Pathophysiology of Type 2 Diabetes in Children and Adolescents

Abstract

Background: The prevalence of type 2 diabetes (DM) in children is disturbingly increasing in parallel with the increasing childhood obesity. Better knowledge regarding the pathophysiology of type 2 DM in children is paramount to devise an effective management plan.

Objective: Discuss the pathophysiology of type 2 DM in children and adolescents.

Methods and Results: This is a comprehensive review of the literature on this topic. Type 2 DM in childhood is viewed as a continuum of insulin resistance (IR) which is determined by an underlying genetic predisposition, intrauterine environment, excessive food consumption, continued rapid weight gain, and poor lifestyle. Besides IR, this is compounded by multiple metabolic defects including β-cell dysfunction and inadequate insulin secretion, α-cell dysfunction, hyperglucagonemia and increased hepatic glucose production, lipotoxicity, inflammation, deficiencies in incretin production and action, and increased renal glucose reabsorption. The confluence of genetic and environmental factors underscores the complexity in disease progression.

Conclusion: A consistent single risk factor for type 2 DM is obesity and related IR and therefore it is essential to curtail the progression of obesity. It is important to investigate the role of stringent dietary and nutritional approaches, medications that enhance β-cell function and insulin sensitivity.

1. INTRODUCTION

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.

2. MATERIALS AND METHODS

We performed a computerized PubMed search of English language original and review articles. This review provides a comprehensive summary of the unique pathophysiology of type 2 DM in children and adolescents.

3. RESULTS AND DISCUSSION

The core metabolic factors in the development of type 2 DM in children:

The core pathophysiologic defects include IR in the liver, muscle, adipose tissue, and eventual β-cell failure (Fig. 1). IR is the earliest metabolic abnormality that is present for years before the onset of type 2 DM. Overweight/obesity, continued weight gain, degree of weight gain, increasing Body Mass Index (BMI) percentiles, and consequent IR are the critical factors associated with the development of type 2 DM in children and adolescents [14-16]. Gaps exist on the best indicator of obesity, especially in ethnic minorities such as South Asians who have a higher predisposition for abdominal and visceral fat accumulation [17]. Therefore, some ethnicities may not require similar degrees of elevated BMI as other ethnicities to manifest type 2 DM [18]. Among the obese individuals, there is heterogeneity of fat composition with varying amounts of Visceral Adipose Tissue (VAT), Subcutaneous Adipose Tissue (SAT), and Brown Adipose Tissue (BAT) [19]. Even though BMI is traditionally considered as an indicator of obesity, excessive VAT predicts the development of cardiometabolic abnormalities such as IR, type 2 DM, chronic low-grade inflammation, atherogenic dyslipidemia, and hypertension [19, 20]. Ectopic fat accumulation includes storage of fat in non-adipose tissue such as myocardial and epicardial fat, intra and retroperitoneal fat, mesenteric fat, etc. On the other hand, brown adipose tissue has a positive influence in preventing type 2 DM. Both BMI and waist circumference areinadequate to assess the visceral adiposity.

Fig. (1).

Pathophysiology of type 2 diabetes in children and adolescents.

HGP- Hepatic Glucose Production, IR- Insulin Resistance, FFA- Free Fatty Acid.

Prevalence of type 2 DM is more common among children in the age group between 10 and 19 years, corresponding to the hormonal dynamics of puberty [6, 8, 21-23]. During puberty, there is a surge in growth hormone and Insulin-like Growth Factor-I (IGF-1), which increases IR [24]. Increased production of growth hormone and IGF-1 leads to IR through increased lipid breakdown and increased Free Fatty Acids (FFA) in the circulation. Almost always, the growth hormone driven IR is transient, and any hyperglycemia reverts to normal after puberty. Similarly, an increase in sex hormones during puberty, especially androstenedione, increases the Acute Insulin Response (AIR), which is an independent predictor of type 2 DM [25, 26]. Girls are more likely to develop type 2 DM than boys [3]. Insulin receptors on β-cells get overstimulated by pubertal estrogen, or environmental/exogenous estrogens, rendering β-cells more vulnerable at the time of higher β-cell turnover. This, in turn, is postulated to result in excessive insulin signaling, exacerbation of IR and ultimately to β-cell exhaustion [27]. Obese children who develop type 2 DM around puberty tend to deteriorate their diabetes control likely due to continued weight gain, increasing the degree of their obesity and persistent IR even post-puberty.

Puberty is not the single inciting factor insofar as many children are diagnosed before the onset of puberty [28, 29]. Maternal health during pregnancy, especially maternal diabetes, birth weight, post-natal rapid weight gain and type of body fat accrual after birth also contribute to the development of type 2 DM later in life [30-33].

The decline in insulin sensitivity heralds the progression from Normal Glucose Tolerance (NGT) to Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) to type 2 DM [34, 35]. The progression from NGT through stages of IFG, IGT and type 2 DM is not always sequential [35-39]. A decreased first phase insulin secretion and glucose disposition index (product of insulin sensitivity and β- cell function) are the hallmark of IGT which can progress to defective second phase insulin secretion [35]. Reduced glucose clearance after an intravenous glucose tolerance test (GTT) and high insulin response following an oral GTT are individual risk factors for type 2 DM [40]. Compensatory hypersecretion of insulin exacerbates oxidative stress, rapid decline in β-cell function and ultimately leads to attenuated insulin secretion [41-43]. The development of IGT indicates a significant functional defect of β-cell, i.e., about 80% of β-cell insulin secretory function is lost [44]. Persistent hyperglycemia further exacerbates β-cell damage (glucotoxicity) [45].

A strong genetic predisposition is a crucial determinant for developing T2DM [46-49]. Parental diabetes is a risk factor for the development of type 2 DM [14]. Factors that trigger the phenotypic expression of the T2DM are the rapidity and degree of weight gain, consumption of high calorie- high fat- high carbohydrate-high protein food, physical inactivity, and certain diabetes- inducing medications which are additive to the genetic susceptibility (gene-environment interaction). Genome-Wide Association Sequence (GWAS) studies have identified more than 65 genetic variants that increase the risk of developing type 2 DM. Most of these several Single Nucleotide Polymorphisms (SNPs) have an independent risk (INCOMPLETE) that is significantly small effect in causing T2DM. These could be modulated in the presence of environmental, non-genetic secondary factors that increase their susceptibility to the phenotypic expression of T2DM. Of these the genetic loci, some of the genes involved in either the production of glucose, β- cell function, insulin sensitivity, insulin signaling, pancreas development, and monogenic diabetes are TCF7L2, PPARG, HNF1A, HNF1B, HNF4A, MC4R, GIPR, GCKR, FTO, KCNJ11, KCNQ1, KCNQ1, GLIS3, NOTCH2, WFS1, IGFBP2, SLC30A8, HHEX, CDKN2A, CF7L2, CDKAL1, JAZF1 [50-59]. Table 1 illustrates common SNPs variants associated with future risk of T2DM. Table summarizes the genetic variants that are significantly associated with the risk of type 2 DM independent of clinical risk factors with their odds ratios.

Table 1.

Common genetic locus associated with risk of type 2 diabetes.

Genetic Locus	SNP	Chromosome	Risk Allele	Published Odds Ratio	Published P Value
NOTCH2	rs10923931	1	T	1.13	6.7X10−6
BCL11A	rs10490072	2	T	1.05	4.9X10−5
THADA	rs7578597	2	T	1.15	1.1X10−4
IGF2BP2	rs1470579	3	C	1.14	8.9X10-16
PPARg	rs1801282	3	C	1.14	1.7X10−6
ADAMTS9	rs4607103	3	C	1.09	3.1X10−4
WFS1	rs10010131	4	G	1.12	0.02
CDKAL1	rs7754840	6	C	1.12	4.1X10-11
VEGFA	rs9472138	6	T	1.06	4.1X10−5
JAZF1	rs864745	7	T	1.10	4.6X10−5
SLC30A8	rs13266634	8	C	1.12	5.3X10−8
CDKNA/2B	rs10811661	9	T	1.20	7.8X10-15
HHEX	rs1111875	10	C	1.13	5.7X10-10
CDC123	rs12779790	10	G	1.11	4.7X10−5
TCF7L2	rs7903146	10	T	1.37	1.0X10−48
KCNJ11	rs5219	11	T	1.14	6.7X10-11
INS	rs689	11	T	1.93	2.0X10-2
DCD	rs1153188	12	A	1.08	3.2X10−5
TSPAN8	rs7961581	12	C	1.09	3.7X10−5
FTO	rs8050136	16	C	1.17	N/A

Legend: Table summarizes the gent variants that are significantly associated with the risk of type 2 DM independent of clinical risk factors with their odds ratios.

Even though traditionally type 2 DM is characterized by the lack of β-cell autoantibodies, antibody positivity is observed in some cases. This variant of type 2 DM is called type 1.5 DM or double DM or latent autoimmune diabetes in youth [60, 61]. Overlap of autoimmunity is thought to accelerate the progression towards β-cell deficiency and insulin dependency. Rapid metabolic decline and accelerated progressions towards insulin tendency are frequently observed in children with type 2 DM [11, 12]. The rapidity of β-cell decline is accelerated in children compared to adults likely due to the vulnerability of the β-cell during a period of dynamic growth and maturation, the synergy between pubertal IR with IR of obesity, severity, and rapidity of weight gain, and the interplay of growth hormone, insulin, estrogen and other sex steroids.

4. INSULIN RESISTANCE

Type 2 DM is a continuum of IR. Even though the risk for IR may be mostly genetically determined, heritability is still not completely understood [62-64]. Moreover, IR is more pronounced by obesity and a sedentary lifestyle. Unlike their adult counterparts, children tend to overproduce insulin disproportionately in response to IR. While hepatic IR and impaired first phase insulin secretion areattributed to the development of IFG, peripheral IR is attributed to the worsening of glucose disposition and IGT. Studies have shown that peripheral IR plays a significant role in the initiation of type 2 DM [65].

Muscle IR contributes to 85-90% of reduced total body glucose disposal in individuals with type 2 DM. Impaired uptake of glucose in the peripheral tissues (liver, adipose tissue, and especially skeletal muscle) and increased HGP, as a result of the loss of negative feedback mechanism from glucose, promote hyperglycemia. The excess accumulation of fat in the liver, muscle and β-cells increase IR in these organs [44]. Increased intramyocellular lipid content is seen in children with obesity and exacerbates IR [66]. Increased FFA in the circulation (lipotoxicity) disrupts insulin signaling pathways and contributes to skeletal muscle insulin resistance. Abnormal insulin signaling underlines the defect in glucose transport [44]. Augmented FFA production in IR/ insulin deficient states can exacerbate HGP [67]. Pro-inflammatory chemokines and cytokines, produced in chronic low-grade obesity-induced inflammation, cause worsening of IR (vide infra).

Mitochondrial dysfunction is also a known factor in the development of IR. The inability of mitochondria in the liver and skeletal muscle to effectively oxidize fatty acids contribute to IR. This, in turn, affects the normal insulin signaling pathway in the peripheral tissues [68].

5. INSULIN SECRETORY DEFICIENCY

Defects in insulin secretion along with IR beget IGT and type 2 DM given the inability of the β-cell to respond to incremental changes in glucose. Insulin secretory defects contribute to the development of elevated fasting glucose and IGT. Similar to IR, insulin secretory defects can occur during the early stages of the disease ultimately resulting in rapid progression of IGT to type 2 DM in children. Impaired insulin secretion is a result of defective production in β-cells as well as decreased β-cell mass, the latter more pronounced among obese children compared to their normal weight counterpart [68, 69]. Studies have shown that insulin secretion in relation to insulin sensitivity is found to decline with the disease progression from IGT to type 2 DM. In addition to IR, adults have an impaired insulin release, even at the early stages of developing IGT [44, 70]. However, among obese children who have IGT, there is no significant impairment in the second phase of insulin secretion in response to IR. However, obese children who have overt type 2 DM manifest impaired β-cell function with combined reduced first phase and second phase insulin release following an oral glucose load [34, 39].

Role of proinsulin: IR in peripheral tissues results in increased production of proinsulin from the pancreatic β-cells. This is accompanied by a defect in the terminal cleavage of proinsulin to insulin leading to hyperproinsulinemia [71]. In children, proinsulin to insulin ratio is found to be increased only during the overt disease, unlike adults where the ratio is increased even as early as at the IGT stage [70, 72]. This could be partly explained by the fact that the production and cellular metabolism of proinsulin are age-dependent [68]. Compared to children with hyperglycemia, adults tend to lose the processing ability at a faster pace [34, 68]. Therefore, proinsulin may not be a reliable marker of β-cell function in IGT stages in children.

6. INCREASED HEPATIC GLUCOSE PRODUCTION

Hepatic IR: Following a meal, the secretion of insulin stimulates liver glucose uptake and glycogen storage which then suppress HGP. Due to hepatic IR, there is a failure to inhibit glycogenolysis and inability to suppress gluconeogenesis. Continued HGP along with reduced glucose uptake in peripheral tissue, such as skeletal muscle, results in persistent hyperglycemia [73]. The antithetical tandem of glucagon and insulin control HGP, by modulating enzyme flux and gene transcription [74]. The increased IR in the brain can augment HGP via neural signaling, independent of hepatic IR.

Hyperglucagonemia: In patients with type 2 DM, as a result of reduced insulin secretion and α-cell insulin resistance, the production of glucagon is not as tightly inhibited, leading to increased HGP [75, 76]. Moreover, there is also enhanced hepatic sensitivity to glucagon. Patients have increased glucagon concentration in the fasting state which is found to increase paradoxically following a carbohydrate meal. This is especially disconcerting given the fact that it occurs in a setting of hyperglycemia and hyperinsulinemia which would typically suppress plasma glucagon levels. Chronic β-cell dysfunction might result in α-cell dysfunction which would be a plausible explanation for this paradoxical glucagon increase postprandially. Increased glucagon secretion by the pancreatic α-cells plays an essential role along with ‘relative’ hypoinsulinemia in the pathogenesis of type 2 DM, i.e., the ‘bi-hormonal hypothesis’ of type 2 DM [76, 77]. In children with type 2 DM, hyperglucagonemia is determined by the duration of diabetes [78]. An increase in the α-cell mass in response to decreasing β-cell mass may also contribute to hyperglucagonemia typical of type 2 DM patients. Hyperglucagonemia plays a vital role in the progression from normoglycemia to IGT and may foretell IGT [77].

7. DYSREGULATION OF FAT METABOLISM

There are multiple dysregulated metabolic pathways ranging from increased FFA flux from adipose tissue, increased hepatic De Novo Lipogenesis (DNL) from excessive carbohydrate consumption, and elevated plasma Triglycerides (TG) that accelerate the progression from normal glucose tolerance to impaired GTT and diabetes.

Elevated FFA: Insulin plays a critical role in adipocyte lipogenesis by stimulating glucose transport and inhibiting lipolysis by Hormone-Sensitive Lipase (HSL). In the postprandial state, insulin ensures TG clearance and FFA delivery to adipocytes by enhancing actions of Lipoprotein Lipase (LPL). In obese individuals, there is adipocyte resistance to the anti-lipolytic actions of insulin and functional impairment in lipid storage in adipocytes which lead to increased FFA flux, systemic inflammation, and increased lipid accumulation in non-adipose tissues, such as skeletal muscle, liver, and β-cells. This fat accretion in non-adipose tissues promotes IR by affecting normal glucose metabolism [78, 79]. Elevated FFAs impede insulin's ability to suppress HGP, stimulate gluconeogenesis, decrease glucose uptake in peripheral tissues, worsen hepatic IR and negatively impact insulin secretion [67, 80-84]. Chronically elevated levels of FFAs cause lipotoxicity, increased HGP, and pancreatic β-cell death [85]. In sum, disturbed fatty acid metabolism in adipose tissue, liver, gut, pancreas, and skeletal muscle acting in concert lead to the increased peripheral IR and insulin deficiency.

Circulating plasma TG and dyslipidemia: Elevated plasma TG is common in IR states, and there is likely a bi-directional relationship between IR and elevated plasma TG. Dyslipidemia is a known risk factor for type 2 DM in children [86]. Increased fasting TG has been associated with IGT in children [38]. Elevated plasma TG interferes with insulin signaling pathways and increases IR and reduction of TG results in lowering of IR [87]. There is enhanced very Low-Density Lipoprotein (VLDL) synthesis which leads to elevated TG and low LDL, and reduced HDL [80, 88].

Lipogenesis in liver: Chronic hyperinsulinemia and excessive carbohydrate consumption stimulate DNL by increased FA synthesis from excessive production of acetyl-CoA subunits generated from glycolysis of refined carbohydrates, glucose and fructose [89] and can lead to fat accumulation in the liver and Non-Alcoholic Fatty Liver Disease (NAFLD). Increased FFA flux from IR can also exceed hepatic capacity for FA oxidation leading to hepatic steatosis [90]. High-fat diets can also trigger increased FA oxidation and generation of acetyl-CoA [91]. NAFLD, in turn, dysregulates gluconeogenesis [92, 93].

Adipocytokines and pro-inflammatory cytokines: Expansion of adipose tissue leads to the overproduction of adipocytokines exacerbating the metabolic dysfunction. Excess or deficiency of adipocytokines such as leptin or adiponectin can unfavorably impact insulin sensitivity [81, 94]. Various pro-inflammatory cytokines augment IR in an obese individual, especially pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF)-α, Interleukin (IL) -1, IL-1β, IL-6, IL-8 and Interferon-α (IFN-α) among several others [95, 96]. Chronic exposure to these inflammatory cytokines leads to the activation of cytokine signaling proteins, inactivation of insulin signaling receptors in the pancreatic β-cells, all of which promote lipolysis, hepatic IR and dyslipidemia. Similarly, intracellular lipid accumulation in liver and skeletal muscle exacerbates IR through proinflammatory cytokines [97]. Besides leading to IR, these pro-inflammatory cytokines along with pancreatic-derived factor (PANDER) also result in pancreatic β-cell apoptosis [98].

8. 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.

Increased renal glucose reabsorption: Renal tubular threshold for glucose reabsorption is raised in individuals with type 2 DM resulting in increased renal reabsorption of glucose [109].

Incretin deficiency or resistance: Incretins are enteroendocrine gut hormones produced following food ingestion and account for nearly 70% of insulin secretion after a meal. Type 2 DM is known to have impaired or absent incretin insulinotropic effect. Studies have shown that apart from the impaired insulinotropic effect, reduced incretin secretion may also contribute to type 2 DM [94, 110]. Glucagon-like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP) are the two key incretins that account for >90% of the incretin effect [44]. GLP-1 promotes β-cell proliferation and survival, suppresses glucagon secretion and alters gastric emptying, all of which contribute to glucose lowering. Also, GLP-1 enhances insulin sensitivity and peripheral glucose utilization. GLP-1 receptor agonist may emerge as a mainstay of treatment for adult type 2 DM. Youth with type 2 DM manifest a reduced incretin effect compared with their normal glucose tolerant counterparts, without significant differences in GLP-1 and GIP concentrations [111].

9. 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.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.