Rising incidence and challenges of childhood diabetes. A mini review

Abstract

Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010 – and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated β-cell destruction in Type 1 diabetes, and the β-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro-and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges.

INTRODUCTION

Childhood diabetes comes in many forms including rare conditions such as neonatal diabetes, chronic disease associated (e.g. with cystic fibrosis) and monogenic diabetes (e.g. maturity onset diabetes of the young). This presentation focuses on the two most common diabetes forms, Type 1 and Type 2 diabetes.

At the start of the 20^th century, Type 1 diabetes was infrequently observed and Type 2 diabetes was a diagnosis made only in adults. Even in the 1980s, there were hardly any pediatric cases of Type 2 diabetes with the exception of reports in minorities such as the Pima Indians (1). With the rise of obesity, this has dramatically changed over the past 30 years. Ever more frequently, the distinction between Type 1 and Type 2 diabetes is difficult since some youths present with features characteristic for both diabetes types (2).

In this review, we address the following relevant questions: What are the important etiologic factors leading to the continuously rising incidence of pediatric Type 1 and Type 2 diabetes? Which are the greatest challenges to be addressed in order to prevent and better treat childhood diabetes?

INCIDENCE AND ETIOLOGY OF TYPE 1 DIABETES IN CHILDREN AND ADOLESCENTS

Formerly known as juvenile or insulin-dependent diabetes, Type 1 diabetes mellitus’ became the generally accepted term with the recognition that older age does not protect from autoimmune diabetes and that many patients with long-standing Type 2 diabetes also require insulin. In contrast to the prevailing dogma that patients with Type 1 diabetes gradually lose all of their insulin-producing β-cells due to a T-cell mediated autoimmune attack, we and others have shown that a few, functional β-cells can be detected in almost all individuals irrespective of the duration of disease (3, 4). These remaining β-cells may present an opportunity for regenerative efforts in the future.

Worldwide, Sardinia in Italy and Finland are hot spots for Type 1 diabetes. In 2005, Finnish adolescents had an annual incidence of 64.2 per 100,000 persons per year (5). In the US, the current estimate is slightly below 30 new diagnoses per 100,000 per year across all ages with a considerable variation in different races and ethnicities (6) (Fig. 1). Overall, the worldwide incidence increases approximately 2–3% per year. In the European Diabetes (EURODIAB) study, it was shown that children <5 years of age belonged to the fastest growing group (7).

Fig. 1.

Rate of new cases of Type 1 and Type 2 diabetes among children, adolescents, and young adults <20 yr of age, by race/ethnicity, between 2002 and 2005. NHW: non-Hispanic whites; NHB: non-Hispanic blacks; H: Hispanics/Latinos; API: Asian/Pacific Islander Americans; Al: American Indians. Source: SEARCH for Diabetes in Youth Study (diabetes.niddk.nih.gov/dm/pubs/statistics/images/DMStats2011-Chart3.jpg&imgrefurl=http).

The value of diabetes registries cannot be overstated (8) since the recognition of geographic and temporal trends depends on the availability of large data sets. Such registries for Type 1 diabetes include the Diabetes Mondiale (DIAMOND) Project (9) worldwide and the EURODIAB study (7). In the US, national registries do not exist, instead local registries have provided important insights [e.g., the Allegheny County Type 1 Diabetes Registry (10)]. Since 2000, a wealth of knowledge in the field of pediatric Type 1 and Type 2 diabetes has been derived from SEARCH for Diabetes in Youth, a large, multicenter, epidemiologic study, conducted in 5 racial and ethnic groups (non-Hispanic whites, African-American, Hispanics, Asian/Pacific Islanders, and American Indians) at 6 sites (California, Colorado, Hawaii, Ohio, South Carolina, and Washington). SEARCH-based publications are summarized at http://www.searchfordiabetes.org/. Fortunately, funding for SEARCH has recently been renewed for an additional 5 years.

An excellent example for a global trend is the higher incidence of Type 1 diabetes in countries further away from the equator. This led to the ‘sunshine hypothesis’, which suggests that exposure to UV-B radiation, which converts 7-dehydrocholesterol to Vitamin D in the skin, is protective against autoimmunity in general, and Type 1 diabetes in particular (11). However, even in countries closer to the equator, more children are diagnosed with Type 1 diabetes, which in part may be related to local customs of protective clothing and prolonged time spent indoors leading to Vitamin D deficiency, but also to the fact that sufficient Vitamin D levels are not protective enough to ward off other etiological factors (12). In support of the ‘sunshine hypothesis’ are also data from NOD mice (13) and streptozotocin-treated rats (14) (two common animal models of Type 1 diabetes), in whom treatment with pharmacologic doses of Vitamin D helped lower the incidence of diabetes. To date, however, there is no good clinical evidence that Vitamin D supplementation prevents Type 1 diabetes in children.

Another explanation for the rising incidence of Type 1 diabetes is the ‘accelerator or overload hypothesis’ (15). Wilkin suggests that Type 1 and Type 2 diabetes are the same disorder of insulin resistance set against different genetic backgrounds. His theory does not argue against the presence of autoimmunity in Type 1 diabetes, only against its causative role. Other investigators may not support this view, but good evidence exists that faster linear growth (16), especially in the first year of life, and increasing body mass (17) contribute to Type 1 diabetes. Increased β-cell stress induced by hyperinsulinemia and decreased insulin sensitivity are plausible contributors to β-cell failure (18, 19). In individuals at risk for Type 1 diabetes, insulin resistance has been associated with progression to overt disease (20). Data from countries such as China, Japan, and Brazil are, however, somewhat difficult to reconcile with the clinical importance of this hypothesis because Type 1 diabetes has remained relatively rare despite the clearly rising incidence of childhood obesity (17).

A third explanation is the ‘hygiene hypothesis’ (21), which suggests that higher living standards associated with reduced exposure to microorganisms may lead to disordered regulation of the immune system. First supportive observations were made with allergic disorders (22) and were subsequently expanded to include autoimmune mediated illnesses. The originally formulated hypothesis had to be modified to accommodate the fact that both, the incidence of Th1- (e.g., Type 1 diabetes) and Th2-(e.g., asthma) mediated conditions increased in parallel. An alternative term ‘microbial deprivation hypothesis’ has been coined, which integrates the beneficial role of myriads of different non-pathogenic, commensal microorganisms, rather than infectious diseases, on proper development of the immune system (23). Specifically, the role of the intestinal microbiome in the pathogenesis of Type 1 diabetes is under intense investigation (24). Other investigators have focused on early infant nutrition (25) and additional environmental factors such as enteroviral infections (26). Knip recently challenged the diabetes research community to go beyond conventional epidemiology and add ‘etiological’ epidemiology in order to generate information on the causes of the rising incidence and prevalence trends (27).

INCIDENCE AND ETIOLOGY OF TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS

Similar to Type 1 diabetes, the nomenclature for Type 2 diabetes has changed. Terms like ‘adult onset’ or ‘non-insulin dependent diabetes mellitus (NIDDM)’ should be avoided for obvious reasons. Type 2 diabetes in youth was very rare until about two decades ago. According to the SEARCH study results, approximately 3000 children and adolescents in the US were diagnosed in 2002–2003 compared to about 1.4 million new cases in adults. Thus, describing its rising incidence as an ‘epidemic’ may still be an exaggeration, but this recent development is certainly of great concern (28).

In contrast to Type 1 diabetes, there is a paucity of ongoing interventional trials in pediatric Type 2 diabetes, which is mostly due to the disease’s recent emergence, but also due to a lack of an effective lobby [i.e., there is no equivalent to the Juvenile Diabetes Research Foundation (JDRF) for Type 2 diabetes]. Furthermore, there are many practical difficulties starting with recruitment (29). The largest and most important prospective, randomized interventional study is the Treatment Options for Type 2 Diabetes in Adolescents & Youth (TODAY) trial, comparing metformin alone, or metformin in combination with rosiglitazone or lifestyle modification (30). Recruitment took 2 years longer than expected, and study results are expected to be available in published form in the New England Journal of Medicine in June 2012.

The pathophysiologic components of insulin resistance and β-cell failure are probably similar in children and adults. In studies of offspring of parents with Type 2 diabetes, an impairment of the acute insulin response was frequently observed, which points to β-cell failure as the primary culprit (31). There are no prospective data available on the time course of β-cell failure in children before and after the diagnosis of Type 2 diabetes, in contrast to existing data in adults [e.g., from the United Kingdom Prospective Diabetes Study (UKPDS)]. Anecdotal reports support the notion that Type 2 diabetes in youth may be a more aggressive and faster progressing disease than in adults (32).

Knowledge of the genetic pathways leading to Type 2 diabetes in adults is rapidly growing (33) and analyses conducted in the TODAY Genetics Study are expected to provide more insights into the inherited predisposition of young individuals with Type 2 diabetes. Clinically, the strong genetic component is easily noticeable since approximately 75% of affected adolescents have first degree relatives with Type 2 diabetes (34). In concert with the genetic make-up, numerous environmental and epigenetic factors further contribute to the development of childhood Type 2 diabetes (Fig. 2).

Fig. 2.

Genetic predisposition and a combination of obesity and β-cell failure lead to Type 2 diabetes. Several epigenetic and environmental factors contribute to both, weight gain and loss of β-cell function. Purple arrows indicate the contribution to obesity, green arrows to β-cell failure. The appropriate references can be found in the text.

Support for the role of epigenetic factors comes from studies in children born to mothers who had undergone bariatric surgery (35). Children who were born before their mothers had weight loss surgery, had a higher risk of obesity and insulin resistance than their siblings born to the same mothers after they had lost weight. Similarly, offspring of mothers with gestational diabetes have a higher risk of developing obesity and Type 2 diabetes compared to offspring of the same mothers born after an earlier pregnancy not yet complicated by gestational diabetes (36). The other side of the coin, represented by studies in offspring of mothers exposed to famine and in children born with intrauterine growth retardation of other/unknown etiology also clearly shows the increased incidence of insulin resistance and Type 2 diabetes later in life (37). Examples of plausible direct and indirect mechanisms creating a pro-inflammatory environment, insulin resistance, and ultimately β-cell exhaustion include changes in the human microbiome (38) and environmental/behavioral stressors such as chronic sleep deprivation (39).

CHILDHOOD DIABETES WITH CHARACTERISTICS OF TYPE 1 AND TYPE 2 DIABETES

Some obese children present with diabetic ketoacidosis, may have autoantibodies to islet cells and glutamic acid decarboxylase but maintain euglycemia without insulin therapy after resolution of the acute metabolic derangement. The period of insulin independence is typically rather short and most children require insulin within a few months. Clinicians have suggested treatment with met-formin in these children in the interim (40). In adults, the phenomenon of ketosis-prone diabetes, which has also been called atypical diabetes, or Type 1B diabetes, has been predominately described in African Americans. Several detailed studies have been undertaken (41), but the exact pathophysiology remains poorly understood. A more common scenario, however, is the presentation of typical features of Type 2 diabetes in a youth, who upon further examination turns out to have signs of β-cell autoimmunity. This occurred in about 10% of children and adolescents who were screened for the TODAY study (2). The term ‘double diabetes’ has been coined by Pozzilli and Buzzetti (42) and aptly describes the dilemma of categorizing this new type of diabetes. It appears reasonable to assume that ‘double diabetes’ represents the presence of autoimmune or Type 1 diabetes in an obese child or adolescent.

TREATMENT OF CHILDHOOD DIABETES

Special consideration of cardiovascular disease

With modem insulin treatment, mortality from Type 1 diabetes has decreased dramatically. Data from the Allegheny County Type 1 Diabetes Registry documented that patients diagnosed between 1965 and 1969 had 40% higher mortality ratios compared to individuals diagnosed a decade later (10). With improvements in management of acute diabetes complications, cardiovascular disease, the number one killer in the US, has become the leading cause of death in patients both with Type 1 diabetes (43) and Type 2 diabetes (44). While hyperglycemia is the single most important risk factor for microvascular disease, glycemia’s direct influence on cardiovascular disease is confounded by numerous other risk factors, including those important in the general population (e.g. hyperlipidemia and smoking), and those more specific to Type 1 diabetes, such as nephropathy (45). In addition, in Type 2 diabetes, the relationship between glycemia and cardiovascular disease appears to be non-linear, with recent major clinical trials demonstrating increased cardiovascular mortality in patients intensively treated to reach very low glycated hemoglobin targets (46).

Traditional risk factors for Type 2 diabetes, such as insulin resistance and subclinical inflammation, have recently also become the focus in the field of Type 1 diabetes research. They may contribute to the increased cardiovascular risk observed in both populations, and are certainly heightened by the increasing prevalence of overweight and obesity in all young diabetes patients (47). Investigators of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study reported that individuals with Type 1 diabetes were half as insulin sensitive as body mass index-matched controls, and insulin resistance predicted the extent of the observed coronary artery calcifications in subjects with and without diabetes (48). Why insulin resistance in Type 1 diabetes is out of proportion to body fatness remains a subject of speculation.

Hyperinsulinemia, whether endogenous (in Type 2 diabetes) or exogenous (in both Type 1 and Type 2 diabetes) may be a major contributor to cardiovascular disease in diabetes. As discussed by Draznin in a recent editorial, insulin is a life-saving hormone, but in high concentrations it can substantially increase cellular mitogenic responsiveness to other growth factors, especially in the presence of insulin resistance (49). One pathway by which this growth-promoting effect occurs is excessive farnesylation and membrane association of Ras proteins, which may promote progression of cancer and vascular disease. The logical therapeutic consequence should be to provide as much insulin as necessary to achieve good blood glucose control, but to effectively improve insulin sensitivity and use insulin-sparing agents.

Beyond conventional pharmacotherapy

For patients with Type 1 and Type 2 diabetes, in addition to the obvious, but challenging choice of lifestyle modifications, numerous pharmacologic approaches have been tried. The insulin sensitizer metformin is the only approved oral agent for treatment of Type 2 diabetes in children (50), and is under study as an adjunct to insulin in children with clinical features of both Type 1 and Type 2 diabetes. Pramlintide, an analog of the β-cell hormone amylin, is Food and Drug Administration-approved in adults with both Type 1 and Type 2 diabetes, and results in improved post-prandial hyperglycemia with reduced insulin doses. Its effects are mostly due to slowed gastric emptying and less glucagon secretion. Numerous clinical trials with this agent are currently underway in pediatric patients. Incretin-based therapies, such the giucagon-like-peptide-1 analog exenatide are approved for treatment of Type 2 diabetes in adults, and are being studied in children with both Type 1 and Type 2 diabetes.

For patients with Type 1 diabetes, perhaps the most intriguing potential insulin-sparing agent is the adipocyte-derived hormone leptin, which was recently shown to normalize blood glucose in combination with low-dose insulin by markedly suppressing glucagon in diabetic mice (51). Leptin would only be expected to be beneficial in normal weight patients with Type 1 diabetes due to the existing leptin resistance in obese patients (thus excluding most individuals with Type 2 diabetes) (52). The recognition of leptin neutralizing antibodies associated with exogenous leptin therapy (in children with lipodystrophy) (53) and in combination with pramlintide in obese adults (54) may, however, prevent its broader application. Immunomodulatory interventions have so far been of limited effectiveness in the treatment of Type 1 diabetes (55) and recent results with the anti CD3 antibody teplizumab (56) and glutamic acid decarboxylase (57) vaccination therapy have been disappointing. Finally, the “artificial pancreas” (continuous blood glucose monitoring combined with a closed loop algorithm to automatically adjust insulin infusion rates in response to blood glucose) holds potential to reduce insulin doses, as well as hypo-and hyperglycemia, in Type 1 diabetes. However, unless insulin is infused directly into the portal vein, this technique will still be associated with peripheral hyperinsulinemia.

In adolescents with Type 2 diabetes, bariatric surgery appears to have similarly promising or even better results regarding improvement of cardiovascular risk factors compared to adults (58), in whom resolution of Type 2 diabetes has been reliably observed in about 80% of patients after gastric bypass (59). Modifications of existing surgical techniques or entirely new approaches, such as the endoscopic insertion of duodenal liners, are promising developments. Prospective clinical trials examining the long-term effects of bariatric surgery in young patients with Type 2 diabetes, such as Teen-Longitudinal Assessment of Bariatric Surgery (TEEN-LABS) (60), are much needed.

CHALLENGES IN THE FIELD OF CHILDHOOD DIABETES

The greatest challenge in the field of Type 1 diabetes is the identification of the initial process that sets off the immune system to attack ‘self’ – in this case pancreatic β-cells. Without this knowledge, it is unlikely that an effective prevention or an ultimate cure can be found. Even if we were capable of generating new β-cells with the help of regenerative medicine or transplanting ample numbers of islets, the underlying immune process will annihilate these efforts. The second greatest challenge is to change our treatment with its intrinsic dangerous acute and long-term effects. Recent JDRF Continuous Glucose Monitoring Study Group results (61) emphasize how commonly prolonged nocturnal hypoglycemia occurs, especially in young individuals, and that various strategies for changes in insulin administration may reduce its frequency. Improved algorithms and mathematical models combined with glucose sensors and insulin pump technology represent an enormous chance to improve quality of life and reduce complications. However, even with the advent of a well-functioning artificial pancreas the problem of non-physiologically high insulin levels in the periphery instead of in the portal vein is not resolved.

In Type 2 diabetes, effective strategies for both prevention and treatment have been well established in adults. Testing and translating these strategies into the pediatric population, however, has proved to be the fundamental challenge. The former surgeon general C. Everett Koop phrased it well: “Drugs don’t work in patients who don’t take them”. Similar to the patient described above, over half of adolescents with Type 2 diabetes fail to return for routine clinical follow-up over 2 years (62), and recruitment into clinical trials has proved equally challenging (29). The TODAY trial strikingly illustrates the medical, psychosocial, and socio-economical challenges faced by youths with Type 2 diabetes: poverty, low parental education, single-parent (or no parent) households, and strong genetic and cultural predisposition for obesity and diabetes (34). Effectively addressing these issues is crucial to optimizing medical management in this growing patient cohort.

The stage for a positive outlook toward the challenges ahead may be set with another quote: Theodore Roosevelt told us that ‘far and away the best prize that life has to offer is the chance to work hard at work worth doing’. Thus, let’s do it.