Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes

Insulin is released in high-frequency pulsatile bursts at intervals of 6-13 min. Intrapancreatic mechanisms are assumed to coordinate pulsatile insuli n release, but small oscillations in plasma glucose concentrations may cont ribute further. To gain additional insight into beta-cell (patho)physiology , we explored the ability of repetitive small glucose infusions (6 mg/kg ov er 1 min every 10 min) to modify rapid pulsatile insulin secretion in 10 ty pe 2 diabetic individuals (plasma glucose 9.3 +/- 1.0 mmol/l, HbA(1c) 7.9 /- 0.5%, mean +/- SE) and 10 healthy subjects. All subjects were investigat ed twice in randomly assigned order: during saline and during glucose expos ure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: n amely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discri minate between diabetic and control subjects (P > 0.20). During glucose ent rainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indica ting more regular insulin time-series in the healthy volunteers. However, n o differences were observed in the diabetic individuals between the glucose and saline conditions. Furthermore, in spite of identical absolute glucose excursions (similar to 0.3 mmol/l) glucose pulse entrainment led to a comp lete (SP: 4.76 +/- 0.62 [range 2.08-7.60] vs. 17.24 +/- 0.93 [11.70-20.58], P < 0.001; AC: 0.01 +/- 0.05 [0.33-0.24] vs. 0.64 +/- 0.05 [0.35-0.83], P < 0.001) or almost complete (ApEn: 1.59 +/- 0.02 [1.48-1.67] vs. 1.42 +/- 0 .05 [1.26-1.74], P < 0.005) separation of the insulin time-series in diabet ic and control subjects. Even elevating the glucose infusion rate in the di abetic subjects to achieve comparable relative land hence higher absolute) glucose excursions (similar to 4.9%) failed to entrain pulsatile insulin se cretion in this group. In conclusion, the present study demonstrates that f ailure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a ma nifest feature of beta-cell malfunction in type 2 diabetes. Whether the mod el will be useful in unmasking subtle (possible prediabetic) defects in bet a-cell sensitivity to glucose drive remains to be determined.