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Elevated ?-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

ABSTRACT: Context:Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth. Objective:To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control. Design and Setting:A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic. Patients and Intervention:Concentrations of ?-hydroxybutyrate, ?-hydroxybutyrate, lactate, and branched-chain amino acids (BCAAs) were measured by nuclear magnetic resonance spectroscopy in 78 nondiabetic adolescents during an oral glucose tolerance test (OGTT). Associations between baseline metabolic alterations and longitudinal changes in glucose control were tested in 16 subjects after a mean follow-up of 2.3 years. Main Outcome Measures:The relationship between metabolite levels, parameters of IR, and glycemic control, and their progression over time. Results:Elevated fasting ?-hydroxybutyrate levels were observed in adolescents with reduced insulin sensitivity after adjusting for age, sex, ethnicity, Tanner stage, and body mass index z-score (P = 0.014). Plasma ?-hydroxybutyrate and BCAAs were increased throughout the course of the OGTT in this group (P < 0.03). Notably, borderline IR was associated with a progressive ?-hydroxybutyrate decrease from elevated baseline concentrations to normal levels (P = 0.02). Increased baseline ?-hydroxybutyrate concentrations were further associated with progressive worsening of glucose tolerance and disposition index. Conclusion:?-Hydroxybutyrate and BCAA concentrations during an OGTT characterize insulin-resistant youth and predict worsening of glycemic control. These findings provide potential biomarkers for risk assessment of type 2 diabetes and new insights into IR pathogenesis.

SUBMITTER: Trico D

PROVIDER: S-EPMC5505187 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

Tricò Domenico D Prinsen Hetty H Giannini Cosimo C de Graaf Robin R Juchem Christoph C Li Fangyong F Caprio Sonia S Santoro Nicola N Herzog Raimund I RI

The Journal of clinical endocrinology and metabolism 20170701 7

<h4>Context</h4>Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth.<h4>Objective</h4>To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control.<h4>Design and setting</h4>A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic.<h4>Patients and intervention</h4>Concentrations of α-hydroxybutyrate, β-hyd ...[more]

PMID: 28482070

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Project description:IntroductionHypoglycemia is a major limiting factor in achieving recommended glycemic targets for people with type 1 diabetes. Exposure to recurrent hypoglycemia results in blunted hormonal counter-regulatory and symptomatic responses to hypoglycemia. Limited data on metabolic adaptation to recurrent hypoglycemia are available. This study examined the acute metabolic responses to hypoglycemia and the effect of antecedent hypoglycemia on these responses in type 1 diabetes.Research design and methodsTwenty-one outpatients with type 1 diabetes with normal or impaired awareness of hypoglycemia participated in a study assessing the response to hypoglycemia on 2 consecutive days by a hyperinsulinemic glucose clamp. Participants underwent a period of normoglycemia and a period of hypoglycemia during the hyperinsulinemic glucose clamp. Plasma samples were taken during normoglycemia and at the beginning and the end of the hypoglycemic period. Metabolomic analysis of the plasma samples was conducted using comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry.ResultsIn total, 68 metabolites were studied. On day 1, concentrations of the branched-chain amino acids, leucine (p=3.8×10-3) and isoleucine (p=2.2×10-3), decreased during hypoglycemia. On day 2, during hypoglycemia, five amino acids (including leucine and isoleucine) significantly decreased, and two fatty acids (tetradecanoic and oleic acids) significantly increased (p<0.05). Although more metabolites responded to hypoglycemia on day 2, the responses of the single metabolites were not statistically significant between the 2 days.ConclusionsIn individuals with type 1 diabetes, one episode of hypoglycemia decreases leucine and isoleucine concentrations. Antecedent hypoglycemia results in the decrement of five amino acids and increases the concentrations of two fatty acids, suggesting an alteration between the two hypoglycemic episodes, which could indicate a possible adaptation. However, more studies are needed to gain a comprehensive understanding of the consequences of these alterations.Trial registration numberNCT01337362.

Dataset Information

Elevated ?-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

Publications

Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

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