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Fatty Acids Prevent Hypoxia-Inducible Factor-1? Signaling Through Decreased Succinate in Diabetes.

ABSTRACT: Hypoxia-inducible factor (HIF)-1? is essential following a myocardial infarction (MI), and diabetic patients have poorer prognosis post-MI. Could HIF-1? activation be abnormal in the diabetic heart, and could metabolism be causing this? Diabetic hearts had decreased HIF-1? protein following ischemia, and insulin-resistant cardiomyocytes had decreased HIF-1?-mediated signaling and adaptation to hypoxia. This was due to elevated fatty acid (FA) metabolism preventing HIF-1? protein stabilization. FAs exerted their effect by decreasing succinate concentrations, a HIF-1? activator that inhibits the regulatory HIF hydroxylase enzymes. In vivo and in vitro pharmacological HIF hydroxylase inhibition restored HIF-1? accumulation and improved post-ischemic functional recovery in diabetes.

SUBMITTER: Dodd MS

PROVIDER: S-EPMC6115650 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes.

Dodd Michael S MS Sousa Fialho Maria da Luz MDL Montes Aparicio Claudia N CN Kerr Matthew M Timm Kerstin N KN Griffin Julian L JL Luiken Joost J F P JJFP Glatz Jan F C JFC Tyler Damian J DJ Heather Lisa C LC

JACC. Basic to translational science 20180828 4

Hypoxia-inducible factor (HIF)-1α is essential following a myocardial infarction (MI), and diabetic patients have poorer prognosis post-MI. Could HIF-1α activation be abnormal in the diabetic heart, and could metabolism be causing this? Diabetic hearts had decreased HIF-1α protein following ischemia, and insulin-resistant cardiomyocytes had decreased HIF-1α-mediated signaling and adaptation to hypoxia. This was due to elevated fatty acid (FA) metabolism preventing HIF-1α protein stabilization. F ...[more]

PMID: 30175272

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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

Fatty Acids Prevent Hypoxia-Inducible Factor-1? Signaling Through Decreased Succinate in Diabetes.

Publications

Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes.

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