NEONATAL DE-AFFERENTATION OF CAPSAICIN-SENSITIVE SENSORY NERVES INCREASES IN-VIVO INSULIN SENSITIVITY IN CONSCIOUS ADULT RATS

Sensory neuropeptides, released from the peripheral nervous system, mi ght modulate glucose homeostasis by antagonizing insulin action. The e ffects of de-afferentation of functional small diameter unmyelinated C -fibres (sensory nerves) on in vivo insulin-mediated intracellular glu cose metabolism were investigated by using euglycaemic insulin (6 and 18 mU/kg.min) clamps with [3-H-3]-glucose infusion in 24 adult rats, t reated neonatally with either capsaicin (CAP) (50 mg/kg) or vehicle (C ON). Following the clamp, skeletal muscle groups, liver and adipose ti ssue were freeze-clamped. At plasma insulin levels of approximately 90 mU/l, CAP-rats showed a 21% increase in whole body glucose uptake com pared with CON (24.4 +/- 1.6 vs 20.1 +/- 0.8 mg/kg . min, p < 0.02), w hich was paralleled by a 20 % increase in whole body glycolysis (12.6 +/- 0.8 vs 10.5 +/- 0.5 mg/kg.min p < 0.05) (concentration of (H2O)-H- 3 in plasma). Whole body skeletal muscle glycogenesis was increased by 80% in CAP-rats (5.7 +/- 0.7 vs 3.1 +/- 0.7 mg/kg . min, p < 0.05) wi th increased muscle glycogen synthase activity. Whole body (muscle, li ver and adipose tissue combined) de novo lipogenesis also was increase d in CAP-rats compared with CON (0.69 +/- 0.10 vs 0.44 +/- 0.06 mg/kg min, p < 0.05) (incorporation of [3-H-3]-glucose counts into glycogen or fat). Hepatic glucose production was lower in CAP-rats compared wit h CON (0.6 +/- 0.6 vs 2.1 +/- 0.7 mg/kg . min, p < 0.05). Plasma gluca gon, corticosterone, epinephrine and norepinephrine levels were reduce d in CAP-rats: 43 +/- 2 compared with 70 +/- 6 pg/ml, 855 +/- 55 compa red with 1131 +/- 138 nmol/l, 513 +/- 136 compared with 1048 +/- 164 p mol/l and 928 +/- 142 compared with 1472 +/- 331 pmol/l, respectively, p < 0.05. At plasma insulin levels of approximately 400 mU/l, CAP-rat s showed no differences in peripheral and hepatic insulin action compa red with CON. We conclude that the removae of endogenous sensory neuro peptides, by de-afferentation of capsaicin-sensitive sensory nerves, i ncreases in vivo insulin sensitivity, but not responsiveness: 1) prima rily through an increased sensitivity of skeletal muscle glycogen synt hesis to insulin; 2) through a reduction in the levels of counter-regu latory hormones, thereby creating a milieu which favours overall in vi vo insulin sensitivity with respect to glucose uptake, glucose product ion, glycolysis, glycogenesis and lipogenesis.