Insulin resistance as the major cause of impaired glucose tolerance: a self-fulfilling prophesy?

Non-insulin-dependent diabetes (NIDDM) is a heterogeneous state involving various degrees of beta-cell dysfunction and insulin resistance, although the relative importance of these two factors is controversial. Several single gene disorders of carbohydrate metabolism have their main pathophysiological defect largely restricted to the beta-cell or to insulin-sensitive tissues. We have noted that with insulin resistance the fasting plasma glucose is often normal and severe hyperglycaemia occurs after a glucose load. By contrast, in glucokinase-deficient diabetes, which is characterised by reduced insulin secretion, the reverse is the case. Supportive evidence showing that beta-cell dysfunction and insulin resistance may have different effects on fasting and post-prandial glucose concentrations comes from studies of identical twins of NIDDM patients, hemi-pancreatectomised normal subjects, and insulin-resistant Asian subjects. NIDDM is usually preceded by a period of less severe hyperglycemia, referred to as impaired glucose tolerance (IGT). Studies of the IGT phase usually conclude that insulin resistance is the major abnormality and is thus the primary defect in NIDDM. However, the definition of IGT is based on the 2 h plasma glucose after an oral glucose-tolerance test without consideration of the fasting glucose concentrations (provided these concentrations are non-diabetic). Our observations suggest that this definition of IGT may result in the over-representation of insulin-resistant individuals and the under-representation of subjects with beta-cell dysfunction in any cross sectional study of IGT. The belief that the prediabetic state of IGT is dominated by insulin resistance may be a self-fulfilling prophesy because of the excessive emphasis put on the post-prandial rather than the fasting state.