Relationship Between Decrements in Glucose Level and Metabolic Response to Hypoglycemia in Absence of Counterregulatory Hormones in the Conscious Dog

Abstract

To determine the relationship between decreases in glucose and metabolic regulation in the absence of counterregulatory hormones, we infused overnight-fasted, conscious, adrenalectomized dogs (lacking cortisol and EPI) with somatostatin (to eliminate glucagon and growth hormone) and intraportal insulin (30 pmol.kg-1.min-1), creating arterial insulin levels of approximately 2000 pM. Glucose was infused during one 120-min period, two 90-min periods, and one 45-min period to establish levels of 5.9 +/- 0.1, 3.4 +/- 0.1, 2.5 +/- 0.1, and 1.7 +/- 0.1 mM, respectively. NE levels were 1.24 +/- 0.23, 1.85 +/- 0.27, 2.04 +/- 0.26, and 2.50 +/- 0.20 nM, respectively. During the euglycemic control period, the liver took up glucose (7.5 +/- 1.9 mumol.kg-1.min-1), but hypoglycemia triggered successively greater rates of net hepatic glucose output (3.0 +/- 0.7, 4.6 +/- 0.9, and 6.9 +/- 1.4 mumol.kg-1.min-1). Total gluconeogenic precursor uptake by the liver increased with hypoglycemia. Intrahepatic gluconeogenic efficiency rose progressively (by 106 +/- 42, 199 +/- 56, and 268 +/- 55%). Both glycerol and NEFA levels rose, indicating lipolysis was enhanced. Net hepatic NEFA uptake and ketone production increased proportionally, but the ketone level rose only with severe hypoglycemia. In conclusion, despite marked hyperinsulinemia and the absence of glucagon, EPI, and cortisol, we observed that lipolysis and glucose and ketone production increase in response to decreases in glucose. This suggests that neural and/or autoregulatory mechanisms can play a role in combating hypoglycemia.

Autoregulation of hepatic glucose production

“…The effect of this change in norepinephrine on glucose metabolism would have been minor, if the change in norepinephrine had been restricted to circulating concentrations only. A 30-fold basal increase in hepatic sinusoidal norepinephrine was required to increase net hepatic glucose output as much as Connolly et al (38) observed at the 1.7 mmol/l hypoglycemic plateau (39). Unfortunately, the rise in circulating norepinephrine observed by Connolly et al (38) re¯ected spillover from the synaptic clefts and thus an enhancement of sympathetic signaling, rather than a hormonal change.…”

“…In addition, comparison of the data of Connolly et al (38) with those of Frizzell et al (33) made it possible to quantify the impact of nonhormonal mechanisms on the response to a glycemic level of ,2.5 mmol/l (a glucose concentration common to both investigations). Nonhormonal mechanisms, possibly including autoregulation, could account for approximately one-quarter of the change in net hepatic glucose balance observed at 2.5 mmol/l glucose (38).…”

“…one which would create a 2-fold rise in circulating norepinephrine) would have on net hepatic glucose output. Nevertheless, the work of Connolly et al (38) conclusively demonstrated in vivo that nonhormonal mechanisms (neural and/or autoregulatory) stimulate net hepatic glucose output in response to insulin-induced hypoglycemia. In addition, comparison of the data of Connolly et al (38) with those of Frizzell et al (33) made it possible to quantify the impact of nonhormonal mechanisms on the response to a glycemic level of ,2.5 mmol/l (a glucose concentration common to both investigations).…”

“…Nevertheless, the work of Connolly et al (38) conclusively demonstrated in vivo that nonhormonal mechanisms (neural and/or autoregulatory) stimulate net hepatic glucose output in response to insulin-induced hypoglycemia. In addition, comparison of the data of Connolly et al (38) with those of Frizzell et al (33) made it possible to quantify the impact of nonhormonal mechanisms on the response to a glycemic level of ,2.5 mmol/l (a glucose concentration common to both investigations). Nonhormonal mechanisms, possibly including autoregulation, could account for approximately one-quarter of the change in net hepatic glucose balance observed at 2.5 mmol/l glucose (38).…”

“…Moreover, adrenergic blockade does not have the same metabolic effect as epinephrine de®ciency resulting from adrenalectomy (37). Connolly et al (38) therefore conducted studies to de®ne more precisely the relationship between plasma glucose concentrations and glucose metabolism in the conscious dog. Adrenalectomized dogs (lacking cortisol and epinephrine) were infused with somatostatin, as well as a high dose of intraportal insulin, resulting in arterial insulin concentrations of ,2000 pmol/l.…”