Improvement of glucose tolerance by nateglinide occurs through enhancement of early phase insulin secretion

Nateglinide is a new, fast-onset, short-acting hypoglycemic agent, which increases early phase insulin secretion and the total amount of insulin secreted. However, it is not clear which of these effects contribute more to the decrease in postprandial plasma glucose (PG). To further clarify the pharmacologic actions of nateglinide, we investigated the changes in PG and insulin levels during meal tolerance tests with and without nateglinide. Subjects were 10 newly diagnosed and untreated inpatients with type 2 diabetes. After diet and exercise therapy for 1 week, nateglinide at 270 mg divided 3 times a day, was started. Meal tolerance tests were performed before (baseline) and after a single nateglinide administration (day 1), after 7 days of repeated administration (day 7), and after cessation of nateglinide on day 8. Mean fasting PG was 146 [plusmn] 6 mg/dl (mean [plusmn] SEM) at baseline and 130 [plusmn] 6 mg/dL on day 7 (P = .0004). The 2-hour postprandial PG level was 226 [plusmn] 10 mg/dL at baseline, 145 [plusmn] 11 mg/dL on day 1 (P = .0008), and 190 [plusmn] 15 mg/dL on day 8 (P = .08, baseline; P = .01, day 7). The mean fasting insulin level was 5.4 [plusmn] 1.0 [mu ]U/mL at baseline and did not change significantly during the study. The 30-minute postprandial insulin level was 14.4 [plusmn] 1.9 [mu ]U/mL at baseline, 39.5 [plusmn] 4.5 [mu ]U/mL on day 1 (P = .0004), and 23.6 [plusmn] 3.6 [mu ]U/mL on day 8 (P = .045, baseline; P = .010, day 7). The total insulin amount, in terms of area under the curve (AUC [middot] IRI), was 3.99 [plusmn] 0.7 [times ] 103 [mu ]U/mL [middot] min at baseline, 5.47 [plusmn] 0.8 [mu ]U/mL [middot] min on day 1 (P = .029), and 6.01 [plusmn] 1.9 [mu ]U/mL [middot] min on day 8 (P = .047 v baseline). The early phase of insulin secretion, based on the ratio of delta IRI to delta PG from fasting to 30 minutes after a meal was 0.15 [plusmn] 0.13 at baseline, 1.44 [plusmn] 0.26 on day 1 (P = .0009) and 0.26 [plusmn] 0.06 on day 8 (P = .05 v day 1). After cessation of nateglinide, the postprandial PG level increased immediately. Although early phase insulin secretion returned nearly to the baseline level, total insulin secretion remained at a high level. These results suggested that early phase insulin secretion contributes more than total insulin secretion to the improvement of postprandial hyperglycemia in type 2 diabetes.