TY - JOUR T1 - Effect of Chronic Hyperglycemia on Glucose Metabolism in Subjects With Normal Glucose Tolerance JF - Diabetes JO - Diabetes SP - 2507 LP - 2517 DO - 10.2337/db18-0439 VL - 67 IS - 12 AU - Shannon, Chris AU - Merovci, Aurora AU - Xiong, Juan AU - Tripathy, Devjit AU - Lorenzo, Felipe AU - McClain, Donald AU - Abdul-Ghani, Muhammad AU - Norton, Luke AU - DeFronzo, Ralph A. Y1 - 2018/12/01 UR - http://diabetes.diabetesjournals.org/content/67/12/2507.abstract N2 - 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. ER -