Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance

Chris Shannon, Aurora Merovci, Juan Xiong, Devjit Tripathy, Felipe Lorenzo, Donald McClain, Muhammad A Abdul-ghani, Luke Norton, Ralph A Defronzo

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Chronic hyperglycemia causes insulin resistance, but the inheritability of glucotoxicity and the underlying mechanisms are unclear. We examined the effect of 3 days of hyperglycemia on glucose disposal, enzyme activities, insulin signaling, and protein O-GlcNAcylation in skeletal muscle of individuals without (FH2) or with (FH+) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-3H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline (n = 5) or glucose (n = 10 FH2 and 10 FH+) infusion to raise plasma glucose by ∼45 mg/dL. At baseline, FH+ had lower insulin-stimulated glucose oxidation and total glucose disposal (TGD) but similar nonoxidative glucose disposal and basal endogenous glucose production (bEGP) compared with FH2. After 3 days of glucose infusion, bEGP and glucose oxidation were markedly increased, whereas nonoxidative glucose disposal and TGD were lower versus baseline, with no differences between FH2 and FH+ subjects. Hyperglycemia doubled skeletal muscle glycogen content and impaired activation of glycogen synthase (GS), pyruvate dehydrogenase, and Akt, but protein O-GlcNAcylation was unchanged. Insulin resistance develops to a similar extent in FH2 and FH+ subjects after chronic hyperglycemia, without increased protein O-GlcNAcylation. Decreased nonoxidative glucose disposal due to impaired GS activation appears to be the primary deficit in skeletal muscle glucotoxicity.

Original languageEnglish (US)
Pages (from-to)2507-2517
Number of pages11
JournalDiabetes
Volume67
Issue number12
DOIs
StatePublished - Dec 1 2018

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Hyperglycemia
Glucose
Glycogen Synthase
Skeletal Muscle
Insulin
Insulin Resistance
Indirect Calorimetry
Proteins
Glucose Clamp Technique
Quadriceps Muscle
Pyruvic Acid
Glycogen
Type 2 Diabetes Mellitus
Oxidoreductases

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Shannon, C., Merovci, A., Xiong, J., Tripathy, D., Lorenzo, F., McClain, D., ... Defronzo, R. A. (2018). Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance. Diabetes, 67(12), 2507-2517. https://doi.org/10.2337/db18-0439

Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance. / Shannon, Chris; Merovci, Aurora; Xiong, Juan; Tripathy, Devjit; Lorenzo, Felipe; McClain, Donald; Abdul-ghani, Muhammad A; Norton, Luke; Defronzo, Ralph A.

In: Diabetes, Vol. 67, No. 12, 01.12.2018, p. 2507-2517.

Research output: Contribution to journalArticle

Shannon, C, Merovci, A, Xiong, J, Tripathy, D, Lorenzo, F, McClain, D, Abdul-ghani, MA, Norton, L & Defronzo, RA 2018, 'Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance', Diabetes, vol. 67, no. 12, pp. 2507-2517. https://doi.org/10.2337/db18-0439
Shannon C, Merovci A, Xiong J, Tripathy D, Lorenzo F, McClain D et al. Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance. Diabetes. 2018 Dec 1;67(12):2507-2517. https://doi.org/10.2337/db18-0439
Shannon, Chris ; Merovci, Aurora ; Xiong, Juan ; Tripathy, Devjit ; Lorenzo, Felipe ; McClain, Donald ; Abdul-ghani, Muhammad A ; Norton, Luke ; Defronzo, Ralph A. / Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance. In: Diabetes. 2018 ; Vol. 67, No. 12. pp. 2507-2517.
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