With the rising prevalence of obesity among minority youth in the United States (US),(1,2) there has been a concurrent rise in associated comorbidities such as youth-onset diabetes and hypertension.(3-6) American Indian/Alaska Native (AI/AN) youth are at high risk for obesity that is a predictor of increased cardiometabolic risk and youth-onset type 2 diabetes (T2D).(7,8) In an AI/AN cohort based in the southwestern US, childhood obesity, glucose intolerance, and hypertension were predictive of premature death before 55 years of age from endogenous causes.(9) In the same cohort, diabetes related renal disease and early mortality was higher among patients in the youth-onset diabetes group than the adult-onset group, possibly due to longer exposure to dysglycemia.(10) In a multi-ethnic cohort in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial, youth with T2D exhibited dyslipidemia and worse cardiovascular risk profile at baseline compared to their age-matched non-obese and non-diabetic peers.(11)

Obesity Related Comorbidities in AI/AN Children: Sarah’s Story
Sarah is a 13-year-old AI female who is a patient at a specialty clinic for children with diabetes and cardiometabolic conditions in Phoenix, Arizona. She was diagnosed with diabetes at age 11, her HbA1c at diagnosis was 9.3% (78.1 mmol/mol). Her C-peptide was elevated, and pancreatic antibodies were negative, consistent with T2D. Given the limited medications approved for treating diabetes in youth, she was started on insulin therapy and metformin following her diagnosis.

Sarah and her mother arrive at the clinic for her scheduled follow-up visit in a transport van after a 5-hour journey through the sweltering desert heat. On arrival, anthropometric measurements are obtained, weight: 122 kg (>99th percentile); height: 163 cm (76th percentile); age-sex specific BMI: 45.9 kg/m2 (170% of 95th percentile). Her age-sex-height specific systolic blood pressure (BP) remains elevated at the 98th percentile, her diastolic BP is normal. Family history is significant for T2D in mother, maternal grandfather, and both paternal grandparents. Mother also suffers from hypertension, hypercholesterolemia, and diabetic kidney disease. Sarah’s physical exam is limited by extreme adiposity. Nuchal acanthosis nigricans is evident with diffuse acanthosis in skin folds.

Over the next three years Sarah’s glycated hemoglobin fluctuates between 7-12% (53.0-107.7 mmol/mol) as her compliance with treatment varies. Her urine albumin/creatinine ratio (ACR) remains normal, but a strong family history and poorly controlled diabetes places her at an elevated risk for future diabetic nephropathy. In this high-risk population with diabetes and nephropathy, albuminuria has been shown to be an independent predictor of increased cardiovascular events, (12) so Sarah’s ACR must be closely monitored.

By age 12, Sarah’s total cholesterol had increased to 237 mg/dL, with a low-density lipoprotein cholesterol (LDL-C) of 174 mg/dL, triglycerides 195 mg/dL, high-density lipoprotein cholesterol (HDL-C) 24 mg/dL, and non-HDL-C 213 mg/dL. Lifestyle modifications were advised, however laboratory tests repeated 6-months later were nearly identical, prompting initiation of atorvastatin therapy at a dose of 10 mg/day. This modifiable risk factor has the potential to worsen Sarah’s future CVD profile if control can’t be obtained with lifestyle modifications and one of the limited medications approved in children.

At age 14, Sarah is diagnosed with non-alcoholic fatty liver disease (NAFLD). Her liver enzymes were elevated with alanine aminotransferase (ALT) of 164 IU/L and aspartate aminotransferase (AST) of 112 IU/L. Hepatic ultrasonography demonstrates hepatomegaly with presence of hepatic steatosis. Due to persistently elevated liver enzymes, a liver biopsy was performed showing grade 2/3 steatosis involving 40-50% of hepatocytes and fibrosis stage 2-3/4. Since NAFLD is associated with both clinical and subclinical CVD, this worsens Sarah’s prognosis considerably.

Sarah and her family would like to make dietary changes; however, their access to groceries is at the local convenience store where yellow onions and iceberg lettuce are the standard “fresh food” options. Sarah also has a sedentary lifestyle and does not play any sports or engage in much physical activity. Sarah is a teenager, but she already has numerous cardiovascular disease (CVD) risk factors that include severe obesity, diabetes, elevated LDL-C and non-HDL-C, low HDL-C, hypertension, and a strong family history. Sarah is a fictional patient, although her story is not.

Cardiovascular Disease Risk Factors in AI/AN
The prevalence of CVD and mortality from coronary heart disease was uncommon in the AI population in the past although the prevalence of CVD risk factors varied among different tribes and geographic areas within the US.(13,14) In recent decades, however, the prevalence of CVD among the AI/AN population has risen dramatically with higher mortality from coronary heart disease and at a younger age compared to other racial and ethnic groups in the US.(15,16) Both biological and environmental factors impact CVD risk. Rapid alterations in lifestyle factors resulting in poor dietary habits and limited physical activity in AI youth have contributed towards obesity, hypertension, dyslipidemia, and diabetes that are important contributors towards CVD risk in this vulnerable population.(17) The Strong Heart Study (SHS), a longitudinal population-based study that examines CVD risk and related conditions in AI communities across Arizona, Oklahoma, and North and South Dakota examined cardiac markers of preclinical disease factors in adolescents 14 to 20 years of age with metabolic risk clustering.(18, 19) Nearly 25% of adolescent participants were diagnosed with metabolic syndrome (MetS) using the modified Adult Treatment Panel III criteria and was associated with higher prevalence of left ventricular hypertrophy and other cardiac dysfunction.(19,20)

Adverse environmental conditions faced by AI/AN communities also impact their cardiometabolic risk status. Food insecurity stemming from economic disparity is a major contributor of obesity and its related conditions and is high among AI/AN communities.(21) Also, access to nutritious food that is affordable remains a challenge especially for rural tribal populations, who often live in “food deserts” with limited access to markets with a variety of healthy food choices.(22) It is estimated that only 25.6% of tribal area population lived within walking distance of a supermarket compared to 58.8% of the US general population.(23)

Lifestyle Modification for Reducing Diabetes and CVD Risk in AI/AN Adults and Children
In adults, the Diabetes Prevention Program (DPP) showed lifestyle interventions were effective in reducing CVD risk factors in patients with T2D with comparable benefits observed within each race/ethnic group including the AI/AN population group.(24,25) The Native Lifestyle Balance (NLB) program has been adapted from the DPP program and has been successfully implemented among AI/AN communities nationwide (https://www.ihs.gov/nlb/), but similar successes were not seen in school-based settings.(26,27) Some of the factors attributed to the lack of success in reducing metabolic risk among elementary school children with lifestyle interventions include extraneous factors such as introduction of satellite television in the community, growth in disposable family incomes paired with increase in the number of local fast-food restaurants, and lack of adequate parental engagement due to job related pressures.(27) More recently, in a randomized pilot study in children living in two AI communities, investigators found significant treatment effects for adiposity measures in the lifestyle intervention group compared to a control group.(28)

Prevention of chronic diseases that have origins in childhood need to be approached from an eco-bio-developmental perspective, a conceptual framework where individuals are nested within microsystems that comprise their family, school, and larger ecosystems of community and society. (29,30) In Sarah’s case she is already burdened with multiple chronic health conditions that are likely to impact her longevity and quality of life. To mitigate this impending health risk for Sarah and other children like her, a community-based approach is needed with involvement of stakeholders to raise awareness about chronic disease prevalence in the community and prevention strategies targeted towards the specific needs of the community.

Disclosure statement: Dr. Sinha has no financial disclosures to report. Dr. Chambers has no financial disclosures to report.

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