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. 2018 Dec;67(12):2507-2517.
doi: 10.2337/db18-0439. Epub 2018 Sep 13.

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

Chris Shannon  1 , Aurora Merovci  1 , Juan Xiong  1 , Devjit Tripathy  1 , Felipe Lorenzo  2 , Donald McClain  2 , Muhammad Abdul-Ghani  1 , Luke Norton  1 , Ralph A DeFronzo  3
Affiliations

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

Chris Shannon et al. Diabetes. 2018 Dec.

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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Figures

Figure 1
Figure 1
Plasma glucose and insulin concentrations during the OGTT performed in NGT individuals with (FH+) and without (FH−) FH of diabetes and in the NGT control group.
Figure 2
Figure 2
FPG (A), insulin (B), and FFA (C) concentrations at baseline and during 3 days of either glucose infusion in NGT individuals without (FH−, n = 10) and with (FH+, n = 10) FH of diabetes, or saline infusion in the NGT control group (n = 5). Data represent mean ± SE and were analyzed using two-way mixed-model (group × time) ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001, vs. control group and vs. baseline.
Figure 3
Figure 3
Insulin-stimulated TGD (total height of bars), nonoxidative glucose disposal (NOGD) (shaded part of bars), and glucose oxidation (GOX) in FH+ and FH− individuals during the euglycemic insulin clamp performed at baseline and after 3 days of glucose infusion. Right panel shows control subjects receiving saline infusion. *P < 0.05, FH+ vs. FH−; †P < 0.05, postglucose infusion vs. baseline.
Figure 4
Figure 4
Glycogen synthesis signaling. A: Skeletal muscle glycogen content at baseline and during 3 days of either glucose infusion in NGT individuals without (FH−, dark bars, n = 10) and with (FH+, white bars, n = 10) FH of diabetes, or saline infusion in the NGT control group (right panel, n = 5). Representative Western blot images of the total and phosphorylated protein expression (top panel) and densitometry quantitation of the phosphorylated-to-total ratio of GS (B) and GSK3β (C). G6P (D) and glycogen (E) concentrations in skeletal muscle of all subjects receiving glucose infusion. Data are expressed as the mean ± SE and were analyzed using two-way repeated-model (clamp × infusion) ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001, for clamp vs. basal; ^P < 0.05 and ^^^P < 0.001, postglucose infusion vs. baseline. CON, control.
Figure 5
Figure 5
PDH regulation and insulin signaling. Representative Western blot images and densitometry quantitation of PDK4 protein expression (A), PDH E1α subunit phosphorylation (B), and Akt phosphorylation (D) and PDH activation status (C) at baseline (black bars) and after 3 days of glucose (white bars) infusion in NGT subjects. Data represent mean ± SE and were analyzed using two-way mixed-model (group × clamp; group × infusion) ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001 for clamp vs. basal; ^P < 0.05 and ^^^P < 0.001, postglucose infusion vs. baseline.
Figure 6
Figure 6
Basal O-GlcNAcylated protein quantification before and after 3 days of saline (white bars) or glucose (black bars) infusion (A) and representative blot for three subjects receiving glucose infusion (B). Basal and insulin-stimulated OGT (C) and GFAT1 (D) quantification before (black bars) and after (white bars) 3 days of glucose infusion and representative blots (E). Data represent mean ± SE and were analyzed using two-way mixed-model (group × clamp; group × infusion) ANOVA. BL, baseline; GLU, glucose.
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