Tri-Point Series: Cause & Effect: Treatment Options, Environmental Factors, and Trial Results Dealing With Type 2 Diabetes in Adolescence

The current epidemic of pediatric obesity is a major contributor to the increased prevalence of insulin resistance, prediabetes, and type 2 diabetes mellitus in adolescents. Insulin resistance and type 2 diabetes are associated with an increased risk of cardiometabolic complications, leading to increased morbidity and mortality across the lifespan. Defining and diagnosing prediabetes and type 2 diabetes remains a challenge in this vulnerable population where the incidence ranges from 8% to 46% of all new diabetes cases referred to pediatric centers. Furthermore, lifestyle interventions do not appear as effective in children as in adults, and treatment options are more limited.

In this article, three experts discuss the challenges and advances in diagnosis and management of type 2 diabetes mellitus in adolescents: A clinical practitioner considers patient management, including treatment options and goals. A clinical researcher discusses the results of three clinical trials and their implications. Finally, a basic researcher reviews recent advances in our understanding of genetic and environmental factors contributing to disease risk.

CLINICAL PRACTITIONER PERSPECTIVE

While type 2 diabetes remains rare in adolescents, the obesity epidemic in childhood has introduced pediatric practitioners to an alarming increase in the number of adolescent patients with type 2 diabetes. These patients present with widely varying degrees of metabolic dysregulation; this presents diagnostic and therapeutic challenges in both the near and long term.

Clinical Presentation

Type 2 diabetes in childhood may present variably as an incidental finding on a blood sugar assessment of an obese adolescent with a dark, velvety skin rash and strong family history of diabetes, or with classical diabetic symptoms of polyuria, polydipsia, and weight loss in an obese pubertal child that may progress to ketoacidosis or hyperosmolar syndrome. Th e polyuria, polydipsia, weight loss, or ketoacidosis picture is similar to new onset type 1 patients, who may also present with obesity, thereby creating considerable confusion as to type of diabetes. Pinhas-Hamiel et al. have itemized frequent commonalities and differences between the two disorders, pointing out that the comorbidities of hypertension and dyslipidemia, in addition to the presence or absence of antibodies, may provide helpful clues to distinguish which form of diabetes is present.

Comorbidities and Complications

The comorbidities and complications of type 2 diabetes may present at the time of diagnosis. The TODAY trial, a study of the management of type 2 diabetes in adolescents with an average of seven months duration of diabetes, found that 26% of patients had blood pressure greater than the 90th percentile with 13.2% greater than the 95th percentile at baseline. At the same time, 79% had low HDL cholesterol (<40mg/dl for males, <50mg/dl for females) and 10% had high triglycerides (>200mg/dl). Eppens et al. observed earlier onset of hypertension and microalbuminuria in type 2 diabetics with similar duration of diabetes and better measures of blood glucose control compared to an age-matched type 1 diabetes population. These findings are supported by epidemiological data from Canada showing a fourfold increase in renal failure compared to age-matched type 1 diabetics as well as decreased 10-year survival.

Management guidelines are of major importance given the diffi culties of accurate diagnoses and implementation of appropriate management strategies, particularly as data demonstrate early and rapid progression of complications.

Management

Consensus guidelines representing the collaborative efforts of the American Academy of Pediatrics, the American Diabetes Association (ADA), the Pediatric Endocrine Society, the American Academy of Family Physicians, and the Academy of Nutrition and Dietetics ( formerly the American Dietetic Association) were recently published and address both diagnosis and management. The guidelines use the established diagnostic criteria of the ADA with emphasis on the need for repeated testing in the absence of symptomatology, and are composed of six key action statements [see table below] that highlight: 1) the need for insulin therapy in many patients with type 2 diabetes; 2) criteria for blood sugar and HgbA1c monitoring; 3) recommendations for nutritional counseling; and 4) the need for lifestyle modification along with medication as initial therapy. They identify, however, the limited repertoire of approved medications for use in the pediatric age group (insulin, metformin).

Furthermore, the TODAY trial documents a limited ability of lifestyle modification with or without metformin to slow the progression of diabetes in these adolescents, with 45.6% reaching treatment failure at a mean of 3.86 years (defined as a HgbA1c ≥ 8% for at least six months or metabolic decompensation requiring the use of insulin). Indeed, the most effective therapy made use of metformin and rosiglitazone, the latter of which is no longer available for use due to an increased risk for cardiovascular events in older adults.

Summary

Clearly, we have much to learn regarding the best treatment for these adolescents. Recognition of the disorder and appropriate management decisions regarding blood glucose control are of major importance to their future well-being. Given the ever increasing number of pharmacologic treatments available to treat type 2 diabetes in adults, research is needed to evaluate the safety and efficacy of these agents in adolescents, with an emphasis on those options that might slow the decline in pancreatic beta cell function.

CLINICAL RESEARCHER PERSPECTIVE

The Contribution of Large Clinical Studies

It is now almost two decades since the first reports of type 2 diabetes and other obesity-related comorbidities in children and adolescents began to appear. During this time, a first wave of important studies began to clarify the parameters of the problem and allowed us to move beyond anecdote and assumption. Th e largest of these studies, SEARCH, HEALTHY, and TODAY, illustrate the power of well-supported research consortia to address complex and diverse pediatric health problems, particularly when these disorders remain relatively rare.

SEARCH, a population-based registry and observational study supported by the Centers for Disease Control (CDC) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), consists of a consortium of six centers reflecting geographic and race/ethnicity diversity of the U.S. population. To date, SEARCH has provided reliable incidence and prevalence data for type 2 diabetes in adolescence and confirmed the age, gender, and race/ ethnicity distributions suggested by earlier case reports. Furthermore, SEARCH demonstrated that, despite a substantial rise in incidence during the late 1990s, type 2 diabetes remains a rare disorder in adolescence, with less than 4,000 new cases diagnosed in the U.S. annually. SEARCH has also provided insight into the clinical course of type 2 diabetes in adolescence and the prevalence of comorbidities.

HEALTHY, a NIDDK-supported study of schoolbased interventions to prevent diabetes in sixth to eighth graders, showed, first of all, that undiagnosed diabetes is rare even in at-risk adolescents, unlike in adults where nearly 50% of cases are undiagnosed. This suggests that type 2 diabetes in adolescence does not have an extended asymptomatic prodrome. In addition, HEALTHY demonstrated the challenges in changing the trajectory of obesity and metabolic risk even with comprehensive interventions.

TODAY, a 15-center, NIDDK-supported study of approaches to treatment of type 2 diabetes in adolescence, demonstrated that type 2 diabetes in adolescence is characterized by more rapid deterioration of beta cell function than in adults, with a majority of adolescents failing oral monotherapy within one year. In addition, lifestyle intervention does not add significantly to oral monotherapy in this population. TODAY has also shown that comorbidities, such as hypertension, dyslipidemia, retinopathy, and albuminuria, are prevalent at diagnosis in adolescents with type 2 diabetes and rise rapidly over the first few years.

Taken together, these studies have given us a much more rigorous understanding of type 2 diabetes in adolescence as a rare disorder disproportionately affecting ethnic, racial, and economic minorities, and that displays apparent biologic differences from type 2 diabetes in adults, including a short prodrome and rapid loss of beta cell function.

Implications of Pathophysiology for Prevention Strategies

Th e challenge for clinical researchers now is to incorporate the information from this first wave of studies into the design of the next round of prevention and treatment trials. In particular, the observation that type 2 diabetes remains rare, even among at-risk adolescence, implies that the progression from at-risk states to overt diabetes is limited, a fact that must be taken into account in the design and testing of prevention strategies.

If progression rates are low, then the most robust interventions will need to be tested in a sufficiently large cohort of the most at-risk adolescents for a sufficiently long duration to demonstrate any effect on the occurrence of overt diabetes. Given this, it is certainly reasonable to question whether such a large-scale trial would be financially and logistically realistic, particularly as type 2 diabetes in adolescents remains a relatively rare disorder. On the other hand, reliance on surrogate outcomes of “risk” for diabetes, such as insulin sensitivity and secretion, or extrapolating from adult interventions brings problems in the face of demonstrated differences in the pathobiology of type 2 diabetes in adolescence.

Investigators will need to consider whether to directly target prevention of diabetes, with the implications for study design that this entails, or whether it is more appropriate to target prerequisites for diabetes, such as obesity and its more common comorbidities such as hypertension, dyslipidemia, and fatty liver disease, with the assumption that successful prevention of prerequisites will inevitably lead to reduction in rates of diabetes without directly testing the latter. As of now, there has been no resolution of this conundrum.

Implications of Demographics for Clinical Trial Design

The second important observation from the first wave of studies, which has implications for the design of clinical research in this population, is the overwhelming predominance of low socioeconomic status in affected individuals. Successful research enrollment and retention in this population requires a high level of cultural sensitivity and experience, as well as sufficient staff and infrastructure to accommodate the frequently disorganized and stressful family situations in which these adolescents live. Therefore, study design and staff training must take into account what is realistic for these adolescents, while being attentive to the requirements of good clinical science.

Implications for Obesity Prevention

Finally, HEALTHY and TODAY have shown that it is difficult to reverse established obesity in at-risk children, and once type 2 diabetes is diagnosed, progression to requiring multiple medications to treat hyperglycemia, hypertension, dyslipidemia, and microalbuminuria is rapid. Above all else, these results make clear that the primary focus of efforts must be on prevention of diabetes through primary prevention of childhood obesity. A large societal effort will be required to accomplish this goal, with particular urgency to reduce pregnancies complicated by obesity and diabetes, which are known to be important risk factors
for off spring.

Summary

SEARCH, HEALTHY, and TODAY have demonstrated the importance of well-supported clinical trials for the study of rare pediatric disorders that cannot be studied at a single institution. Taken together, these trials have provided rigorous insight into early onset type 2 diabetes and delineated the parameters for the next cycle of studies addressing this biologically fascinating, but socioeconomically troubling disorder. The design of future studies in the prevention and treatment of type 2 diabetes in adolescence will need to address the low prevalence of type 2 diabetes in the population, the apparent rapid progression of beta cell failure in those individuals who develop diabetes, and, above all, the challenging sociodemographics of the at-risk population. However, lessons learned from SEARCH, HEALTHY, and TODAY will prove invaluable.

BASIC RESEARCHER PERSPECTIVE

At the heart of the epidemic of obesity and type 2 diabetes is a harmful interaction between components of an “obesogenic” environment and one’s individual genetic predispositions. This interaction is highlighted by classic examples such as the high rate of type 2 diabetes among individuals of Pima ancestry living in the Southwestern U.S. versus genetically matched counterparts living in rural Mexico. We are now beginning to understand the science behind how environmental factors and genes interact to create a “perfect storm” that, along with inactivity, sets children up for obesity and associated metabolic complications.

Genetic Factors

Millenia of genetic pressure have rendered human beings efficient at storing calories in white adipose tissue in order to survive periods when food is scarce. Unfortunately, the maintenance of these “thrifty” genes in the population may now render some individuals vulnerable to the ill effects of excess energy storage, given the overabundance of food in the developed world.

Though we do not know all the polymorphisms in our genome that are beneficial during starvation but detrimental when food is abundant, new genome-wide approaches are allowing us to tackle this important question. Although genome-wide association studies have been successful in finding single nucleotide polymorphisms (SNPs) in various genes that predict type 2 diabetes risk, these SNPs only account for a minority of the overall risk predicted based on family history alone. Therefore, there is much to the genetic risk that is still not understood. However, with newer deep sequencing technologies, we are now able to survey the entire genome with much higher resolution in order to identify a wider array of genetic alterations that predispose to type 2 diabetes and other diseases associated with obesity.

Additionally, we can now analyze the entire genome for transcriptional modulators and epigenetic factors that affect gene regulation and the pattern in which genes are turned “off ” and “on.” In this way, we are beginning to approach an era of “precision medicine” in which we will be able to provide infants and children with a genetic analysis of their diabetes risk and make appropriate patient-specific interventions.

Environmental Factors

What are the interacting environmental factors that enhance type 2 diabetes risk? Emerging research is focusing on dietary fats, carbohydrates, commensal microbes, and disruptive environmental chemicals and toxins. Dietary fats have been extensively studied for their metabolic impact. Obese individuals who never develop type 2 diabetes are more likely to accrue fat in subcutaneous depots (e.g., thighs, buttocks), whereas individuals who develop type 2 diabetes tend to accrue fat preferentially in visceral depots deep within the abdomen.

Such visceral adiposity is associated with fatty build-up in insulin-responsive, non-adipose tissues such as the liver, skeletal muscle, and pancreas, and in immune cells such as macrophages. This ectopic fat deposition alters the function of these cells and tissues, promoting inflammation and insulin resistance. Recent studies have focused on the predisposition of individuals to developing visceral and ectopic lipid deposition as independent risk factors for the development of type 2 diabetes. As an example, magnetic resonance spectroscopy showed that the lean, disease-free off – spring of patients with known type 2 diabetes are more likely to have ectopic lipid deposition in their skeletal muscle than are children born to disease-free parents. Determining what factors promote ectopic lipid deposition and how these lipids alter cellular function may lead to new ways to mitigate type 2 diabetes.

Storage and Inflammatory Effects of Fats

Ectopic lipid deposition is associated with low-grade inflammation in insulin-responsive tissues, and the intersection of immune and metabolic function is a major area in diabetes research. Beyond macrophages, this inflammatory response involves several immune cell types and secreted factors, including cytokines such as IL-1β and chemokines such as monocyte chemoattractant factor 1 (MCP-1). Many of these factors are being studied as biomarkers, and recent advances in high-throughput screening hold promise for discovering what circulating type 2 diabetes biomarkers are best at predicting type 2 diabetes risk in children.

What fats promote type 2 diabetes? A burgeoning literature points to saturated and trans fats as fueling tissue inflammation and metabolic compromise. In addition to red meat, these pro-inflammatory fats are enriched in processed foods. Th e ability to feed a large, growing global population relies on mass-produced processed foods, which particularly in emerging nations are sold primarily to children. Scientists, clinicians, and policy makers will want to focus on how to reduce the metabolic impact of pro-inflammatory fats present in these foods.

Sugars, Toxins, and the Obesogenic Enterotype

Commensal gut bacteria may also mediate dietinduced inflammation. Th e gut bacterial “enterotype” of an individual shifts in response to diet-induced obesity. This shift has the potential to modulate intestinal immune function and influence metabolic pathways. Interestingly, emerging research is focusing on whether shifts in gut microbiota can occur in response to exposures early in life, setting up a predisposition to obesity.

Excess sugars in foods and beverages can also alter cellular metabolism, for example in the liver. In addition to removing sugary products from the lives of children, determining the cellular effects of excess sugars may help identify new ways to prevent type 2 diabetes.

Environmental toxins and chemicals may have genetic, epigenetic, and potentially post-translational effects that also alter metabolic and inflammatory function. Given that young people are highly exposed to such agents, from pesticides to plastics, it is important to explore the link between these exposures and type 2 diabetes throughout human development. Indeed, recent work strongly suggests that maternal environmental exposures and nutrition can lead to fetal metabolic “reprogramming” that can produce longstanding consequences and impact type 2 diabetes risk after birth. Understanding the molecular determinants of fetal reprogramming may yield new approaches to control type 2 diabetes risk in children.

Summary

The link between genetic, nutritional, and other environmental factors on obesity and metabolic disease is being studied with more breadth and depth than ever before. New genetic, lipidomic, biochemical, and imaging modalities are being used to measure type 2 diabetes risk and to characterize early phenotypic changes that may serve as biomarkers for later disease. These approaches show promise as tools to help clinicians accurately detect type 2 diabetes risk early in life and off er personalized strategies to mitigate this risk and/or prevent type 2 diabetes altogether.

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