Youth-onset type 2 diabetes mellitus: an urgent challenge

Abstract

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Figure 1 |. Long-term complications of youth-onset T2DM.

The 15-year cumulative incidences of hypertension, diabetic kidney disease, dyslipidemia (that is, low-density-lipoprotein or triglyceride dyslipidemia), neuropathy and any microvascular disease in participants with youth-onset type 2 diabetes mellitus (T2DM) in the TODAY trial.

Figure 2 |. Odds of long-term complications in children and adolescents with T2DM versus those with T1DM.

Forest plot showing odds ratios and 95% confidence intervals of diabetes complications in adolescents and young adults with type 2 diabetes mellitus (T2DM) versus those with T1DM in the SEARCH study^,. After adjustment for established risk factors measured over time, participants with T2DM had significantly higher odds of diabetic kidney disease (DKD; defined as the presence of albuminuria (≥30 μg/mg of creatinine) or reduced kidney function (estimated glomerular filtration rate ≤60 ml/min/1.73m²)), retinopathy (determined using graded digital fundus images), and peripheral neuropathy (defined using the Michigan Neuropathy Screening Instrument) than those with T1DM. The odds of cardiovascular autonomic neuropathy (heart rate variability abnormalities), arterial stiffness (pulse wave velocity ≥90^th centile of controls) and hypertension (blood pressure levels ≥95^th centile for age) did not differ significantly between the two groups.

Figure 3 |. Potential mechanisms responsible for the aggressive clinical phenotype in youth-onset T2DM.

Several factors might contribute to the more aggressive phenotype in youth onset versus adult-onset type 2 diabetes mellitus (T2DM). The more severe glycaemic phenotype in youth-onset than in adult-onset T2DM might be partly explained by worse pancreatic β-cell function, leading to more rapid β-cell failure^–. Early development of insulin resistance might lead to increased insulin secretion, driving β-cell failure and thereby lowering insulin clearance. Demand on the pancreas might be highest during adolescence owing to the marked insulin resistance of puberty^,–. Lower adherence to medical therapy, lifestyle modifications^, and self-monitoring as well as less aggressive medical treatment and fewer treatment options^– might also contribute to poorer glycaemic control and higher rates of complications in youth compared with adults with T2DM. Youth with T2DM are generally a more disadvantaged group than adults with T2DM so might have less access to quality healthcare, healthy food choices and opportunities for physical activity. Other factors that are associated with historical disadvantage, including depression, poorer sleep quality, low birth weight, and childhood exposure to stressors, including systemic racism, and environmental pollutants^–, might also increase the risk of youth-onset T2DM and the aggressiveness of the disease. Exposure to diabetes in utero is associated with higher BMI in childhood and increased risk of insulin resistance and T2DM in youth^–. In utero exposure to diabetes might also result in impaired nephron development, which increases the risk of DKD in later life^,,,, as well as other developmental disruptions that could accelerate the appearance and severity of diabetes complications. Genetic factors might contribute to the more aggressive clinical phenotype that is associated with youth-onset compared with adult-onset T2DM.

Figure 4 |. Greater loss of β-cell function in youth-onset versus adult-onset T2DM.

The Restoring Insulin Secretion (RISE) Study used hyperglycemic clamps to examine insulin sensitivity and β-cell function in a | adults and b | youth with impaired glucose tolerance or recently diagnosed T2DM at baseline, after 12 months of treatment for hyperglycemia with either insulin glargine and metformin or metformin alone, and at 15 months of follow-up (3 months after discontinuation of treatment). Insulin secretion determined using an arginine stimulation test (acute c-peptide response to arginine at maximal glycemic potentiation [ACPRmax]) is shown on the y axes and insulin sensitivity (glucose infusion rate by steady state insulin concentrations [M/I]) is shown on the x-axes. The solid black lines in the vector plots illustrate the relationship between insulin secretion (that is, β-cell response) and insulin sensitivity at baseline. The numbered boxes represent the mean values for each cohort at baseline (0), 12 months (12) and 15 months (15) and the ellipses around the boxes represent the 95% confidence intervals. The dotted lines show the trajectory of mean values from baseline to 12 months of intervention and to 15 months of follow-up. Values above the solid black line represent improved β-cell function and those below this line represent worse β-cell function compared to baseline. At baseline, youth were markedly more insulin resistant and had much higher insulin secretion than adults despite similar levels of glycemia. After 12 months of treatment, β-cell function had deteriorated in youth but not in adults. The two interventions did not differ substantially in their effects on β-cell function in either age group. The difference in β-cell function outcomes in response to treatment in youths and adults supports a more adverse trajectory of β-cell deterioration in youth. Reprinted with permission from ref , American Diabetes Association.