Type 2 diabetes in children

The emergence of type 2 diabetes mellitus (T2DM) in childhood is likely due to a combination of nature and nurture. The major etiologic factor is obesity, although the in-utero environment, birth weight, early childhood nutrition, puberty, sex, ethnicity, and genetics also play a role in the development of insulin resistance and predisposition to T2DM in childhood.[4][26] Infants born small for gestational age and those born with macrosomia are also at increased risk for the development of obesity, metabolic syndrome, and T2DM in childhood.[27][28]

Obesity

The recent rapid increase in the prevalence of T2DM in young patients is most likely due to changes in the environment: most importantly, the increasing prevalence of obesity.[26]
Most children have overweight (body mass index [BMI] 85th to 95th percentile for age and sex) or obesity (BMI >95th percentile) at diagnosis.
Children with obesity have hyperinsulinism, and they have approximately 40% lower insulin-stimulated glucose metabolism compared with children without obesity.[29][30][31]
Total obesity is not as important as location of adipose tissue in causing insulin resistance.[32] Visceral fat is more metabolically active than subcutaneous fat in producing adipokines that cause insulin resistance.[33]

In-utero environment

Studies in the Pima Indians of Arizona found that children exposed to a diabetic intrauterine environment had a 3.7 times increased risk of developing childhood T2DM as compared with siblings born before the mother became diabetic.[34]

Birth weight and early childhood nutrition

The association of lower birth weight with later development of insulin resistance, impaired glucose tolerance, or T2DM suggests that in-utero programming limits beta-cell capacity and induces insulin resistance in peripheral tissues.[35]
Rapid catch-up weight gain between birth and age 2 years in babies born with a low birth weight has also been found to be associated with increased central adiposity and insulin resistance.[36][37]
It is currently unclear whether the association of low birth weight with insulin resistance, glucose intolerance, and central adiposity is primarily due to the prenatal growth restraint and limited nutrients in utero, to the rapid postnatal catch-up growth, or to a combination of both these factors.
Breast-feeding during infancy has been suggested to be protective against the development of T2DM in later childhood.[38] Breast-feeding reduces the odds ratio for childhood obesity by approximately 20% as compared with formula feeding.[39] This reduction is thought to be due, in part, to the fact that breast-feeding results in lower rates of infant weight gain as it provides more appropriate caloric intake at a critical stage in development than bottle feeding, which is more likely to be associated with over-feeding and obesity.
An association between high protein intake in infancy and later obesity has also been suggested.[39] Protein intake is 55% to 80% higher per kilogram of body weight in bottle-fed than in breastfed infants.[39]

Puberty

The average age of diagnosis of T2DM in children/adolescents is 13.5 years (i.e., during puberty).[22]
Compared with prepubertal children or young adults, puberty is associated with relative insulin resistance, reflected by a two- to threefold increase in the peak insulin response to oral or intravenous glucose and a 30% lower insulin-mediated glucose disposal.[30]
When present with preexisting insulin resistance, puberty may precipitate beta cell failure.[30]

Sex

In young-onset type 2 diabetes, females are affected more than males.[9]

Ethnicity/race

The majority of childhood-onset T2DM occurs in children from a high-risk racial/ethnic background.[9] These include African-American, Hispanic, American-Indian, and Asian or Pacific Islander.[10][11]
Although the risk groups can vary from country to country, the most at-risk group globally are Asian Indians.[12] As compared with white children, those of Asian Indian ancestry manifest adiposity, insulin resistance, and metabolic perturbations of obesity earlier in life, and have a tendency toward central adiposity even with a similar BMI.[13]
Ethnic differences in insulin sensitivity are indicated by greater insulin responses to oral glucose in African-American children and adolescents compared with European-American children, adjusted for weight, age, and pubertal stage.

Genetic predisposition

An underlying genetic predisposition is emphasized by the fact that only a minority of children with obesity develop T2DM.
Other evidence supporting a genetic etiology comes from family clustering and segregation analyses indicating a 3.5 times greater risk of developing T2DM in siblings of affected individuals as compared with the general population, and from studies of monozygotic twins indicating an 80% to 100% concordance.[40]
T2DM in children and adolescents, as in adults, is polygenic. More than 20 loci have been linked to or associated with T2DM in adults, the most important being NIDDM1, described among Mexican-American sibships in Starr County, Texas.[41]

Inflammatory cytokines and hormones, secreted by excess adipose tissue, are associated with a diminished ability of insulin-sensitive tissues to respond to insulin at a cellular level.[32] This insulin resistance is the first step in the development of type 2 diabetes mellitus (T2DM).

Visceral fat is more metabolically active than subcutaneous fat in producing adipokines that cause insulin resistance. The amount of visceral fat in adolescents with obesity directly correlates with basal and glucose-stimulated insulin levels and inversely with insulin sensitivity.[42] Removal of subcutaneous adipose tissue in adults, with liposuction, does not significantly alter levels of adipokines, insulin sensitivity, or other risk factors for coronary heart disease (e.g., hypertension, dyslipidemia), thus emphasizing the importance of the location of excess adipose tissue.[43]

Beta cells of the pancreas, early in the disease, compensate for this cellular insulin resistance by increasing insulin secretion. Eventually, however, the compensatory beta cell response fails and glucose intolerance develops. Failure of the beta cell to produce sufficient insulin to allow appropriate glucose utilization at the cellular level is the underlying cause of the transition from insulin resistance to clinical T2DM.

Autoimmune T2DM is seen in 15% to 30% of clinical T2DM in childhood. Adults with T2DM who are diabetes-specific antibody-positive have less overweight, are younger, and more likely to require insulin than those who are antibody-negative.

Elevated ceramide in skeletal muscle and an elevated hepatic alanine aminotransferase are also both associated with a decline in insulin sensitivity and the development of T2DM.[44][45]

Due to the overlap in pathophysiology between diabetes, cardiovascular disease, obesity, and chronic kidney disease, some groups argue that these conditions should be considered to be on a single spectrum known as cardiovascular-kidney-metabolic (CKM) syndrome. The American Heart Association, notably, has endorsed this terminology and advocates screening from age 3 years.[46] See Screening for more information.

Classification of diabetes mellitus in children[1][2]

Type 1 diabetes (cell destruction, usually leading to absolute insulin deficiency)

Immune-mediated
Idiopathic.

Type 2 diabetes (predominant insulin resistance with relative insulin deficiency or a predominant secretory defect with insulin resistance).

Other specific types

Genetic defects of cell function (e.g., maturity-onset diabetes of youth)
Genetic defects in insulin action (e.g., lipoatrophic diabetes)
Diseases of the exocrine pancreas (e.g., cystic fibrosis)
Endocrinopathies (e.g., Cushing syndrome)
Drug- or chemical-induced (e.g., glucocorticoids)
Infections (e.g., congenital rubella)
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes (e.g., Prader-Willi syndrome)
Gestational diabetes mellitus.

Etiology

Pathophysiology

Classification