Compromised Hormonal Counterregulation, Symptom Awareness, and Neurophysiological Function After Recurrent Short-Term Episodes of Insulin-Induced Hypoglycemia in IDDM Patients

Abstract

To test the hypothesis that recurrent short-term hypoglycemic episodes may impair hormonal counterregulation, symptom awareness, and neurophysiological function during subsequent hypoglycemia, we examined two groups of IDDM patients (n = 18), neither of whom exhibited signs of autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed three days apart with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' awareness of and response to hypoglycemia was evaluated. In the intervention group (n = 11), three short-term hypoglycemic episodes preceded the second clamp study. Counterregulatory hormones increased significantly during hypoglycemia, but adrenaline (P < 0.03), cortisol (P < 0.01), and ACTH (albeit not significant) showed a blunted response after repetitive hypoglycemic events. In this group, the perception of hypoglycemic symptoms was significantly reduced and was most evident for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and warmness (P < 0.03). The deterioration of neurophysiological function, as assessed from the middle latency auditory evoked potentials, was more pronounced in the intervention group (latency shift of the Pa component, P < 0.05). These data suggest that alterations of neuroendocrine counterregulation, symptom perception, and certain aspects of cerebral function may occur as a consequence of recurrent short-term hypoglycemic episodes. These adaptation phenomena may contribute to the increased incidence of severe hypoglycemia in IDDM patients on intensive insulin therapy.

Modulation of Hunger by Plasma Glucose and Metformin

“…Previous studies (12)(13)(14)(15)(16)(17)(18) investigating symptomatic responses to recurrent hypoglycemia did not focus on feelings of hunger. Typically, data on hunger ratings were not analyzed separately but were pooled with rating scores of other hypoglycemic symptoms.…”

“…Thus, hunger may occur at higher plasma glucose levels in those patients than in healthy subjects and may be increased during plasma glucose-lowering therapies. On the other hand, repeated episodes of low plasma glucose have been shown to decrease plasma glucose thresholds for hormonal counterregulation and symptoms (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22), suggesting a rapid adaptation of the brain to such conditions. Whether a similar adaptation also exists in regard to feelings of hunger is not known.…”

Improvement of Impaired Counterregulatory Hormone Response and Symptom Perception by Snort-Term Avoidance of Hypoglycemia in IDDM

“…Improvement of symptom awareness comprised the overall perception of symptoms and, more specifically, the autonomic symptoms of heart pounding and sweating. Adaptation to recurrent hypoglycemic episodes has recently been shown in nondiabetic subjects (1) and IDDM patients (3,5). In fact, Lingenfelser et al (3) demonstrated that alterations of neuroendocrine counterregulation and symptom perception do occur within 2 days after three short-term hypoglycemic events (<2.2 mmol/1).…”

“…E vidence has emerged in healthy subjects (1,2) and diabetic patients (3)(4)(5) that recurrent short-term hypoglycemic episodes compromise hormonal counterregulation and symptom awareness during subsequent hypoglycemia. The question arises as to whether such defective responses may be improved or even restored (6).…”

Neurophysiological Impairments in IDDM Patients During Euglycemia and Hypoglycemia

“…Thus, acute deteriorations of glucose homeostasis are likely to cause an instant, but temporary, impairment of cerebral functions (1)(2)(3). Recurrent hypoglycemic episodes over days were also shown to reversibly impair cerebral function, as assessed from neurophysiological measurements (4). Chronic hyperglycemia prevails in IDDM; thus, long-term changes caused by glucotoxicity are likely to occur in brain morphology (5).…”