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Time (minutes)

• Normal glucose tolerance (n=54) Impaired glucose tolerance (n = 16) —■— Type 2 diabetes (n = 12)

Figure 2 Venous plasma glucose levels during OGTT in subjects with normal impaired glucose tolerance, impaired glucose tolerance, and diabetes. From Ahren B, unpublished data. Means ± SEM are shown.

cutoff values are shown in Table 1. Note that the mode of measuring glucose is important with regard to the cutoff values used.

Limitations of the Oral Glucose Tolerance Test

An important limitation of the OGTT is the variability in results when the test is repeated. Actually, the coefficiency of variance (CV) is usually 15% and in some studies 20%, which is higher than that for most other clinical tests. It is not clear why OGTT has such a high CV. The variance is not, however, dependent on CV in the measurement of glucose, which is a procedure with very small error and CVs usually below 3%. Therefore, biological variation probably explains the high CV of OGTT. Factors explaining this variation may be preceding diet, exercise, emotions, stress, drugs taken for various diseases, and gender, which are all factors influencing gastric emptying, carbohydrate absorption, islet hormone secretion, hepatic glucose production, and peripheral glucose uptake (i.e., all processes contributing to the 2-h glucose value). Because of the high variability in the 2-h glucose value, a diagnosis of IGT or diabetes, particularly if intervention is planned, should not be based on a single OGTT. Instead, a clinical recommendation is to perform two OGTTs and use the mean of the two 2-h glucose values as the diagnostic value. The time interval between the two OGTTs should not exceed 3 months.

Metabolic Basis for Oral Glucose Tolerance

Oral ingestion of glucose initiates a series of metabolic perturbations, which comprise the 2-h glucose value. These metabolic perturbations are complex and involve glucose entering the bloodstream, changes in neural activity and islet hormone secretion, suppression of hepatic glucose production, and stimulation of peripheral glucose uptake. From a quantitative standpoint, of most importance with regard to the 2-h value are the changes in islet hormone secretion, which include stimulation of insulin secretion and inhibition of glucagon secretion, and the suppression of hepatic glucose production. In fact, there is an inverse linear relation between the inhibition of hepatic glucose production and the 2-h glucose value and, similarly, a linear inverse relation between stimulation of the early (first 30min) insulin secretion and 2-h glucose. This section briefly summarizes these processes.

A first series of events in the OGTT is initiated during the anticipation of the oral glucose ingestion, through olfactory stimuli and through receptors located in the oral cavity. This response is called the cephalic phase and activates sensory nerves, which give input to the central nervous system. This information is integrated in the hypothalamus for initiation and adjustment of a vagal nerve response to release insulin from the pancreatic islets. Therefore, when analyzed in detail, there is an increase in circulating insulin after glucose or meal ingestion already before glucose levels become elevated. After passage of glucose through the oral cavity, glucose passes to the stomach and through a regulated mechanism delivered into the gut. Since glucose is a monosugar, it is readily absorbed in the small intestine and reaches the splanchnic venous drainage. Glucose then passes to the portal vein and the liver. In the portal vein, glucose activates glucosensitive receptors, which through afferent sensory nerves send signals centrally to the brain for further integration with the previous signals in the hypothalamus for adjustment of efferent nerve activity. Furthermore, glucose in the liver inhibits hepatic glucose production, which is high after the overnight fast. Then, glucose passes to the general circulation to reach the pancreatic islets and the peripheral cells. The glucose load to the gut also stimulates the release of intestinal hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1). These hormones then pass through the circulation to reach the pancreas, where they stimulate insulin secretion and, as for GLP-1, inhibit glucagon secretion. In the pancreatic islets, vagal activation, intestinal hormones, and glucose stimulate insulin secretion, and glucose, GLP-1, and insulin inhibit glucagon secretion. These islet responses are of major importance for a normal glucose tolerance, and defects in these islet responses are major determinants of IGT and type 2 diabetes. Following passage of insulin into the venous drainage of the pancreas, the islet hormones reach the portal vein and the liver, and a main function of insulin is to potently suppress hepatic glucose production. This is a major process with regard to the degree of hyperglycemia during the test; in subjects with inappropriately high hepatic glucose production, the glucose level after oral glucose is high. This suppression of hepatic glucose production is augmented by the reduction in circulating levels of glucagon, which is initiated by the direct action of glucose and GLP-1 on the glucagon-producing cells and also by the action of insulin to inhibit glucagon secretion. After the liver, glucose and insulin reach the peripheral circulation and peripheral cells, where glucose is transported across the cell membranes and therefore leaves the circulation. In most cells, a major proportion of glucose uptake is sensitive to insulin; therefore, the amount of insulin, in relation to the insulin sensitivity of the cell, is of major importance for the delivery rate of glucose. However, insulin-independent mechanisms also exist, even in tissues, which are also insulin sensitive, and glucose uptake is thus also dependent on glucose. Of most importance for glucose disposal after oral glucose is the muscle cells, which have a high capacity for glucose uptake. From all these processes, the glucose level at 2 h can be determined.

It is important to realize that the metabolic processes underlying glucose tolerance are different from those underlying the fasting glucose value. Fasting glucose is mainly determined by hepatic glucose delivery during the night, which in turn is governed by the ability to maintain normal basal insulin and glucagon levels. Therefore, mechanisms underlying IFG include defective insulin secretion, defective suppression of glucagon secretion, defective sensitivity in the liver for the action of insulin, and defective peripheral glucose disposal at low glucose levels, which is a sign of insulin resistance. Although mechanisms underlying fasting and 2-h glucose values differ, there is a high correlation between fasting and 2-h glucose values in normal subjects, as shown in Figure 3. Nevertheless, there is a limited overlap between IGT and IFG in a population; in fact, most subjects with IGT have normal fasting glucose, and most subjects with IFG have a normal 2-h glucose value. This suggests that different pathophysiological processes underlie IGT and IFG, which in turn suggests that OGTT should be undertaken more frequently than performed today.

Differential Tests for Glucose Tolerance

Diagnoses of type 2 diabetes or stages preceding its occurrence can be undertaken by other means

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