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

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-; 10 FH+) infusion to raise plasma glucose by ∼45 mg/dL.At baseline, FH+ had lower insulin-stimulated oxidative (GOX) and total (TGD), but similar non-oxidative (NOGD) glucose disposal and basal endogenous glucose production (EGP) compared to FH-. Following three days of glucose infusion, basal EGP and GOX were markedly increased, whilst NOGD 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, pyruvate dehydrogenase and Akt, but protein O-GlcNAcylation was unchanged.Insulin resistance develops to a similar extent in FH- and FH+ subjects following chronic hyperglycemia, without increased protein O-GlcNAcylation. Decreased NOGD due to impaired glycogen synthase activation appears to be the primary deficit in skeletal muscle glucotoxicity.