Hypoglycemia-associated autonomic failure in diabetes

Abstract

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia, as well as sleep or prior exercise, causes both defective glucose counterregulation (by attenuating the adrenomedullary epinephrine response, in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by attenuating the sympathoadrenal, largely the sympathetic neural, response) and thus a vicious cycle of recurrent hypoglycemia. Albeit with different time courses, the pathophysiology of defense against hypoglycemia – no decrease in therapeutic insulin, no increase in glucagon and an attenuated increase in sympathoadrenal activity – is the same in type 1 diabetes and advanced type 2 diabetes. Hypoglycemia unawareness is reversible by 2–3 weeks of scrupulous avoidance of hypoglycemia in most affected patients. The pathophysiology of HAAF in diabetes explains why the incidence of hypoglycemia increases as patients approach the absolute endogenous insulin deficient end of the disease, provides a comprehensive set of risk factors including those indicative of HAAF, and leads logically to the practice of hypoglycemia risk factor reduction. Because of the risk of hypoglycemic mortality, presumably from cardiac arrhythmias, glycemic goals in diabetes should be individualized, based in part on the risk of hypoglycemia. By practicing hypoglycemia risk reduction – addressing the issue, applying the principles of aggressive glycemic therapy and considering both the conventional risk factors and those indicative of HAAF – it is possible to both improve glycemic control and reduce the risk of hypoglycemia in many patients with diabetes.

Introduction

Diabetes mellitus is common. It is estimated that 285 million people worldwide had diabetes in 2010; this number is projected to increase by ~ 50%, to 438 million people, by the year 2030 (International Diabetes Federation, 2009). Glycemic control – lowering plasma glucose concentrations closer to the nondiabetic range – delays the microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy) in type 1 diabetes mellitus (T1DM) (Diabetes Control and Complications Trial (DCCT), 1993) and in type 2 diabetes (T2DM) (UK Prospective Diabetes Study (UKPDS) Group, 1998a, UK Prospective Diabetes Study (UKPDS) Group, 1998b). It may also delay the macrovascular complications of diabetes (coronary, cerebral, and peripheral atherosclerosis) (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, 2005, Holman et al., 2008). However, glucose-lowering with a sulfonylurea or a glinide or with insulin introduces the risk of iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes (Cryer, 2009a). Iatrogenic hypoglycemia causes recurrent morbidity in most people with T1DM and many with advanced T2DM, and is sometimes fatal. In addition, it generally precludes maintenance of euglycemia over a lifetime of diabetes, and thus, full realization of the vascular benefits of glycemic control. Finally, it impairs defenses against subsequent hypoglycemia and thus causes a vicious cycle of recurrent hypoglycemia.

Hypoglycemia in diabetes is fundamentally iatrogenic, the result of therapeutic hyperinsulinemia caused by treatment with a sulfonylurea or a glinide or with insulin. But, because of the effectiveness of the normal defenses against hypoglycemia – the glucose counterregulatory mechanisms – hypoglycemia in diabetes is typically the result of the interplay of therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations (Cryer, 2009a). Attenuated adrenomedullary epinephrine and sympathetic neural responses to falling glucose levels play a key role in that pathophysiology, albeit in the unique setting of absent insulin and glucagon responses to falling glucose levels in T1DM and advanced T2DM (Cryer, 2009a). (In the presence of normal insulin and glucagon responses, attenuated sympathoadrenal responses to falling plasma glucose concentrations would not cause clinical problems.) This functional and at least partially reversible sympathoadrenal failure, termed hypoglycemia-associated autonomic failure (HAAF) in diabetes (Cryer, 2009a), is distinct from classic diabetic autonomic neuropathy which is structural and largely irreversible (Tesfaye et al., 2010).