Importance of Early Phase Insulin Secretion to Intravenous Glucose Tolerance in Subjects with Type 2 Diabetes Mellitus

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Abstract
Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insu- lin secretion is hypothesized to be important in the deterio- ration of glucose tolerance. To determine whether enhance- ment of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insuli- notropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secre- tion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 2.1 yr, x SEM; body mass index 29.7 1.0 kg/m2; fasting plasma glucose 8.1 0.1 mM). -Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide ad- ministration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide en- hanced glucose-induced insulin release, compared with pla- cebo (area under the curve 15-300 min: nateglinide 23,595 11,212 pM/min, glyburide 54,556 15,253 pM/min, placebo 10,242 2,414 pM/min). The profiles of insulin release demon- strated significant enhancement of release between 15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 0.04%/min), but it did not increase significantly with glyburide (0.79 0.04%/min), compared with placebo (0.76 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose con- centration with glyburide (3.8 0.2 mM), compared with nateglinide (5.0 0.2 mM) and placebo (5.9 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the ki- netics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further re- duction in glucose levels and a lower nadir. (J Clin Endocrinol Metab 86: 5824 -5829, 2001)

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