Munn, S. R.

Although it is well known that somatostatin inhibits net insulin secretion, it is unknown whether this is achieved by regulation of the basal or pulsatile components of insulin secretion and, if the latter, whether this is through modulation of pulse mass or frequency. We addressed these questions with a canine model. Portal vein blood was sampled at 1-min intervals in five dogs for 60 min before (basal) and 90 min after ingestion of 30 g glucose on two different occasions, during a saline (SAL) or a somatostatin (SMS, 175 ng/min) infusion. Plasma glucose concentrations were similar during SAL and SMS. SMS had no effect on pulse frequency before (8.4 +/- 0.7 vs. 9.2 +/- 1.0 pulses/h, SMS vs. SAL, P = 0.54) or after glucose (13.3 +/- 1.1 vs. 11.6 +/- 0.9 pulses/h, SMS vs. SAL, P = 0.22). In contrast, SMS decreased insulin pulse mass in the postabsorptive (84 +/- 28 vs. 214 +/- 73 pmol/pulse, SMS vs. SAL, P < 0.05) and fed states (676 +/- 143 vs. 913 +/- 183 pmol/pulse, SMS vs. SAL, P < 0.05). In the postabsorptive state, SMS decreased insulin clearance by approximately 50% (0.32 +/- 0.04 vs. 0.60 +/- 0.09 l/min, P < 0.05), but after glucose ingestion, insulin clearance was comparable during SMS or SAL (0.72 +/- 0.04 vs. 0.80 +/- 0.08 l/min, P = 0.4). SMS appeared to alter insulin clearance through modulation of insulin pulse amplitude, because in the postabsorptive state clearance was closely correlated to the pulse amplitude (r = + 0.87, P < 0.0001). In conclusion, somatostatin regulates the rate of insulin secretion by selective inhibition of pulsatile insulin secretion. Regulation of secretory burst mass (and amplitude) may secondarily influence transhepatic and thus total body clearance of endogenously secreted insulin and thereby serve as a novel mechanism to dictate the systemic insulin concentration.

The purpose of the present study was to determine the contributions of discrete insulin secretory bursts vs. basal insulin release to total insulin secretion in vivo. Quantification of the partitioning of pulsatile and basal insulin secretion is complicated by physiological delivery of these pulses into the portal vein and the absence of validated methods of measuring the rates of pulsatile and basal insulin secretion in vivo. We therefore 1) developed a canine model with chronically implanted portal vein catheters, 2) validated an established deconvolution technique as well as a novel direct catheterization technique (Clustcath) for measurement of pulsatile and nonpulsatile insulin secretion rates in this model, and 3) applied these methods to study insulin secretion in the overnight-fasted dog in vivo to determine the contribution of pulsatile vs. basal insulin secretion to total rates of endogenous insulin secretion. Rates of total, pulsatile, and nonpulsatile endogenous insulin secretion measured by Cluscath closely parallel those measured by deconvolution analysis (54 +/- 15 vs. 51 +/- 11, 38 +/- 12 vs. 36 +/- 11, and 16 +/- 4 vs. 14 +/- 4 pmol/min, respectively). Clustcath and deconvolution indicated that the majority of insulin was secreted as pulses (70 +/- 6 and 66 +/- 7%, respectively). These data infer that any process that selectively decreases the pulsatile component of insulin secretion (e.g., diabetes mellitus) will likely have a major impact on total insulin secretion.

Little is known about the optimal experimental conditions for assessing pulsatile insulin secretion in vivo. To address this, we employed a recently validated canine model (n = 12) to determine the consequences of 1) sampling from the systemic circulation (SC) vs. the portal vein (PV), 2) sampling intensity and duration, and 3) deconvolution vs. cluster analysis on assessing pulsatile insulin secretion. PV vs. SC sampling resulted in a approximately 40% higher pulse frequency by deconvolution (9.0 +/- 0.5 vs. 6.6 +/- 0.9 pulses/h, P < 0.02) and cluster analysis (7.5 +/- 0.3 vs. 5.6 +/- 0.6 pulses/h, P < 0.01) due to a higher signal-to-noise ratio (19 +/- 4.8 PV vs. 12 +/- 1.8 SC). PV sampling also disclosed a higher calculated contribution of the pulsatile vs. nonpulsatile mode of delivery to total insulin secretion (57 +/- 4 vs. 28 +/- 5%, P < 0.001). Analysis of the relevance of sampling intensity revealed that 1-min data yielded a markedly higher estimate of pulse frequency with PV sampling than 2-min data (9.0 +/- 0.5 vs. 5.4 +/- 0.5, P < 0.02, deconvolution; 7.5 +/- 0.3 vs. 4.3 +/- 0.6 pulses/h, P < 0.001, cluster). Optimal sampling duration was shown to be 40 min or more. We conclude that the resolving power of the analytical tool, the anatomic site of blood withdrawal, the frequency of blood sampling, and the duration of the total observation interval all significantly influence estimated insulin secretory pulse frequency and the fraction of insulin secreted in pulses. With the assumption that PV 1-min insulin data constitute the "gold standard," our in vivo inferences of 7.5-9.0 insulin pulses/h closely recapitulate in vitro islet secretory activity.