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A Potential Important Role of Skeletal Muscle in Human Counterregulation of Hypoglycemia

Carl T. Hayden Veterans Affairs Medical Center (C.M.), Department of Endocrinology and Metabolism, Phoenix, Arizona 85012; University of Giessen, Third Medical Department (C.M., P.S., N.S., M.E., R.G.B., T.L.), 35390 Giessen, Germany; and University of Rochester (J.G.), Department of Medicine, Rochester, New York 14627

Address all correspondence and requests for reprints to: Christian Meyer, M.D., Carl T. Hayden Veteran Affairs Medical Center, Department of Endocrinology, 650 East Indian School Road, Phoenix, Arizona 85012. E-mail: christian.meyer{at}med.va.gov.

Context: During hypoglycemia, systemic glucose uptake (SGU) decreases and endogenous glucose release (EGR) increases. Skeletal muscle appears to be primarily responsible for the reduced SGU and may be important for the increased EGR by providing lactate for gluconeogenesis (GN).

Objective: The objective of the study was to test the hypothesis that reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation using systemic isotopic techniques in combination with forearm net balance measurements.

Setting: The study was conducted at the University of Giessen Clinical Research Center.

Participants: Nine healthy volunteers participated in the study.

Intervention: A 2-h hyperinsulinemic euglycemic clamp (blood glucose 4.4 mM) was followed by a 90-min hypoglycemic clamp (blood glucose 2.6 mM).

Results: Compared with the euglycemic clamp, SGU decreased (21.0 ± 2.0 vs. 29.6 ± 1.8 µmol·kg body weight^–1·min^–1; P < 0.001), whereas EGR (11.2 ± 1.7 vs. 4.9 ± 1.3 µmol·kg body weight^–1 ·min^–1; P < 0.003), arterial lactate concentrations (1051 ± 162 vs. 907 ± 115 µM; P < 0.02), systemic lactate release (23.5 ± 0.9 vs. 17.1 ± 0.9 µmol·kg body weight^–1·min^–1; P < 0.001), and lactate GN (4.50 ± 0.60 vs. 2.74 ± 0.30 µmol·kg body weight^–1·min^–1; P < 0.02) increased during hypoglycemia; the proportion of lactate used for GN remained unchanged (38 ± 4 vs. 32 ± 3%; P = 0.27). Whole-body muscle glucose uptake decreased approximately 50% during hypoglycemia (6.4 ± 1.9 vs. 13.6 ± 2.9 µmol·kg body weight^–1·min^–1; P < 0.001), which accounted for approximately 85% of the reduction of SGU. Whole-body muscle lactate release increased 6.6 ± 1.6 µmol·kg body weight^–1· min^–1 (P < 0.01), which could have accounted for all the increase in systemic lactate release and, considering the proportion of lactate used for GN, contributed 1.4 ± 0.4 µmol·kg body weight^–1·min^–1 (25%) to the increase in EGR.

Conclusions: Reduced muscle glucose uptake and increased muscle lactate release both make major contributions to glucose counterregulation in humans.

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