Concordant induction of rapid in vivo pulsatile insulin secretion by recurrent punctuated glucose infusions

Insulin is largely secreted as serial secretory bursts superimposed on basal release, insulin secretion is regulated through changes of pulse mass and frequency, and the insulin release pattern affects insulin action. Coordinate insulin release is preserved in the isolated perfused pancreas, suggesting intrapancreatic coordination. However, occurrence of glucose concentration oscillations may influence the process in vivo, as it does for ultradian oscillations. To determine if rapid pulsatile insulin release may be induced by minimal glucose infusions and to define the necessary glucose quantity, we studied six healthy individuals during brief repetitive glucose infusions of 6 and 2 mg · kg^-1 · min^-1 for 1 min every 10 min. The higher dose completely synchronized pulsatile insulin release at modest plasma glucose changes (~0.3 mM= ~5%), with large (~100%) amplitude insulin pulses at every single glucose induction (n = 54) at a lag time of 2 min (P < 0.05), compared with small (10%) and rare (n = 3) uninduced insulin excursions. The smaller glucose dose induced insulin pulses at lower significance levels and with considerable breakthrough insulin release. Periodicity shift from either 7-to 12-min or from 12- to 7-min intervals between consecutive glucose (6 mg · kg^-1 · min^-1) infusions in six volunteers revealed rapid frequency changes. The orderliness of insulin release as estimated by approximate entropy (1.459 ± 0.009 vs. 1.549 ± 0.027, P = 0.016) was significantly improved by glucose pulse induction (n = 6; 6 mg · kg^-1 · min^-1) compared with unstimulated insulin profiles (n = 7). We conclude that rapid in vivo oscillations in glucose may be an important regulator of pulsatile insulin secretion in humans and that the use of an intermittent pulsed glucose induction to evoke defined and recurrent insulin secretory signals may be a useful tool to unveil more subtle defects in β-cell glucose sensitivity.