Abnormal Glucose Handling by the Kidney in Response to Hypoglycemia in Type 1 Diabetes
The frequent occurrence of hypoglycemia in people with type 1 diabetes is attributed to abnormalities in the blood glucose counterregulatory response. In view of recent findings indicating that the kidney contributes to prevent and correct hypoglycemia in healthy subjects, we decided to investigate the role of renal glucose handling in hypoglycemia in type 1 diabetes. Twelve type 1 diabetic patients and 14 age-matched normal individuals were randomized to hyperinsulinemic-euglycemic (n = 6 diabetic subjects and n = 8 control subjects) or hypoglycemic (n = 6 each) clamps with blood glucose maintained either stable near 100 mg/dl (5.6 mmol/l) or reduced to 54 mg/dl (3.0 mmol/l). All study subjects had their renal vein catheterized under fluoroscopy, and net renal glucose balance and renal glucose production and utilization rates were measured using a combination of arteriovenous concentration difference with stable isotope dilution technique. Blood glucose and insulin were comparable in both groups in all studies. In patients with diabetes, elevations in plasma glucagon, epinephrine, and norepinephrine were blunted, and both the compensatory rise in endogenous glucose production and in the net glucose output by the kidney seen in normal subjects with equivalent hypoglycemia were absent. Renal glucose balance switched from a mean ± SE baseline net uptake of 0.6 ± 0.4 to a net output of 4.5 ± 1.3 μmol · kg−1 · min−1 in normal subjects, but in patients with diabetes there was no net renal contribution to blood glucose during similar hypoglycemia (mean ± SE net glucose uptake [baseline 0.7 ± 0.4] remained at 0.4 ± 0.3 μmol · kg−1 · min−1 in the final 40 min of hypoglycemia; P < 0.01 between groups). We conclude that adrenergic stimulation of glucose output by the kidney, which represents an additional defense mechanism against hypoglycemia in normal subjects, is impaired in patients with type 1 diabetes and contributes to defective glucose counterregulation.
Address correspondence and reprint requests to Eugenio Cersosimo, MD, PhD, Texas Diabetes Institute, 701 S. Zarzamora, MS 10-5, San Antonio, TX 78207-5209. Phone (210) 358-7000; Fax (210) 358-7235.
Received for publication 28 February 2001 and accepted in revised form 13 June 2001.
No abbreviations used.