IN THE ABSENCE OF COUNTERREGULATORY HORMONES, THE INCREASE IN HEPATICGLUCOSE-PRODUCTION DURING INSULIN-INDUCED HYPOGLYCEMIA IN THE DOG IS INITIATED IN THE LIVER RATHER THAN THE BRAIN

We have previously demonstrated that the liver can release glucose in response to insulin-induced hypoglycemia, despite the absence of gluca gon, epinephrine, cortisol, and growth hormone. The aim of this study was to determine whether this is activated by liver or brain hypoglyce mia, We assessed the response to insulin-induced hypoglycemia in the a bsence of counterregulatory hormones in overnight-fasted conscious adr enalectomized dogs that were given somatostatin and intraportal insuli n (30 pmol . kg(-1) . min(-1)) for 360 min. Glucose was infused to mai ntain euglycemia for 3 h and then to allow limited peripheral hypoglyc emia for the next 3 h. During peripheral hypoglycemia, five dogs recei ved glucose via both carotid and vertebral arteries to maintain cerebr al euglycemia (H-EU group) concurrently with peripheral hypoglycemia, while six dogs received saline in these vessels to allow simultaneous cerebral and peripheral hypoglycemia (H-HY group). Throughout the stud y, arterial insulin was 1,675 +/- 295 and 1,440 +/- 310 pmol/l in the H-HY and H-EU groups, respectively. Glucose fell from 6.2 +/- 0.3 to 2 .1 +/- 0.0 mmol/l and from 5.8 +/- 0.3 to 1.9 +/- 0.1 mmol/l in the la st hour in the H-HY and H-EU groups, respectively (P < 0.05 for both). Norepinephrine rose from 1.12 +/- 0.35 to 2.44 +/- 0.69 nmol/l and fr om 1.09 +/- 0.07 to 1.74 +/- 0.16 nmol/l in the last hour in the H-HY and H-EU groups, respectively (P < 0.05 for both; no difference betwee n groups). Glucagon, epinephrine, and cortisol were below the limits o f detection. The liver switched from uptake to output of glucose durin g peripheral hypoglycemia in both the H-HY (-7.1 +/- 2.1 to 5.4 +/- 3. 1 mu mol . kg(-1) . min(-1)) and H-EU (-7.9 +/- 3.5 to 3.4 +/- 1.7 mu mol . kg(-1) min(-1)) groups (P < 0.05 for both; no difference between groups). Alanine levels and net hepatic alanine uptake fell similarly in both groups. There were increases (P < 0.05) in glycerol (12 +/- 3 to 258 +/- 47 mu mol/l) and nonesterified fatty acid (194 +/- 10 to 5 40 +/- 80 mu mol/l) levels and in total ketone production (0.4 +/- 0.1 to 1.1 +/- 0.2 mu mol . kg(-1) . min(-1)) in the H-HY group, but thes e parameters did not change in the H-EU group. These data clearly indi cate that the Lipolytic and hepatic responses to hypoglycemia are driv en by differential sensing mechanisms. Thus, during insulin-induced hy poglycemia, when counterregulatory hormones are absent, liver hypoglyc emia triggers the increase in hepatic glucose production, whereas cere bral hypoglycemia causes the increases in lipolysis and ketogenesis.