Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents

OBJECTIVES: To compare insulin sensitivity and pancreatic beta-cell function measured by the euglycemic and the hyperglycemic clamp, with simple estimates of insulin sensitivity and pancreatic beta-cell function in youth.Study design We measured insulin sensitivity with a euglycemic clamp and first- and second-phase insulin secretion with a hyperglycemic clamp in 156 AA and white youths. Estimates of insulin sensitivity (fasting insulin level [I(F)], the ratio of fasting glucose [G(F)] to I(F) [G(F)/I(F)], homeostasis model assessment estimate of insulin sensitivity [HOMA IS], and quantitative insulin sensitivity check index [QUICKI]) and estimates of pancreatic beta-cell function (I(F), the ratio of I(F) to G(F) [I(F)/G(F)], and homeostasis model assessment estimate of pancreatic beta-cell function [HOMA %B]) were derived from fasting measurements. RESULTS: In the total group, IS(Eu) correlated strongly with I(F) (r=-0.92), G(F)/I(F) (r=0.92), HOMA IS (r=0.91), and QUICKI (r=0.91) (P<.01). First-phase and second-phase insulin secretion correlated with I(F), I(F)/G(F), and HOMA %B (first-phase insulin secretion: r=0.76, 0.79, 0.82; second-phase insulin secretion: r=0.83, 0.86, 0.86, respectively; P<.01). CONCLUSIONS: Simple estimates of insulin sensitivity and pancreatic beta-cell function using fasting insulin and glucose levels serve as surrogate measures of insulin sensitivity and secretion in nondiabetic youths. The validity of these conclusions in children with impaired glucose tolerance and type 2 diabetes mellitus remains to be determined.     

Racial and etiopathologic dichotomies in insulin hypersecretion and resistance in obese children

OBJECTIVES: To assess insulin dynamics to oral glucose tolerance testing in obese children, denoting individual contributions of insulin hypersecretion versus resistance to racial and etiopathogenetic specificity. STUDY DESIGN: We performed 3-hour oral glucose tolerance testing in 113 nondiabetic obese children (age 13.6 +/- 3.1 years; 41 male, 78 female; 37 black, 41 white; 35 with central nervous system [CNS] insult). The corrected insulin response (CIRgp; measuring beta-cell secretion) and the composite insulin sensitivity index (CISI) were computed and log-transformed, and each was modeled in terms of the other, plus race/etiology, age, sex, body mass index z score, glucose tolerance, pubertal status, and geographic location. RESULTS: A scatterplot of logCIRgp versus logCISI showed that racial and etiopathogenetic groups plotted in different areas. CISI (controlled for CIRgp and other variables) was only 13% lower in blacks than in whites ( P = .32). Conversely, CIRgp (controlled for CISI and other variables) was 49% higher in blacks ( P = .028). CNS insult exhibited a 40% higher CIRgp ( P = .054) and 11% higher CISI ( P = .42) than intact white subjects. CONCLUSIONS: Insulin hypersecretion and resistance are distinct phenomena in childhood obesity. Insulin hypersecretion appears to be the more relevant insulin abnormality both in obese blacks and in CNS insult.     

Waist circumference, blood pressure, and lipid components of the metabolic syndrome

OBJECTIVES: To examine whether waist circumference (WC) predicts blood pressure (BP) and lipid components of the metabolic syndrome independent of body mass index (BMI) percentile in youths. STUDY DESIGN: The study group comprised 70 African-American youths and 97 Caucasian youths. Outcome measures included BP, lipid profile, and abdominal adipose tissue (AT). RESULTS: Both BMI percentile and WC were significantly (P < .05) associated with daytime and nighttime systolic and diastolic BP, triglycerides (TG), high-density lipoprotein (HDL), and TG/HDL ratio independent of race. In African-Americans and Caucasians, WC remained a significant (P < .05) correlate of daytime (r = .50 and .59, respectively) and nighttime (r = .49 and .62, respectively) systolic BP, and in Caucasians, TG, HDL, TG/HDL, and very-low-density lipoprotein after controlling for BMI percentile. After accounting for age, sex, and race, the addition of WC to BMI percentile increased the variance (R(2)) in systolic BP by 15% (P < .05). The inclusion of WC with BMI percentile explained an additional 3% and 7% of the variance in TG and HDL, respectively (P < .05). CONCLUSIONS: The prediction of childhood obesity-related health risks is significantly improved by the inclusion of WC in addition to BMI percentile. This observation supports the notion that WC should be included in the evaluation of childhood obesity along with BMI percentile to identify those at increased health risks due to excess abdominal fat.     

Progression from normal glucose tolerance to type 2 diabetes in a young girl: longitudinal changes in insulin sensitivity and secretion assessed by the clamp technique and surrogate estimates

The pathophysiology of type 2 diabetes (T2DM) involves insulin resistance and relative insulin deficiency in at-risk youth. We-report longitudinal changes in insulin sensitivity and secretion in a high-risk African-American youth with obesity and polycystic ovary syndrome who progressed from normal glucose tolerance to impaired glucose tolerance to T2DM within 5 yr. This report demonstrates that in our patient: (i) insulin resistance was the pre-existing abnormality, but it was the marked decline in insulin secretion which led to T2DM and (ii) surrogate estimates of insulin sensitivity using fasting glucose and insulin concentrations were not reliable indices in reflecting the changes in in vivo insulin sensitivity in this case.     

Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease

OBJECTIVE: To describe the clinical characteristics of nonalcoholic fatty liver disease (NAFLD) in children, including insulin resistance, and to test for correlation with liver pathology. STUDY DESIGN: A retrospective review of children with biopsy-proven NAFLD at Children's Hospital San Diego from 1999 to 2002. Liver biopsy specimens were independently reviewed by two pathologists. RESULTS: Children with NAFLD (n=43) were mostly male (70%), Hispanic American (53%) and obese (88%). The criteria for insulin resistance were met by 95% of subjects. Steatosis was predicted by the combination of quantitative insulin sensitivity check index, age, and ethnicity (P<.0001). Portal inflammation was predicted by the combination of ALT and fasting insulin (P=.0009). Perisinusoidal fibrosis was predicted by the combination of AST, fasting insulin, and BMI Z score (P<.0001). Portal fibrosis was predicted by the combination of right upper quadrant pain and homeostasis model assessment of insulin resistance (P=.0028). CONCLUSIONS: We identified significant predictors of liver pathology in children with NAFLD. Children being evaluated for NAFLD should be screened for insulin resistance, which is nearly universal and correlates with liver histology.