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 insulin release, but small oscillations in plasma glucose concentrations may contribute further. To gain additional insight into β-cell (patho)physiology, we explored the ability of repetitive small glucose infusions (6 mg/kg over I rain every 10 min) to modify rapid pulsatile insulin secretion in 10 type 2 diabetic individuals (plasma glucose 9.3 ± 1.0 mmol/l, HbA₁(c) 7.9 ± 0.5%, mean ± SE) and 10 healthy subjects. All subjects were investigated twice in randomly assigned order: during saline and during glucose exposure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: namely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discriminate between diabetic and control subjects (P > 0.26). During glucose entrainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indicating more regular insulin time-series in the healthy volunteers. However, no differences were observed in the diabetic individuals between the glucose and saline conditions. Furthermore, in spite of identical absolute glucose excursions ~0.3 mmol/l) glucose pulse entrainment led to a complete (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 diabetic and control subjects. Even elevating the glucose infusion rate in the diabetic subjects to achieve comparable relative (and hence higher absolute) glucose excursions (~4.9%) failed to entrain pulsatile insulin secretion in this group. In conclusion, the present study demonstrates that failure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a manifest feature of [β-cell malfunction in type 2 diabetes. Whether the model will be useful in unmasking subtle (possible prediabetic) defects in β-cell sensitivity to glucose drive remains to be determined.