Pancreatic insulin secretion is a dynamic process exhibiting both high-frequency (8-15 min) and low-frequency (80-120 min) pulsations. The latter is referred to as ultradian or anabolic pulsations. Neither the physiologic function of this form of pulsatility nor the mechanism(s) of its coupling with periodic changes in plasma glucose are clear. The overall goal of this application is to define the in vivo function of ultradian insulin secretory pulses and of concomitant pulsations in plasma glucose in normal man. The hypotheses to be tested are: 1. Increasing insulin demand is met by increases in the tonic and pulsatile modes of ultradian insulin secretion and concomitant pulsations in plasma glucose with increasing pulse amplitude; 2. Ultradian pulsations in plasma glucose are closely coupled with ultradian pulsations in insulin secretion via periodic changes in peripheral glucose uptake; 3. Ultradian insulin pulsatility secures optimal sensitivity of peripheral tissues to insulin-stimulated glucose uptake; and 4. Ultradian glucose pulsations exert a physiologic role facilitating optimal insulin effects on peripheral glucose disposal and efficient sensorship of the B-cell pulsatile secretion.
The specific aims are: 1. To determine the effects of graded enhancement of B-cell activity in response to iv glucose on the absolute and relative amplitudes of the ultradian insulin secretion pulsatility and on the concomitance and amplitude of plasma glucose pulsations; 2. To determine the relationships of insulin secretion and plasma glucose pulses to periodic fluctuations in peripheral glucose uptake; 3. To determine the effects of administered pulsatile vs constant insulin infusion on the periodic fluctuations in glucose removal and overall insulin sensitivity; 4. To determine the effects of administered pulsatile insulin with and without suppression or enhancement of glucose pulsations on peripheral glucose disposal and overall insulin sensitivity; and 5. To determine the effects of suppressed or enhanced plasma glucose pulsations on ultradian insulin secretion pulse amplitude and the overall insulin output. These studies will further define the relationship between insulin secretion and insulin actions and hence clarify the role of the B-cell activity in the pathogenesis of insulin resistance and NIDDM.
|Sonnenberg, G E; Krakower, G R; Hoffmann, R G et al. (2001) Plasma leptin concentrations during extended fasting and graded glucose infusions: relationships with changes in glucose, insulin, and FFA. J Clin Endocrinol Metab 86:4895-900|