Evidence for a vicious cycle of exercise and hypoglycemia in type 1 diabetes mellitus

Abstract

Exercise is a cornerstone of diabetes management as it aids in glycemic control, weight management, reducing blood pressure, and improving the quality of life of patients. Unfortunately, owing to the complexity and difficulties of regulating exogenous insulin in a physiologic manner during exercise, physical activity often results in hypoglycemia in patients with type 1 diabetes mellitus (type 1 DM). When glucose levels fall below threshold glycemic levels, neuroendocrine, autonomic nervous system (ANS), and metabolic glucose counterregulatory mechanisms are activated. These hypoglycemic counterregulatory mechanisms in type 1 DM can be blunted irreversibly by disease duration or by acute episodes of prior stress. These reduced (or absent) counterregulatory responses result in a threefold increase in severe hypoglycemia when intensive glycemic control is implemented in type 1 DM. Much recent work has been focused on determining the in vivo mechanisms responsible for causing the increased incidence of severe hypoglycemia in type 1 DM. Studies from several laboratories have demonstrated the role played by episodes of antecedent hypoglycemia in producing blunted glucose counterregulatory responses during subsequent exposures of hypoglycemia. Until recently, the mechanisms responsible for exercise related hypoglycemia in type 1 DM have been attributed to relative or absolute increases of insulin levels or incomplete glycogen repletion after physical activity. Owing to the qualitative similarity of neuroendocrine, ANS, and metabolic responses to hypoglycemia and exercise, we have hypothesized that neuroendocrine and ANS counterregulatory dysfunction may also play an important role in the pathogenesis of exercise-related hypoglycemia in type 1 DM. Vicious cycles can be created in type 1 DM, where an episode of hypoglycemia or exercise can feed forward to downregulate neuroendocrine and ANS responses to a subsequent episode of either stress, thereby creating further hypoglycemia. This article will review the recent work that has studied the contribution of counterregulatory dysfunction to exercise-induced hypoglycemia in type 1 DM.

Quantifying the Acute Changes in Glucose with Exercise in Type 1 Diabetes: A Systematic Review and Meta-Analysis

“…In type 1 diabetes, excessive therapeutic insulin levels inhibit hepatic glucose production, which is required to meet the glucose demand by exercising muscles, leading to an increased risk of hypoglycemia [3]. Activation of counter-regulatory hormones, which normally contribute to restoration of glucose levels and triggering of neuroglycopenic symptoms during exercise, is reduced or absent [4].…”

“…Continuous exercise of moderate intensity is associated with a greater risk of hypoglycemia in type 1 diabetes [3]. More vigorous activity induces a rise in catecholamines, Cortisol, and growth hormone, resulting in hyperglycemia [7].…”

The Barrier of Hypoglycemia in Diabetes

“…The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes (Fig. 2) posits that recent antecedent hypoglycemia (1,8,9), as well as prior exercise (28) or sleep (29), causes both defective glucose counterregulation (by reducing increments in epinephrine in the setting of absent decrements in insulin and absent increments in glucagon during subsequent hypoglycemia) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses during subsequent hypoglycemia) and, therefore, a vicious cycle of recurrent iatrogenic hypoglycemia. Perhaps the most compelling support for the concept of HAAF is the finding, in three independent laboratories (30 -32), that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine component of defective glucose counterregulation in most affected patients.…”

Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition

“…These syndromes increase the risk of severe iatrogenic hypoglycemia ϳ6-fold (5) and 25-fold or more (6,7), respectively, in type 1 diabetes. Because of the key pathophysiological role of the attenuated sympathoadrenal response, which is typically caused by recent antecedent hypoglycemia (1-3), but also follows exercise (8) and occurs during sleep (9), this phenomenon has been termed hypoglycemia-associated autonomic failure (HAAF) in diabetes (1)(2)(3). A similar phenomenon of reduced sympathoadrenal responses to hypoglycemia after a period of antecedent hypoglycemia can be produced in normal subjects and serves as a human model to study the mechanisms of HAAF (10).…”