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 Abdul-Ghani, Luke Norton, Ralph A. DeFronzo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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
Issue number12
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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