Over the past 20 years, the prevalence of type 2 diabetes mellitus (DM) among children and adolescents has increased several folds in the United States [1-4] and the world [5, 6].
This increase among the pediatric age group is aligned with a parallel increase in childhood obesity.
Notwithstanding that the prevalence of obesity is no longer increasing in the United States, the prevalence of type 2 DM has increased thrice in this age group,
related to the increasing degree of severe childhood obesity among children and adolescents.
Compared to adults with type 2 DM who develop secondary complications at a later age despite being insulin resistant for years, children develop clinical DM and complications more rapidly and aggressively [7].
Adolescents with type 2 DM have very poor treatment outcomes and a rapid decline in their glycemic control with the current treatment protocols [8-12].
Patients with type 2 DM have a cluster of metabolic risk factors including obesity, Insulin Resistance (IR), hyperglycemia, dyslipidemia, hypertension, ectopic fat deposition and inflammation which predispose them to future cardiovascular disease (CVD) [5].
Data from the SEARCH for Diabetes in Youth study (SEARCH study) and the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial revealed a higher prevalence of atherogenic dyslipidemia, hypertension and albuminuria among youth with type 2 DM [11, 13].
Early onset of type 2 DM and prolonged exposure to these metabolic abnormalities amplifies the long-term micro and macrovascular complications of these children.
Microvascular complications are present even as early as the diagnosis which infers an earlier appearance of clinical complications as opposed to children with type 1 DM.
The purpose of this article is to provide in-depth pathophysiology of type 2 DM in children which may provide a roadmap of potential management strategies.
ROLE OF DIET
Dietary management is an integral part of diabetes management. High caloric, high fat and high carbohydrate diet have been implicated in the development of T2DM.
The standard American Diet, characterized by a high proportion of processed starches, high glycemic load, and added sugars, exacerbate these stresses on the physiological processes that regulate glucose metabolism.
Currently, there are no evidence-based guidelines or recommendations for macronutrient composition for children with type 2 DM.
Remission of type 2 DM in adults was successfully reported with a very low-calorie diet [99].
However, there is limited data from Randomized Clinical Trials (RCTs) to support the effectiveness of these recommendations to induce meaningful reductions in the incidence of childhood type 2 DM.
Weight loss through caloric restriction is unlikely to be practical in a growing population of children.
Glucotoxicity and lipotoxicity which ensue during
pre-diabetic IR state and following a dietary overload of glucose and FFA are factors which generate Reactive Oxygen Species (ROS) and oxidative stress with resultant generation of inflammatory mediators.
The excess carbohydrate consumption is well known to enhance insulin release, trigger and worsen IR with the resultant increase in dyslipidemia and hyperglycemia.
Short-term studies in adults suggest that, without restricting calories, change in diet composition alone by reducing intake of carbohydrate sources such as added sugars, high glycemic grains, and fructose can achieve weight loss and improved insulin sensitivity [100-102].
In adults with type 2 DM, a low carbohydrate diet resulted in a better lowering of HbA1C compared to low-fat diet, despite similar weight loss [103].
Theoretically low carbohydrate diet results in lower glycemic index foods, lesser carbohydrate consumption and improved insulin sensitivity [104].
High protein diet and increased circulating levels of branched-chain amino acids (BCAA), such as isoleucine, leucine, and valine could also serve as risk factors for developing type 2 DM [105]. Elevated circulating BCAA is thought to predict IR in obese children [106] and predict deterioration of glycemic control in adolescents [107].
The implication of macronutrient composition of the diet is not completely clear [108] and warrants further investigation with the comparison between low carbohydrate and low-fat dietary modalities long term.
FACTORS INHERENT TO THE PANCREAS
Size of the pancreas: In children without DM, the parenchymal and fat volume of the pancreas increase linearly up until the age of 20.
Increase in BMI has a positive association
with pancreas volume [112].
Obese individuals have a larger pancreas size compared to overweight individuals, and the latter exceeds those of normal weight [113].
Since obesity and IR are interrelated and concomitant, an increased pancreas size among individuals with IGT and insulin resistance can be postulated.
However, with prolonged hyperglycemia in long-standing type 2 DM and with the progressive decline in insulin secretion, pancreas volume may actually decrease.
Currently, there are no studies which analyze the volume of the pancreas in children and adolescents with type 2 DM.
Autopsy studies have shown significant loss of β-cell volume from NGT to overt type 2 DM in adults, and this finding suggests that 50% of the β-cell volume is diminished by the ‘pre-diabetes’ stage [114].
Magnetic Resonance Imaging (MRI) in adults with type 2 DM showed a 33% decrease in pancreatic volume among those with recently diagnosed type 2 DM compared to normal individuals.
Ectopic fat deposition and increased pancreatic fat content are associated with type 2 DM and a reduction in pancreatic TG deposition with weight loss correlates with improved insulin secretion.
This infers that increased pancreatic fat deposition among obese individuals attenuates insulin secretory ability that reverts with weight reduction [115].
Furthermore, amylin is deposited in the pancreatic islet cells in individuals with long-standing hyperglycemia and is thought to affect the β-cell function adversely.
CONCLUSION
The pathophysiology of type 2 DM in children and adolescents has some unique components. The progression of the disease occurs at a more rapid pace leading to the development of comorbidities at an early age which reinforces the need for early detection at the pre-diabetes stage.
There are several deficiencies in the current management approach. A major hurdle is how to prevent or treat IR early insofar as the progression from IR to type 2 DM is a continuum.
Intuitively, because the initial inciting factor is IR, an intense lifestyle program to ameliorate continued weight gain is mandatory to halt the progression of type 2 DM.
Even though there is ample evidence that weight gain and increasing BMI percentiles are the culprits in the epidemic of type 2 diabetes in children, aggressive management of obesity is not incorporated as part of the treatment.
We need to amend strategies for patient education since the current patient education techniques have not inevitably translated to behavioral changes. It is essential to alter the trajectory of the weight gain to prevent the development of diabetes.
Even though adult data are showing that restricting calories can result in the remission of type 2 DM [99], dietary modifications focusing on calorie restriction are harder to initiate and sustain in children.
It is essential to have an acceptable and sustainable dietary intervention where calories are not restricted.
Prospective RCTs concerning the macronutrient composition of diet for obese children are indicated.
Earlier diagnosis and management of diabetes increased the chance of durable glycemic control, and hence early identification of cases of type 2 DM is important [116].
A paradigm shift focusing on how to effectively treat the functional β-cell defects, β-cell loss, and other metabolic defects, while allowing for weight loss is paramount.
Even though traditional insulin treatment for uncontrolled type 2 DM corrects the glucotoxicity and lipotoxicity, the core metabolic defect, namely, IR, is not ameliorated by insulin treatment.
Moreover, insulin treatment is expensive, not well tolerated, leads to weight gain, and involves significant involvement from families and providers which result in barriers to medication adherence.
The currently approved metformin is a mild insulin sensitizer with reports of poor treatment adherence and poor glycemic control outcomes [8, 9, 11, 12].
There are no comparative studies on
insulin treatment vs. other agents in literature
in children with type 2 DM.
Well-designed prospective pediatric RCTs are needed to replicate their encouraging results in adults.
