TY - JOUR
T1 - Effect of chronic hyperglycemia on glucose metabolism in subjects with normal glucose tolerance
AU - Shannon, Chris
AU - Merovci, Aurora
AU - Xiong, Juan
AU - Tripathy, Devjit
AU - Lorenzo, Felipe
AU - McClain, Donald
AU - Abdulghani, Muhammad
AU - Norton, Luke
AU - DeFronzo, Ralph A.
PY - 2018/12/1
Y1 - 2018/12/1
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
2
) or with (FH
+
) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-
3
H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline (n = 5) or glucose (n = 10 FH
2
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
2
. 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
2
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
2
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.
AB -
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
2
) or with (FH
+
) family history of type 2 diabetes. Twenty-five subjects with normal glucose tolerance received a [3-
3
H]glucose euglycemic insulin clamp, indirect calorimetry, and vastus-lateralis biopsies before and after 3 days of saline (n = 5) or glucose (n = 10 FH
2
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
2
. 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
2
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
2
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.
UR - http://www.scopus.com/inward/record.url?scp=85056802237&partnerID=8YFLogxK
U2 - 10.2337/db18-0439
DO - 10.2337/db18-0439
M3 - Article
C2 - 30213826
AN - SCOPUS:85056802237
VL - 67
SP - 2507
EP - 2517
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 12
ER -