Insulin and Glucose Dynamics During Puberty and Relationship to Risk for Youth-Onset Type 2 Diabetes

Stats

During early puberty, youth with obesity compared to normal weight youth have:

• 3x lower insulin sensitivity
• 3x higher average insulin secretion

Research background: role of puberty in insulin and glucose changes and development of type 2 diabetes

Research from the Department of Endocrinology at Children’s Hospital Colorado provides new information about insulin and glucose dynamics in healthy normal weight youth and in youth with obesity during puberty. The incidence of youth-onset type 2 diabetes (TD2) is still relatively low, but with the rising rates of pediatric obesity, the condition is becoming more common.

It’s well understood that insulin does not work as well during puberty as it does before and after this stage of development. In healthy children, this does not cause diabetes or significantly affect blood sugar because the body can compensate by making more insulin. In fact, this is thought to be an important part of the adolescent growth spurt. In some children, the body can’t compensate for worsening insulin resistance during puberty. These youth get diabetes early, and peak onset occurs at the time of the worst insulin resistance.

Health Influences of Puberty (HIP), a longitudinal study designed by endocrinologist Megan M. Kelsey, MD, and other researchers at Children’s Colorado, explored relationships between the metabolic changes of puberty and youth-onset TD2. An overview of three published manuscripts from the HIP study are summarized as follows:

• HIP Aim 1: A longitudinal study comparing insulin sensitivity and secretion and other metabolic changes in normal weight versus youths with obesity during puberty
• HIP Aim 2: A clinical trial of the impact of metformin treatment during puberty in obese children for prevention of youth-onset TD2
• HIP HBA1c: A longitudinal study identifying potential factors associated with HbA1c changes during puberty and defining normal glycemia and prediabetes in adolescents

The collective findings will help identify who is at highest risk for developing youth-onset TD2, which is more aggressive when it occurs in children.

Research methods: studying metabolic changes during puberty, metformin treatment

The longitudinal studies evaluated the natural trajectory of insulin sensitivity and other metabolic changes during puberty in healthy normal weight youth and in obese youth, while a randomized controlled trial assessed the impact of metformin treatment in youth with obesity and normal blood sugar levels at baseline.

Youth were recruited from general pediatrics and Lifestyle Medicine Weight Program clinics at Children’s Colorado and in the Denver, metro area.

Tanner (T) stage was assessed every six months and most participants underwent three study visits: at baseline (T2-T3) and when they reached T4 and T5.

Before each visit, participants ate a standard macronutrient diet and restricted exercise for three days. The visits included intravenous glucose tolerance testing, fasting laboratory studies and dual X-ray absorptiometry to measure percent fat mass.

The investigators calculated insulin sensitivity, acute insulin response to glucose (AIRg), and disposition index (DI). They used AIRg to estimate insulin secretion and DI as a measure for beta cell response in relation to insulin sensitivity. A decline in DI precedes T2D onset in both youth and adults.

The interventional arm was a double-blind randomized placebo-controlled trial of metformin in children with obesity and normal blood sugar levels at baseline. Investigators randomized these children to treatment with metformin or placebo starting at the baseline visit and continuing through the T5 pubertal stage. Youth in the clinical trial had a fourth study visit six months after stopping the intervention so investigators could check for any lasting effects of active treatment.

Research results: insulin and glucose dynamics affect who develops TD2 during puberty

HIP Aim 1: obese youth had lower insulin sensitivity and higher AIRg at every pubertal stage

Fifty-four participants completed the study. Insulin sensitivity and DI decreased and AIRg increased in both youth with normal weight and obesity as they advanced through puberty, with no significant group differences in the change over time. Obesity had a significant impact on insulin sensitivity and response at any given time point, however. Insulin sensitivity was almost 3-fold lower and AIRg 3-fold higher in early puberty in youth with obesity.

There were no group differences in DI at any time point or in DI change over time.

Despite the impact of obesity on insulin sensitivity, youth with obesity mostly maintained enough insulin secretion to compensate for insulin resistance. This is demonstrated by a similar DI compared to normal-weight youth despite the high prevalence of risk factors for youth-onset T2D (ie, family history, Hispanic ethnicity, female sex).

HIP AIM 2: effects of two years of metformin treatment

The study included 20 children with obesity who were randomized to metformin treatment and 24 youth who received placebo. The two groups were well matched for race/ethnicity and family history of diabetes and for baseline age, Tanner stage and BMI; 80% of participants were Hispanic.

Both groups had an overall decline over time in insulin sensitivity, AIRg and DI. There were no significant differences in changes in these factors between the metformin- and placebo-treated youth.

DI was higher in the metformin group at the T4 visit after a mean of 1.4±0.58 years of treatment but the benefit was absent at the T5 visit.

Children with the highest DI at baseline had the greatest drop in DI. Only two girls developed diabetes (one in the metformin group and one in the placebo group). Both were outliers at baseline, with a high DI at baseline and a rapid decline in DI during the study.

Metformin treatment did improve BMI, body fat percentage and waist circumference:

• BMI adjusted for children’s ages and gender (BMIz) decreased in the metformin group and increased in the placebo group; youth who took metformin retained the decrease 6 months after stopping treatment.
• The increase in waist circumference was much smaller in the metformin group versus the placebo group; this effect was still apparent, though reduced at 6 months post-treatment.
• Body fat percentage was lower in the metformin group, though this improvement was lost at 6 months post-treatment.

Improvements in body composition and weight status did not result in improvements in other health outcomes like cholesterol, blood pressure or blood glucose levels during the time of the treatment.

HIP Hba1C 1: puberty associated with rising HbA1c

Youth with obesity had higher BMIs and body fat percentage and lower insulin sensitivity and adiponectin. HbA1c increased significantly in normal weight youth at T4 and T5 compared with baseline, but not in youth with obesity.

HbA1c was higher in youth with obesity versus normal weight youth at T4 and T5. Although the overall HbA1c distribution was wider in youth with obesity, it overlapped between youth with normal weight and obesity.

The increase in HbA1c did not relate to DI. Study authors noted this was a surprising finding, particularly given that their earlier analysis found that DI decreases during puberty in both study groups. Lower adiponectin was significantly associated with higher HbA1c.

Research discussion and conclusions: challenges of early intervention and prevention

The HIP study found insulin resistance and insulin hypersecretion is already present in youth who are at an unhealthy weight at the earliest stage of puberty and before development of significant glucose abnormalities.

At any given time, insulin sensitivity was almost three-fold lower and AIRg three-fold higher in early puberty in youth with obesity versus normal weight youth. However, the trajectories of change in insulin sensitivity and beta cell function were unexpectedly similar between youth with normal weight and obesity.

Inclusion of known risk factors for diabetes, such as race/ethnicity, sex and percentage body fat in the predictive models failed to uncover predictors of change in DI during puberty, demonstrating the challenge of finding youth most in need of early intervention to prevent T2D. The HIP study did find that a high DI early in puberty may be a risk factor for a rapid decline in beta cell function.

Both youth with normal weight and obesity had a mild rise in HbA1c during puberty. If HbA1c, and by extension glycemia, increases in all youth during adolescence, then current criteria for prediabetes in adolescents based on adult norms may not be valid. Although HbA1c was, on average, higher in youth with obesity, the overall distribution overlapped between youth with normal weight and obesity.

Even when started early in puberty, before dysglycemia develops, metformin treatment did not prevent beta cell function decline during adolescence. Metformin treatment did confer some potential cardiometabolic benefits, including improvements in BMI, body fat percentage and waist circumference.

Additional studies are needed to better identify youth at highest risk for early onset diabetes, to improve understanding of glucose homeostasis mediators during puberty, and to define normal glycemia during adolescence. In addition, given the rapidly progressive nature of youth-onset T2D, further research is needed to develop preventive strategies that can be implemented before at-risk children begin puberty.