Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients
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Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients. / Vestergaard, Henrik; Bjørbaek, C.; Hansen, T.; Larsen, F. S.; Granner, D. K.; Pedersen, O.
In: The Journal of Clinical Investigation, Vol. 96, No. 6, 1995, p. 2639-45.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients
AU - Vestergaard, Henrik
AU - Bjørbaek, C.
AU - Hansen, T.
AU - Larsen, F. S.
AU - Granner, D. K.
AU - Pedersen, O.
PY - 1995
Y1 - 1995
N2 - After entering the muscle cell, glucose is immediately and irreversibly phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II. Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle. Reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp. These findings [correction of finding] are consistent with a defect in glucose transport and/or phosphorylation. In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state. HKII activity in a supernatant of muscle extract accounted for 28 +/- 5% in NIDDM patients and 40 +/- 5% in controls (P = 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 +/- 4 and 47 +/- 7% (P = 0.02) when measured at 0.11 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P = 0.02 and P = 0.02, respectively). In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively). In conclusion, NIDDM patients are characterized by a reduced activity and a reduced gene expression of HKII in muscle which may be secondary to the metabolic peturbations. HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle.
AB - After entering the muscle cell, glucose is immediately and irreversibly phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II. Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle. Reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp. These findings [correction of finding] are consistent with a defect in glucose transport and/or phosphorylation. In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state. HKII activity in a supernatant of muscle extract accounted for 28 +/- 5% in NIDDM patients and 40 +/- 5% in controls (P = 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 +/- 4 and 47 +/- 7% (P = 0.02) when measured at 0.11 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P = 0.02 and P = 0.02, respectively). In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively). In conclusion, NIDDM patients are characterized by a reduced activity and a reduced gene expression of HKII in muscle which may be secondary to the metabolic peturbations. HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle.
KW - Adult
KW - Aged
KW - Base Sequence
KW - Blood Glucose
KW - Case-Control Studies
KW - DNA Primers
KW - Diabetes Mellitus, Type 2
KW - Fasting
KW - Fatty Acids, Nonesterified
KW - Female
KW - Gene Expression
KW - Glucose Clamp Technique
KW - Glycogen Synthase
KW - Hexokinase
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Isoenzymes
KW - Male
KW - Middle Aged
KW - Molecular Sequence Data
KW - Muscle, Skeletal
KW - Polymerase Chain Reaction
KW - RNA, Messenger
KW - Reference Values
KW - Statistics, Nonparametric
KW - Comparative Study
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1172/JCI118329
DO - 10.1172/JCI118329
M3 - Journal article
C2 - 8675629
VL - 96
SP - 2639
EP - 2645
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -
ID: 174866704