Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans

To examine the potential contribution of precursor substrates to renal gluc oneogenesis during hypoglycemia, 14 healthy subjects had arterialized hand vein and renal vein (under fluoroscopy) catheterized after an overnight fas t. Net renal balance of lactate, glycerol, alanine, and glutamine was deter mined simultaneously with systemic and renal glucose kinetics using arterio venous concentration differences and 6-[H-2(2)]glucose tracer dilution. Ren al plasma flow was measured by para-aminohippurate clearance and was conver ted to blood flow using the mathematical value (1-hematocrit). Arterial and renal vein samples were obtained in the postabsorptive state and during a 180-min hyperinsulinemic period during either euglycemia or hypoglycemia. I nsulin increased from 49 +/- 14 to 130 +/- 25 pmol/l (hypoglycemia) and to 102 +/- 10 pmol/l (euglycemia). Arterial blood glucose decreased from 4.5 /- 0.2 to 3.0 +/- 0.1 mmol/l during hypoglycemia but did not change during euglycemia (4.3 +/- 0.2 mmol/l). After 150 min, endogenous glucose producti on reached a plateau value that was higher during hypoglycemia (10.3 +/- 0. 6 mu mol . kg(-1) . min(-1)) than during euglycemia (5.73 +/- 0.6 mu mol . kg(-1) . min(-1), P < 0.001). Hypoglycemia was associated with a rise in re nal glucose production (RGP) from 3.0 +/- 0.7 to 5.4 +/- 0.6 mu mol . kg(-1 ) . min(-1) (P < 0.05), although glucose utilization remained the same (2.0 +/- 0.8 vs. 2.1 +/- 0.6 mu mol . kg(-1) . min(-1)). As a result, net renal glucose output increased from 1.0 +/- 0.3 to 3.3 +/- 0.40 mu mol . kg(-1) . min(-1). Elevations in net renal uptake of lactate (2.4 +/- 0.5 to 3.5 +/ - 0.7 vs. 2.8 +/- 0.4 mu mol . kg(-1) . min(-1)), glycerol (0.6 +/- 0.3 to 1.3 +/- 0.5 vs. 0.4 +/- 0.2 mu mol . kg(-1) . min(-1)), and glutamine (0.7 +/- 0.2 to 1.1 +/- 0.3 vs. 0.1 +/- 0.3 mu mol . kg(-1) . min(-1)) during hy poglycemia versus euglycemia (P < 0.05) could account for nearly 60% of all glucose carbons released in the renal vein during hypoglycemia. Our data i ndicate that extraction of circulating gluconeogenic precursors by the kidn ey is enhanced and responsible for a substantial fraction of the compensato ry rise in RGP during sustained hypoglycemia. Increased renal gluconeogenes is from circulating substrates represents an additional physiological mecha nism by which the decrease in blood glucose concentration is attenuated in humans.