2-deoxy-D-glucose-induced hyperglycemia: role for direct sympathetic nervous system activation of liver glucose...

The hypothalamus plays an important integrative role in the control of peripheral metabolism, achieved by modulation of autonomic outflow to the endocrine pancreas, the liver and the adrenal medulla. This study examines the role of direct sympathetic nervous system control of hepatic glucose output during neuroglycopenia induced by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG). Steady-state tracer methodology was used to directly measure hepatic glucose output (Ra) in pentobarbitone-anesthetised male Wistar rats (220-320 g). Administration of 500 mg/kg 2-DG i.p. produced an increase in Ra from a control value of 7.3 +/- 0.3 mg/kg.min (n = 4) to 15.2 +/- 2.2 mg/kg.min-1 (n = 8), corresponding to an increase in plasma glucose (PG) from 6.4 +/- 0.1 mmol/l to 10.1 +/- 0.4 mmol/l. This rise was countered by the sympathetic noradrenergic blocker guanethidine (100 mg/kg i.p.), reducing Ra to 10.4 +/- 0.9 mg/kg.min-1 and PG to 6.1 +/- 0.3 mmol/l (n = 8), despite markedly lower plasma insulin (PI) levels (2-DG: PI = 94.7 +/- 18.6 mU/l (n = 7), 2-DG + guanethidine: PI = 41.4 +/- 3.3 mU/l (n = 8). Hyperglycemia and elevated liver glucose output were maintained in ADX animals treated with 2-DG, indicating an absence of adrenal-medullary influence (2-DG: Ra = 15.2 +/- 2.2 mg/kg.min-1, 2-DG + ADX = 15.6 +/- 1.0 mg/kg.min-1). Elevated Ra in the 2-DG + ADX was maintained despite markedly elevated insulin levels 349.3 +/- 72.6 mU/l (n = 7)).(ABSTRACT TRUNCATED AT 250 WORDS)