Preface to the Third Edition

Diabetes is an increasingly common disease. It is estimated that the prevalence of diabetes will rise from 415 million people in the year 2015 to 642 million people worldwide by the year 2040¹  and that the total diabetes prevalence (diagnosed and undiagnosed cases) will increase from 14% in 2010 to 25–28% of the U.S. population by 2050.²  The most common forms of the disease are type 1 diabetes (T1D), the result of absolute insulin deficiency from its clinical onset; and type 2 diabetes (T2D), the result of relative insulin deficiency in the setting of insulin resistance early in its course and absolute insulin deficiency later. Approximately 95% of affected people have T2D.

Over time, diabetes can cause unique microvascular complications—retinopathy, nephropathy, and neuropathy—and a substantially increased risk for macrovascular atherosclerotic complications—myocardial infarction, cerebrovascular accidents, and peripheral vascular disease. These long-term complications are undoubtedly multifactorial in origin, but it is now well established, at least for microvascular disease, that hyperglycemia is one important factor. Maintenance of plasma glucose concentrations closer to the nondiabetic range partially prevents or delays microvascular complications in T1D^3,4  and in T2D.^5,6  It may reduce macrovascular complications in T1D^7,8  and T2D,⁹  although that remains to be documented.¹⁰ 

Unfortunately, with current treatment regimens, it is not possible to maintain euglycemia over a lifetime of diabetes in the vast majority of people with diabetes because of the barrier of iatrogenic (treatment-induced) hypoglycemia.^10–15  Pending the prevention and cure of diabetes, maintenance of euglycemia without hypoglycemia will require new treatment methods that provide plasma glucose regulated insulin replacement or secretion, that is, closed-loop insulin replacement, transplantation of β-cell-containing tissue, or expansion of β-cell mass.

The biochemistry, physiology, and pathophysiology of intermediary metabolism, with a focus on glucoregulation and hypoglycemia, have been reviewed,^{11–15,16–18}  and the history of hypoglycemia in the 20th century has been summarized.¹¹  The impact of hypoglycemia was first documented in 1921 when a dog convulsed and then died after injection of extracted insulin; hypoglycemia was recognized to be a complication of insulin treatment of diabetes shortly thereafter.¹⁹ 

Hypoglycemia is both a clinical and a physiological term. Unequivocal demonstration of clinical hypoglycemia requires documentation of Whipple’s triad²⁰ : symptoms, signs, or both, consistent with hypoglycemia; a reliably measured low plasma glucose concentration; and resolution of those symptoms and signs after the plasma glucose level is raised.¹⁵  In healthy individuals, symptoms of hypoglycemia develop at an arterialized venous plasma glucose concentration of 50–55 mg/dL (2.8–3.0 mmol/L).¹⁶  From a physiological perspective, however, the glycemic threshold is at a higher glucose level. Arterialized venous plasma glucose concentrations just below the postabsorptive physiological range, that is, <70 mg/dL (<3.9 mmol/L), trigger physiological defenses against falling plasma glucose concentrations, including further decrements in the secretion of insulin and initial increments in the secretion of glucose counterregulatory hormones, such as glucagon and epinephrine.¹⁶  Indeed, the latter higher plasma glucose concentration, with or without symptoms, has been recommended as a pragmatic alert level for people with diabetes who are at high risk for clinical hypoglycemia.^21–24 

This third edition of Hypoglycemia in Diabetes is updated and expanded but retains its focus on the clinical problem of hypoglycemia in diabetes. That problem is approached from the perspective of the pathophysiology of glucose counterregulation, the mechanisms that normally effectively prevent or correct hypoglycemia,¹⁶  in T1D and advanced T2D.^{12–15,17,18}  Insight into that pathophysiology leads to increased understanding of the frequency of, risk factors for, and prevention of iatrogenic hypoglycemia in people with diabetes.

• Philip E. Cryer, M.D.

  Professor of Medicine Emeritus

  Washington University in St. Louis