Validation of HbA1c of 6.5% for diagnosing diabetes mellitus via the use of taxometric analysis.

PURPOSE: Previous studies in which authors examined the internal and external validity of a glycemic cut-point for diagnosis of diabetes mellitus have provided mixed results. The purpose of the current study was to test the internal validity of the HbA1c 6.5% cut-point with taxometric analysis. METHODS: Data on 14,798 participants were obtained from the National Health and Nutrition Examination Survey, years 1999-2008. Fasting plasma glucose and HbA1c were submitted to the taxometric procedures MAMBAC (mean above minus below a cut) and MAXSLOPE (MAXimum SLOPE). The comparison curve fit index was the outcome measure, with values less than 0.40 and greater than 0.60 indicative of dimensional and categorical solutions, respectively. RESULTS: In the full sample, MAXSLOPE and MAMBAC procedures yielded CCFIs of 0.778 and 0.872, respectively. Analyses were repeated in subgroups by age, sex, fasting insulin level, ethnicity, and year; the lowest comparison curve fit index measurement from any analysis was 0.706. CONCLUSIONS: These results support a categorical overdimensional model of diabetes, consistent with the new HbA1c cut-point recommendation.

U.S. News and World Report's rankings of the top 50 children's hospitals for diabetes and endocrinology reflect reputation more than objective measures.

The objective of this short communication was to evaluate the roles of reputation and objective measures in U.S. News rankings of the top 50 children's hospitals for diabetes and endocrinology. Analysis was performed on data obtained from the 2011 to 2012 report. Reputation scores exhibited more variance (CV = 158%) compared to objective measures (average CV = 14%). Ranking hospitals based on reputation, compared to total score, identified the same top hospital, same top five hospitals, and 90% of the same top 10 hospitals. Ranking based on total objective score resulted in different top hospitals, 60% of the same top five hospitals, and 50% of the same top 10 hospitals. Hospital total rank was strongly associated with reputation rank (rho2 = 0.78) and moderately associated with objective rank (rho2 = 0.48). Objective rank was minimally associated with reputation rank (rho2 = 0.19). Among the top 50 children's hospitals in diabetes and endocrinology, standings reflect reputation more than objective measures.

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

CONTEXT: Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone. PATIENT: We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations. RESULTS: The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif. CONCLUSIONS: Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.

Impact on bone of an estrogen receptor-alpha gene loss of function mutation.

CONTEXT: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha. OBJECTIVE: Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha heterozygosity on spine density and adult height in an extended pedigree. DESIGN AND PARTICIPANTS: A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER-alpha and single contact evaluation of the kindred were performed. MAIN OUTCOME MEASURES: Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER-alpha mutation carrier status and spine aBMD. RESULTS: Bone biopsy revealed marked osteopenia (cortex: 641 microm), low trabecular volume (10.6%), decreased thickness (76.2 microm), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (Z score -3.85) in 3.5 yr. Bone age advanced from 15-17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (-0.84 +/- 0.26 vs. -0.64 +/- 0.16). CONCLUSION: Homozygous ER-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD.

Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations.

Although glycogen storage disease type 0 (GSD0) is included in the differential diagnosis of ketotic hypoglycemia, it usually is not considered in the evaluation of glucosuria or hyperglycemia. We describe two children with GSD0, confirmed by mutation analysis, who had glucosuria and hyperglycemia. Because of the variable presentation of this disorder and previous dependence on liver biopsy to confirm diagnosis, it is likely that GSD0 is underdiagnosed.