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Is Strict Glycemic Control of Diabetes Necessary and Feasible in Most Children and Adolescents?

Department of Pediatrics Children’s Medical Services Center Gainesville, Florida 32608

	Introduction

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THIS question, at least the second part, was a whole lot easier to answer 20 yr ago, when urine glucose measurement was telling us little or nothing about glycemic control (1), than it is today. We now have improved insulin preparations and delivery systems, means of short-term and long-term metabolic monitoring, more practical and patient friendly dietary recommendations, and improved understanding of psychosocial issues and educational techniques. We also have the evidence that striving for near normal glycemic control is possible and reduces the risks of long-term complications. Nonetheless, the physiologic replacement of insulin remains an elusive goal. As Robert Tattersall noted years ago, insulin is given in the wrong place (SC instead of portal), at the wrong time (often after the blood glucose is elevated), and in the wrong amounts (not enough for the meal and too much for the fast).

The first part of the question posed in this controversy finds no disagreement. In fact, Silverstein and Malone (2) rejected the title assigned to them, Strict Glycemic Control Is Not Necessary and Not Practical in Most Children with Type 1 Diabetes, removing the first not. In the enthusiasm to apply the lessons from the Diabetes Control and Complications Trial (DCCT), it should not be forgotten that substantial risk remained despite the impressive effort and improvement in glycemic control. This relation tempers risk-benefit considerations in children. Furthermore, it cannot be gleaned from the DCCT whether strict control before adolescence is important for the reduced risk of complications. When the clock starts running for complications has been the subject of considerable discussion, with the general consensus that the clock starts with the onset of diabetes but speeds up markedly with maturation. There are few data to use for assessing a risk benefit ratio of strict control in the preadolescent patient. Complications have been recorded before or early in adolescence, with severely compromised control. Such patients also have limited joint mobility (LJM), growth failure, and delayed sexual maturation (3). Tamborlane and Grey (4) include short adult stature as one of the reasons for strict control, particularly during the pubertal growth spurt. The data for relative short stature resulting from childhood diabetes predate the modern treatment era, however. As these authors note, the general diabetes control in the child and adolescent population has improved substantially since the start of the DCCT. Twenty years ago, we found that 37% of children without LJM and 77% with LJM were less than the 25th percentile height for age (5). Currently, only 22% of those without LJM and 33% of those with LJM are less than the 25th percentile, and the prevalence of LJM has decreased 4-fold (6). These results further indicate overall improved control in the past 20 yr. They also indicate that the clock starts running early, because LJM is an indicator of increased risk for long-term complications.

The feasibility part of the question, encompassing issues of resource availability and safety, as well as treatment methods, provides the faint whiff of controversy in this topic. Tamborlane and Grey (4) consider that the average HgbA_1c levels in pediatric diabetes clinics currently being comparable to those achieved by adolescents in the DCCT is an argument for the feasibility of strict control. It is difficult, however, to see how generally good control in a population or in an individual is assurance that strict control is attainable. They define a group of adolescents in whom they have effectively worked toward this goal, finding considerably less hypoglycemia with pump administration than with multiple injection. As Silverstein and Malone (2) caution, however, it is not appropriate to apply this experience, which requires a certain level of maturity and personal commitment, to younger children whose diabetes is managed by someone else. They further caution that intensive therapy involves behavioral change, and families with minimal resources, psychosocial problems, and instability, and lacking in social support, will be incapable of sustaining a child in this endeavor.

In both of the discussions, the worries about neurocognitive effects of hypoglycemia are expressed, of greatest concern with the youngest patients. Silverstein and Malone (2) thoroughly review the numerous studies of neurocognitive changes related to early-onset diabetes and to hypoglycemia. One comes away from this discussion especially concerned about long-term effects on the developing brain of the increased risk of apparent and unrecognized hypoglycemia with tight control during the first 7–10 yr of life. Also worrisome is the diminution of the sleep-associated blood pressure decline with intensive therapy, which might have long-term effects on cardiovascular disease risk.

Both sets of contributors emphasize individualizing goals to obtain the best diabetic control possible for that individual and family, an objective that has not changed over the decades, although, happily, the expectations have. The authors also emphasize the problem of finding the money and personnel needed for broad application of intensive therapy as in the DCCT model. Not only efficacy, but safety, depends on the intensity of involvement with the treatment team.

Tamborlane and Grey (4) note that the use of the more rapid onset and shorter-acting insulin that has been modified to have less self affinity (lispro) can reduce the risk of hypoglycemia. Other modifications are being made to the insulin molecule to produce the ideal long-acting no-peak basal requirement (7). Inhaled insulin, with a rapidity of onset and duration of action comparable to lispro, though inefficient with 30% absorption, offers the advantage of needless administration (8).

The enthusiasm expressed by Tamborlane and Grey (4) for continuous online measurement of plasma glucose levels as potentially the most important advance in the past 20 yr would be appropriate if such were the start of a true automatic pancreas, activating implanted pumps with glucagon and insulin. What is available is a long way from this. The device discussed is used intermittently to provide a true 24-h profile of SC fluid glucose concentration, which is correlated to plasma glucose by frequent calibration using the patient’s blood glucose monitor. The wonderful thing about this device is that a several day profile can be obtained in real-life for planning insulin injections or pump setting. It has to be downloaded by the physician, and in no way can it be used continuously or for immediate or day-to-day decision-making. These limitations have not been clear in the popular press. How useful this device will be in children and adolescents remains to be seen. The phenomenal day-to-day variability in activity, emotional status, and eating behavior, particularly among adolescents, may limit the value of an occasional profile.

The viewpoints expressed by the two groups of correspondents are fundamentally similar and differ primarily in emphasis, both viewpoints summarized in the goal noted above. The reader will take from these articles that which fits his or her particular philosophy and bias. This was emphasized to me some 20 yr ago when I was speaking in a large city that had two university children’s hospitals. After my talk at one of these hospitals the physician who practiced pediatric diabetology thanked me heartily for emphasizing the realities and limitations in treating children with diabetes, because students and residents came from the other hospital having been taught that rigid control was necessary and feasible, which at that time meant negative glucosuria and, not infrequently, seizures. The next day I spoke at the other hospital, following which the pediatric diabetologist was effusive in her appreciation for my emphasizing the importance of tight control, especially for the students and residents who were from the hospital where the diabetologist believed in "loose control." Same talk!

	References

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1. Malone JI, Hellrung JM, Malphus EW, Rosenbloom AL, Grgic A, Weber FT. 1976 Good diabetic control—a study in mass delusion. J Pediatr. 88:943–947.[Medline]
2. Silverstein JH, Malone JI. 1999 Strict glycemic control is necessary but not practical in most children with type 1 diabetes. J Clin Endocrinol Metab. 85:518–522.[Free Full Text]
3. Grgic A, Rosenbloom AL, Weber FT, Giordano B, Malone JI, Shuster JJ. 1976 Joint contracture: common manifestation of childhood diabetes mellitus. J Pediatr. 88:584–588.[CrossRef][Medline]
4. Tamborlane WV, Grey M. 1999 Is strict glycemic control of diabetes necessary and feasible in most children and adolescents? J Clin Endocrinol Metab. 85:515–518.[Free Full Text]
5. Rosenbloom AL, Silverstein JH, Lezotte DC, Riley WJ, Maclaren NK. 1982 Limited joint mobility in diabetes mellitus of childhood: natural history and relationship to growth impairment. J Pediatr. 101:874–878.[Medline]
6. Infante JR, Rosenbloom AL, Silverstein JH, Garzarella L, Pollack BH. Limited joint mobility (LJM) and stature in childhood type 1 diabetes (DM1): improved methods of control are making a difference. Proceedings of the 81st Annual Meeting of The Endocrine Society, San Diego, CA, 1999.
7. Rosskamp RH, Park G. 1999 Long-acting insulin analogs. Diabetes Care. 22(Suppl 2):B109–B123.
8. Gelfand RA, Schwartz SL, Horton M, Law G, Pun EF. 1998 Pharmacological reproducibility of inhaled human insulin pre-meal dosing in patients with type 2 diabetes mellitus (NIDDM). Diabetes. 47(Suppl 1):A99.

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