Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach

Abstract

OBJECTIVE In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity. CONCLUSIONS We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.

Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity

“…In our study, the cell size distribution profile of abdominal SAT biopsies revealed fewer but larger adipocytes in participants classified as hypersecretors, in whom adipose hypertrophy prevails over hyperplasia. Furthermore, a larger adipocyte size at baseline was associated with short-term increases in β-cell glucose sensitivity, possibly perpetuating chronic hyperinsulinemia, which is noteworthy in a population where β-cell function generally deteriorates over time ( 12 , 59 ). These observations align with the current knowledge that hypertrophic adipocytes are less susceptible to insulin antilipolytic action and may provide a chronic FFA overload to the β-cell ( 28 ) to enhance insulin secretion ( 31 , 32 ).…”

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity

“…More than one-third of U.S. adolescents with obesity have a prediabetes glycemic profile (9,10), with ~35% progressing to persistent dysglycemia or overt diabetes during adulthood (11). Unlike the gradual prolonged metabolic changes preceding adult-onset type 2 diabetes (T2D), a rapid progression of dysglycemia and β cell failure in the context of insulin resistance occurs in youth-onset T2D (12)(13)(14)(15) with at least 1 diabetes complication occurring before the age of 30 years (16). Neverthless, there are no approved drugs to treat prediabetes in youths with a temporally limited window of intervention to prevent diabetes complications after the disease onset.…”

The World Congress of Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDC)

“…Sonia Caprio began a set of talks on the progression from childhood risks to diseases in adults, describing her studies of the four classes of obese youth with progressively worsening glucose tolerance, in association with hyperinsulinemia, decreased insulin sensitivity, decreased insulin clearance, and increased liver fat. 21 Petter Bjornstad reviewed an analysis of 517 persons with youth‐onset type 2 diabetes followed from 2011, at mean age 14, for an average 7.5 years, with HbA1c increasing from 6.0% to 9.3%; both hyperfiltration and insulin resistance tracked with development of microalbuminuria in 55% of the group, with an additional 17% developing hyperfiltration (estimated glomerular filtration rate ≥ 135). 22 A study of 161 Pima Indians with type 2 diabetes who underwent renal biopsy showed that, compared with adult‐onset, youth‐onset diabetes was associated with greater levels of albuminuria and with greater glomerular basement membrane width and mesangial fractional volume independent of historic A1c control, age, and duration, with the youth‐onset group having greater risk of progression to kidney failure.…”

“…Sonia Caprio began a set of talks on the progression from childhood risks to diseases in adults, describing her studies of the four classes of obese youth with progressively worsening glucose tolerance, in association with hyperinsulinemia, decreased insulin sensitivity, decreased insulin clearance, and increased liver fat 21 . Petter Bjornstad reviewed an analysis of 517 persons with youth‐onset type 2 diabetes followed from 2011, at mean age 14, for an average 7.5 years, with HbA1c increasing from 6.0% to 9.3%; both hyperfiltration and insulin resistance tracked with development of microalbuminuria in 55% of the group, with an additional 17% developing hyperfiltration (estimated glomerular filtration rate ≥ 135) 22 .…”