Impaired glucose tolerance (IGT) as a clinical entity has gained increased attention in recent years. Three main factors can account for this. First, the recognition of increased risk for cardiovascular disease that is associated with IGT has resulted in a plea to recognize IGT as a disease state in its own right. Secondly, the role of IGT as a risk factor for diabetes has been accepted by the scientific community, despite caveats about the use of the oral glucose tolerance test (OGTT) in its diagnosis. For example, it functions as the primary screening tool and the basis for intervention in the multicenter National Institutes of Health–sponsored Diabetes Prevention Project. The increased risk in IGT amounts to a 3–9% likelihood per year of developing type 2 diabetes. Thirdly, new options for treatment of IGT have emerged. This emergence is a by-product of the dramatic increase in the availability of oral agents for treatment of type 2 diabetes, which also provides new opportunities for preventive strategies. To justify the risks of pharmacological treatment in a prediabetic state, identification of people at high risk for diabetes is required. Hence, the choice of IGT. Focus on IGT has also been associated with attempts to understand underlying mechanisms; greater understanding may help improve prediction of diabetes and enhance development of targeted therapies. In this issue, Larsson and Ahrén report on defects in islet physiology that may contribute further to our understanding of the pathogenesis of IGT.

In a population-based study of postmenopausal Swedish women, these investigators studied IGT, applying World Health Organization criteria to an OGTT. Of 108 women evaluated, 34% had IGT. This group had slightly elevated systolic blood pressure and serum triglyceride levels, although BMI measurements, waist-to-hip ratios, and body fat content were similar to those of the normal glucose tolerance group (NGT). Insulin sensitivity was measured using a glucose clamp, and insulin and glucagon secretion were evaluated using glucose and arginine infusions. Women with IGT were shown to have both insulin resistance and reduced insulin secretion; the latter was particularly evident when expressed in terms of each subject’s insulin sensitivity as a disposition index. The utility of this approach was well demonstrated, because insulin secretion, though similar in both groups, was found to be significantly reduced when evaluated in relation to the degree of insulin resistance present. The investigators also found hyperglucagonemia, manifesting as an increase in arginine-stimulated secretion and a reduced suppressibility of glucagon during hyperglycemia. A novel aspect of this study is the finding that there was an inverse relationship between insulin sensitivity and glucagon secretion in these subjects. Previous studies support the concept that glucagon may be involved in the pathogenesis of IGT. This concept derives from studies of glucagon suppressibility during oral glucose loading. The normal physiological suppression of glucagon secretion in response to elevated plasma glucose is lost in diabetes and is also impaired in IGT.

A concomitant decrease in early insulin secretion in response to oral glucose is also observed. This combined defect alters the insulin-to-glucagon ratio and, as a result, leads to failure of the normal suppression of endogenous glucose production that occurs after oral glucose ingestion. This, in turn, contributes to elevated plasma glucose concentrations that are characteristic of IGT. Insulin resistance also plays a role in IGT by impairing glucose disposal and providing resistance to hepatic insulin action. However, secretory abnormalities can cause IGT in the absence of insulin resistance. Shah et al. studied normal subjects with a combined hormonal defect, i.e., insulin secretion and glucagon suppressibility were both reduced experimentally during glucose loading. This experiment resulted in a marked reduction in glucose tolerance with a failure to suppress endogenous glucose production. When normal suppressibility of glucagon was allowed to occur, endogenous glucose production and glucose tolerance were normalized. These authors suggest that improving postprandial suppressibility of plasma glucagon may be a therapeutic target in IGT. What are the mechanisms responsible for the abnormalities in glucagon secretion that occur in IGT?

Both exaggerated responses to secretagogues and failure of suppressibility of glucagon are tied to abnormal _-cell function. Types 1 and 2 diabetes and IGT each have different degrees of insulin-secretory dysfunction, and all are associated with abnormal regulation of glucagon secretion. This is explained by the inhibitory effect of insulin on glucagon release and by evidence for local control of _-cell function by insulin within the islet. Reducing the inhibitory influence of insulin can account for a difference in both the tonic control and the stimulation of glucagon secretion observed in IGT. Thus, abnormalities in glucagon that are characteristic of IGT can be explained by dysfunction in islet secretion. However, resistance to secreted products of the islets may also play a role. This was illustrated by Kulkarni et al., who demonstrated the functional importance of insulin receptors in the islets of Langerhans in a model of insulin resistance of the _-cell. Using a tissue- specific _-cell insulin-receptor knockout mouse, they found impaired insulin secretion due (presumably) to reduction of a stimulatory influence of insulin on the _-cell. If resistance to insulin action occurs in the _-cell, it may also apply to the _-cell and thereby contribute to a reduction in the ability of insulin to inhibit glucagon secretion.