Metabolic and Genetic Characterization of Prediabetic States

Non-insulin-dependent diabetes mellitus (NIDDM)' is phenotypically heterogenous and may therefore not be explained by one simple pathophysiological mechanism. Despite the heterogenous nature of the disease, the major form as discussed in this review is linked to overweight, arterial hypertension, dyslipidemia, and macroangiopathy (coronary heart disease), all conditions which become more common with aging (1). This form of NIDDM seems to be growing worldwide in the footsteps of Westernized life style. Around 3% in the Western world suffers from the disease, but in subjects 60 yr and older, the prevalence is as high as 10-20% (2). In certain ethnic populations as the Pima Indians and the Nauruans the prevalence approaches 40% (2). Therefore, NIDDM imposes an enormous burden on the health care system all over the world. In general, the goals of treatment are achieved in only a small subset of patients, but nevertheless progression of macroangiopathy is a more severe problem than worsening of glycemia. The overall mortality rate in patients with NIDDM is two to three times higher than in control subjects, primarily due to excess mortality of coronary heart disease (2). Of note, 40% of patients already suffer from clinical macroangiopathy at diagnosis, indicating that these complications may not be secondary to the diabetic state itself, but rather a part of the NIDDM syndrome, also referred to as Syndrome X or "The Insulin Resistance Syndrome" (1). Resistance to the action of insulin on glucose metabolism in skeletal muscle has been proposed as the inherited basis for this syndrome and since insulin resistance is observed several decades before the onset of hyperglycemia an early detection can open the prospect of intervention in order to prevent the disease process (4-7). The present review discusses the metabolic and genetic background of NIDDM together with the current knowledge of the sequence of events leading to NIDDM. Based on that a new