Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians

Abstract

Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5–20 years) and adulthood (ages 20–45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.

Energy expenditure in obese children with pseudohypoparathyroidism type 1a

“…Heterozygous and homozygous mutations in MC4R are well documented in humans to lead to a syndrome of early-onset obesity, hyperinsulinemia, increased bone mineral density, and accelerated linear growth. (3, 4) Similarities between the obesity syndromes in mc4r and gnas exon 1 knockout mice, along with the coupling of the MC4R through G s α support the possibility of abnormal MC4R function in PHP-1a. Mice have paternal imprinting of gnas in the paraventricular nucleus of the hypothalamus, an important site of MC4R action.…”

“…(3, 4) Both the MC4R and G s α murine models demonstrate insulin resistance and impaired glucose tolerance that may develop prior to the onset of obesity. (5-7) In our study, we found that 4 of 6 children with PHP-1a had already developed hyperinsulinemia and insulin resistance, however, we did not find evidence that that the insulin resistance in PHP-1a is more severe or earlier in onset than in obese controls.…”

One-hour and two-hour postload plasma glucose concentrations are comparable predictors of type 2 diabetes mellitus in Southwestern Native Americans

“…To evaluate 1 h-PG and 2 h-PG as predictors of type 2 diabetes in Groups 1 and 2, proportional hazard analysis was used to calculate HRs for development of type 2 diabetes, adjusting for baseline age, sex, BMI and SWNA heritage status. The fraction of SWNA heritage (in eighths, ranging from 0/8 to 8/8) was determined from personal history and family data, as previously described [33]. For this study, SWNA heritage was considered a dichotomous variable (those with 8/8 SWNA heritage vs those less than 8/8 SWNA heritage).…”

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

“…16 Two variants were described as GOF in a prior study: V103I 17 and I251L. 17 One variant, F202L, 27, 28 was described as non-function-altering in prior studies.…”

“…Decreased stimulated cAMP generation previously reported. 16 Surface expression, ligand binding, and basal activity have not been reported.cCategorized as GOF because V103I previously reported to have decreased agouti-related peptide potency, while I251L has increased basal activity. 17 …”