Proinsulin in Girls: Relationship to Obesity, Hyperinsulinemia, and Puberty

Abstract

In adults with impaired glucose tolerance (IGT) and obesity (OB), an elevated proinsulin (PI) is predictive of type 2 diabetes mellitus (DM) and precedes the diagnosis by 5-20 yr. In type 2 DM, the PI is disproportionately elevated, i.e. increased PI/insulin ratio (PI/I). Few studies have evaluated PI in children at risk for type 2 DM. In the face of the current epidemic, we evaluated the relationship of PI and PI/I to IGT, insulin resistance (IR) defined by homeostasis model of assessment (HOMA), degree of OB, and stage of puberty in 70 girls (mean age 10.8 yr; body mass index z-score 3.5; ethnicity 64% Hispanic, 19% white, 16% African-American, and 1% other). Family history of DM was reported in 83%, and acanthosis nigricans was present in 80%. Subjects underwent a 2-h oral glucose tolerance test with glucose, insulin, and PI determinations every 30 min. All had normal hemoglobin A1c and fasting glucose. Five had IGT. With higher HOMA-IR, PI increased (P < 0.05), yet the ratio of fasting PI/I was lower (P < 0.05). Girls with body mass index z-score greater than 4 (n = 29) had higher PI than nonobese girls (n = 19, P < 0.05), but PI/I ratios were not different. PI-0 was increased in late puberty (n = 29), compared with prepuberty (n = 26, P < 0.05), but PI/I ratios showed no statistical difference. We found PI increased with increasing IR and OB in girls. Overall, PI/I was not different, suggesting the elevated PI reflects increased beta-cell output proportional to the elevated insulin in these groups and not a defect in PI processing or secretion. In fact, the lower fasting PI/I of the highest HOMA-IR quartile vs. the lowest HOMA quartile indicates more efficient conversion of PI to I in the presence of increasing IR in these girls.

Measurement of Cord Insulin and Insulin-Related Peptides Suggests That Girls Are More Insulin Resistant Than Boys at Birth

“…The higher proinsulin-to-insulin ratio and percentage of proinsulins in girls in our study could theoretically be due to either decreased clearance or differences in conversion of proinsulin to insulin (19). Higher proinsulin(s) have been found in neonates previously (11,12), and this may be part of the neonatal transition reflecting immaturity of the fetal ␤-cell and/or ␤-cell secretory granule.…”

“…Our finding that insulin and insulin propeptides in cord blood are higher in girls than in boys is consistent with an intrinsic difference between the sexes, which is unlikely to be determined by environmental factors. Other research has suggested that in childhood, girls are more insulin resistant than boys with higher insulin and proinsulin concentrations and more adipose tissue from age Ն5 years, and these differences could not be explained by other known determinants of insulin concentrations (1,3,4,6,19). We think that because girls are born smaller (lighter and shorter), with greater skinfold thickness, and in the presence of higher insulin concentrations than boys but with no corresponding increase in cord glucose concentrations, they are intrinsically more insulin resistant.…”

Association of Raised Liver Transaminases With Physical Inactivity, Increased Waist–Hip Ratio, and Other Metabolic Morbidities in Severely Obese Children

“…Fasting insulin, HOMA, and QUICKI have been shown to correlate with euglycemichyperinsulinemic clamp studies and have been used previously in children and adolescents (12,13). WFH and %BF by BIA and DEXA were used as measures of the severity of obesity.…”

Can Waist Circumference Identify Children With the Metabolic Syndrome?

“…24,25 Consistent with the present study, increased proinsulin levels with increasing insulin resistance in obese girls suggested that elevated proinsulin concentrations reflect increased ␤-cell output proportional to the elevated insulin concentrations in this group and not a defect in proinsulin processing or secretion. 8 The use of acanthosis nigricans as a predictive marker of hyperinsulinemia has become a common practice. Previous studies have associated the presence of acanthosis nigricans with high insulin levels, thus identifying a subgroup believed to be at greater risk for T2DM.…”