Diabetes in Children and Adolescents: A Guide to Diagnosis and Management

By William V. Tamborlane

Currently, available information on pediatric and adolescent diabetes is limited to chapters in larger books covering the broader topic of pediatric endocrinology, and these do not have the space to delve into specific topics. This concise, timely book contains everything that a practicing provider needs to know in order to provide comprehensive, up-to-date care for children and adolescents with diabetes, from the latest methods for diagnosing various types of diabetes to integrating cutting-edge technology in the care of this patient population. Initial management, the use of insulin pumps, continuous glucose monitoring, and automated insulin delivery are discussed in detail, as are nutrition therapy, exercise, psychosocial challenges, acute and long-term complications, and future directions for treatment and research. Further, this book provides clinicians with guidelines for the implementation of best practices as outlined by leading associations such as the American Diabetes Association (ADA) and International Society of Pediatric and Adolescent Diabetes (ISPAD).   
The Yale Children’s Diabetes Program has been ranked among the best in the United States, including clinicians and researchers who are world-renowned for their efforts in improving the care of children with diabetes. This wealth of knowledge and experience positions the author team well as experts in this field.

• Language: English
• Publisher: Springer International Publishing
• Release date: Feb 12, 2021
• ISBN: 9783030641337

Book preview

Part IType 1 Diabetes

© Springer Nature Switzerland AG 2021

W. V. Tamborlane (ed.)Diabetes in Children and AdolescentsContemporary Endocrinologyhttps://doi.org/10.1007/978-3-030-64133-7_1

1. Introduction

William V. Tamborlane¹  

(1)

Yale-New Haven Children’s Hospital, Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA

William V. Tamborlane

Email: [e-mail]

Keywords

Pediatrics Type 1 diabetes Type 2 diabetes Treatment of diabetes

Introduction

To paraphrase Charles Dickens, it has been the best of times, as well as the worst of times, for youth with type 1 diabetes (T1D). As will be described in the first section of this book, there has been a virtual explosion in the development of advanced diabetes technologies during the past 20 years, such as new and improved insulin pumps and more accurate, real-time continuous glucose monitors (CGMs) for youth with T1D. Indeed, CGMs have been approved for use as a replacement for blood glucose meter measurements and begun to fill the full potential of insulin pump therapy by its incorporation into semi-automatic integrated insulin pump/glucose sensor systems. In these systems, insulin pump infusion rates are partially regulated automatically by changes in sensor glucose concentrations transmitted to mini-computers imbedded in the patient’s insulin pump. The first integrated devices that have been approved by regulatory agencies have been called hybrid closed-loop systems because patients still must activate their pumps manually to administer large boluses of insulin prior to meals and large snacks. However, changes in the rate of insulin infusion between meals and during the overnight period are controlled automatically based on changes in sensor glucose readings. There no longer are pre-programed basal infusion rates when these systems are running under automatic control between meals and during the overnight period. Moreover, integrated and stand-alone CGMs can transmit sensor data to the cloud and have those data transmitted to smart phones. Such devices are very popular with parents of young children with type 1 diabetes because they can follow changes in their child’s glucose levels over their phones in real time.

Nevertheless, too many youth with T1D fail to make use of new advanced diabetes technologies, HbA1c levels remain too high, and episodes of severe hypoglycemia and diabetes ketoacidosis occur too often, especially in adolescents with T1D.

Additionally, a plethora of drugs in more than four new drug classes have been approved for use in adults with type 2 diabetes (T2D). Until recently, however, the only drug that was approved for use in children and adolescents with T2D that was based on the results of a small randomized clinical trial was metformin, a drug that was approved for use in youth with T2D more than 20 years ago. In the second section of this book, we will explain why it has been so difficult to successfully complete randomized clinical trials to demonstrate the efficacy and safety of new drugs in youth with T2D. We will also indicate that we may be about to transform the treatment of pediatric T2D in the near future.

Putting Advances in Treatment of T1D in Perspective

At the successful completion of the Diabetes Control and Complications Trial (DCCT), which demonstrated the ability of intensive therapy to delay or prevent the development of diabetes complications in 1993, the DCCT Chair, Oscar Crofford, said, This is not the beginning of the end of T1D but rather the end of the beginning of trying to effectively manage T1D. Dr. Crofford foresaw the many challenges that patients and practitioners still faced in achieving and maintaining improved outcomes of diabetes. With this in mind, it is worthwhile to briefly review how far we have advanced in treating youth with T1D.

I began my postdoctoral fellowship in pediatric endocrinology at Yale in 1975, having just completed pediatric residency at Georgetown University. As chief resident at Georgetown, I helped institute a new way to treat children and adolescents with T1D who were admitted to the hospital for treatment of diabetic ketoacidosis. The new method of low-dose intravenous infusions of regular insulin (instead of large subcutaneous injections of insulin) was based on a paper by Professor George Alberti and colleagues published in the British Medical Journal [1]. Consequently, this approach has become the well-established standard of care for treatment of diabetic ketoacidosis. As a result, treatment of diabetes became an area of special interest for me [2].

Unfortunately, I didn’t realize how poor the treatment of youth withT1D was at that time. Specifically, regular, NPH, and Lente were the only insulins available and these were injected only once or twice a day. These agents were produced from insulin that was extracted from beef and pork pancreases, and their time-action profiles did not match the rates of carbohydrate absorption during meals and they were full of impurities that contributed to the development of lipoatrophy at injection sites. Even the syringes being used during in the 1960s and 1970s pale in comparison to today’s pens and tiny microneedles.

In what I like to call the Bad Old Days of Diabetes, we also did not have an effective way of monitoring treatment, since self-blood glucose meter monitoring wasn’t invented until 1979–1980. Instead, for years, youngsters were instructed to check the presence or absence of glucose in their urine, three or four times a day. In retrospect, this was a totally worthless endeavor. According to one of our parents, adjusting insulin doses based on monitoring urine glucose is like trying to hit a baseball by its shadow. Another parent told me, it’s like driving a car that only registers speeds over 180 miles/hour. One of the early pioneers in the development of blood glucose monitoring had T1D, himself. He told me that he started measuring fingerstick blood glucose levels because he couldn’t understand why he felt like he was hypoglycemic even when his urine still tested positive for glucose.

Of course, we tortured our T1D patients even further by asking them to collect all of their urine on the day prior to their scheduled visit, in four separate aliquots: breakfast to lunch, lunch to dinner, dinner to bedtime, and overnight. We even scheduled our diabetes clinics on Monday, so families could bring in these collections immediately after the weekend. Incredibly, we often adjusted breakfast and dinner insulin doses based on 1 day of urine collections—ALSO WORTHLESS! In retrospect, in those days, we simply gave enough insulin to encourage normal growth and to prevent diabetic ketoacidosis. It’s no surprise that once we were able to measure HbA1c levels, almost all of our patients had values that were >11.0%.

Turning the Corner

1979–1980 saw the introduction of the first tools that provided more physiologic insulin delivery and better ways to monitor blood glucose control. Our contribution was to show that the continuous subcutaneous infusion of insulin by a miniaturized infusion pump was a more physiologic and effective method of replacement of insulin in T1D than one or two daily injections of insulin [3]. The success of insulin pump therapy was followed by the introduction of multiple daily injections of short- and long-acting insulins; both pumps and injections came to be known as basal/bolus therapy. At the same time, the ability to monitor the effectiveness of treatment of diabetes was transformed by the introduction of self-monitoring of blood glucose (SMBG) and the realization that measuring glycosylated hemoglobin (especially HbA1c) provided a simple test that reflected average blood glucose levels over the past 3 months.

These advances made the DCCT possible, since we were able to achieve and maintain HbA1c levels that were substantially lower in participants randomized to the intensive treatment group than the conventional treatment group during the 10 years of that study (Fig. 1.1). Even more important, the DCCT conclusively established that lowering blood glucose and HbA1c to levels as close to normal as possible could delay or prevent the development of diabetic retinopathy (the primary outcome of that study), as well as other diabetes-related vascular complications [4, 5]. Long-term follow-up of DCCT participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study has continued to demonstrate the benefits of strict metabolic control [6, 7]. One of the truly amazing aspects of DCCT/EDIC is that nearly all participants have continued to be seen for follow-up for more than 35 years.

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Fig. 1.1

Differences in HbA1c levels in patients randomized to the conventional and intensive treatment groups in the 10 years of treatment in the Diabetes Control and Complications Trial (DCCT). (From the DCCT Study Group (Ref. [4] below))

So, What’s the Problem?

While most of the participants who were randomized to the intensive treatment group in the DCCT did very well in achieving strict metabolic control of diabetes. The rate of severe hypoglycemia increased by threefold, especially in individuals with the lowest HbA1c levels [4]. Moreover, the assistance and encouragement provided to participants by our dedicated cadre of nurse coordinators played a very important role in the success of the DCCT, which was difficult to simulate in clinical practice. Indeed, HbA1c levels increased from ~7.0 to ~8.0% in the prior intensive treatment group when they returned to regular clinical practice, whereas HbA1c fell from ~9.0 to only 8.0% in the former conventional group who received training in intensive treatment at the end of the DCCT (Fig. 1.2).

../images/477065_1_En_1_Chapter/477065_1_En_1_Fig2_HTML.png

Fig. 1.2

Changes in HbA1c in the two former treatment groups in EDIC

Consequently, considerable effort has been spent over the past 27 years to increase the efficacy of insulin treatment without increasing the rates of severe hypoglycemia. These efforts have resulted in the introduction of both fast-acting and long-acting insulin analogs, increased use of new and improved insulin pumps, and development of real-time continuous glucose monitors of sufficient accuracy to replace the need for SMBG testing. It should be noted, however, that none of these advances reduced the burdens of managing T1D or parental fears of hypoglycemia and diabetic ketoacidosis.

The continuing challenges of treatment of T1D, especially in adolescents, is well illustrated by initial data collected regarding clinical outcomes in the T1D Exchange Clinic Registry of >26,000 patients with T1D in the USA [8]. Across all age groups, teenagers between 13 and 18 years of age had the highest HbA1c levels, reaching values just below 9.0%, not far removed from baseline HbA1c levels of teenagers enrolled in the DCCT more than 35 years ago. Indeed, few patients in this age group achieved target HbA1c levels <7.5% and it took until age 30 for HbA1c levels to fall to values seen in older adults (i.e., ~7.5%). I like to call this the Peter Pan scenario, namely, young adult males who fail to mature until past 30 years of age. Moreover, follow-up data from the T1D Exchange Registry showed that HbA1c levels actually increased in adolescents, the risk of severe hypoglycemia and DKA remained high, and ≤50% of pediatric patients were using advanced diabetes technologies [9].

Is There a Light at the End of the Tunnel?

My colleagues and I strongly believe that we are poised at the edge of transformational advances in the treatment of youth with T1D, namely, significant advances in therapy that improve clinical outcomes, while simultaneously decreasing the burdens of diabetes treatment. Consequently, we have dedicated the first section of this book to a number of chapters describing the advances that have had the greatest impact on the treatment of youth with T1D, including the state of the art in insulin pumps, the newest generation of continuous glucose monitoring (CGM) devices, and, most importantly, the integration of CGM into semi-automatic, hybrid insulin pump/CGM systems.

Our book chapters will cover bread and butter issues like the following:

The pathophysiology of type 1 and type 2 diabetes

Diagnosing diabetes

Initial management of youth with type 1 diabetes

Types and actions of different insulins

Insulin pump therapy

Monitoring glycemic control

Important educational and life-style factors like the following:

Medical nutrition therapy

Exercise and diabetes

Psychosocial challenges of T1D

Other factors like the following:

Acute complications of diabetes

Sick day management

Screening for co-morbidities

Adjunctive therapies not named insulin

Screening for co-morbidities

Patients’ views of the challenges of managing T1D as a child and adolescent

Automated insulin delivery systems

What About Pediatric Type 2 Diabetes (T2D)?

The obesity epidemic in the USA and around the world has been accompanied by the relatively recent discovery that obese youngsters can develop T2D, usually between the age of 10 and 18 years. Consequently, we have committed the second section of this book to the challenges of caring for youth with T2D. The TODAY study demonstrated that most adolescents with new-onset T2D can be adequately managed by metformin alone, even if they require initial treatment with insulin to rapidly correct glucotoxicity [10]. However, the TODAY study also demonstrated that metformin monotherapy often fails rapidly, requiring addition of a second drug to maintain target HbA1c levels [11]. While adults with T2D have a plethora of choices of new drugs for add-on treatment to metformin, insulin was the only other drug approved for use in youth with T2D for the past 20 years. Unfortunately, the efficacy of insulin for rescue treatment of youth with T2D has generally been disappointing for many reasons. Consequently, it is very encouraging that treatment choices for youth with T2D are beginning to expand, as illustrated by the approval of use of the GLP1 agonist, liraglutide [12], and the approaching completion of several other pivotal trials of other new drugs for treatment of youth with T2D [13]. Since virtually all youth with T2D are obese or overweight, the approval of new medications for treatment of obesity may also benefit youth with T2D. Hopefully, we’re about to turn the corner from the worst to the best decade for treatment of pediatric T2D; only time will tell.

References

1.

Page MM, Alberti KG, Greenword R, Gumaa KA, Lowy C, Nabarro JD, Pyke DA, Sonksen PH, Watkins PJ, West TE. Treatment of diabetic coma with continuous low-dose infusion of insulin. Br Med J. 1974;2:687–90.PubMedPubMedCentral

2.

Tamborlane WV, Genel M. Discordant correction of hyperglycemia and ketoacidosis with low-dose insulin infusion. Pediatrics. 1978;61:125–7.PubMed

3.

Tamborlane WV, Sherwin RS, Genel M, Felig P. Reduction to normal of plasma glucose in juvenile diabetics by subcutaneous administration of insulin with a portable infusion pump. N Engl J Med. 1979;300:573–8.PubMed

4.

The DCCT Research Group. The effect of intensive diabetes treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. N Engl J Med. 1993;329:977–86.

5.

The DCCT Research Group. The effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: the Diabetes Control and Complications Trial. J Pediatr. 1994;125:177–88.

6.

Nathan DM. for the DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37:9–16.PubMed

7.

DCCT/EDIC Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381–9.

8.

Miller KM, Foster NC, Beck RW, Bergenstal RM, Dubose S, DiMeglio LA, Maahs DM, Tamborlane WV. Current state of type 1 diabetes treatment in the US: updated data from the T1D exchange clinic registry. Diabetes Care. 2015;38:971–8.PubMed

9.

Foster NC, Miller KM, DiMeglio LA, Maahs DM, Tamborlane WV, Bergenstal R, Clements M, Rickels MR, Smith E, Olson BA, Garg SK, Beck RW. State of type 1 diabetes management and outcomes from the T1D exchange in 2016-2018: comparison with 2010-2012. Diabetes Technol Ther. 2019;21:66–72.PubMedPubMedCentral

10.

Laffel L, Chang N, Grey M, Hale D, Higgins L, Hirst K, Izquierdo R, Larkin M, Macha C, Pham T, Wauters A, Weinstock RS. for the TODAY Study Group. Metformin monotherapy in youth with recent onset type 2 diabetes: experience from the prerandomization run-in phase of the TODAY study. Pediatr Diabetes. 2012;13:369–73.PubMed

11.

TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–56.PubMedCentral

12.

Tamborlane WV, Fainberg U, Frimer-Larsen H, Hafez M, Hale PM, Jalaludin MY, Kovarenko M, Libman I, Lynch J, Rao PV, Shehadeh N, Turan S, Weghuber D, Barrientos-Pérez M, Barrett T. Liraglutide in children and adolescents with type 2 diabetes. NEJM. 2019;381:637–46.PubMed

13.

Van Name M, Klingensmith K, Nelson B, Wintergerst K, Mitchell J, Norris K. Tamborlane WV for the Pediatric Diabetes Consortium. Transforming performance of clinical trials in pediatric type 2 diabetes – a consortium model. Diabetes technology and therapeutics. Diabetes Technol Ther. 2020;22:330–6.PubMed

© Springer Nature Switzerland AG 2021

W. V. Tamborlane (ed.)Diabetes in Children and AdolescentsContemporary Endocrinologyhttps://doi.org/10.1007/978-3-030-64133-7_2

2. Pathophysiology of Types of Pediatric and Adolescent Diabetes

Stephan Siebel¹  , Pamela Hu¹   and Rachel Perry²  

(1)

Yale-New Haven Children’s Hospital, Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA

(2)

Yale University School of Medicine, Cellular & Molecular Physiology and Internal Medicine (Endocrinology), New Haven, CT, USA

Stephan Siebel (Corresponding author)

Email: [e-mail]

Pamela Hu

Email: [e-mail]

Rachel Perry

Email: [e-mail]

Keywords

Insulin secretionC-peptideInsulin actionHLADiabetic ketoacidosis

Introduction

Diabetes mellitus encompasses a group of multifactorial, genetically heterogeneous metabolic disorders all of which result in defective glucose metabolism secondary to absolute or relative insulinopenia or both. Even though the etiology may vary among different types of diabetes, they all share a common pathophysiology of hyperglycemia, leading to polyuria, polydipsia, weight loss, and eventually resulting in microvascular and macrovascular complications that increase morbidity and mortality for people with diabetes. Table 2.1 summarizes the different types of diabetes.

Table 2.1

Different type of diabetes