AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 290: E523-E529, 2006. First published October 25, 2005; doi:10.1152/ajpendo.00392.2005
0193-1849/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
290/3/E523    most recent
00392.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nunemaker, C. S.
Right arrow Articles by Satin, L. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nunemaker, C. S.
Right arrow Articles by Satin, L. S.

Insulin secretion in the conscious mouse is biphasic and pulsatile

Craig S. Nunemaker,1 David H. Wasserman,2 Owen P. McGuinness,2 Ian R. Sweet,3 Jeanette C. Teague,3 and Leslie S. Satin1

1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia; 2Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee; and 3Department of Physiology, University of Washington, Seattle, Washington

Submitted 22 August 2005 ; accepted in final form 17 October 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Islets in most species respond to increased glucose with biphasic insulin secretion, marked by a sharp first-phase peak and a slowly rising second phase. Mouse islets in vitro, however, lack a robust second phase. To date, this observation has not been extended in vivo. We thus compared insulin secretion from conscious mice with isolated mouse islets in vitro. The arterial plasma insulin response to a hyperglycemic clamp was measured in conscious mice 1 wk after surgical implantation of carotid artery and jugular vein catheters. Mice were transfused using clamps with blood from a donor mouse to maintain blood volume, allowing frequent arterial sampling. When plasma glucose in vivo was raised from ~5 to ~13 mM, insulin rose to a first-phase peak of 403 ± 73% above basal secretion (n = 5), followed by a rising second phase of mean 289 ± 41%. In contrast, perifused mouse islets (~75 islets/trial) responded with a similar first phase of 508 ± 94% (n = 4) but a smaller and virtually flat second phase of 169 ± 9% (n = 4, P < 0.05). Furthermore, the slope of the second-phase response differed significantly from zero in mice (2.63 ± 0.39%/min, P < 0.01), in contrast to perifused islets (0.18 ± 0.14%/min, P > 0.30). Mice also displayed pulsatile patterns in insulin concentration (period: 4.2 ± 0.4 min, n = 8). Conscious mice thus responded to increased glucose with biphasic and pulsatile insulin secretion, as in other species. The robust second phase observed in vivo suggests that the processes needed to generate second-phase insulin secretion may be abrogated by islet isolation.

insulin; secretion; first phase; second phase; biphasic; mouse; in vivo; pulses; pulsatile

INSULIN SECRETION OCCURS IN A BIPHASIC MANNER in response to rapid increases in glucose concentration (2, 8, 20, 45). First-phase secretion consists of a sharp peak that occurs within 2–5 min of a glucose challenge (29). It is generally accepted that the first-phase peak results from the glucose stimulus increasing beta-cell ATP/ADP to close ATP-dependent K+ (KATP) channels, and in turn, depolarizing the beta-cell membrane potential. This results in the opening of voltage-gated calcium channels, promoting the influx of calcium and secretion of an immediately releasable pool of granules (15, 37, 46). Second-phase secretion consists of a sustained elevation of insulin secretion, which rises over a period of several minutes (2, 8, 20, 45) and is typically accompanied by insulin pulses occurring at 5- to 15-min intervals (34).

This description of biphasic insulin secretion is typical of nearly all species, whether measured from in vivo plasma concentrations (6, 7), perfused pancreas (8, 12), or perifused islets in vitro (21). A notable exception is the isolated mouse islet, which displays a small and relatively static second phase after a fairly typical first-phase response. This type of flat second phase has been observed using a variety of mouse preparations, including the perfused pancreas and cultured islets, and is seen in several different mouse strains (4, 13, 23, 26, 42, 56, 57).

To determine whether second-phase secretion in the mouse is the result of a physiological difference between mice and other species or results from the removal of the pancreas from its native environment requires the direct measurement of insulin from mice in vivo. To date, a detailed secretory profile of insulin release from conscious mice has been lacking because of technical challenges with surgical procedures, glycemic clamping of small and delicate blood vessels, and maintaining sufficient blood volume to permit rapid sampling of plasma. We have overcome these limitations and report the successful use of a hyperglycemic clamp in conscious mice to assess first-phase, second-phase, and pulsatile patterns of insulin secretion. We thus demonstrate a new technique that will allow investigators to measure patterns of insulin secretion in various transgenic mouse models.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Male Swiss-Webster mice (20–35 g) were used for all experiments using protocols in accordance with the Animal Care and Use Committee of Virginia Commonwealth University, Vanderbilt University, or the University of Washington, consistent with National Institutes of Health guidelines. Unless otherwise stated, all chemicals used in these experiments were obtained from Sigma-Aldrich (St. Louis, MO).

Measuring insulin and glucose concentration in conscious mice. The surgical procedures used were similar to those described previously (14, 30, 38). Mice were anesthetized with pentobarbitol sodium (70 mg/kg body wt). The left common carotid artery was catheterized for sampling of arterial blood with a two-part catheter consisting of PE-10 (inserted in the artery) and Silastic (0.025 in. OD) tubing. The right jugular vein was catheterized for infusions with a Silastic catheter (0.025 in. OD). The free ends of the catheters were tunneled under the skin to the back of the neck, where they were attached via stainless steel connectors to lines made of Micro-Renathane (0.033 in. OD), which were exteriorized and sealed with stainless steel plugs. Lines were flushed daily with 10–50 µl of saline containing 200 U/ml heparin and 5 mg/ml ampicillin. Animals were individually housed, and body weight was recorded daily for 5–7 days after surgery.

Food was withheld from each mouse at 5:00 PM on the day before an experiment. On the morning of each study, conscious mice were placed in a 1-liter plastic container lined with bedding, and the Micro-Renathane tubing (22 cm long, 0.033 in. OD) was connected to the catheter leads. After ~1 h, two blood samples were taken 5 min apart to measure baseline glucose and insulin. Next, a variable infusion of 50% dextrose solution was infused in the jugular vein to increase the glucose to 200–250 mg/dl (mean: 230 ± 8 mg/ml among all 11 mice). This infusion produces a glucose concentration of ~13 mM in the mouse compared with basal glucose levels of ~5 mM. One of two protocols was then implemented to collect blood samples. For protocol 1, a rapid-sampling period was initiated immediately after dextrose infusion to assess both first- and second-phase insulin secretion (n = 6 mice). Blood samples (60 µl) were collected every minute for 20–30 min (in the case of one mouse, sampling was made at 2-min intervals). For protocol 2, blood collection for insulin measurements was delayed for 40–60 min to assess pulsatility under conditions of elevated, steady-state glucose (n = 5 mice).

To avoid decreases in blood cell volume from sampling, a constant supply of blood (70 µl/min) was infused from a donor mouse throughout the sampling period for both protocols. Replacement of red blood cells at a constant rate is more effective and less disruptive to the mouse than replacement of red cells as a bolus. Although we cannot rule out that this constant infusion can, in principle, affect the neuroendocrine responses to hyperglycemia, we have observed that this procedure does not increase plasma catecholamines (3).

Blood was collected from the same arterial catheter to measure glucose and insulin. Glucose was measured using a HemoCue B-Glucose Analyzer (HemoCue, Lake Forest, CA), which accurately measures blood glucose within a range of 0–400 ± 6 mg/dl using 5 µl of blood. Immunoreactive insulin was assayed in duplicate using a double-antibody method (28) with reagents obtained from Linco Research (St. Charles, MO). The intra- and interassay variabilities for insulin were 6–10% and 4–7%, respectively.

Insulin secretion from dissociated islets. Mice were killed, and islets were isolated by collagenase digestion from the mouse pancreas, as previously described (47). RPMI-based medium was replaced with a low-glucose Krebs solution containing (in mM) 2.8 glucose, 102 NaCl, 5 KCl, 1.2 MgCl2, 2.7 CaCl2, 20 HEPES, 5 NaHCO3, and 1 mg/ml BSA, pH 7.4. Islets were incubated for 60 min to allow sufficient time for adjustments in metabolism to occur. After 60 min, samples were collected at 2-min intervals for 10 min, and then the low-glucose solution was removed and replaced with a high-glucose solution containing (in mM) 11.1 glucose, 132 NaCl, 5 KCl, 1.2 MgCl2, 1 CaCl2, 10 HEPES, 5 NaHCO3, and 1 mg/ml BSA, pH 7.3. Samples were then collected at 2-min intervals for the first 10 min and then at 5-min intervals for the next 20 min. Insulin was measured as previously described (39, 51).

It should be noted that, although a similar relative shift of ~8 mM glucose was used for in vitro and in vivo experiments, the basal and stimulated glucose concentrations differed between in vivo (~5 and ~ 13 mM) and in vitro (2.8 and 11.1 mM) studies. Because different tissue preparations (whole animal, perfused pancreas, isolated islets, or dispersed beta-cells) can display different thresholds for glucose activation (17, 52), we experimentally determined that a step from 2.8 to 11.1 mM glucose produced basal and first-phase secretory responses that were qualitatively and quantitatively similar to the in vivo findings compared with other glucose concentrations (using 5 mM glucose as a basal concentration, for example, generated a weak first-phase response). This strategy, we hoped, would provide a more accurate assessment of second-phase differences. Previous studies have established that mouse islets demonstrate a small and static second phase under a variety of different glucose challenges (4, 13, 23, 26, 42, 56, 57), so our choice of glucose concentrations may not have mattered. For example, shifting glucose from 1.66 to 11.1 mM in two groups of islets still resulted in a small, static second phase (153 ± 50) following a substantial first-phase response (1,112 ± 137%). Because of the large first-phase response, data from these two groups were used in calculating the slope of second-phase secretion only.

Statistics and pulse detection. First-phase peak and second-phase plateau were expressed as a percentage of basal insulin to permit a direct comparison between insulin concentrations measured in the whole mouse vs. insulin secretion from perifused islets. First- and second-phase secretion comparisons between mice and perifused islets were made using the Mann-Whitney test because of the nonparametric nature of the data, although the data were also found to be significant using a two-tailed t-test assuming unequal variance. The rate of second-phase increase for mice and perifused islets was determined by linear regression, and the slopes were compared with a slope of zero to determine statistical significance. Pulses of insulin were identified with the pulse detection algorithm Cluster (31, 50) using the following parameters: 1-min minimum peak size, 1-min minimum nadir size, 2.0 for t-score to detect peaks and nadirs, and no minimum value for peak amplitude. False positives were kept to <5% by using the intra-assay variance as a SD for each data point of a given record of insulin concentration. To improve the detection of possible false negatives, the data were reanalyzed using a t-score of 1, producing the same results.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Biphasic insulin secretion in conscious mice and perifused mouse islets. Because mouse islets display an atypically flat second phase compared with the islets of most other species, the goal of this study was to determine if insulin secretory patterns measured in vivo in conscious mice similarly lack second-phase secretion. As shown in Fig. 1, insulin levels increased sharply and transiently before falling to a second-phase plateau above basal secretion in both conscious mice and islets in vitro in response to increased glucose. The second phase shown in the two in vivo examples in Fig. 1A, however, continually rose throughout the experiment, in contrast to the relatively flat second phase observed for groups of ~75 perifused mouse islets measured in vitro (Fig. 1B), indicating that mice indeed display a second phase of secretion in vivo.


Figure 1
View larger version (29K):
[in this window]
[in a new window]
  		Fig. 1. Second-phase insulin secretion differs between conscious mice in vivo and mouse islets in vitro. A and B: examples of insulin measurements demonstrating a biphasic response from conscious mice in vivo (A) and from groups of perifused islets in vitro (B). Dotted lines indicate the mean basal insulin levels measured before glucose was increased.

 
The mean values of in vivo insulin during basal, first-phase peak, and second-phase insulin secretion were 98.7 ± 20.8, 346.1 ± 57.1, and 263.1 ± 46.7 pmol/l, respectively (n = 5). A summary of biphasic secretion comparing in vivo and in vitro findings is shown in Fig. 2. Both first and second phases are represented in Fig. 2A as a percentage of basal secretion measured before the glucose challenge. First-phase secretion for mice (403 ± 73%, n = 5) did not significantly differ (P > 0.41) from the first phase of insulin secretion for isolated mouse islets in vitro (508 ± 94%, n = 4).


Figure 2
View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2. Summary of the two phases of insulin secretion from conscious mice and perifused mouse islets. A: first- and second-phase insulin secretion displayed as the percentage of basal insulin levels. *Significant difference between mice in vivo and perifused mouse islets in vitro (P < 0.05). B: mean insulin patterns for 5 mice and 4 groups of mouse islets displayed as a percentage of the peak first-phase secretion.

 
Second-phase secretion, in contrast, differed significantly (P < 0.05) between conscious mice (289 ± 41%, n = 5) and mouse islets (169 ± 9%, n = 4), as evidenced by the mean percent increase over basal secretion during exposure to 11.1 mM glucose. In addition, the trajectory of the secretory profiles differed, with a continuously rising second phase observed in mice (slope: 2.63 ± 0.39%/min, P < 0.01 against a slope of 0), compared with the second phase seen in mouse islets in vitro (slope: 0.18 ± 0.14%/min, P > 0.30, not statistically different from a slope of 0, n = 6). This is shown in Fig. 2B in which insulin profiles were normalized to the first-phase peak and presented as an average of five mice and four groups of mouse islets.

To ensure that the rising second phase we observed in vivo was not the result of inadequate glycemic clamp, glucose measurements were compared between the first 5 min and the last 5 min of the second-phase response for each mouse. In four of five mice, the increase in mean glucose from the beginning of the second phase to the end of the experiment was only 6 ± 10%, whereas insulin concentration rose 76 ± 27% during the second phase for these same four mice. The remaining mouse was less adequately clamped, with glucose at the end of the experiment rising 102%, although the increase in insulin was even greater, rising 216% from beginning to end. These data thus indicate that insulin concentration increased during the second phase even when glucose concentrations were well clamped.

Pulses in insulin during second-phase secretion. A more detailed analysis of the insulin patterns observed during second-phase secretion revealed distinct pulses in 9 of 11 mice. Our earliest experiment involved measuring insulin at 2-min intervals, as shown in Fig. 3A. Two pulses in Fig. 3A were detected at 8-min intervals using Cluster analysis, although two additional smaller pulses could be detected only when the pattern was analyzed assuming no SD in the sampling, yielding a 4.7 ± 0.7-min pulse interval. We stress that these two minor pulses could not be detected using the appropriate parameters for Cluster analysis and suggest more rapid sampling was needed. Thus insulin secretion was measured at 1-min intervals in all subsequent experiments. The example in Fig. 3B demonstrates clearly defined pulses at 4.5 ± 0.5-min intervals.


Figure 3
View larger version (21K):
[in this window]
[in a new window]
  		Fig. 3. Mice display pulsatile insulin patterns. A and B: representative examples of pulsatile insulin patterns after the first-phase peak with samples taken at 2-min intervals (A) and 1-min intervals (B). *Peaks in insulin concentration as detected by Cluster analysis. #Peaks detected by Cluster assuming no variance. Dotted lines are drawn at the mean basal insulin levels. C: representative example of insulin and glucose measured together 1 h after glucose was increased.

 
We also determined that the insulin patterns remained oscillatory well after the initial glucose challenge. Figure 3C shows the glucose concentration for the full 83-min sampling period and plasma insulin for the last 13 min. Two basal readings of both insulin and glucose were taken before dextrose infusion. The glucose concentration doubled in the mouse within minutes, but blood sampling for insulin was delayed an additional 60 min, since only enough blood was available to take 10–20 samples. Pulsatile insulin secretion continued, as demonstrated by the two prominent peaks observed in Fig. 3C measured 1 h after the initial increase in blood glucose (representative of experiments in 5 mice). Glucose sampling confirmed that the glucose concentration was stable in the mouse during this time period.

The pulse characteristics of peak interval, width, peak height as percent above baseline, and area are summarized in Table 1 for all nine mice in which pulsatile insulin was detected. No differences were observed between protocols 1 and 2 in any pulse characteristics (P ≥ 0.35, n = 4 for each protocol). For the two mice in which pulses of insulin secretion were not detected, insulin was collected using protocol 1 for one mouse and protocol 2 for the other mouse. Mean values for each pulse characteristic shown in Table 1 were obtained using records from the eight mice in which insulin was sampled at 1-min intervals (mouse 102–04 was excluded because of the different sampling rate).


View this table:
[in this window]
[in a new window]
  		Table 1. Insulin pulse characteristics

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
It has been suggested that first-phase insulin secretion is mediated by the "consensus KATP pathway," whereas the second phase is mediated by another mechanism, variously referred to as the "KATP channel-independent pathway" (41, 44), the "nonionic pathway" (2), and the "amplifying pathway" (16). This second-phase pathway was first identified in mouse islets (10, 11) and rat islets (40). Subsequent comparative studies between mouse and rat islets have established that stimulation of this pathway is less robust in mouse islets in vitro (4, 23, 26, 42, 56). This finding has led to several reports investigating the mechanisms underlying the different degrees of stimulation of second-phase secretion in mouse and rat islets, including glyceraldehyde (23), cAMP (26), protein kinase A (48), phospholipase C (53, 56), and amino acids (25, 55) and has even led to speculation that the mouse may not be a good model for examining insulin secretion as it relates to humans, which have a robust second phase (26).

In this report, we provide a detailed description of insulin secretory patterns in conscious mice. Our findings suggest that, as in other species, mice respond to a sharp increase in glucose with biphasic insulin secretion, specifically with a more robust second-phase response than suggested by in vitro studies (4, 23, 26, 42, 56). Although our findings do not address the intracellular pathways involved in second-phase secretion, our findings do indicate that insulin secretion at the whole animal level is likely to be more similar to that of other species. This suggests that, in mice, an important in vivo input to the pancreas or to the islets might be lost after islet isolation. This input may consist of nervous innervation of the pancreas [1 or important circulating factors, such as incretins (9a)]. Islet isolation and culturing may also cause changes in gene expression (18, 24, 54) or insulin granule dynamics (37, 45, 46) that do not occur to the same extent in islets from other species. Future studies will be required to more fully address these possibilities.

It should be noted that insulin absorption and degradation by the liver, which can be up to 80% in humans (27) and ~50% in dogs (19, 33), as well as arterial blood circulation, are confounding factors in any attempt at a direct comparison of in vivo and in vitro studies. Our comparisons were thus based on percentage changes within the patterns of insulin secretion from mice and within patterns of insulin secretion from perifused islets. Although it can be argued that such comparisons are suspect nonetheless, the key finding of a rising second phase in insulin secretion in vivo, but not in vitro, was also validated by comparing the slopes of second-phase secretion independently of one another against a slope of zero. This demonstrated that the trajectory of mouse insulin secretion was clearly rising and the trajectory of mouse islets was statistically flat.

We also observed that, as in other species, mouse insulin secretion is pulsatile. Although it should be noted that a small subset of pulsatile insulin data was published elsewhere (32), the more detailed analysis in the present study demonstrates that mouse insulin patterns occur with a period of ~4 min. Although we attempted to assess pulses as accurately as possible (see MATERIALS AND METHODS), there are limitations to pulse analysis that can result in the detection of false positive and/or false negative pulses (34, 43). By analyzing records as short as 20–30 min, we increase the possibility of errors in accurately measuring pulse characteristics. It should be stressed, however, that these studies are technically difficult. For example, to generate a 30-min record of insulin secretion, ~2 ml of blood must be collected, which is nearly the total blood volume of the mouse. Although we used blood from a donor mouse to maintain overall red blood cell volume (see MATERIALS AND METHODS), continuing to take additional samples beyond 30–40 min would begin to reduce the red blood cell volume, which could begin to adversely affect the mouse. Although a longer duration of insulin secretion from the mouse would thus be preferable for evaluating secretory patterns, this is not presently feasible.

Despite these caveats, pulsatile secretion is observed in other species and thus not unexpected in mice. We observed robust and regular patterns of pulsatile insulin in several mice at similar intervals ranging from ~=3–6 min, as assessed by visual inspection in addition to rigorous pulse analysis, suggesting these are valid pulse intervals for the mouse. Although insulin pulses have been reported to have periods of 5–15 min in other species (see review in Ref. 34), recent studies using improved sampling and analysis techniques suggest that insulin pulses may actually occur at intervals nearer to 5 min in rodent species (22, 35) and in humans (36, 43). Of interest, a pulse interval of 3–5 min is consistent with the period of rhythms in mouse islet fuel metabolism, electrical activity, intracellular calcium, and secretion measured in vitro (5, 9, 31, 49, 58).

In conclusion, this study confirms that mice respond to increased glucose with a first-phase peak and subsequent insulin pulses, as do other species. The robust second phase observed in conscious mice contrasts with the small, flat second phase reported in mouse islets in vitro and confirmed in this report, suggesting that an important physiological mechanism needed to generate second-phase insulin secretion may be diminished or lost in dissociated mouse islets in vitro. At the level of the animal, however, insulin secretion in the conscious mouse displays phases and pulses similar to those of other species. This study thus validates mice as a model for measuring insulin secretion and opens the door for investigators to study insulin secretion in various transgenic mouse models.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1 DK-46409 to L. S. Satin and F32 DK-065462 to C. S. Nunemaker and the Vanderbilt Mouse Metabolic Phenotyping Center (DK U24-DK-59637).


   ACKNOWLEDGMENTS
 
We thank Tasneem S. Ansari, Jessica A. Potts, and Carlo Malabanan for performing the difficult procedures required to measure insulin secretion in the conscious mouse. We also thank Drs. Geoffrey Sharp and Susanne Straub for valuable editorial comments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. S. Satin, Dept. of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980524, Richmond, VA 23298 (e-mail: lsatin{at}hsc.vcu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Ahren B. Autonomic regulation of islet hormone secretion–implications for health and disease. Diabetologia 43: 393–410, 2000.[CrossRef][ISI][Medline]
  2. Aizawa T, Sato Y, and Komatsu M. Importance of nonionic signals for glucose-induced biphasic insulin secretion. Diabetes 51, Suppl 1: S96–S98, 2002.[Abstract/Free Full Text]
  3. Ayala JE, Bracy DP, McGuinness OP, and Wasserman DH. Considerations in designing the hyperinsulinemic-euglycemic clamp in the conscious mouse. Diabetes. In press.
  4. Berglund O. Different dynamics of insulin secretion in the perfused pancreas of mouse and rat. Acta Endocrinol 93: 54–60, 1980.
  5. Bergsten P, Grapengiesser E, Gylfe E, Tengholm A, and Hellman B. Synchronous oscillations of cytoplasmic Ca2+ and insulin release in glucose-stimulated pancreatic islets. J Biol Chem 269: 8749–8753, 1994.[Abstract/Free Full Text]
  6. Blackard WG and Nelson NC. Portal and peripheral vein immunoreactive insulin concentrations before and after glucose infusion. Diabetes 19: 302–306, 1970.[ISI][Medline]
  7. Cerasi E and Luft R. Plasma insulin response to sustained hyperglycemia induced by glucose infusion in human subjects. Lancet 2: 1359–1361, 1963.[Medline]
  8. Curry DL, Bennett LL, and Grodsky GM. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83: 572–584, 1968.[ISI][Medline]
  9. Dahlgren GM, Kauri LM, and Kennedy RT. Substrate effects on oscillations in metabolism, calcium and secretion in single mouse islets of Langerhans. Biochim Biophys Acta 1724: 23–36, 2005.[Medline]
  10. Efendic S and Portwood N. Overview of incretin hormones. Horm Metab Res 36: 742–746, 2004.[CrossRef][ISI][Medline]
  11. Gembal M, Detimary P, Gilon P, Gao ZY, and Henquin JC. Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells. J Clin Invest 91: 871–880, 1993.[ISI][Medline]
  12. Gembal M, Gilon P, and Henquin JC. Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. J Clin Invest 89: 1288–1295, 1992.[ISI][Medline]
  13. Gerich JE, Charles MA, and Grodsky GM. Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. J Clin Invest 54: 833–841, 1974.[ISI][Medline]
  14. Grodsky GM, Ma YH, Cullen B, and Sarvetnick N. Effect on insulin production sorting and secretion by major histocompatibility complex class II gene expression in the pancreatic beta-cell of transgenic mice. Endocrinology 131: 933–938, 1992.[Abstract]
  15. Halseth AE, Bracy DP, and Wasserman DH. Overexpression of hexokinase II increases insulinand exercise-stimulated muscle glucose uptake in vivo. Am J Physiol Endocrinol Metab 276: E70–E77, 1999.[Abstract/Free Full Text]
  16. Henquin JC. Cell biology of insulin secretion. In: Joslin's Diabetes Mellitus, edited by Kahn CR and Weir GC. Philadelphia, PA: Lea & Febiger, 1994, p. 56–80.
  17. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49: 1751–1760, 2000.[Abstract]
  18. Hopcroft DW, Mason DR, and Scott RS. Structure-function relationships in pancreatic islets: support for intraislet modulation of insulin secretion. Endocrinology 117: 2073–2080, 1985.[Abstract]
  19. Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, Rorsman P, and Renstrom E. CaV2 E.3 calcium channels control second-phase insulin release. J Clin Invest 115: 146–154, 2005.[CrossRef][ISI][Medline]
  20. Kaden M, Harding P, and Field JB. Effect of intraduodenal glucose administration on hepatic extraction of insulin in the anesthetized dog. J Clin Invest 52: 2016–2028, 1973.[ISI][Medline]
  21. Komatsu M, Sato Y, Aizawa T, and Hashizume K. KATP channel-independent glucose action: an elusive pathway in stimulus-secretion coupling of pancreatic beta-cell. Endocr J 48: 275–288, 2001.[ISI][Medline]
  22. Lacy PE, Walker MM, and Fink CJ. Perifusion of isolated rat islets in vitro. Participation of the microtubular system in the biphasic release of insulin. Diabetes 21: 987–998, 1972.[ISI][Medline]
  23. Larsen MO, Elander M, Sturis J, Wilken M, Carr RD, Rolin B, and Porksen N. The conscious Gottingen minipig as a model for studying rapid pulsatile insulin secretion in vivo. Diabetologia 45: 1389–1396, 2002.[CrossRef][ISI][Medline]
  24. Lenzen S. Insulin secretion by isolated perfused rat and mouse pancreas. Am J Physiol Endocrinol Metab Gastrointest Physiol 236: E391–E400, 1979.[Abstract/Free Full Text]
  25. Levisetti MG and Polonsky KS. Diabetic pancreatic beta cells ARNT all they should be. Cell Metab 2: 78–80, 2005.[CrossRef][ISI][Medline]
  26. Liu YJ, Cheng H, Drought H, MacDonald MJ, Sharp GW, and Straub SG. Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH. Am J Physiol Endocrinol Metab 285: E380–E389, 2003.[Abstract/Free Full Text]
  27. Ma YH, Wang J, Rodd GG, Bolaffi JL, and Grodsky GM. Differences in insulin secretion between the rat and mouse: role of cAMP. Eur J Endocrinol 132: 370–376, 1995.[Abstract]
  28. Meier JJ, Veldhuis JD, and Butler PC. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes 54: 1649–1656, 2005.[Abstract/Free Full Text]
  29. Morgan CR and Lazarow A. Immunoassay of pancreatic and plasma insulin following alloxan injection of rats. Diabetes 14: 669–671, 1965.[ISI][Medline]
  30. Nesher R and Cerasi E. Modeling phasic insulin release: immediate and time-dependent effects of glucose. Diabetes 51, Suppl 1: S53–S59, 2002.[Abstract/Free Full Text]
  31. Niswender KD, Shiota M, Postic C, Cherrington AD, and Magnuson MA. Effects of increased glucokinase gene copy number on glucose homeostasis and hepatic glucose metabolism. J Biol Chem 272: 22570–22575, 1997.[Abstract/Free Full Text]
  32. Nunemaker CS and Satin LS. Comparison of metabolic oscillations from mouse pancreatic beta cells and islets. Endocrine 25: 61–67, 2004.[CrossRef][ISI][Medline]
  33. Nunemaker CS, Zhang M, Wasserman DH, McGuinness OP, Powers AC, Bertram R, Sherman A, and Satin LS. Individual mice can be distinguished by the period of their islet calcium oscillations: is there an intrinsic period which is imprinted in vivo? Diabetes 54: 3517–3522, 2005.[Abstract/Free Full Text]
  34. Polonsky K, Jaspan J, Emmanouel D, Holmes K, and Moossa AR. Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. Acta Endocrinol 102: 420–427, 1983.
  35. Porksen N, Hollingdal M, Juhl C, Butler P, Veldhuis JD, and Schmitz O. Pulsatile insulin secretion: detection, regulation, and role in diabetes. Diabetes 51, Suppl 1: S245–S254, 2002.[Abstract/Free Full Text]
  36. Porksen N, Munn S, Steers J, Veldhuis JD, and Butler PC. Effects of glucose ingestion versus infusion on pulsatile insulin secretion. The incretin effect is achieved by amplification of insulin secretory burst mass. Diabetes 45: 1317–1323, 1996.[Abstract]
  37. Pørksen N, Nyholm B, Veldhuis JD, Butler PC, and Schmitz O. In humans at least 75% of insulin secretion arises from punctuated insulin secretory bursts. Am J Physiol Endocrinol Metab 273: E908–E914, 1997.[Abstract/Free Full Text]
  38. Rorsman P and Renstrom E. Insulin granule dynamics in pancreatic beta cells. Diabetologia 46: 1029–1045, 2003.[CrossRef][ISI][Medline]
  39. Rottman JN, Bracy D, Malabanan C, Yue Z, Clanton J, and Wasserman DH. Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice. Am J Physiol Endocrinol Metab 283: E116–E123, 2002.[Abstract/Free Full Text]
  40. Satin LS, Tavalin SJ, Kinard TA, and Teague J. Contribution of L- and non-L-type calcium channels to voltage-gated calcium current and glucose-dependent insulin secretion in HIT-T15 cells. Endocrinology 136: 4589–4601, 1995.[Abstract]
  41. Sato Y, Aizawa T, Komatsu M, Okada N, and Yamada T. Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell. Diabetes 41: 438–443, 1992.[Abstract]
  42. Sato Y and Henquin JC. The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism. Diabetes 47: 1713–1721, 1998.[Abstract]
  43. Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren PO, and Magnuson MA. Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem 277: 37176–37183, 2002.[Abstract/Free Full Text]
  44. Song SH, Kjems L, Ritzel R, McIntyre SM, Johnson ML, Veldhuis JD, and Butler PC. Pulsatile insulin secretion by human pancreatic islets. J Clin Endocrinol Metab 87: 213–221, 2002.[Abstract/Free Full Text]
  45. Straub SG, James RF, Dunne MJ, and Sharp GW. Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets. Diabetes 47: 758–763, 1998.[Abstract]
  46. Straub SG and Sharp GW. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev 18: 451–463, 2002.[CrossRef][ISI][Medline]
  47. Straub SG and Sharp GW. Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. Am J Physiol Cell Physiol 287: C565–C571, 2004.[Abstract/Free Full Text]
  48. Sweet IR, Cook DL, Wiseman RW, Greenbaum CJ, Lernmark A, Matsumoto S, Teague JC, and Krohn KA. Dynamic perifusion to maintain and assess isolated pancreatic islets. Diabetes Technol Ther 4: 67–76, 2002.[CrossRef][Medline]
  49. Takahashi N, Kadowaki T, Yazaki Y, Ellis-Davies GC, Miyashita Y, and Kasai H. Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells. Proc Natl Acad Sci USA 96: 760–765, 1999.[Abstract/Free Full Text]
  50. Tornheim K. Are metabolic oscillations responsible for normal oscillatory insulin secretion? Diabetes 46: 1375–1380, 1997.[Abstract]
  51. Veldhuis JD and Johnson ML. Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol Endocrinol Metab 250: E486–E493, 1986.[Abstract/Free Full Text]
  52. Verchere CB, D'Alessio DA, Prigeon RL, Hull RL, and Kahn SE. The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells. Diabetes 49: 1477–1484, 2000.[Abstract]
  53. Weir GC, Leahy JL, Barras E, and Braunstein LP. Characteristics of insulin and glucagon release from the perfused pancreas, intact isolated islets, and dispersed islet cells. Horm Res 24: 62–72, 1986.[ISI][Medline]
  54. Zawalich WS, Bonnet-Eymard M, and Zawalich KC. Insulin secretion, inositol phosphate levels, and phospholipase C isozymes in rodent pancreatic islets. Metabolism 49: 1156–1163, 2000.[CrossRef][ISI][Medline]
  55. Zawalich WS, Bonnet-Eymard M, and Zawalich KC. Signal transduction in pancreatic beta-cells: regulation of insulin secretion by information flow in the phospholipase C/protein kinase C pathway. Front Biosci 2: d160–d172, 1997.[Medline]
  56. Zawalich WS, Yamazaki H, Zawalich KC, and Cline G. Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets. J Endocrinol 183: 309–319, 2004.[Abstract/Free Full Text]
  57. Zawalich WS, Zawalich KC, and Kelley GG. Regulation of insulin release by phospholipase C activation in mouse islets: differential effects of glucose and neurohumoral stimulation. Endocrinology 136: 4903–4909, 1995.[Abstract]
  58. Zawalich WS, Zawalich KC, Tesz GJ, Sterpka JA, and Philbrick WM. Insulin secretion and IP levels in two distant lineages of the genus Mus: comparisons with rat islets. Am J Physiol Endocrinol Metab 280: E720–E728, 2001.[Abstract/Free Full Text]
  59. Zhang M, Goforth P, Bertram R, Sherman A, and Satin L. The Ca2+ dynamics of isolated mouse beta-cells and islets: implications for mathematical models. Biophys J 84: 2852–2870, 2003.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Biophys. JHome page
C. S. Nunemaker, R. Bertram, A. Sherman, K. Tsaneva-Atanasova, C. R. Daniel, and L. S. Satin
Glucose Modulates [Ca2+]i Oscillations in Pancreatic Islets via Ionic and Glycolytic Mechanisms
Biophys. J., September 15, 2006; 91(6): 2082 - 2096.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
290/3/E523    most recent
00392.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nunemaker, C. S.
Right arrow Articles by Satin, L. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nunemaker, C. S.
Right arrow Articles by Satin, L. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.