AN exceedingly large number of studies have convincingly demonstrated that insulin resistance occurs in association with a variety of physiological and pathophysiological states, including obesity, noninsulin-dependent diabetes mellitus (NIDDM), polycystic ovary syndrome (PCOS), and the constellation of central obesity, hypertension, glucose intolerance, and hyperlipidemia known as metabolic syndrome or syndrome X (1, 2)(Table 1). In addition, a number of rare, albeit very interesting, syndromes characterized by extreme insulin resistance have been described over the past 20 yr (3, 4). These syndromes are not only clinically important, but have also significantly contributed to our knowledge of the mechanisms of insulin action and resistance.

In this review, we focus on syndromes characterized by extreme insulin resistance. We present the tools and criteria for the diagnosis of severe insulin resistance and review the clinical phenotypes of type A and type B syndromes of insulin resistance, the HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, Rabson-Mendenhall syndrome, leprechaunism, and lipodystrophy (3, 4). Subsequently, we discuss our current knowledge of the underlying pathophysiological mechanisms and explore the current therapeutic approach to these syndromes as well as potential future directions for research in the area.