Diabetes, volume 67, issue 12, pages 2507-2517

Effect of Chronic Hyperglycemia on Glucose Metabolism in Subjects With Normal Glucose Tolerance

Christopher E Shannon 1
Aurora Merovci 1
Juan Xiong 1
Devjit Tripathy 1
Felipe Lorenzo 2
Donald McClain 2
Ralph DeFronzo 1
Luke Norton 1
RALPH A. DeFRONZO 1
Show full list: 9 authors
Publication typeJournal Article
Publication date2018-09-13
Journal: Diabetes
scimago Q1
SJR2.541
CiteScore12.5
Impact factor6.2
ISSN00121797, 23724765, 1939327X
Endocrinology, Diabetes and Metabolism
Internal Medicine
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 (FH−) 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 FH− 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 FH−. 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 FH− 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 FH− 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.

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