The overall goal of the SOLAR Diabetes Project (SOLAR = Study of Latino Adolescents at Risk) is to examine mechanisms underlying changes in beta-cell function in the progression towards type 2 diabetes in overweight Hispanic children during the critical period of pubertal development. Progress: In the second funding cycle we added 32 new papers. We showed that 13% of the cohort had persistent pre-diabetes over several years, and this was associated with a 32% lower beta-cell function, and an accelerated gain in visceral fat over time. Moreover, beta-cell compensation to the progressive insulin resistance was adequate in early maturation, but after Tanner stage 3, there is a failure to increase compensatory insulin secretion. We have also observed initial trends suggesting greater disruption in beta-cell compensation in extreme obesity and in females.
In Specific Aim 1, we will extend and enhance the SOLAR cohort through: a) continued tracking into young adulthood and, b) targeted recruitment of additional participants, including 60 new children with extreme obesity (BMI percentile >99th percentile for age). In Hypothesis 1, we propose that the development of type 2 diabetes will be characterized by gradual deterioration in insulin secretion relative to the degree of insulin resistance (failure of beta-cell function), with the development of type 2 diabetes being predicted by the slope (rate of fall over time) and intercept (initial starting point at the projected time of zero years) from the decline in beta-cell function over time.
Specific Aim 2 will examine the mechanism of the failure in beta-cell compensation in late pubertal development. We will recruit a new group of males and females already at Tanner stage 3 who are either moderately obese (85th to 95th percentile for BMI) or extremely obese (>99th percentile for BMI). We will evaluate longitudinal changes in insulin sensitivity, insulin secretion, beta-cell compensation, body composition, abdominal fat distribution, and ectopic fat in whole liver and pancreas. Ectopic fat will be assessed using 3-dimensional MRI at 3-Tesla and Iterative Decomposition using Echo-Asymmetry in the Least squares sense (IDEAL), an optimal fat-water signal separation method. In Hypothesis 2, we propose that in extreme childhood obesity, there is a "saturation" of adipose tissue expansion during pubertal development, forcing deposition of fat into ectopic depots, which in turn adversely affects beta-cell function, and that these effects will be exacerbated in females by the negative effects of excess androgens on greater ectopic fat deposition and disrupted beta-cell function in extreme obesity. The overall significance of this renewal is that further studies of the metabolic changes occurring during the critical period of puberty will shed light on the pathogenesis of type 2 diabetes, both in the short-term during childhood, and longer term into adulthood. Ultimately, this information will be useful for clinical monitoring of children at risk, and for designing interventions during the critical period of puberty that could be effective for long-term prevention of type 2 diabetes.
Puberty is a critical transition period in childhood development for many reasons, including metabolic changes that increase the risk of developing type 2 diabetes in childhood or in early adulthood. These changes seem to be exacerbated in Hispanic children, especially those who are very overweight and in females. This project aims to understand how the metabolic changes during the pubertal transition affect eventual risk of type 2 diabetes. Greater understanding of the specifics of these changes and how they affect diabetes risk will be useful for developing new clinical tools for monitoring and identifying children at greatest risk and for optimizing interventions during this critical period designed for long-term prevention of type 2 diabetes.
|Gyllenhammer, L E; Alderete, T L; Toledo-Corral, C M et al. (2016) Saturation of subcutaneous adipose tissue expansion and accumulation of ectopic fat associated with metabolic dysfunction during late and post-pubertal growth. Int J Obes (Lond) 40:601-6|
|Toledo-Corral, Claudia M; Alderete, Tanya L; Richey, Joyce et al. (2015) Fasting, post-OGTT challenge, and nocturnal free fatty acids in prediabetic versus normal glucose tolerant overweight and obese Latino adolescents. Acta Diabetol 52:277-84|
|House, B T; Shearrer, G E; Miller, S J et al. (2015) Increased eating frequency linked to decreased obesity and improved metabolic outcomes. Int J Obes (Lond) 39:136-41|
|Kayser, Brandon D; Toledo-Corral, Claudia M; Alderete, Tanya L et al. (2015) Temporal relationships between adipocytokines and diabetes risk in Hispanic adolescents with obesity. Obesity (Silver Spring) 23:1479-85|
|Alderete, Tanya L; Toledo-Corral, Claudia M; Goran, Michael I (2014) Metabolic basis of ethnic differences in diabetes risk in overweight and obese youth. Curr Diab Rep 14:455|
|Alderete, Tanya L; Toledo-Corral, Claudia M; Desai, Preeya et al. (2013) Liver fat has a stronger association with risk factors for type 2 diabetes in African-American compared with Hispanic adolescents. J Clin Endocrinol Metab 98:3748-54|
|Kim, Joon Young; Goran, Michael I; Toledo-Corral, Claudia M et al. (2013) One-hour glucose during an oral glucose challenge prospectively predicts Î²-cell deterioration and prediabetes in obese Hispanic youth. Diabetes Care 36:1681-6|
|Walker, Ryan W; Sinatra, Frank; Hartiala, Jaana et al. (2013) Genetic and clinical markers of elevated liver fat content in overweight and obese Hispanic children. Obesity (Silver Spring) 21:E790-7|
|Davis, Jaimie N; Gunderson, Erica P; Gyllenhammer, Lauren E et al. (2013) Impact of gestational diabetes mellitus on pubertal changes in adiposity and metabolic profiles in Latino offspring. J Pediatr 162:741-5|
|Toledo-Corral, Claudia M; Vargas, Lisa G; Goran, Michael I et al. (2012) Hemoglobin A1c above threshold level is associated with decreased Î²-cell function in overweight Latino youth. J Pediatr 160:751-6|
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