standardized report of the mean glucose, time-in-range, and time-below-range. For time-in-tight range refers to the percentage of time glucose levels remain within a narrower, more stringent target range. When using the AGP to monitor glycemia, a goal of time-in-range of > 70% with a time-below-range of < 4% may be used as a glycemic control goal, along with the goal of an HbA1C target of < 7% (< 53 mmol/mol). Metrics recorded over a 14-day period should include (9, 13, 14):

• Time-in-tight-range: > 70% between 70 and 140 mg/dL (4 and 7.8 mmol/L)

• Time-in-range: > 70% between 70 and 180 mg/dL (4 and 10 mmol/L)

• Time-below-range: < 4% < 70 mg/dL (< 4 mmol/L) and < 1% < 54 mg/dL (< 3 mmol/L)

• Time-above-range: < 25% > 180 mg/dL (> 10 mmol/L) and < 5% > 250 mg/dL (> 13.9 mmol/L)

HbA1C levels correlate well to the percentage of time that blood glucose levels remain in the normal range (70 to 180 mg/dL [4 to 10 mmol/L]), termed the percentage time-in-range. Time-in-range is commonly used as a therapeutic goal to assess the efficacy of the insulin regimen in combination with HbA1C level. A 10% change in time-in-range corresponds to approximately a 0.8 percentage point change in HbA1C. For example, a time-in-range of 80% corresponds to an HbA1C level of 5.9% (41 mmol/mol), 70% corresponds to 6.7% (50 mmol/mol), 60% corresponds to 7.5% (58 mmol/mol), and 40% corresponds to 9% (75 mmol/mol) (15).

In addition to time-in-range, CGM provides information related to average sensor glucose, time-above-range (> 180 mg/dL [> 10 mmol/L]) and time-below-range (< 70 mg/dL [< 4 mmol/L]), glycemic variability, glucose management indicator, and information related to adherence (eg, active CGM time, days worn).

Another type of CGM report is the glucose management indicator, which provides an estimated HbA1C from mean CGM glucose levels, preferably from ≥ 14 days of data.

Modifying disease progression references

1. 1. Haller MJ, Bell KJ, Besser REJ, et al. ISPAD Clinical Practice Consensus Guidelines 2024: Screening, Staging, and Strategies to Preserve Beta-Cell Function in Children and Adolescents with Type 1 Diabetes. Horm Res Paediatr. 2024;97(6):529-545. doi:10.1159/000543035

2. 2. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes [published correction appears in N Engl J Med. 2020;382(6):586]. N Engl J Med. 2019;381(7):603-613. doi:10.1056/NEJMoa1902226

3. 3. Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021;13(583):eabc8980. doi:10.1126/scitranslmed.abc8980

4. 4. Ramos EL, Dayan CM, Chatenoud L, et al. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes. N Engl J Med. 2023;389(23):2151-2161. doi:10.1056/NEJMoa2308743

5. 5. Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes. 2022;13(10):835-850. doi:10.4239/wjd.v13.i10.835

6. 6. Forlenza GP, McVean J, Beck RW, et al. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2023;329(12):990-999. doi:10.1001/jama.2023.2064