Etiology
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.[5][21] Infants born small for gestational age and those born with macrosomia are at increased risk for the development of obesity, metabolic syndrome, and T2DM in childhood.[22][23]
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.[21]
Most children have overweight (body mass index [BMI] 85th to 95th percentile for age and sex) or obesity (BMI >95th percentile) at diagnosis. UK audit data has shown that over 90% of children and young people with T2DM are also living with obesity or overweight.[24] Global prevalence of obesity among pediatric patients with T2DM has been reported as 75%.[25]
Total obesity is not as important as location of adipose tissue in causing insulin resistance.[26] Visceral fat is more metabolically active than subcutaneous fat in producing adipokines that cause insulin resistance.[27]
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.[28]
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.[29]
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.[30][31]
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.[32] Breast-feeding reduces the odds ratio for childhood obesity by approximately 20% as compared with formula feeding.[33] 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.[33] Protein intake is 55% to 80% higher per kilogram of body weight in bottle-fed than in breastfed infants.[33]
Puberty
The average age of diagnosis of T2DM in children/adolescents is 14 years (i.e., during puberty) and most children are diagnosed between ages 10 and 19 years.[17][34]
During puberty, there is a surge in growth hormone and insulin-like growth factor-I (IGF-1), which increases insulin resistance. Almost always, this insulin resistance is transient and any hyperglycemia reverts to normal after puberty.[34] In addition, an increase in sex hormones during puberty, especially androstenedione, increases the acute insulin response, which is an independent predictor of T2DM.[34]
When present with preexisting insulin resistance, puberty may precipitate beta cell failure; therefore, young people with obesity, who tend to be more insulin-resistant than those without obesity at the onset of puberty, are more likely to progress to T2DM at this point.[35] Data suggest that young people with obesity do not recover insulin sensitivity at the end of puberty, which may have a negative impact on beta-cell function during this time.[35]
Puberty also heralds a period of change in other cardiometabolic risk factors, such as lipid profile, blood pressure, and adipokines. This has significant implications for young people with obesity: there is evidence that puberty is one of the greatest risk factors for transition from metabolically healthy to unhealthy obesity.[35]
Sex
In young-onset type 2 diabetes, females are affected more than males.[12] One 2021 UK audit found that 64% of children with T2DM were female.[24]
Ethnicity/race
The majority of childhood-onset T2DM occurs in children from a high-risk racial/ethnic background.[12] These include African-American, Hispanic, American-Indian, and Asian or Pacific Islander.[13][14]
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.[36]
Genetic predisposition
An underlying genetic predisposition is emphasized by the fact that only a minority of children with obesity develop T2DM.[3]
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.[37] In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study of American youth with recent-onset T2DM, almost 60% reported at least one parent, full sibling, or half-sibling with diabetes, rising to almost 90% when grandparents were included.[38]
T2DM in children and adolescents, as in adults, is polygenic. While there have been rapid advances in the understanding of the genetics of T2DM in adults, the genetics of T2DM in youth remain largely understudied. In 2021, the Progress in Genetic studies of youth-onset diabetes (ProDiGY) consortium published the first genome-wide association study on youth-onset T2DM, identifying seven crucial loci in the genome, including rs7903146 in TCF7L2, rs72982988 near MC4R, rs200893788 in CDC123, rs2237892 in KCNQ1, rs937589119 in IGF2BP2, rs113748381 in SLC16A11, and rs2604566 in CPEB2, which may play a significant role in early detection of the disease in the future.[39]
Pathophysiology
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.[40] 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.[41] 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.[42]
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.[40]
Elevated ceramide (a type of sphingolipid that demonstrates cellular toxicity and proinflammatory actions) in skeletal muscle and elevated hepatic alanine aminotransferase levels are also both associated with a decline in insulin sensitivity and the development of T2DM.[43][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
Classification of diabetes mellitus in children
Diabetes is classified conventionally into the following clinical categories:[1][2]
Type 1 diabetes (due to autoimmune beta-cell destruction, usually leading to absolute insulin deficiency)
Type 2 diabetes (due to a nonautoimmune progressive loss of adequate beta-cell insulin secretion, frequently on the background of insulin resistance and metabolic syndrome)
Specific types of diabetes due to other causes, for example:
Monogenic diabetes syndromes (e.g., maturity-onset diabetes of the young, neonatal diabetes)
Genetic defects in insulin action (e.g., lipoatrophic diabetes)
Diseases of the exocrine pancreas (e.g., cystic fibrosis, pancreatitis, neoplasia, trauma/pancreatectomy, hemochromatosis, transfusion-related iron overload)
Endocrinopathies (e.g., Cushing syndrome, hyperthyroidism, acromegaly, pheochromocytoma)
Drug- or chemical-induced (e.g., with glucocorticoid use, in the treatment of people with HIV, or post-organ transplantation)
Infections (e.g., congenital rubella, enterovirus, cytomegalovirus)
Uncommon forms of immune-mediated diabetes (e.g., anti-insulin receptor antibodies, polyendocrine autoimmune deficiencies APS I and II)
Other genetic syndromes sometimes associated with diabetes (e.g., Prader-Willi syndrome, Down syndrome, Klinefelter syndrome, Turner syndrome, porphyria)
Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation or other types of diabetes occurring throughout pregnancy, such as type 1 diabetes).
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