Plasma Glucose Concentrations at the Onset of Hypoglycemic Symptoms in Patients with Poorly Controlled Diabetes and in Nondiabetics

Abstract

We tested the hypothesis that during decrements in plasma glucose concentration, symptoms of hypoglycemia may occur at higher glucose concentrations in patients with poorly controlled insulin-dependent diabetes mellitus than in persons without diabetes. Symptoms of hypoglycemia and counterregulatory neuroendocrine responses were quantified during hypoglycemic and euglycemic clamp studies in eight patients with insulin-dependent diabetes mellitus selected because their hemoglobin A1 levels were above 10 percent. These data were compared with similar observations in 10 nondiabetic subjects studied previously. Glycemic thresholds--the plasma glucose concentrations during each hypoglycemic clamp study at which a given symptom or biochemical measurement first exceeded its 95 percent confidence interval determined in the euglycemic clamp studies--were calculated for each variable. The mean (+/- SE) glycemic threshold for the symptoms of hypoglycemia was 4.3 +/- 0.3 mmol per liter (78 +/- 5 mg per deciliter) in patients with poorly controlled diabetes--significantly higher (P less than 0.001) than the value of 2.9 +/- 0.1 mmol per liter (53 +/- 2 mg per deciliter) in subjects without diabetes. The mean glycemic thresholds for growth hormone, epinephrine, and cortisol secretions were not significantly different in the two groups. Thus, during decreases in the plasma glucose concentration, patients with poorly controlled insulin-dependent diabetes mellitus may experience symptoms of hypoglycemia at higher plasma glucose concentrations than persons without diabetes. The mechanism underlying this observation remains to be defined.

The sympathetic response to euglycaemic hyperinsulinaemia

“…Elevation of plasma insulin to a mean steadystate level of 46 mU/1 [22] or 100-200 mU/1 failed to elevate plasma catecholamines [23,24], whereas other investigations have found minor but significant elevations of plasma noradrenaline at plasma insulin concentrations ranging from a level corresponding to postprandial hyperinsulinaemia in normal and insulin-resistant subjects, i. e. less than 100 mU/1 [25] to supraphysiological levels [6,7,26]. The occasional failure to observe increases in plasma noradrenaline may be methodological, as moderate hyperinsulinaemia is apparently a weak sympathetic stimulus.…”

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

“…Whereas the glycaemic thresholds for these responses (mean arterialised venous plasma glucose concentrations of about 4.5 mmol/l (81 mg/dl), 3.7 mmol/l (67 mg/dl) and 3.0 mmol/l (54 mg/dl) respectively) are reproducible in healthy subjects [13,14,15], they shift to higher plasma glucose concentrations in poorly controlled diabetes [16,17] and to lower plasma glucose concentrations following episodes of hypoglycaemia [18,19,20,21]. These threshold shifts are of considerable relevance to the pathogenesis of iatrogenic hypoglycaemia in diabetes.…”

Defining and Reporting Hypoglycemia in Diabetes

“…An event during which the person with diabetes reports any of the typical symptoms of hypoglycemia, and interprets those as indicative of hypoglycemia, but with a measured plasma glucose concentration Ͼ70 mg/dl (3.9 mmol/l). This category reflects the fact that patients with chronically poor glycemic control can experience symptoms of hypoglycemia at plasma glucose levels Ͼ70 mg/dl (3.9 mmol/l) as plasma glucose concentrations decline toward that level (27,28). Though causing distress and interfering with the patient's sense of well-being, and potentially limiting the achievement of optimal glycemic control, such episodes probably pose no direct harm and therefore may not be a suitable outcome measure for clinical studies that are aimed at evaluating therapy, but they should be reported.…”