Adolescent Health Care: A Practical Guide

Chapter 10

Diabetes Mellitus

Donald P. Orr

Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia is associated with long-term microvascular (retinopathy, nephropathy, and neuropathy) and accelerated macrovascular (coronary artery disease and stroke) complications. The direct and indirect costs of diabetes care in the United States were estimated at $132 billion in 2002; the medical conditions associated with diabetes among older adults account for a significant share of these costs.

If all adults with type 1 DM received intensive treatment with the goal of achieving normal glycemia, it is estimated they would gain approximately 7.7 additional years of sight, 5.8 additional years free from end-stage renal disease, and 5.6 additional years free from lower extremity amputation. Compared with conventionally treated patients (typically those receiving only two insulin injections), the average individual would gain 15.3 years of life free from any significant microvascular or neurological complications. Another computer simulation estimated that for 13- to 24-year olds diagnosed with type 1 DM, intensive therapy would increase life expectancy from 56.51 to 60.87 years. Intensive therapy would be cost-effective at $13,599 per discounted life-year and from $22,576 to $9,626 per discounted quality-adjusted life-year (Meltzer et al., 2000). Comparable clinical trials of intensified treatment for individuals with type 2 DM have demonstrated a significant reduction in risk for microvascular complications; the effect of strict glycemic control on macrovascular complications is less clear. Risk for these is reduced with intensive treatment of hypertension and dyslipidemia.

Classification and Etiology

Classification of diabetes is based on the presumed etiology, rather than the mode of treatment (i.e., insulin vs. no insulin) (American Diabetes Association, 2005). The more common types of diabetes include the following (see Table 10.1 for characteristics of type 1, type 2, maturity-onset diabetes of youth [MODY], and atypical forms):

  1. Type 1 DM is the result of beta-cell destruction, usually leading to absolute insulin deficiency. Adolescents are usually symptomatic at presentation and at risk for ketoacidosis.
  2. Immune mediation: Type 1 DM is linked to the major histocompatibility genes associated with diabetes, human leukocyte antigen DQ (Devendra et al., 2004). It is believed to be mediated by T cells that recognize beta-cell-specific antigens. The immune changes may be detected many months to years before the onset of diabetes. Multiple antibodies have been observed that are directed against islet cells (islet cell antibody [ICA]), insulin, glutamate decarboxylase (anti-GAD65), receptor-linked tyrosine phosphatases (IA-2, IA-2β); antibodies are present in 85% to 90% of children and adolescents at the time of diagnosis and persist for years. It appears that African-Americans may have a lower prevalence of these antibodies than whites. A later onset is associated with a longer duration of symptoms, higher serum C-peptide concentrations (more beta-cell reserve), and a lower frequency of ICA.
  3. Idiopathic: Nonimmune mediated diabetes is uncommon and appears to occur more frequently in adults of African or Asian descent. Atypical diabetes mellitus (ADM), once considered a subtype of MODY, has been identified in approximately 10% of African-Americans with youth-onset diabetes; it is also recognized among Asians. ADM presents clinically as acute-onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis (DKA) and requires insulin during the initial treatment. Approximately 50% of patients with ADM are obese. The specific defect(s) remains unknown (Sobngwi et al., 2002).
  4. Type 2 DM may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect that results in insulin resistance. It is characterized by decreased muscle glucose uptake, increased hepatic glucose production, impaired insulin secretion, and probable overproduction of free fatty acids by fat cells, which further stimulates gluconeogenesis, decreases postprandial hepatic glucose uptake, and may increase muscle insulin resistance, further impairing insulin secretion. Dyslipidemia, metabolic syndrome, and a family history of type 2 DM are common.
  5. Other specific types are as follows:
  6. Specific genetic defects of beta-cell function have been identified.
  • MODY: MODY is associated with monogenetic defects in beta-cell function, impaired insulin

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secretion with minimal or no defects in insulin action, autosomal dominant inheritance, and onset usually before the age of 25 years (Fajans et al., 2001).

Classic MODY is seen predominantly in nonobese whites, is nonketotic, and is generally not insulin requiring at diagnosis. It represents <% of cases of childhood diabetes in whites. It is seen in all racial/ethnic groups. Six specific types have been identified with varying levels of insulin deficiency.

  • Mitochondrial DNA: This very rare form of diabetes is a characterized by specific genetic defect and is almost always associated with other symptoms—deafness, neurological disorders, cardiac failure, renal failure, and myopathy. The mutations may be sporadic or maternally inherited.
  1. Various genetic defects of insulin action are known. These include type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome, lipoatrophic diabetes, and others.
  2. Diseases of the exocrine pancreas leading to destruction of endocrine function are:
  3. Cystic fibrosis: Cystic fibrosis-related diabetes (CFRD) is common among adolescents and young adults with cystic fibrosis with increasing prevalence with age. In one large U.S. study, more than 40% of patients older than 30 years were identified with CFRD (Moran et al., 1998). It is more common among women and those with ΔF508 genotype. CFRD is associated with decreased pulmonary function, protein catabolism and loss of weight. It results primarily from insulinopenia, although insulin resistance may be observed during periods of infection. Insulin resistance may be severe during steroid treatments for pulmonary inflammation. Insulin treatment is associated with increased body weight and improvement in pulmonary function.
  4. Others: Pancreatitis, trauma/pancreatectomy, neoplasia, hemochromatosis, fibrocalculous pancreatopathy.
  5. Endocrinopathies including acromegaly, Cushing syndrome, hyperthyroidism, and pheochromocytoma.
  6. Drugs including glucocorticoids, pentamidine, protease inhibitors, thyroid hormone, diazoxide and thiazides.
  7. Genetic syndromes sometimes associated with diabetes are Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Laurence-Moon syndrome, myotonic dystrophy, and Prader-Willi syndrome.
  8. Gestational diabetes mellitus (GDM). The risk for subsequent development of diabetes is elevated; approximately 17% develop type 1 DM and 17% to 70% develop type 2 DM.

TABLE 10.1
Characteristics of the Common Types of Diabetes

 

Type 1

Type 2

Atypical

Maturity-Onset Diabetes of Youth

From Rosenbloom AL, Joe JR, Young RS, et al. Emerging epidemic of type 2 diabetes in youth. Diabetes Care 1999;22:345, with permission.

Age

Childhood

Pubertal

Pubertal

Child, adolescent (usually age <5)

Onset

Acute; severe

Mild to severe; often insidious

Acute; severe

Mild; insidious

Insulin secretion

Very low

Variable

Moderately low

Variable

Insulin sensitivity

Normal

Decreased

Normal

Normal

Insulin dependence

Permanent

No, until late

Variable

Usually no, until late

Racial/ethnic groups at increased risk

All (low in Asians)

African-Americans, Hispanic-Americans, Native Americans

African-Americans

All

Genetics

Polygenic

Polygenic

Presumed autosomal dominant

Autosomal dominant

Proportion of those with diabetes

10%–20%

~80%

5%–10%

Rare

Association with:Obesity

No

Strong

Variable

No

Acanthosis nigricans

No

Yes

No

No

Autoimmune etiology

Yes (small subset non autoimmune type)

No

No

No

Epidemiology

  1. Prevalence
  2. Type 1 DM: The prevalence of type 1 DM varies by race/ethnicity and country, with the highest rates in

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areas most distant from the equator. It is estimated that there are more than 500,000 individuals in the United States with type 1 DM. The prevalence is approximately 1.7 per 1,000 persons younger than 19 years. The incidence is increasing by 3% to 4% annually worldwide. The increase is greatest among younger patients; the ages of peak incidence in the United States remain late childhood and early-to-mid adolescence (Gale, 2002).

  1. Type 2 DM: There has been a steady worldwide increase in the prevalence of type 2 DM. By 2030, the total number of people with diabetes is projected to increase worldwide by 30.3% to 366 million. Type 2 DM accounts for up to 20% of the diabetes cases diagnosed in children and adolescents in some large diabetes centers (Bloomgarden, 2004).
  • Racial distribution: Within the United States, African-Americans have a twofold increased risk; Hispanics, a 2.5-fold increase; and Native Americans, a fivefold increase compared with whites.
  • Gender: The risk is slightly higher for females and those living in poverty, probably secondary to the added risk of obesity.
  • Family history: More than 40% of the children of parents with type 2 DM have a lifetime risk of developing type 2 DM.
  1. Emergence of diabetes during adolescence, and glycemic control
  • Insulin sensitivity decreases significantly at sexual maturity rating (SMR) 2, remains constant from SMR 2 through 4, and returns almost to prepubertal levels by SMR 5.
  • Girls and African-Americans are more insulin resistant; this is only partially explained by higher body mass index (BMI). The decreased sensitivity to insulin is not explained by sex steroids and is presumed to be associated with peripheral effects of growth hormone (Amiel et al., 1986; Moran et al., 1999).
  • Obesity has increased, with an estimated 16.7% of boys and 15.4% of girls aged 12 to 19 years as overweight (BMI above the 95th percentile). The prevalence of obesity is higher among minority youths and poor populations. Children and adolescents are more sedentary.
  • A recent large study demonstrated that more than 14% of moderately obese (average BMI 33.4) and 20% of severely obese (average BMI 40.6) children and adolescents had impaired glucose tolerance (IGT) and 39% and 50% respectively had metabolic syndrome. Metabolic syndrome increased with increasing insulin resistance; it was somewhat less common among African-Americans (Weiss et al., 2004). IGT is a significant risk factor for type 2 DM.

Diagnosis

The level of fasting plasma glucose (FPG) has been recommended for screening and diagnosing DM in most circumstances (Table 10.2). This has replaced the traditional oral glucose tolerance test (OGTT) because it is cumbersome and costly, underutilized, and the repeated test reproducibility of the 2-hour postprandial glucose (PG) level is worse than that of the FPG. Hemoglobin AIc (HbAIc) (a specific glycated protein) is not recommended for the diagnosis of diabetes. Impaired fasting glucose (IFG) level and IGT results are now considered to indicate prediabetes, but are not, of themselves, diagnostic of diabetes. These groups are at increased risk for developing diabetes and the test should be repeated in 3 months.

  • FPG ≤100 mg/dL (5.6 mmol/L): normal fasting glucose
  • FPG 100 to 125 mg/dL (5.6–6.9 mmol/L): IFG, prediabetes
  • 2-hour postload glucose 140 to 199 mg/dL (7.8–11.1 mmol/L): IGT, prediabetes
  • FPG ≥126 mg/dL (7.0 mmol/L): provisional diagnosis of diabetes (the diagnosis must be confirmed, as described in subsequent text).

TABLE 10.2
American Diabetes Association, 2005, Criteria for the Diagnosis of Diabetes Mellitus

 FPG, fasting plasma glucose; PG, postprandial glucose; OGTT, oral glucose tolerance test.
 From The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2005; 28(Suppl 1):S37, with permission.

 

1.  Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dL (11.1 mmol/L); casual is defined as any time or day without regard to time since last meal
Or

2.  FPG ≥126 mg/dL (7.0 mmol/L); fasting is defined as no caloric intake for at least 8 hr
Or

3.  2-hr PG ≥200 mg/dL (11.1 mmol/L) during an OGTT; the test should be performed as described by the World Health Organization using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water

In the absence of acute metabolic decompensation, these criteria should be confirmed by repeated testing on a different day

The third measure (OGTT) is not recommended for routine clinical use

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Screening

  1. Type 1 DM: No screening is recommended.
  2. Type 2 DM
  3. Screen with FPG testing every other year, starting at 10 years or at onset of puberty, if puberty occurs at a younger age.
  4. Screen
  • Overweight patients (those with a BMI above the 85th percentile for age and sex, those with weight for height above the 85th percentile, or weight of >120% of ideal for height weight) plus
  • Those who have any two of the following risk factors:
  • Family history of type 2 DM in first- or second-degree relative
  • Race/ethnicity: Native American, African-American, Hispanic, Asian/Pacific Islander
  • Signs of insulin resistance or conditions associated with insulin resistance, such as acanthosis nigricans, hypertension, dyslipidemia, and polycystic ovary syndrome

Prevention

  1. Type 1 DM: There is no effective prevention at this time.
  2. Type 2 DM: Several studies of adults with IGT have shown that lifestyle changes (intensive physical activity, reduced intake of carbohydrates and weight loss if indicated) reduce the risk for progression to diabetes by approximately 60%; metformin in combination with standard recommendations for diet and exercise decreased the risk by 31% (Knowler et al., 2002; Tuomilehto et al., 2001).

Evaluation and Treatment

The initial use of insulin in an adolescent newly diagnosed with diabetes does not commit to extended use if the clinical course suggests type 2 (obese, strong family history of type 2 DM, absence of ketonemia with insulin omission) or MODY. At initial presentation, the state of hydration and acid–base balance determine the need for fluids and insulin. (See any standard textbook of medicine, pediatrics, and endocrinology for treatment of DKA.) It is important to determine the type of diabetes to the extent possible because the underlying diagnosis will guide the management. Measurement of autoantibodies may be useful if the etiology is unclear; for example, obese African-Americans with ketonemia in whom ATM is suspected. If type 1 DM is diagnosed, measurement of thyroid hormone levels is indicated because of associated thyroiditis in 10% to 15% of patients. Type 2 DM usually has an insidious presentation and is suggested by obesity, acanthosis, hypertension, dyslipidemia, or strong family history of type 2 DM. Normal weight and mild symptoms suggest very early type1DM or MODY.

  1. Education: In addition to the recommended information about diabetes, blood glucose (BG) testing, hypoglycemia, hyperglycemia, and insulin administration, education and periodic education by a certified diabetes educator should include information about alcohol use, use of contraception, and the importance of preconception counseling to decrease risk for pregnancy complications. (See the “Web Sites” section at the end of this chapter for help in identifying an educator.)
  2. Meals, food, and nutrition: There is no standard American Diabetes Association (ADA) meal plan; rather, diet is adjusted for the individual to provide sufficient calories and nutrients to grow/maintain weight; limiting fat to 30% or less of total calories is encouraged. Weight reduction and exercise are important for those who are overweight, particularly if they have type 2 DM. “Carbohydrate counting” is replacing the “exchange system” because it permits greater flexibility and offers the potential for adjusting the dose of short-acting and rapid-acting insulin before each meal on the basis of the amount of carbohydrate consumed at each meal. In this system, 15 g of carbohydrate is equivalent to one carbohydrate. This is estimated from package labels that list the carbohydrate content per serving and standard servings of milk (1 cup), fruit, juice (1/2 cup), and starch/bread; vegetables or meat (approximately one third carbohydrate per serving) may or may not be counted depending on the degree of glycemic control targeted. Fast-food carbohydrate counting guides are available from major fast-food companies, often through their corporate Web sites.
  3. Accessing glycemic control: The goal is to lower BG level, and resultant HbAIcto achieve maximum prevention of complications, taking into account patient safety and the ability to carry out the treatment regimen. Although normal levels of BG are the goal (70–120 mg/dL before meals and fasting), most patients (adult and adolescent) are not able to achieve consistently normal levels of glycated hemoglobin. Any lowering of glycated hemoglobin will reduce the risks of long-term complications.
  4. Capillary BG testing—testing is recommended before meals and bedtime snack—more frequent if “normal” BG levels are the objective. Testing at 2 to 3 a.m. is useful for evaluating nighttime hypoglycemia and fasting hyperglycemia (the dawn phenomenon). The recommended frequency of testing for type 2 DM is not well defined, but daily fasting blood glucose (FBG) and a random premeal BG test should be sufficient once effective control has been achieved. Devices to measure capillary BG must demonstrate that 95% of the tests are within 10% to 15% of the true BG value. They are usually calibrated to plasma glucose, which is higher than whole BG (see the “Web Sites” section).
  5. Glycated hemoglobin should be measured at each visit (generally quarterly) and the results discussed with the adolescent and parent in relation to BG test results. Glycated hemoglobin values reflect the average BG over the previous 8 to 12 weeks, so BG records must also be examined to identify swings in BG that would not be evident in the percentage of glycated hemoglobin. Several different assays are available, each with its own reference (nondiabetic) range. It has been suggested that all glycated hemoglobin assays be standardized and reported in values equivalent to HbAIc(which was used in the Diabetes Control and Complications Trial [DCCT]). Point-of-care testing for HbAIc is available. Having the results of the glycated hemoglobin level available at the time of the visit has been shown to result

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in significantly improved control among adults. Discussing the results at the next visit or by telephone is less satisfactory. On the basis of the DCCT HbAIc values, the target HbAIclevel is ≤7%. The need for an individualized approach to insulin therapy in patients with diabetes is important. In addition, certain subgroups of patients with the diagnosis can be differentiated from each other according to the pattern of BGs over the course of a day, as has been recently reviewed (Mooradian et al., 2006). Examples of these patterns include: “round-the-clock” hyperglycemia, fasting hyperglycemia and daytime euglycemia; and daytime hyperglycemia with fasting euglycemia.

  1. Insulin: Human insulins (DNA origins) have almost entirely replaced older animal preparations. Insulin analogs in which one or more amino acids have been substituted on the α chain or β chain afford more specific patterns of release. Rapid-acting preparations include lispro (Humalog), aspart (NovoLog) and glulisine (Apidra). They have a more rapid onset and shorter duration of action; they may be given before or immediately after meals, affording less immediate postprandial hyperglycemia and subsequent hypoglycemia. Two extended acting analogs are available; glargine (Lantus) and detemir (Levemir) have an onset of 2 to 4 hours. Glargine provides a peakless duration of >24 hours while detemir has a somewhat shorter duration of 12 to 20 hours and may require twice daily administration. Neither should be mixedwith other insulin preparations (Table 10.3).
  2. Insulin delivery devices: Many different devices are available, allowing adolescents to manage their diabetes more easily (see the “Web Sites” section).
  3. Insulin syringes: These are available in 0.3-, 0.5-, and 1.0-mL sizes with needles of 28, 29, or 30 gauge and 8.0- or 12.7-mm length. Adolescents usually prefer one type over another.
  4. Insulin pens: These are disposable devices that are prefilled or hold cartridges of 300 units of short-acting, rapid-acting, Neutral Protamine Hagedorn (NPH), 70/30 (70% NPH/30% regular), 75/25 (75% NPH/25% lispro or aspart), and glargine insulins. These devices are approximately the size of a large fountain pen and can be carried easily in a purse or shirt pocket. Disposable needles (29, 30, and 31 gauge, and 12.7, 8, 6, and 5 mm) must be prescribed separately. Pens and insulin cartridges from different manufacturers are not always interchangeable.
  5. Continuous subcutaneous insulin infusion (CSII) (external insulin pumps): These permit ultimate flexibility in designing an insulin regimen, compensating for exercise, variations in carbohydrate intake including delayed meals and the dawn phenomenon. They are particularly useful for individuals who experience severe, recurrent nocturnal hypoglycemia and erratic day-to-day schedules with respect to meal times and exercise. Multiple basal insulin rates can be preprogrammed. The patient must determine the amount of insulin to be delivered for each mealtime or corrective bolus, and instruct the pump to deliver this amount at the correct time. Some systems contain an integrated BG meter and can be programmed to calculate bolus insulin doses based on carbohydrate consumed and level of BG. Candidates for pumps are very motivated, test at least four times daily (and often include 2 to 3 a.m. testing when required), actively monitor carbohydrate intake, adjust insulin doses with each meal and snack, and have frequent contact with the diabetes team. Individuals with serious psychological problems are generally poor candidates for pump therapy. Several studies have demonstrated improved glycemic control among adolescents and adults who desire more intensive diabetes, who are randomly assigned to insulin pumps compared to MDI regimens. Adolescents who wish to use CSII should be referred to a diabetes team experienced with CSII and adolescents (see the “Web Sites” section).
  6. Inhaled insulin: In combination with injected longacting insulin, inhaled insulin has been demonstrated in phase 3 clinical efficacy trials to be safe and as effective in controlling BG as rapid-acting injectable insulin (Hollander et al., 2004; Quattrin et al., 2004; Rave et al., 2005). This agent is Food and Drug Administration (FDA) approved. It may be useful for individuals with type 2 DM who have difficulty administering rapid-acting insulin by injection.
  7. Treatment of patients who require insulin: Insulin therapy is always necessary for type 1 DM, and for those with insulin deficiency. Although insulin remains the recommended pharmacologic treatment for GDM, several studies have demonstrated that among those not controlled by diet, glyburide is safe and as effective as insulin (Saade, 2005).

TABLE 10.3
Characteristics of Human Insulin Preparations

Informal Description

Proprietary or Other Name

Onset (hr)

Peak (hr)

Effective Duration (hr)

Maximum Duration (hr)

Technical Description

Adapted from Orr DP. Contemporary management of adolescents with diabetes mellitus. Part 2: type 2 diabetes. Adolesc Health Update 2000;12(3):3, with permission.

Rapid acting

Lispro, aspart, glulisine

0.25

1–2

2–3

4

Insulin analog

Short acting

Regular

0.5–1.0

2–3

3–6

4–6

Insulin

Intermediate acting

Neutral protamine hagedorn (NPH)

2–4

4–10

10–16

14–18

Insulin isophane (suspension)

Long acting

Detemir

1–2

8–11

12–20

14–22

 
 

Glargine

2–4

None

>24

24–36

Analog

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  2. Insulin regimens—MDIs of insulin are preferred. The greater number of injections (three or more) offers more flexibility to accommodate varied intake, exercise, and meal times, and has the potential for improved glycemic control. Simply adding prelunch short- or rapid-acting insulin to a standard twice daily insulin regimen will decrease presupper hyperglycemia, with less risk of hypoglycemia associated with a very large prebreakfast dose of intermediate-acting insulin. With the exception of a bedtime snack to prevent nocturnal hypoglycemia, snacks usually are no longer required with MDI—an advantage for busy adolescents and those who wish to maintain a target weight.
  3. Contemporary MDI insulin regimens are based on the use of a longer acting insulin (e.g., glargine or detemir) to provide basalinsulin requirements (suppression of hepatic glucose production in the fasting state) and premeal boluses of rapid-acting insulin to cover the amount of carbohydrate consumed (food dose) and to correct for fluctuations in premeal BG (corrective dose). Descriptions of traditional twice-daily split-mixed insulin regimens using rapid- and intermediate-acting insulins can be found in standard textbooks dealing with diabetes.

BOLUS INSULIN DOSE = FOOD DOSE + CORRECTIVE DOSE

  • Food dose to cover carbohydrates at meal or snack
  • One unit of short- or rapid-acting insulin will usually “cover” approximately 8 to 15 g of carbohydrate (carbohydrate to insulin ratio of 8 to 15), meaning that one unit of rapid-acting insulin will be required for each 8 to 15 gm of carbohydrate consumed.
  • To estimate the grams of carbohydrate covered by one unit of short- or rapid-acting insulin use the rule of 450/500 = (450 for short-acting or 500 for rapid-acting insulin)/total daily dose (TDD) of all insulins in 24 hours. Note that if the patient is poorly controlled and TDD is >1.4 U/kg, reduce by 20%.
  • Food dose = grams of carbohydrate consumed/carbohydrate to insulin ratio
  • Corrective dose—adjusting the dose of short- or rapid-acting insulin administered before meals takes into account the fact that BG varies from day to day depending on carbohydrate intake at previous meals, the time that previous dose was administered, the amount of interval exercise, and the rate of insulin absorption from subcutaneous tissues. The corrective dose of insulin is added to the food dose and administered before or after that meal. The corrective dose may also be used to correct for hyperglycemia at other times of the day, independent of meals.
  • One unit of rapid- or short-acting insulin will usually lower BG 25 to 100 mg/dL depending on the individual's sensitivity to insulin (insulin sensitivity factor)
  • The rule of 1,500/1,800 may be used to estimate more closely the initial “insulin sensitivity factor” (the estimated point drop in BG per unit of short- or rapid-acting insulin) used for the corrective dose:
  • The sensitivity factor= (1,500/TDD for short-acting insulin) and (1,800/TDD for rapid-acting insulin) (ADA, 2005)
  • Corrective dose = (measured BG—target BG)/insulin sensitivity factor

BASAL INSULIN DOSE

  • Basal insulin dose = Approximately 40% to 50% of TDD on previous insulin regimen.
  • Administer 40% to 45% of TDD as glargine insulin as single injection once daily or detemir as twice daily injections before breakfast and at bedtime.
  • The following is an example to change from twice-daily insulin dosing to multiple dosing for a 15- year-old girl weighing 50 kg and using rapid-acting insulin (current TDD = 50 units of insulin):
  1. Basal insulin: 20 units of glargine with breakfast, dinner, or bedtime (40% of previous TDD)
  2. “Insulin sensitivity factor”: 1,800/50 = 36-mg drop per unit of rapid-acting insulin.
  3. Target BG = 120 mg/dL
  4. Carbohydrate covered by one unit of insulin from the rule of 450/5,000: 450 for rapid-acting insulin/TDD = 450/50 = 9 g of carbohydrate per unit of rapid-acting insulin.
  5. Bolus insulin doses = (grams of carbohydrate eaten/carbohydrate to insulin ratio) + (BG–target BG)/insulin sensitivity factor.
  6. For example, to calculate a premeal bolus insulin dose from previous description: if premeal BG = 250 mg/dL and 60 g carbohydrate consumed bolus rapid-acting dose = 60 g of carbohydrate/9 + (250–120)/36 = approximately 10 units of rapid-acting insulin.

Insulin doses are adjusted after 5 to 7 days on the basis of the pattern of BG levels.

  1. Treatment of type 2 DM and MODY: Treatment should be based on the known pathophysiology—insulin resistance, hepatic overproduction of glucose, and relative insulin deficiency.

 .    Acute management of newly diagnosed symptomatic patients: Individuals who are ketotic and those with significant hyperglycemia at diagnosis (BG >250 mg/dL) will initially require insulin therapy to reduce BG levels. Several studies of adults and adolescents have demonstrated that several months of intensive treatment with insulin results in improved glycemic control 1 year later. Metformin therapy, an insulin-sensitizing agent, is generally begun when the patient is no longer ketotic. Insulin can be slowly withdrawn over the subsequent 3 to 4 months as glycemic control is achieved. Although type 2 DM is a progressive disease that will eventually require exogenous insulin, modifications in diet and exercise are the mainstay of treatment.

  1. Patients with insidious onset and mild hyperglycemia can be initially managed with diet and exercise as described in following text.
  • Diet: Carbohydrates should be distributed throughout the day to include snacks. Limiting the amount of carbohydrate takes into account the inherently abnormal insulin secretory pattern. Weight loss will increase insulin sensitivity because it reduces visceral adipose tissue. The effect of carbohydrate restriction (as part of

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total caloric reduction) may be seen within 4 days, with a reduction in postprandial BG. The effects of weight loss may take months and will be reflected in lower FBG levels and resultant decreased HbAIc. Studies of obese adults with type 2 DM suggest that an FBG of <180 mg/dL after individuals have lost 2.3 kg has a 62% positive predictive value that diet therapy will be effective in achieving control; the positive predictive value is 79% after 4.5 kg has been lost (Watts et al., 1991).

  • Exercise: Exercise will increase insulin sensitivity independent of weight loss. At least 20 to 30 minutes of anaerobic activity at least three times per week is recommended. Vigorous walking is an acceptable introductory activity for the sedentary patient.
  • Oral hypoglycemic therapy: Failure to see improvement in FBG (HbAIc≤8%) in the face of substantial weight loss or after 3 months suggests that diet and exercise alone will be insufficient to achieve satisfactory control. Initiate oral hypoglycemic agent or insulin therapy. Approximately 25% of adults will achieve an HbAIc≤8% on monotherapy, 50% will see a partial response, and 25% will fail to respond to a single oral agent. Insulin remains the recommended option for treatment of diabetes during pregnancy in the United States. However, several large studies have demonstrated that glyburide is safe and effective for the treatment of GDM. Referral to a high-risk obstetrical program is indicated.

Oral hypoglycemic agents will generally be required at some point in the treatment of type 2 DM. Many agents are available. Each group targets different metabolic components—insulin secretory defect, elevated hepatic glucose output, and insulin resistance. Key points include the following: The response to oral agents follows a sigmoid curve, with a rapid rise in therapeutic activity, leveling off, and then gradual tapering to maximal therapeutic effect; half the maximal dose yields more than half the maximal effect (60%–80%); and side effects increase slowly at low doses and then more rapidly at higher doses.

  • Biguanide (metformin) is the first-line oral hypoglycemic agent for obese adolescents (and those who are unable to achieve acceptable glycemic control with diet and exercise) because it is not associated with weight gain. It lowers FBG, by reducing hepatic glucose output and improves lipid profiles, with a reduction in total cholesterol, low density lipoprotein cholesterol (LDL-C), and triglycerides, as well as an increase in high density lipoprotein cholesterol (HDL-C). The major side effects are mild gastrointestinal (GI) symptoms that generally resolve; side effects may be minimized by increasing the dose slowly. Hypoglycemia is uncommon, and lactic acidosis, a potentially serious condition associated with the predecessor biguanide (phenformin), is extremely rare with the only available agent in this class, metformin. Discontinue and ensure adequate hydration before contrast studies that may impair renal function and with dehydration.
  • Sulfonylurea (SU) drugs and the related meglitinides (repaglinideand netaglinide) enhance insulin release from the beta cell and may decrease insulin resistance. Use is often associated with weight gain, which tends to further increase insulin resistance. Potential interactions with sulfonamides, fluconazole, and ciprofloxacin may result in hypoglycemia. SU drugs generally may be given as a single morning dose. The meglitinides also enhance insulin secretion but operates through a mechanism different from that of SU drugs; they must be administered before each meal.
  • Glucosidase inhibitors delay the absorption of carbohydrate from the intestine, reducing the rise in BG levels after a meal. They are most useful when employed in conjunction with other hypoglycemic agents to assist in managing postprandial hyperglycemia. They are not associated with weight gain or hypoglycemia. They must be given before each meal, not exceeding three times per day. Slowly increasing the dose tends to decrease the common GI symptoms (e.g., crampy abdominal pain, loose stools, and flatus).
  • Thiazolidinediones (“insulin sensitizers”) increase insulin action in muscle, adipose tissue, and probably in the liver. The newer thiazolidinediones (pioglitazone and rosiglitazone) do not appear to be associated with serious hepatotoxicity noted with the predecessor troglitazone. Neither is approved for use in patients younger than 16 years. Thiazolidinediones alone or combined with metformin have demonstrated to increase levels of HDL-C and to decrease levels of free fatty acids with variable effects on levels of triglycerides. Rosiglitazone has been shown to increase levels of LDL-C. Liver enzymes must be periodically monitored. These agents do not represent the initial pharmacotherapeutic agent for adolescents with type 2 DM.

Consider combining oral agents or adding insulin when a single medication has not achieved the desired degree of control. Combining agents takes advantage of their additive effects because each operates through different physiological mechanisms, is generally associated with fewer side effects, and has a lower cost (if doses are lower). When combining oral agents, increase the dose of the first drug until maximum dose has been reached or side effects limit further increases. Add the second medication at the lowest dose and increase slowly, watching out for hypoglycemia. If target levels of BG have not been achieved in 4 to 6 months, the addition of insulin is indicated. Some clinicians would choose to add insulin instead of a second oral agent.

Insulin may be used as a single nighttime dose of an intermediate-acting NPH or single dose of long-acting glargine at any time of day (to lower FBG) or in divided doses as with type 1 DM. Adding a single dose to an oral regimen is advantageous because lower doses of insulin and the oral agent may be used. Begin with a single dose of intermediate-acting insulin with the bedtime snack or long-acting insulin at dinner. An initial dose of 5 to 10 units is safe. Increase the dose until the desired level of FBG is achieved. Adolescents who have a large carbohydrate intake at dinner may benefit from the addition of regular or rapid-acting insulin with this meal; this dose of short-acting insulin is adjusted based on bedtime BG levels.

Complications, Associated Conditions, and Follow-Up Care

  1. Autoimmune disorders (type 1 DM only): Approximately 10% to 15% of patients with type 1 DM develop autoimmune thyroiditis. Initial antithyroid antibody levels

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do not predict subsequent involvement. Because presentation is usually asymptomatic, annual thyroid studies to detect hypothyroidism are recommended; thyroidstimulating hormone is generally sufficient. Other autoimmune diseases affecting the adrenal, pituitary, ovary, or parathyroid are uncommon.

  1. Microvascular complications: Microvascular complications are directly correlated with the level of glycemic control and duration of diabetes and are exacerbated by hypertension.
  2. Retinopathy: A yearly dilated funduscopic examination is recommended.
  3. Nephropathy: Annual screening for urinary albumin is recommended. The level of random urinary microalbumin: creatinine ratio is highly correlated with timed specimens. Meticulous attention to blood pressure (BP) is important (both systolic and diastolic); attempt to maintain BP ≤130/80 mm Hg. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists and improved control represent the treatments for persistent microalbuminuria because they have been shown to delay the progression of nephropathy.
  4. Neuropathy: Neuropathy is rarely symptomatic during adolescence. Examination of the feet for pulses, sensation, deep tendon reflexes, hygiene, calluses, and evidence of infection is indicated. The Semmes-Weinstein monofilament test for sensation is a rapid, sensitive screening test for distal sensory neuropathy. Painful distal neuropathy occurs uncommonly in this age-group. Desipramine and amitriptyline are equally effective treatments (Max et al., 1992). Gabapentin is effective, but more expensive and may be considered as an alternative treatment (Backonja, 1999; Morello et al., 1999).

Symptomatic autonomic neuropathy (heart rate invariability and/or postural hypotension) and gastroparesis (postprandial nausea or vomiting, postprandial hypoglycemia, and diarrhea or constipation) are very rare in this age-group.

  1. Macrovascular complications: Macrovascular complications are rarely symptomatic during adolescence and young adulthood. Diabetes-associated accelerated cardiovascular disease may not be preventable with improved glycemic control, although the risk is decreased with tight control of hypertension and hyperlipidemia (Turner et al., 1998; UK Prospective Diabetes Study Group, 1998).
  2. Dyslipidemia: Dyslipidemia is common in type 2 DM and in poorly controlled type 1 DM. It increases the risk for cardiovascular disease twofold to fourfold and reflects various degrees of insulin resistance, obesity, diet, and poor glycemic control. The typical pattern is elevated triglycerides and decreased HDL-C. Although all hypoglycemic agents used in adolescents tend to lower triglycerides and LDL-C, if LDL-C levels of <100 mg/dL have not been attained with better glycemic control, weight loss (if indicated), and reduced intake of saturated fat, treatment with lipid-lowering medications is indicated. New-generation “statin” drugs are generally preferred. Yearly measurement of fasting lipid profiles is recommended among those with previously abnormal profiles or ongoing poor glycemic control. Measurement every 5 years is sufficient if initial LDL-C is <100 mg/dL (American Diabetes Association, 2005).
  3. Hypertension: Hypertension, even with mild elevations, (>130/80 mm Hg) is associated with an increased risk of microvascular complications. The appearance often coincides with the onset of persistent microalbuminuria. ACE inhibitors/receptor antagonists are the drugs of choice.
  4. Gluten sensitivity: Gluten sensitivity is estimated to be present in 5% of individuals with type 1 DM. The benefit of universal screening of all individuals with type 1 DM is not established. Evaluate with Ig-A antiendomysial or Ig-A antitissue transglutamase antibodies if symptoms are suggestive of malabsorption or unexplained postprandial hypoglycemia.
  5. Eating disorders: Eating disorders may complicate treatment of diabetes. Disordered eating (including underdosing or omission of insulin) may be present in up to 30% of women with type 1 DM, but the prevalence of eating disorders mentioned in Diagnostic and Statistical Manual of Mental Disorders, fourth editionis probably not higher than expected. The coexistence of eating disorders and diabetes is associated with noncompliance with treatment for diabetes and an increased risk of retinopathy (Rydall et al., 1997). Suspect eating disorders when the HbAIc is high and weight loss or excess concerns about weight are present.
  6. Hypoglycemia: Severe hypoglycemia is common with intensified regimens targeting euglycemia. An episode of severe hypoglycemia increases the risk for additional hypoglycemia because it is associated with a reduced magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction during subsequent hypoglycemia. These return to normal with strict avoidance of hypoglycemia.
  7. Alcohol use: As with healthy adult populations, moderate alcohol use among individuals with older-onset diabetes (older than 30 years) has been shown to reduce the risk of coronary heart disease-related death (Valmadrid et al., 2000). Alcohol use is not recommended for minor adolescents including those with diabetes. For those who do drink, provide education about its potential to cause hypoglycemia. Alcohol tends to inhibit gluconeogenesis and interfere with the counterregulatory responses to insulin-induced hypoglycemia. It also impairs judgment. Severe hypoglycemia may result many hours after consumption of as little as 2 oz of alcohol, particularly on an empty stomach. Anticipatory guidance should include moderation, eating additional carbohydrates at the time of alcohol consumption, and informing others that they have diabetes.

Special Considerations for Compliance with Adolescents

Managing teens with DM can be difficult, particularly for those with poorly controlled DM. Some suggestions include the following:

  1. Identify the reason for poor control and develop a strategy for remediation. Serious psychopathology (including eating disorders) and recurrent DKA are indications for referral.
  2. Identify one reasonable and measurable target behavior for action (number of BG tests, recording carbohydrates at a specific meal, self-insulin adjustment based on BG or carbohydrate intake).

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  1. Identify short-term reinforcers relevant to the adolescent—fewer symptoms (hypoglycemia or nocturia), improved physical performance, more flexibility in timing and content of meals, rewards from parents, and greater independence.
  2. Establish realistic time frame for accomplishment based on behavior and goal (e.g., average FBG will be 20% lower over the next 2 weeks). Remember glycated hemoglobin levels reflect average blood sugar level over 8 to 12 weeks. Even a 1% reduction (12%–11%) over this period is significant.
  3. Provide frequent feedback; see the adolescent more frequently.
  4. Examine the extent of parental support and monitoring; more support and monitoring by parents of midadolescents is associated with increased BG testing and lower HbAIc(Anderson et al., 1997).
  5. Group coping-skill training improves long-term glycemic control and quality of life (Grey et al., 2000).
  6. Consider referral to a diabetes specialist if control has not improved within 6 months.
  7. For life-threatening, recurrent DKA or long-standing very poor control (HbAIc≥12%) refractory to other measures, consider the use of a single daily dose of insulin, monitored by an adult to prevent recurrent DKA.
  8. Regular 30% TDD, NPH 60% TDD, lantus 10% TDD given as two injections in the morning.
  9. Expect subsequent HbAIcto be 10% or less.

Portions of this chapter have been previously published (Orr, 2000a, b).

Web Sites

For Professionals

http://www.diabetes.org. Web site of the ADA.

http://www.jdf.org. Juvenile Diabetes Foundation.

http://diabetes.niddk.nih.gov/. National Institute of Digestive Disease and Kidney.

http://www.aadenet.org. Association of Certified Diabetes Educators.

http://www.aace.com/clin/guidelines/diabetes_2002.pdf. Diabetes Clinical Guidelines of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Manufacturers of insulin and diabetes supplies have Web sites that provide useful information about products.

For Consumers

http://www.diabetesmonitor.com. Diabetes Monitor.

http://www.childrenwithdiabetes.com. Children with Diabetes.

http://www.childrenwithdiabetes.com/d_06_150.htm. Software to download GB meter results to computer.

http://www.childrenwithdiabetes.com/d_0i_000.htm. Information about BG meters.

http://www.fatcalories.com/. Nutrition in the fast Lane.

For Professionals or Patients

http://www.cdc.gov/diabetes/. Website developed by the Centers for Disease Control and Prevention

http://www.joslin.org/main.shtml. Joslin Diabetes Program

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