Abnormal Glucose Handling by the Kidney in Response to Hypoglycemia in Type 1 Diabetes

Abstract and Introduction

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.

Intensive therapy that effectively lowers mean blood glucose concentrations toward the nondiabetic range increases the risk of severe iatrogenic hypoglycemia in people with type 1 diabetes^[1]. This has been largely attributed to compromised counterregulation, which includes defective hormonal responses and hypoglycemia unawareness. It is known that in patients with C-peptide–negative diabetes of long duration, lower blood glucose concentrations are required to elicit autonomic nervous system and symptomatic responses to hypoglycemia. As a consequence, compensatory adjustments in the rates of endogenous glucose production and utilization are delayed, and result in severe and prolonged hypoglycemia^[2]. The fact that patients with renal insufficiency are also at increased risk for developing hypoglycemia^[3] has raised the question of whether glucose handling by the kidney plays a role in the body’s defense against hypoglycemia. Although the mechanisms behind the episodes of hypoglycemia in patients with renal insufficiency are not as clearly defined as in diabetes, it is conceivable that the kidney plays a more critical role in the maintenance of blood glucose concentration than previously appreciated.

The biochemical capacity and physiological reserve of the kidney to produce and release glucose into the circulation have been characterized and were emphasized several years ago by a series of studies performed in fasting humans. Using arteriovenous glucose concentration differences, Cahill et al.^[4,5,6] demonstrated that the net contribution of the kidney to blood glucose, which was negligible in the initial 24 h, increased significantly with prolonged fasting, such that by the fourth week of fasting, the kidney was responsible for one-half of the total glucose appearing in the circulation. Our understanding of the role of the kidney in glucose homeostasis has improved substantially with the recent development of an isotopic method capable of partitioning individual rates of renal glucose production and utilization^[7]. There is now evidence that in healthy individuals renal glucose production is stimulated by epinephrine^[8] and suppressed by insulin^[9], and that increased glucose production by the kidney contributes to maintenance of blood glucose even in early fasting^[10]. Additionally, and perhaps of greater clinical significance, mild-to-moderate hypoglycemia sustained by continuous insulin infusion is associated with net glucose output by the kidney. This is primarily due to enhanced rates of renal glucose production combined with minimal or no changes in renal glucose utilization^[11,12]. The reversal to net glucose output by the kidney during sustained hypoglycemia appears to complement the simultaneous rise in glucose production by the liver, thus contributing to the attenuation of the fall and restoration of normal blood glucose concentration^[13]. These adaptive changes in glucose kinetics are brought about by the counterregulatory response, which includes immediate release of glucagon and epinephrine into the circulation and neural sympathetic activation. Since glucagon secretion in response to hypoglycemia, which affects primarily the liver, is lost early in patients with type 1 diabetes^[14], prevention of hypoglycemia relies entirely on adrenergic mechanisms^[15]. Thus, we have postulated that adjustments in renal glucose handling in these patients must play an important role in defense against hypoglycemia. This study was therefore undertaken to examine the hypothesis that inadequate renal response to hypoglycemia contributes to the defective blood glucose counterregulation in patients with type 1 diabetes.

Diabetes. 2001;50(9) © 2001 American Diabetes Association, Inc.

Cite this: Abnormal Glucose Handling by the Kidney in Response to Hypoglycemia in Type 1 Diabetes - Medscape - Sep 01, 2001.