This Article Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Silverstein, J. H. Articles by Malone, J. I. Search for Related Content PubMed Articles by Silverstein, J. H. Articles by Malone, J. I.

Strict Glycemic Control Is Necessary But Not Practical in Most Children with Type 1 Diabetes

University of Florida Gainesville, Florida 32608

John I. Malone

University of South Florida–Tampa Tampa, Florida

	Introduction

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 
LIMITED enthusiasm about the intensified approach to diabetes management in children comes from the evidence that type 1 diabetes with onset before 5 yr of age is associated with reduced neuropsychiatric function later in life. There is also evidence that children with diabetes onset between 5 and 9 yr of age also have some impairment of neuropsychiatric function when compared with siblings or other children of the same age who do not have diabetes. The primary accepted cause of this neurocognitive impairment is severe hypoglycemia, as there is evidence that hypoglycemic seizures cause cognitive decline. This is a topic of some importance because more intensified therapy designed to lower the glycated hemoglobin and the risk of microvascular complications of diabetes has also been shown to triple the frequency of severe hypoglycemia in comparison to conventional therapy. This review will discuss the complications of intensive therapy, with particular emphasis on the neurocognitive risks of hypoglycemia, impact of nocturnal hypoglycemia, and current ability to predict hypoglycemia.

This issue has come to the forefront because the Diabetes Control and Complications Trial (DCCT) showed that intensified therapy did, indeed, result in a reduction in the risk of microvascular disease. The method by which intensified therapy was provided was with multiple doses of insulin given before mealtime or the use of continuous sc insulin infusion with a pump. This required the frequent monitoring of blood glucose values before each meal and the active involvement of the patient in making adjustments for blood sugar levels outside the targeted range for premeal blood sugar levels. A side effect of this type of therapy was an increased incidence of severe hypoglycemia, defined as an episode in which the patients required the help of others to increase the blood sugar so that they could take care of themselves. There was a concern about how this increased frequency of severe hypoglycemia might affect the central nervous system, but studies that were performed during the DCCT indicated that individuals over the age of 13 suffered no long-term adverse effects. The DCCT study group concluded that because they had no subjects less than 13 yr of age and brain development continues until 9 or 10 yr of age, they could not make any recommendations about safety of intensive therapy in younger patients.

In the DCCT, the predictors of severe hypoglycemia were a history of severe hypoglycemia, lower recent hemoglobin A_1C, and presence of hypoglycemia unawareness (1). The adolescent patients had more frequent hypoglycemia than did the adults. No predictive model, however, was sufficiently sensitive to adequately identify candidates for intensive therapy who were at increased risk for hypoglycemia. The study conclusion was that efforts to maintain premeal and bedtime blood glucose levels between 3.9 and 6.7 mmol/L (70 and 120 mg/dL) will more than double the risk of severe hypoglycemia while causing temporary neurological impairment sufficient to prevent self-treatment. The critical question is whether the benefits of intensified diabetes management to reduce microvascular damage during prepubertal years is more important than the potential neurocognitive damage.

	Neurocognitive risks of hypoglycemia

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 
Several studies indicate that neurocognitive damage may be the most important consequence of hypoglycemia in young children. Rovet and Ehrlich (2) found that children with early onset diabetes, before 5 yr of age, scored significantly lower than normal in fine motor abilities and continuous performance attention tasks at 3 and 7 yr after diabetes diagnosis. The same authors found that 27 children in whom diabetes was diagnosed before 4 yr of age, especially females, scored lower on tests of visual spatial function than did 24 children who were more than 4-yr-old at the time of diagnosis and 30 sibling controls. A regression analysis showed that the age of onset of diabetes, as well as duration and history of hypoglycemic seizures, was associated with reduced visual spatial function. Although the children diagnosed young had decreased math abilities, there was no difference in verbal abilities unless the children had extensive school absence (3). Many of the children with diabetes diagnosed earlier than 4 yr of age had school problems, with 6 of 27 (37%) being in special education classes and 4 failing their grade, in contrast to 2 of 30 siblings who had failed a grade in school and of whom none were in special education. Ryan et al. (4) studied 125 adolescents with diabetes divided by age of diagnosis (before and after 5 yr) and 83 controls without diabetes. Those with early onset diabetes, in comparison to the later onset had decreased IQ on the WISC/R (P = 0.0005), decreased school achievement (P = 0.0001), decreased visual spatial ability, decreased memory (P = 0.0004), decreased motor speed, and decreased eye/hand coordination (4). Ack et al. (5) found that Stanford Binet measured IQs were lower in children with diabetes diagnosed under 5 yr of age than in their siblings. This was not true if diabetes was diagnosed after 5 yr of age (5). Holmes and Richman (6) also found decreased intelligence as measured by WISC/R or WAIS in children with diabetes onset less than 5 yr of age (6). In a study of electroencephalographs of more than 300 patients with diabetes, abnormalities were more common in children whose diabetes onset was between 2 and 5 yr of age or in those who had previous episodes of severe hypoglycemia (7).

The observation of decreased visual spatial function and intelligence in early onset diabetes is consistent with the time in which myelin is being formed during neural development, 2–4 yr of age. Diabetes affects myelination in diabetic rats because of defective incorporation of acetate and glucose into nerve lipids, as well as excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components (8). It is likely that the metabolic perturbations of diabetes have similar effects in the developing human brain. Many types of metabolic abnormalities have adverse effects on neurological development during brain growth and maturation, making it likely that hyperglycemia, as well as hypoglycemia, has adverse effects on neurological and neuropsychiatric development during early childhood.

In older children, on the other hand, abnormal neurocognitive function may be related only to the presence of severe hypoglycemia that results in seizures. Kaufman et al. (9) assessed neurocognitive functioning in 54 children 5–10 yr of age, 26 of whom were less than 5-yr-old at diagnosis. Thirteen age-matched nondiabetic siblings served as controls. Eight of 19 patients with a history of severe hypoglycemia experienced seizures; those with seizures had impaired fine motor and memory scores compared with patients without seizures (P < 0.01–0.03). Overall, there was no difference in neurocognitive functioning between the patients with diabetes and their nondiabetic siblings. The observation that patients with the lowest hemoglobin A_1C values had better academic achievement may be biased by the possibility that lower hemoglobin A_1C is achieved only by those children and families who have the cognitive skills and stability necessary for the most successful diabetes management (9).

These results are consistent with those of Rovet et al. (3) who found that, after 7 yr of diabetes, those children with a history of hypoglycemic seizures were more likely to decline in verbal intelligence than those without seizures. In addition, patients with a history of seizures demonstrated deficits in perceptual, motor, memory, and attention tasks, verbal learning, and executive processing (1).

In intensively treated patients who developed type 1 diabetes in adulthood no differences in psychometric test results were noted when those with a history of hypoglycemic coma were compared with those who did not develop coma and to healthy controls (10). These findings concur with those from the DCCT. This contrasts with a study of 13 children with type 1 diabetes mellitus treated with either an insulin pump or three to four injections daily who were compared with 12 children treated with two injections per day, and to a control group of 16 children who did not have diabetes. Similar to the findings in the DCCT, the intensively treated patients had three times more episodes of severe hypoglycemia than did conventionally treated patients. After 2–2.5 yr, the intensively treated patients had decreased ability with spatial memory tasks and pattern recognition compared with the patients treated with conventional treatment. All patients with diabetes had decreased performance on motor speed tasks compared with control children (11).

One of the most important unanswered questions in pediatric diabetology today is the effect of lesser degrees of hypoglycemia on neurocognitive functioning. In a longitudinal study from time of diagnosis of 23 children with diabetes onset before 5 yr of age, investigators recorded mean HgbA_1C and frequency of logbook blood glucose readings less than 2.8 mmol/L (50 mg/dL) and families documented the number of episodes of severe hypoglycemia. There was an inverse relationship between the frequency of asymptomatic hypoglycemia and scores on the revised Stanford Binet abstract/visual reasoning scale (r, -0.42; P = 0.022). This led to the conclusion that frequent asymptomatic episodes of hypoglycemia in children diagnosed at an early age resulted in decreased abstract reasoning (12). Reich et al. (13) found that 24 children had reduced motor performance and decreased attention and memory with acute hypoglycemia, which recovered slowly after feeding. This might affect school performance and explain the observed deterioration of verbal functioning over time in children with diabetes (13).

	Nocturnal hypoglycemia (NH)

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 
The effect of NH on neurocognitive function is an important consideration, as NH is more common than previously appreciated. The DCCT found that severe hypoglycemia occurred most often during sleep, with 43% of the episodes occurring between midnight and 0800 h (14). Appleton et al. (15) found that 13 of 29 prepubertal children had NH, defined as a blood glucose less than 3.5 mmol/L, (54 mg/dL) on the first study night, and 7 others had NH on a subsequent night. The median glucose nadir was 1.9 mmol/L (34 mg/dL), and the median duration of hypoglycemia was 270 min (range, 30–630). Higher insulin dose more than 0.8 u/kg·day (P = 0.006) and midnight blood glucose less than 7.2 mmol/L (130 mg/dL) predicted hypoglycemia. Although NH was followed by increased risk of depression, there were no effects on cognitive function (15).

NH, defined as a glycemic level less than 3.3 mmol/L (59 mg/dL), occurred in 49% of 150 children 2–16-yr-old monitored hourly overnight. Half of the episodes were asymptomatic. Two thirds of initial episodes occurred between 2200 and 2400 h and would have been missed in practice because most physicians advise checking for NH at 0100–0300 h. The predictors of NH were: two or more episodes of severe hypoglycemia in the previous month [odds ratio (OR), 2.8; P = 0.004], more than 5% of logbook glucose readings less than 3.3 mmol/L (59 mg/dL) during the preceding month (OR, 2.61; P = 0.04), young age (OR, 0.87; P = 0.0001), insulin dose more than 0.7 u/kg·day [relative risk (RR), 1.96; P < 0.001] in prepubertal children, and more than 1.2 u/kg·day in pubertal children (RR, 2.15; P < 0.001). Blood glucose levels were lower the morning after the episode in children with NH compared with those who did not develop hypoglycemia [i.e., 0700 h blood glucose <6.7 mmol/L (120 mg/dL) gave a positive predictive value of 62% with a negative predictive value of 90% (P < 0.0001)]. Low pre-dinner and 2200-h blood glucose levels also predicted NH, with a pre-dinner blood sugar less than 5.2 mmol/L (94 mg/dL) having a RR of 1.83 (P < 0.0001) and a 2200-h blood glucose level less than 6.7 mmol/L (121 mg/dL) having a RR of 2.3 (P < 0.0001).

Another study of 61 children, aged 2.6–8.5 yr, examined home blood glucose levels obtained at dinner, bedtime, 2300 h, 0200 h, and breakfast and found that 37.8% of children had levels below 3.5 mmol/L (64 mg/dL), 17% less than 3.06 mmol/L (55 mg/dL), 13% less than 2.5 mmol/L (45 mg/dL), and 8% were less than 2.0 mmol/L (36 mg/dL). NH was associated with lower glycated hemoglobin levels and young age, with 57% of children less than 5 years of age experiencing NH compared with 36% of children 5–8.5 yr of age (P < 0.001). Younger children were also less able to recognize the symptoms of NH. A blood glucose level of less than 7 mmol/L (128 mg/dL) at 2300 h was the best predictor for hypoglycemia at 0200 h (17). Feeding extra carbohydrate at dinner to a child with low pre-dinner blood glucose levels did not prevent NH.

The largest study of predictors of hypoglycemia in children was a cross-sectional survey of 22 pediatric departments from 18 countries in Europe, Japan, and North America. A single blood sample was obtained from 1443 boys and 1430 girls and sent to a central laboratory in Steno, Denmark, for hemoglobin A_1C determination. The age range of the children was 1–18 yr, with a median diabetes duration of 4 yr. Demographic information, insulin regimen, and number of severe hypoglycemic episodes, defined as unconsciousness or seizures occurring within the 3 months before the data collection, were recorded. Young age was a strong predictor of hypoglycemia, with a decreased incidence of 8.4% with each year of age; the incidence of severe hypoglycemic episodes in the 142 patients in the 0–4 yr age range was 59 per 100 patient years, 32% for the 468 patients in the 5–8 yr age range, and 18% in the 764 patients who were 9–12-yr-old. The other significant variable was hemoglobin A_1C, with a decrease in severe hypoglycemia of 21% for each increase in hemoglobin A_1C of 1%. Interestingly, patients in the eight centers with average subject hemoglobin A_1C levels below the overall mean did not have a significantly greater incidence of hypoglycemia than the eight centers whose patients had mean hemoglobin A_1C levels above the overall mean (18). It must be emphasized that in this large study only 34% of the children had hemoglobin A_1C levels less than 8%.

	Non-CNS complications of hypoglycemia

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 
It has been demonstrated that recurrent short-term hypoglycemia impairs hormonal counterregulation and symptom awareness (19). Intensive treatment (IT) not only increases the risk of recurrent hypoglycemia but also increases hepatic and peripheral sensitivity to insulin, further increasing the risk for severe hypoglycemia. In the early stages of diabetes the capacity to release glucagon during hypoglycemia is lost and, as the duration of the disease increases, the response of the other major counterregulatory hormone, epinephrine, may also decrease. Intensive insulin therapy seems to lead to further deterioration of hypoglycemic counterregulation and loss of hypoglycemia awareness. Lingenfelser et al. (20) performed two sequential euglycemic hypoglycemic clamp studies 3 days apart in 18 patients with type 1 diabetes. Eleven of these patients had three short-term hypoglycemic episodes before the clamp study; in those patients, there was a blunted response of epinephrine (P < 0.03) and cortisol (P < 0.01) after the repeated lows. GH was unaffected. The symptoms of hypoglycemia were decreased in the group with repeated hypoglycemia, especially for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and feelings of warmth (P < 0.05). Furthermore, there was decreased neurophysiological functioning determined by looking at the latency shift of auditory evoked potentials, a measure of the midbrain/auditory cortex (20). Because children exhibit both greater epinephrine responses and at higher blood glucose levels than do adults (21), the impairment of epinephrine secretion described above may be of particular concern for children, decreasing the ability of the child to identify hypoglycemia, thus delaying treatment. This may well result in more episodes of severe hypoglycemia. Indeed, of the hypoglycemic episodes that occurred while subjects were awake in the DCCT, 36% were not accompanied by warning symptoms (15). This is consistent with the finding that IT sufficient to decrease mean HgbA_1C levels from 10–12% to 7–8% decreases normal hormonal counterregulatory responses and lowers the blood glucose level at which hypoglycemia is recognized.

An additional adverse effect of IT is the blunting of the normal 10% or more decline in blood pressure (BP) during sleep. Diurnal ambulatory BP monitoring revealed no effect on daytime BP, but the nocturnal decline in both systolic and diastolic BP was less in 18 IT patients than in 18 computed tomography (CT) subjects (6% vs. 12% decrease in systolic BP, P < 0.01; 7% vs. 27% drop in diastolic BP, P < 0.01) (22). This is of concern in that recent studies have shown that lack of the nocturnal decrease in BP is associated with increased cardiovascular disease in subjects who do not have diabetes. The mechanism for this decreased nocturnal decline in BP was assumed to be an increase in catecholamine levels secondary to hypoglycemia, but neither blood glucose nor catecholamines were measured in these subjects.

	Discussion

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 
The benefits of intensified therapy in the DCCT for preventing or slowing the progression of microvascular disease were so compelling that clinicians have invested substantial effort to achieve the best possible control in all individuals with diabetes. IT, however, is more costly than CT, due to the more frequent physician and treatment team involvement and the greater use of diabetes supplies. Outside the DCCT the annual cost of intensive therapy using multiple daily injections was $2337 per patient, of pump therapy $4650, and of conventional therapy $1666 (23).

Not all children will be able to succeed with an intensified approach to diabetes management no matter how many resources are provided. Yet, determining which children are able to achieve excellent metabolic control without developing undue adverse reactions is problematic. The positive benefits attributed to intensified therapy during the DCCT were shown to accrue to individuals actively involved in the management of their blood sugar levels. It has never been shown that an outside individual managing the diabetes of younger children will result in similar beneficial reduction in microvascular disease. Intensive therapy involves behavioral change (24). Families with minimal financial resources, psychosocial problems, unstable lifestyles, and who lack personal commitment or social support systems are unlikely to successfully manage intensive therapy.

A 10% diminution in hemoglobin A_1C level was associated with a 40–45% lower risk for progression of retinopathy in the DCCT. It has been reported that the risk of developing complications increased dramatically when the glycated hemoglobin level was greater than two percentage points (>8% in DCCT) above the upper limits of normal (6% in DCCT) (25). The DCCT study group, however, indicates that the risk of developing retinopathy is a continuum during the progression of A_1C increase and there is no break-point where the risk of retinopathy dramatically increases. It has been estimated that for every 1% rise in glycated hemoglobin above 8% sustained for 3 or more years there was a 40–50% increase in the risk of developing microvascular disease (26).

Krolewski et al. (27) measured urinary albumin excretion in 1613 patients with type 1 diabetes and found that the prevalence of microalbuminuria rose steeply above a hemoglobin A₁ value of 10.1% (equivalent to a hemoglobin A_1C value of 8.1%). In this report, the odds of microalbuminuria increase by a factor of 2.4 as the hemoglobin A₁ increases from 10.1% to 12.1%, whereas the odds of developing microalbuminuria increase by only a factor of 1.3 when the hemoglobin A₁ increases from 8.1 to 10.1 (27). Thus, it would be helpful to identify a glycated hemoglobin level that would minimize development of complications later in life while keeping the adverse effects of intensive therapy to a minimum. The adverse events of IT were reported in a meta-analysis performed by Egger et al. (28) of 14 trials comparing 1028 patients treated with IT to 1039 patients receiving conventional treatment. The OR for hypoglycemia in the IT group was 2.99 (2.45–3.64), ketoacidosis (DKA) 1.74 (1.27–2.38), and for death from all causes 1.40 (0.65–3.01). The OR for DKA was dependent on type of IT used, with an OR of 7.20 for patients using the pump and 1.13 for patients taking multiple daily injections. Of the 26 patient deaths, 2 occurred in the IT group and were attributed to "sudden death," but none were proven to be the result of hypoglycemia. Five additional individuals in the IT group died as the result of DKA, whereas no one in the CT group died because of an acute complication of diabetes (P = 0.007) (28).

Although a normal hemoglobin A_1C level is the goal of therapy, the risk of severe hypoglycemia requires modification of this goal in most pediatric patients until we have a more effective and safe way to manage type 1 diabetes. This is particularly important for young children because they are at greatest risk for the development of severe hypoglycemia and brain injury, whereas they are less likely to recognize hypoglycemia and have little or no input into their diabetes management. Health care providers have been challenged to provide intensive therapy, but the goals of such therapy need to be individualized so as to avoid the significant adverse effects of such therapy. As R. Lorenz has said, "The challenge has many facets. Most physicians practicing today are not skilled in using the new treatment methods. The US health care system is not structured or financed in ways that facilitate optimal care of patients with diabetes. There are insufficient numbers of educators and nutritionists with the requisite knowledge and skills and too few settings where team care is available" (29).

As young children mature, goals should change and therapy adjusted to meet the evolving abilities of the child. Several large studies have demonstrated that only one third of children and adolescents are able to achieve HgbA_1C levels less than 8%. Because not all children will be able to successfully incorporate an intensified diabetes management regimen into their daily lives, it is important to set realistic and achievable goals for each patient. Intensification of treatment should occur only when the child and his/her support system understand the challenge and responsibility and are ready to accept it. This approach facilitates patient compliance, minimizes feelings of failure, and allows for incremental improvements in self diabetes management.

In summary, all patients with type 1 diabetes should receive treatment that maintains normal blood sugars as consistently as possible. The most effective treatment (intensified therapy) currently available (although quite crude and unsophisticated) requires frequent (4–10/day) blood glucose measurements and frequent adjustments in insulin, food, and exercise. This approach has not been shown to be either effective or safe for controlling blood glucose levels in children less than 13 yr of age. We must continue, however, to provide intensive involvement in the management of diabetes in these young children who are so dependent on their families and the medical community until we have an effective method to normalize their blood glucose.

	References

Top Introduction Neurocognitive risks of... Nocturnal hypoglycemia (NH) Non-CNS complications of... Discussion References

 

1. The Diabetes Control and Complications Trial Research Group. 1995 Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial. Diabetes Care. 18:1415–1427.[Abstract]
2. Rovet J, Ehrlich RM. 1999 The effect of hypoglycemic seizures on cognitive function in children with diabetes: a 7-year prospective study. J Pediatr. 134:503–506.[CrossRef][Medline]
3. Rovet JF, Ehrlich RM, Hoppe M. 1988 Specific intellectual deficits in children with early onset diabetes mellitus. Child Dev. 59:226–234.[CrossRef][Medline]
4. Ryan C, Vaga A, Drash A. 1985 Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics. 75:921–927.[Abstract/Free Full Text]
5. Ack M, Miller I, Weil WB. 1961 Intelligence of children with diabetes mellitus. Pediatrics. 25:764–770.
6. Holmes CS, Richman LC. 1985 Cognitive profiles of children with insulin-dependent diabetes. J Dev Behav Pediatr. 6:323–326.[Medline]
7. Gilhaus KM, Daweke H, Lulsdor F, Sachsse R, Sachsse B. 1973 EEG-Veranderengen Bei Diabetischen Kindren. Deutsche Medizinische Wocherschrift. 98:1449–1454.
8. Vlassara H, Brownlee M, Cerami A. 1983 Excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. Diabetes. 32:670–674.[Abstract]
9. Kaufman FR, Epport K, Halverson M. 1997 Neurocognitive functioning in children diagnosed with diabetes before age 10 years. Diabetes. 46:67A.
10. Kramer L, Fasching P, Madl C, et al. 1998 Previous episodes of hypoglycemic coma are not associated with permanent cognitive brain dysfunction in IDDM patients on intensive insulin treatment. Diabetes. 47:1909–1914.[Abstract]
11. Hersey T, Bhagava N, Sadler M, White N, Craft S. 1999 Conventional versus intensive diabetes therapy in children with type 1 diabetes. Diabetes Care. 22:1318–1324.[Abstract]
12. Golden M, Ingersoll GM, Brack CJ, Russell BA, Wright JC, Huberty TJ. 1989 Longitudinal relationship of asymptomatic hypoglycemia to cognitive function in IDDM. Diabetes Care. 2:89–93.
13. Reich, Jill N, Kaspar C, et al. 1990 Effect of hypoglycemic episodes on neuropsychological functioning in diabetic children. J Clin Exp Neuropsych. 12:613–626.[Medline]
14. The Diabetes Control and Complications Trial Research Group. 1991 Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med. 90:450–459.[Medline]
15. Appleton M, Beards F, Dungar DB, Ellard S, Hattersley A, Matyka KA. 1998 Genetic testing for maturity onset diabetes of the young in childhood hyperglycemia. Arch Dis Child. 78:552–554.[Abstract/Free Full Text]
16. Beregszàszi M, Tubiana-Rufin N, Benali K, Noël M, Bloch J, Czernichow P. 1997 Nocturnal hypoglycemia in children and adolescents with insulin dependent diabetes mellitus: prevalence and risk factors. J Pediatr. 131:27–32.[CrossRef][Medline]
17. Porter PA, Keating B, Byrne G, Jones TW. 1997 Incidence and predictive criteria of nocturnal hypoglycemia in young children with insulin dependent diabetes mellitus. J Pediatr. 130:366–372.[CrossRef][Medline]
18. Mortensen HB, Hougaard P. 1997 Comparison of metabolic control in cross-sectional study of 2,873 children and adolescents with IDDM from 18 countries. Diabetes Care. 20:715–720.
19. The Diabetes Control and Complications Trial Research Group. 1991 Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med. 90:450–459.
20. Lingenfelser T, Renn W, Sommerwerck U, et al. 1993 Diabetes. 42:610–618.[Abstract]
21. Jones TW, Borg WP, Boulware SD, McCarthy G, Sherwin RS, Tamborlane WV. 1995 Enhanced adrenal medullary response and increased susceptibility to neuroglycopenia. Mechanisms underlying the adverse effects of sugar ingestion in healthy children. J Pediatr. 126:171–177.[CrossRef][Medline]
22. Azar ST, Birbari A. 1998 Nocturnal blood pressure elevation in patients with type 1 diabetes receiving intensive insulin therapy compared with that in patients receiving conventional insulin therapy. J Clin Endocrinol Metab. 83:3190–3193.[Abstract/Free Full Text]
23. Herman WH, Dasbach EJ, Songer TJ, Eastman RC. 1997 The cost effectiveness of intensive therapy for diabetes mellitus. Endocrinol Metab Clin North Am. 26:679–695.[CrossRef][Medline]
24. Lorenz RA, Bubb J, Davis D, et al. 1996 Changing behavior practical lessons from the Diabetes Control and Complications Trial. Diabetes Care. 19:648–652.[Medline]
25. Tamborlane WV, Ahern J. 1997 Implications and results of the Diabetes Control and Complications Trial. Pediatr Clin North Am. 44:285–299.[CrossRef][Medline]
26. Edelman SV. 1998 Importance of blood glucose control. 1998 Med Clin North Am. 82:665–87.
27. Krolewski AS, Laffel L MB, Krolewski M, Quinn M, Warram JH. 1995 Glycated hemoglobin and the risk of microalbuminuria in patients with insulin dependent diabetes mellitus. N Engl J Med. 332:1251–1255.[Abstract/Free Full Text]
28. Egger M, Davey-Smith G, Stettler C, Diem P. 1997 Risk of adverse effects of treatment in insulin-dependent diabetes mellitus: a meta-analysis. Diabetes Med. 14:919–928.[CrossRef][Medline]
29. Lorenz R. 1998 The problem with intensive therapy. Diabetes Care. 21:2021–2022.[Medline]

This article has been cited by other articles:

				A. T. Soliman, M. Omar, M. M. Rizk, A. El Awwa, and F. M. AlGhobashy Glycaemic Control with Modified Intensive Insulin Injections (MII) Using Insulin Pens and Premixed Insulin in Children with Type-1 Diabetes: A Randomized Controlled Trial J Trop Pediatr, August 1, 2006; 52(4): 276 - 281. [Abstract] [Full Text] [PDF]

				A. L. Rosenbloom Is Strict Glycemic Control of Diabetes Necessary and Feasible in Most Children and Adolescents? J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 514 - 515. [Full Text]

This Article Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Silverstein, J. H. Articles by Malone, J. I. Search for Related Content PubMed Articles by Silverstein, J. H. Articles by Malone, J. I.