Dataset Information

Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.

ABSTRACT: Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and ?-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of ?-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute insulin response [AIRg]) evaluating T2D-susceptibility variants (n = 57) in Hispanic Americans from the GUARDIAN Consortium (n = 2,560). Basal and dynamic measures were genetically correlated (HOMAB-AIRg: ?G = 0.28-0.73; HOMAIR-SI: ?G = -0.73 to -0.83) with increased heritability for the dynamic measure AIRg Significant association of variants with dynamic measures (P < 8.77 × 10(-4)) was observed. A pattern of superior performance of AIRg was observed for well-established loci including MTNR1B (P = 9.46 × 10(-12)), KCNQ1 (P = 1.35 × 10(-4)), and TCF7L2 (P = 5.10 × 10(-4)) with study-wise statistical significance. Notably, significant association of MTNR1B with AIRg (P < 1.38 × 10(-9)) was observed in a population one-fourteenth the size of the initial discovery cohort. These observations suggest that basal and dynamic measures provide different views and levels of sensitivity to discrete elements of glucose homeostasis. Although more costly to obtain, dynamic measures yield significant results that could be considered physiologically "closer" to causal pathways and provide insight into the discrete mechanisms of action.

SUBMITTER: Palmer ND

PROVIDER: S-EPMC4915581 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.

Palmer Nicholette D ND Wagenknecht Lynne E LE Langefeld Carl D CD Wang Nan N Buchanan Thomas A TA Xiang Anny H AH Allayee Hooman H Bergman Richard N RN Raffel Leslie J LJ Chen Yii-Der Ida YD Haritunians Talin T Fingerlin Tasha T Goodarzi Mark O MO Taylor Kent D KD Rotter Jerome I JI Watanabe Richard M RM Bowden Donald W DW

Diabetes 20160503 7

Type 2 diabetes (T2D) is a heterogeneous disorder with contributions from peripheral insulin resistance and β-cell dysfunction. For minimization of phenotypic heterogeneity, quantitative intermediate phenotypes characterizing basal glucose homeostasis (insulin resistance and HOMA of insulin resistance [HOMAIR] and of β-cell function [HOMAB]) have shown promise in relatively large samples. We investigated the utility of dynamic measures of glucose homeostasis (insulin sensitivity [SI] and acute i ...[more]

PMID: 27207554

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Project description:BackgroundWith the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development.Subjects/methodsCross-sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for β-cell function, insulin sensitivity and insulin secretion were calculated.ResultsNineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and β-cell function, although their glycated hemoglobin (HbA1c) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0-120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA1c among obese children.ConclusionsChildren with identified PD had changes of several markers for β-cell function, insulin sensitivity and resistance before changes in HbA1c occurred. The lower disposition index indicates that these children have already inadequate β-cell compensation for the degree of insulin resistance.

Dataset Information

Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.

Publications

Improved Performance of Dynamic Measures of Insulin Response Over Surrogate Indices to Identify Genetic Contributors of Type 2 Diabetes: The GUARDIAN Consortium.

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