Effects of somatostatin on pulsatile insulin secretion: elective inhibition of insulin burst mass

1996 ◽  
Vol 270 (6) ◽  
pp. E1043-E1049 ◽  
Author(s):  
N. Porksen ◽  
S. R. Munn ◽  
J. L. Steers ◽  
J. D. Veldhuis ◽  
P. C. Butler
Keyword(s):  
Insulin Secretion ◽  
Pulse Amplitude ◽  
Selective Inhibition ◽  
Canine Model ◽  
Pulse Frequency ◽  
Insulin Clearance ◽  
Glucose Ingestion ◽  
Total Body ◽  
Pulsatile Insulin Secretion ◽  
Body Clearance

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.

Alterations in pulsatile insulin secretion in the Zucker diabetic fatty rat

1994 ◽  
Vol 267 (2) ◽  
pp. E250-E259 ◽  
Author(s):  
J. Sturis ◽  
W. L. Pugh ◽  
J. Tang ◽  
D. M. Ostrega ◽  
J. S. Polonsky ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Spectral Power ◽  
Pulse Amplitude ◽  
Ringer Solution ◽  
Cellular Level ◽  
Diabetic Rats ◽  
Male Rats ◽  
Perfused Pancreas ◽  
Isolated Perfused Pancreas ◽  
Pulsatile Insulin Secretion

Insulin secretion from the isolated perfused pancreas is characterized by pulses occurring every 5-15 min. The present experiments were performed to explore the role of glucose in regulating these pulses. The pancreata from 12 Wistar (W), 12 Zucker diabetic fatty (ZDF), and 6 nondiabetic lean Zucker control (ZC) male rats were isolated and perfused at 37 degrees C with an oxygenated Krebs Ringer solution containing bovine serum albumin and glucose. In W and ZDF, insulin secretion was pulsatile during constant glucose, as assessed by pulse analysis (ULTRA). The pulse period in W was significantly shorter than in ZDF (7.1 +/- 0.6 vs. 14.7 +/- 1.0 min; P < 0.001), whereas the median relative pulse amplitude was not different. When glucose was administered as a series of 10-min sine waves, spectral analysis showed that the normalized spectral power at 10 min was greater in W and ZC compared with ZDF (34.2 +/- 5.9 and 32.9 +/- 2.9 vs. 3.2 +/- 0.9; P < 0.0001), demonstrating entrainment of the insulin pulses to the exogenous glucose oscillations in W and ZC but not in ZDF. Furthermore, in ZDF, the insulin secretory rates were not higher when 28 mM rather than 7 mM glucose were used. In additional studies, islets of Langerhans from one W, three ZDF, and three ZC rats were isolated and perifused using an oscillatory glucose concentration. Single and groups of islets were studied. Islets from diabetic rats demonstrated the same lack of entrainment by glucose seen in the perfused pancreas, suggesting that the defect is at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Insulin Pulse Characteristics and Insulin Action in Non-Diabetic Humans

2021 ◽  
Author(s):  
Marcello C Laurenti ◽  
Chiara Dalla Man ◽  
Ron T Varghese ◽  
James C Andrews ◽  
John G Jones ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Action ◽  
Univariate Analysis ◽  
Glucose Production ◽  
Pulse Amplitude ◽  
Endogenous Glucose Production ◽  
Deuterated Water ◽  
Endogenous Glucose ◽  
Pulse Characteristics ◽  
Pulsatile Insulin Secretion

Abstract Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On one occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used Approximate Entropy (ApEn) to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R 2 = 0.16) and insulin pulse amplitude (R 2 = 0.09), correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex and weight these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis), or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in non-diabetic humans.

The mass, but not the frequency, of insulin secretory bursts in isolated human islets is entrained by oscillatory glucose exposure

2006 ◽  
Vol 290 (4) ◽  
pp. E750-E756 ◽  
Author(s):  
R. A. Ritzel ◽  
J. D. Veldhuis ◽  
P. C. Butler
Keyword(s):  
Insulin Secretion ◽  
Sampling Site ◽  
Pulse Frequency ◽  
Human Islets ◽  
Pulse Interval ◽  
Pacemaker Activity ◽  
Glucose Exposure ◽  
Pulsatile Insulin Secretion

Insulin is secreted in discrete insulin secretory bursts. Regulation of insulin release is accomplished almost exclusively by modulation of insulin pulse mass, whereas the insulin pulse interval remains stable at ∼4 min. It has been reported that in vivo insulin pulses can be entrained to a pulse interval of ∼10 min by infused glucose oscillations. If oscillations in glucose concentration play an important role in the regulation of pulsatile insulin secretion, abnormal or absent glucose oscillations, which have been described in type 2 diabetes, might contribute to the defective insulin secretion. Using perifused human islets exposed to oscillatory vs. constant glucose, we questioned 1) whether the interval of insulin pulses released by human islets is entrained to infused glucose oscillations and 2) whether the exposure of islets to oscillating vs. constant glucose confers an increased signal for insulin secretion. We report that oscillatory glucose exposure does not entrain insulin pulse frequency, but it amplifies the mass of insulin secretory bursts that coincide with glucose oscillations ( P < 0.001). Dose-response analyses showed that the mode of glucose drive does not influence total insulin secretion ( P = not significant). The apparent entrainment of pulsatile insulin to infused glucose oscillations in nondiabetic humans in vivo might reflect the amplification of underlying insulin secretory bursts that are detected as entrained pulses at the peripheral sampling site, but without changes in the underlying pacemaker activity.

Impact of sampling technique on appraisal of pulsatile insulin secretion by deconvolution and cluster analysis

1995 ◽  
Vol 269 (6) ◽  
pp. E1106-E1114 ◽  
Author(s):  
N. Porksen ◽  
S. Munn ◽  
J. Steers ◽  
J. D. Veldhuis ◽  
P. C. Butler
Keyword(s):  
Cluster Analysis ◽  
Insulin Secretion ◽  
Mode Of Delivery ◽  
Pulse Frequency ◽  
Resolving Power ◽  
Anatomic Site ◽  
Sampling Intensity ◽  
And Cluster Analysis ◽  
Pulsatile 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.

Anesthesia rapidly suppresses insulin pulse mass but enhances the orderliness of insulin secretory process

2001 ◽  
Vol 281 (1) ◽  
pp. E93-E99 ◽  
Author(s):  
Stephen J. Vore ◽  
E. Dale Aycock ◽  
Johannes D. Veldhuis ◽  
Peter C. Butler
Keyword(s):  
Insulin Secretion ◽  
Secretory Activity ◽  
Canine Model ◽  
Pulse Frequency ◽  
Insulin Concentration ◽  
Secretory Process ◽  
Plasma Insulin Concentration ◽  
Abrupt Decrease ◽  
Independent Amplitude

Induction of anesthesia is accompanied by modest hyperglycemia and a decreased plasma insulin concentration. Most insulin is secreted in discrete pulses occurring at ∼6- to 8-min intervals. We sought to test the hypothesis that anesthesia inhibits insulin release by disrupting pulsatile insulin secretion in a canine model by use of direct portal vein sampling. We report that induction of anesthesia causes an abrupt decrease in the insulin secretion rate (1.1 ± 0.2 vs. 0.7 ± 0.1 pmol · kg−1 · min−1, P < 0.05) by suppressing insulin pulse mass (630 ± 121 vs. 270 ± 31 pmol, P < 0.01). Anesthesia also elicited an ∼30% higher increase in insulin pulse frequency ( P < 0.01) and more orderly insulin concentration profiles ( P < 0.01). These effects were evoked by either sodium thiamylal or nitrous oxide and isoflurane. In conclusion, anesthesia represses insulin secretion through the mechanism of a twofold blunting of pulse mass despite an increase in orderly pulse frequency. These data thus unveil independent amplitude and frequency controls of β-cells' secretory activity in vivo.

scholarly journals Diazoxide Attenuates Glucose-Induced Defects in First-Phase Insulin Release and Pulsatile Insulin Secretion in Human Islets

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3399-3405 ◽  
Author(s):  
Soon H. Song ◽  
Christopher J. Rhodes ◽  
Johannes D. Veldhuis ◽  
Peter C. Butler
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Cell Mass ◽  
Fold Increase ◽  
Pulse Amplitude ◽  
Human Islets ◽  
Pulsatile Insulin Secretion ◽  
Induced Defects ◽  
First Phase Insulin Release

Abstract Humans with type-2 diabetes mellitus (TTDM) have hyperglycemia (∼11 mm) and impaired glucose-mediated insulin secretion characterized by impaired first-phase insulin release (FPIR) and pulsatile insulin release. Culture of islets from nondiabetic humans in very high glucose concentrations (∼20–30 mm) for 96 h causes impaired FPIR. We sought to determine 1) whether human islets cultured at a glucose concentration of approximately 11 mm (comparable to TTDM) recapitulates impaired insulin secretion in TTDM, specifically impaired FPIR and insulin pulse mass with an increased proinsulin/insulin (PI/I) secretion ratio; and 2) whether these changes can be attenuated by addition of diazoxide to islets cultured with 11 mm glucose. Islets cultured with 11 mm glucose for 96 h had 75% depleted insulin stores (P &lt; 0.05), decreased FPIR and insulin pulse mass (P &lt; 0.05), and an approximately 3-fold increase in the ratio of PI/I islet content and in secretion ratio (P &lt; 0.05). Addition of diazoxide to islets cultured with 11 mm glucose decreased insulin secretion during static incubation, leading to relative preservation of insulin stores and enhanced insulin secretion during subsequent perifusion; FPIR increased by 162% (P &lt; 0.05) and insulin pulse mass by 150% (P &lt; 0.05) vs. no diazoxide. The mean islet PI/I content and islet PI/I secretion ratio were also decreased by approximately 70% (P &lt; 0.05) by prior addition of diazoxide to islets during culture with 11 mm glucose. FPIR and insulin pulse mass were related to islet insulin stores (P &lt; 0.001 for FPIR and P &lt; 0.001 for pulse amplitude). In conclusion, the pattern of defects of insulin secretion present in TTDM (impaired FPIR and pulsatile insulin secretion, increased PI/I ratio) can be recapitulated in human islets cultured with 11 mm glucose for 96 h. These defects can be at least partially offset by concurrent inhibition of insulin secretion by diazoxide, which also preserves insulin stores. Defective insulin secretion in TTDM may be, at least in part, due to depletion of available insulin stores secondary to chronic increased demand (insulin resistance and hyperglycemia) in the setting of a decreased β-cell mass.

scholarly journals Adaptations in pulsatile insulin secretion, hepatic insulin clearance, and β-cell mass to age-related insulin resistance in rats

2008 ◽  
Vol 295 (4) ◽  
pp. E832-E841 ◽  
Author(s):  
Aleksey V. Matveyenko ◽  
Johannes D. Veldhuis ◽  
Peter C. Butler
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Portal Vein ◽  
Cell Mass ◽  
Systemic Circulation ◽  
Insulin Clearance ◽  
Β Cell ◽  
Age Related ◽  
Pulsatile Insulin Secretion ◽  
Hepatic Insulin Clearance

In health insulin is secreted in discrete insulin secretory bursts from pancreatic β-cells, collectively referred to as β-cell mass. We sought to establish the relationship between β-cell mass, insulin secretory-burst mass, and hepatic insulin clearance over a range of age-related insulin sensitivity in adult rats. To address this, we used a novel rat model with chronically implanted portal vein catheters in which we recently established the parameters to permit deconvolution of portal vein insulin concentration profiles to measure insulin secretion and resolve its pulsatile components. In the present study, we examined total and pulsatile insulin secretion, insulin sensitivity, hepatic insulin clearance, and β-cell mass in 35 rats aged 2–12 mo. With aging, insulin sensitivity declined, but euglycemia was sustained by an adaptive increase in fasting and glucose-stimulated insulin secretion through the mechanism of a selective augmentation of insulin pulse mass. The latter was attributable to a closely related increase in β-cell mass ( r = 0.8, P < 0.001). Hepatic insulin clearance increased with increasing portal vein insulin pulse amplitude, damping the delivery of insulin in the systemic circulation. In consequence, the curvilinear relationship previously reported between insulin secretion and insulin sensitivity was extended to both insulin pulse mass and β-cell mass vs. insulin sensitivity. These data support a central role of adaptive changes in β-cell mass to permit appropriate insulin secretion in the setting of decreasing insulin sensitivity in the aging animal. They emphasize the cooperative role of pancreatic β-cells and the liver in regulating the secretion and delivery of insulin to the systemic circulation.

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