Pediatric type 2 diabetes mellitus complications: a systematic review of the literature

The incidence and prevalence of type 2 diabetes mellitus (T2DM) are increasing worldwide in the pediatric population. The increase has been attributed to obesity, lack of physical activity, improper diet, and family medical history. Type 2 diabetes mellitus has serious complications for children, including cardiovascular problems, dyslipidemia, hypertension, nonalcoholic fatty liver disease, pancreatic problems, pulmonary problems, and renal injury. Unfortunately, T2DM and its complications in the pediatric population remain largely understudied. As such, diabetes researchers, educators, and clinicians are forced to rely on information collected on adults with T2DM which may or may not be applicable to children with T2DM.

The foci of this paper are the epidemiology and pathophysiology of T2DM complications that occur in the pediatric population based on manuscripts that specifically address pediatric, not adult, T2DM. It is hoped that this review may be used as a basis to advance research on T2DM among children and, ultimately, to promote the timely and appropriate management and treatment of T2DM in children order to avoid the serious complications. The review does not address complications in the adult population. No inferences are made on metabolic syndrome; all the articles mentioned address T2DM. Also, the paper does not focus on the treatment of T2DM or its complications in children. Finally, it does not address research about type one diabetes mellitus (T1DM), nor does it make any inferences from T1DM to T2DM. It should be noted that many complications that occur among pediatric patients with T2DM can also present among adults with T2DM. But, that may not be true for everything.

Review
Type 2 diabetes mellitus (T2DM) was traditionally a disease of adulthood. Currently, the incidence and prevalence of T2DM are increasing among children and adolescents. In one study, about 45% of new cases of diabetes mellitus (DM) in the pediatric population were estimated to be T2DM [1]. However, firm rates of both incidence and prevalence of T2DM in children and adolescents are not available since T2DM is not reportable in any jurisdiction [2].
Because childhood risk factors for both cardiovascular disease (CVD) and T2DM may carry over into adulthood, universal screening of triglycerides, body mass index (BMI), and blood pressure (BP) has been advocated [3]. However, even the choice of screening methodology for T2DM among adolescents remains controversial [4]. The problem is compounded by the fact that most obese youth who are screened for diabetes also have normal fasting glucose levels [5].
The risk factors for the increase of T2DM in the pediatric population include obesity or BMI greater than 85% (which currently has a rate of about 49.3%) [6] and other causes (including increased consumption of cheap foods such as high fructose corn syrup) [7]. Childhood obesity is even a problem in some developing countries. For example, 41.8% of children in Mexico, 22.1% of children in Brazil, 22.0% of children in India, and 19.4% of children in Argentina are classified as obese [8]. As the incidence of T2DM is dramatically increasing among the pediatric population, so will the complications of the disease. This has been attributed to the population's limited physical activity [9,10]. The increasing problem of T2DM is also aggravated by the fact that the disease progresses faster among obese children than among adults [11]. Another challenge is that T2DM can be controlled by diet and exercise in only less than 10% of children with T2DM, thereby necessitating pharmacologic interventions [6].
Another factor in the increase of T2DM in children and adolescents is genetic influence. A strong family history of diabetes (FHD) is present in 45% to 80% of children 2 with T2DM [6]. Having diabetic parents is a risk factor for the development of T2DM among pre-pubertal Malays [12]. Children born to mothers with T2DM are particularly at increased risk for the disease when compared to children whose fathers had T2DM. The risk is higher for boys than for girls [13]. More females than males are diagnosed with T2DM during puberty; however, among adults, more males than females are diagnosed with T2DM [14]. An FHD is reflected in significantly lower serum adiponectin levels, independent of obesity. Yet, impaired glucose tolerance is about four times higher in obese children with a positive FHD than those who do not have a positive FHD [15]. Nevertheless, even though genetic factors are suggested by a strong FHD for T2DM, the molecular genetics is difficult to explain because of the very few subjects available for research and weak diagnostic criteria [16].
Nongenomic factors also play a role in the increase of T2DM in children and adolescents. Ninety-five percent of children in Canada with T2DM are obese and 37% already have at least one complication on initial diagnosis of T2DM [17]. In a study in the United States (US), overweight and obesity were present in 10.4% and 79.4% respectively of pediatric patients with T2DM [18]. Finally, in a study in Japan, obesity was noted in 83% of the children with T2DM [19]. Also, in Japan, insulin resistance, a feature of T2DM, was noted to gradually increase with the increase in weight in these children [20]. Another factor, besides obesity, in the development of pediatric T2DM is the peak of physiological insulin resistance. The age of 13.5 years can bring about overt DM in persons at risk for the disease [21]. The problem is compounded among female adolescents. Earlier pubertal timing has also been associated with development of T2DM and cardiovascular disease later in life [22]. Possible factors include reductions in insulin sensitivity and β-cell function, along with increased total and truncal fat, in females who undergo early onset of menarche [23].
Much of the information applied to pediatric type 2 diabetics has been adopted directly from studies addressing adults with T2DM. For example, increasing insulin doses are required for pediatric patients, but not for adult patients, with T2DM. Second, if the child has ketoacidosis at initial diagnosis of T2DM, β-cell decline will be greater over time [24]. However, information regarding adults with T2DM may not always be applicable to children with the disease. Unfortunately, the literature on T2DM among the pediatric population remains limited. As such, much of the management and treatment for both T2DM and its complications in the pediatric population are based mostly on information gathered from the adult population [25]. The lack of information about pediatric T2DM may influence the care delivered by healthcare professionals. Wong, Potter, Mulvaney, Russell, and Schlundt [26] reported a wide variation in the management of pediatric T2DM. Even the diagnosis of T2DM is variable; many children with T2DM are incorrectly diagnosed as having T1DM [21]. On the other hand, some children with T1DM are incorrectly diagnosed as having T2DM. One reason for the misdiagnosis is that many children with T1DM are also overweight at initial diagnosis [27]. Finally, glucose homeostasis alterations in obese adolescents can present before alterations in glucose tolerance occur; as such, complications such as cardiovascular disease may have begun by the time of the T2DM diagnosis [28].
Because there is very limited information about the incidence, glycemic control, and early treatment of pediatric T2DM [29], it is important that critical gaps in literature be addressed. This paper is a systematic review of the current literature regarding pediatric T2DM and its complications. It aims to highlight what is known about pediatric T2DM and the complications of the disease in the pediatric population. It is hoped that this review may be used as a basis for a more timely and appropriate management and treatment of pediatric T2DM to avoid serious long-term complications. Only studies directly addressing pediatric T2DM have been included in this manuscript. Information is presented about the following T2DM complications in the pediatric population: cardiac complications, dyslipidemia, hypertension, nonalcoholic fatty liver disease, pancreatic complications, pulmonary complications, and renal injury.

Cardiovascular complications
Cardiorespiratory fitness is usually low among children with T2DM. Regular physical activity is recommended to increase cardiovascular health and decrease long-term complications from DM [30]. One long-term complication may be coronary heart disease. One reason for possible future coronary heart disease is that high density lipoprotein (HDL) size shifts to smaller particles in children with T2DM. A major cause for the shift is insulin resistance [31]. Insulin resistance that develops during a person's youth can lead to increases in both morbidity and mortality across that person's lifespan [32]. One pharmacologic intervention used to counter insulin resistance in pediatric patients has been the administration of Metformin [32,33].
The changes that occur for T2DM are mirrored by the changes observed for obesity [34]. For example, carotid intima-media thickness (CIMT) has been noted to be thicker and stiffer among obese adolescents with T2DM than among lean adolescents without T2DM [35]. The change in CIMT results in reduction in flow-mediated dilation [36] and indicates a possible trend toward concentric remodeling [37]. Duration of diabetes, poor glycemic control, increased C-reactive protein, and body mass index have been shown to be correlated positively with increased CIMT [38]. Even race may play a role in vascular stiffness among adolescents with T2DM; African-American adolescents with T2DM have greater vascular stiffness than do age-matched Caucasian adolescents with T2DM [39]. Urbina, Gao, Kloury, Martin and Dollan (2012) concluded that the increased arterial stiffness was associated with obesity and blood pressure, but not necessarily insulin resistance [40]. Regardless of the causative factor, the vascular changes can predispose obese adolescents with T2DM to stroke and myocardial infarction later in life [35].
In addition to macrovascular changes, T2DM can also present with major microvascular induced complications. In a study conducted in south India on 368 children and adolescents with T2DM, 26 Even the brain might be affected by microvascular changes that occur from T2DM even before the onset of macrovascular disease [45]. Adolescents with T2DM were found to have significant reductions in hippocampal and prefontal volumes along with higher rates of global cerebral atrophy. Possibilities for causation include endothelialdependent vasodilation impairment by T2DM and reduced cerebrovascular reactivity to CO2. Previously, the effect of T2DM had been shown in older adults with T2DM and impaired cognitive function [45].

Dyslipidemia
Dyslipidemia occurs in individuals with T2DM and in those who are obese. In pediatric patients, dyslipidemia is significantly worse among those with T2DM when compared to those who are obese but without T2DM. Even with tight glycemic control, the dyslipidemia may persist. Nevertheless, primary data on dyslipidemia in pediatric T2DM patients remain limited [46]. The problem is compounded by differences among ethnic groups. For example, Canadian Aboriginal children with T2DM were less likely to present with dyslipidemia than White children with T2DM [17].
Elevated triglycerides occurred in the majority of Japanese pediatric patients with T2DM. Control of elevated triglycerides is important in preventing the development of cardiovascular disease [19] as dyslipidemia (including elevated triglycerides) is also a risk factor for the development of cardiovascular disease and atherosclerosis [46]. Malays (including Filipinos) are one group at high risk for both T2DM and dyslipidemia; the high incidence even occurs in the pediatric population [12]. However, even though T2DM, dyslipidemia, and hypertension during childhood may be antecedents for adult cardiovascular disease, screening for T2DM, dyslipidemia, and hypertension is not routinely practiced for pediatric patients [47].

Hypertension
Hypertension (HTN)  The development of HTN also varies according to ethnicity. Malays (including Filipinos) have a higher risk for developing pediatric T2DM than other Asian groups [52]. Hypertension is a prevalent comorbidity or complication among Malay children with T2DM for which prevalence is similar to that in developed countries [53].

Nonalcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) is indicated by elevated serum liver enzyme levels because of infiltration and accumulation of large triglyceride droplets within hepatocytes [48,54]. In one study conducted in Canada, adolescents with T2DM had nearly three times as much hepatic triglyceride as adolescents of a comparable weight but without T2DM [55]. As a consequence of the elevated tryglyceride levels, NAFLD is associated with hypertriglyceridemia [54], elevated alanine transaminase (ALT) levels and vitamin D deficiency [56]. Elevated liver fat in obese Hispanic adolescents was also associated with elevated/increased serum IL-8, nerve growth factor (NGF), acute insulin response to glucose (AIR) and homeostasis model assessment of insulin resistance (HOMA-IR) [57]. Unfortunately, NAFLD is the most common cause of childhood liver disease [54] and is common in pediatric patients with T2DM, dyslipidemia, and abdominal obesity [58,59]. Approximately 3% to 10% of children overall and 40% to 70% of obese children have NAFLD [60,61]. But, the situation is far from hopeless. Nonalcoholic fatty liver disease, as well as reduced insulin sensitivity, may be reversible by application of even a short-term diet and exercise program that induces weight loss [62]. If left untreated, however, NAFLD is progressive and may ultimately lead to cirrhosis later in either childhood or adulthood [63,64]. Other complications for NAFLD include a possible progression to hepatocarcinoma, liver-related death in adulthood [63], and development of cardiovascular disease [59].
A diagnosis based upon elevated liver enzymes is not necessarily sufficient to diagnose NAFLD. If ALT levels are elevated three times the upper limit of normal for more than six months, an abdominal examination using ultrasound should be performed to rule out the possibility of viral hepatitis [64]. Liver biopsy is required for accurate diagnosis and staging of the NAFLD [65].

Pancreatic complications
First-phase insulin and C-peptide decline in obese adolescents with T2DM. β-cell function in overweight and obese adolescents is impaired relative to insulin sensitivity [66]. This is due to the β-cell function rapidly declining, even without significant changes occurring concurrently, with peripheral or hepatic insulin sensitivity [67]. At the time of diagnosis with T2DM, adolescents already present with β-cell dysfunction that is comparable to that observed in their adult counterparts [68]. In response to β-cell dysfunction, Sajaarda, Michaliszyn, Lee, Tfayli, and Bacha (2012) recommended the use of HbA(1c) to be used as a screening tool to investigate the progression and even reversal of T2DM risk in such adolescents [66].

Pulmonary complications
Peak oxygen intake (indexed to fat mass) is adversely affected by T2DM during adolescence. When adolescents (aged 13-18 years old) were subjected to a graded maximal cycle ergometer test to exhaustion with indirect calorimetry, those with T2DM had 11% lower peak oxygen intake than their counterparts who had a similar weight but without T2DM [55].
Type 2 diabetes mellitus can also adversely affect breathing during sleep. Insulin sensitivity is negatively correlated with sleep fragmentation and intermittent hypoxemia in adolescent males. This was shown to be independent of age and adiposity. Moreover, it may be a precursor to the development of T2DM in obese adolescents due to the emergence of metabolic impairment [69].

Renal injury
Chronic kidney disease and end-stage renal disease (ESRD) can have their origins in childhood, particularly for children who are obese and have T2DM. Kidney failure caused by either type 1 or type 2 DM is uncommon during childhood. Children with T2DM are at higher risk for developing primary renal disease (e.g., IgA nephropathy, membranoproliferative glomerulonephritis) [70,71] and a four-fold increased risk for developing renal failure [72]. Children with T2DM also have a high risk of ESRD during early adulthood [73].
Years of hyperglycemia exert a contributing factor to the development of long-term complications [74]. As such, children diagnosed with T2DM should be screened with regards to glomerular filtration rate (GFR), blood pressure, and urinary albumin excretion rate (U-AER) [75]. Detection of microalbuminuria is the earliest possible marker for renal disease; it is also an independent predictor for future cardiovascular morbidity and mortality [70,76]. However, renal disease cannot be reliably determined solely by clinical and laboratory findings. Renal biopsy is needed to provide accurate diagnosis [77].

Conclusions
Although T2DM incidence and prevalence are increasing in the pediatric population, little is known about its serious complications in this population. Moreover, even when research is reported on the complications, the end results are still expressed in adulthood. Yet, the pathogenesis toward those end results needs to be investigated. Currently, diabetes researchers, educators, and clinicians rely mostly on information collected on adults with T2DM which may or may not be applicable to children with T2DM. To date, a number of complications have been identified regarding T2DM in children and adolescents including cardiovascular (coronary heart disease, macrovascular and microvascular changes, HTN), metabolic (dyslipidemia), hepatic (NAFLD), pancreatic (β-cell dysfunction), pulmonary (altered peak oxygen intake, sleep disorders), and renal (chronic kidney disease, ESRD). However, a high likelihood exists that other complications can be identified with further clinically oriented research. It is hoped that this review of literature may be used as a basis for a more timely and appropriate management and treatment of pediatric T2DM in order to avoid the aforementioned serious long-term complications.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
DJ and JJ both have made substantial and equal contributions to the following: conception of this manuscript, acquisition of data, writing of the manuscript, and checking it regularly and critically for important intellectual content. Both have read and given final approval of the version to be published.