help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
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
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, J.-M.
Right arrow Articles by Bergsten, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, J.-M.
Right arrow Articles by Bergsten, P.
Endocrinology Vol. 140, No. 9 3999-4004
Copyright © 1999 by The Endocrine Society

ARTICLES

Preserved Pulsatile Insulin Release from Prediabetic Mouse Islets1

Jian-Man Lin, Johnny Sternesjö, Stellan Sandler and Peter Bergsten

Department of Medical Cell Biology, Uppsala University, SE-751 23 Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. Peter Bergsten, Department of Medical Cell Biology, Uppsala University, Box 571, SE-751 23 Uppsala, Sweden. E-mail: Peter.Bergsten{at}medcellbiol.uu.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
During the development of type I diabetes, the plasma insulin pattern changes. Because the islet secretory pattern has been implicated in this phenomenon, insulin release was measured from female nonobese diabetic (NOD) mouse islets isolated at different ages. Islets from 5-week-old mice were used as controls because they had no infiltrating mononuclear cells and insulin release rose almost 9-fold with maintained oscillatory frequency when the glucose concentration was raised from 3 to 11 mM. Islets isolated from 13- and 25-week-old mice were infiltrated with mononuclear cells. In these islets, increase in the glucose concentration from 3 to 11 mM only doubled insulin release. However, despite the cellular infiltration, insulin release was pulsatile. Islets from 13-week-old mice had reduced glucose oxidation rate. Culture of such islets for 7 days at 11.1 mM glucose causes a decrease in the number of mononuclear cells infiltrating the islets, which in the present study was accompanied by a normalization of both glucose oxidation and glucose-induced insulin release. In the presence of the mitochondrial substrate {alpha}-keto-isocaproate (5 mM) both control and infiltrated islets responded with pronounced insulin pulses with similar amplitudes. The results suggest that the deranged plasma insulin pattern observed during the development of type I diabetes may be related to decrease in the insulin pulse amplitude rather than loss of the pulsatile release from the islets.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PLASMA INSULIN of normal subjects is oscillatory (1, 2), reflecting coordinated pulsatile release from the islets of Langerhans (3, 4). The pulsatile delivery of insulin from the pancreas is important for the hypoglycemic effect of insulin (5), probably by keeping the insulin receptor expression high in target tissue (6). The loss of regular plasma insulin oscillations observed both during the development of type I and in type II diabetes has therefore been associated with receptor down-regulation precipitating glucose intolerance (7, 8, 9). It has been suggested that the deranged plasma insulin pattern could be due to loss of pulsatile insulin release from the islets of diabetics (10). Attempts to restore the oscillatory plasma insulin pattern have therefore focused on the investigation of mechanisms regulating the pulsatile behavior of the pancreatic ß-cell (11). Due to methodological limitations it has, however, not been possible to verify that the pulsatile secretory pattern of the diabetic ß-cell or islet is lost. With the aid of a sensitive insulin assay (4), we have now been able to monitor the dynamics of insulin release from islets isolated from the prediabetic nonobese diabetic (NOD) mouse. This animal spontaneously develops an insulin-dependent diabetes mellitus (12, 13), which strongly resembles type I diabetes in the human (14). In the current study we present the first dynamic secretory measurements from single islets of NOD mice. The results call for a reevaluation of the causes for the deranged plasma insulin pattern in diabetics.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
Reagents of analytical grade and deionized water were used. Collagenase, HEPES, and BSA (fraction V; BSA) were obtained from Roche Molecular Biochemicals GmbH (Mannheim, Germany). Tetramethylbenzidine and insulin-peroxidase was bought from Sigma Chemical Co. (St. Louis, MO). The rat insulin standard was from Novo Nordisk (Bagsvaerd, Denmark). IgG-certified microtiter plates were purchased from Nunc (Roskilde, Denmark). The mouse insulin antibodies were raised in our laboratory from guinea pigs.

General design of experiments
Pancreatic islets were collagenase isolated from female NOD mice aged 5, 13, or 25 weeks, from an inbred local colony (15, 16). The incidence of diabetes is approximately 75% by 30 weeks of age in the females of the colony. Islets were either perifused directly or after 7 days in culture in RPMI 1640 medium supplemented with 10% FCS and 5.6 or 11.1 mM glucose. Individual islets were perifused in a medium supplemented with 1 mg/ml BSA and containing (in mM): NaCl 125, KCl 5.9, MgCl2 1.2, CaCl2 1.28, and HEPES 25, titrated to pH 7.4 with NaOH. Glucose and {alpha}-keto-isocaproic acid (KIC) was added to the perifusion medium in concentrations indicated in the tables and figures.

Islet morphology
Individual islets were ranked as regards inflammation according to stereomicroscopic morphology after isolation and after culture (cf 15). Both freshly isolated and cultured islets from 5-week-old NOD mice had normal islet morphology (N) with no apparent mononuclear cell infiltration. Freshly isolated islets from 13- and 25-week-old NOD mice showed either periinsular mononuclear cell infiltration (PI) or insulitits with mononuclear cells infiltrating the islet (I). After 7 days culture virtually no mononuclear cells were left in islets from 13-week-old mice, which were considered normal (N). A nearly normal morphological appearance (NN) with some mononuclear cells still present was evident in islets from 25-week-old mice cultured for 7 days.

Measurements of insulin release
Individual islets were placed in a 10 µl-chamber and perifused at 37 C in the presence or absence of 3 mM glucose (4). A flow rate of 150–200 µl/min was established using a peristaltic pump. After 60 min the perifusate was collected in 20-sec fractions and immediately cooled on ice. In islets perifused in the presence of 3 mM glucose, the sugar concentration was raised to 11 mM and subsequently 5 mM KIC was added to the perifusion medium. Islets were also stimulated by 5 mM KIC in the absence of glucose. The fractions were analyzed for insulin by a competitive ELISA with the insulin-capturing antibody immobilized directly in the solid phase (4). The rate of insulin release was normalized to dry weight after freeze-drying and weighing the islets on a quartz fiber balance.

Measurements of glucose oxidation rate
Groups of 10 islets were transferred to glass vials (17) containing 100 µl Krebs-Ringer bicarbonate buffer containing 10 mM HEPES and D-[U-14C]glucose (Amersham Pharmacia Biotech, Amersham, UK) and nonradioactive glucose to a final concentration of 16.7 mM and a specific activity of 0.5 µCi/mM. The islet glucose oxidation rate was subsequently measured as previously described (18).

Data analysis
The frequencies of pulsatile insulin release were analyzed by Fourier transformation using the Igor software (Wave Metrics Inc., Lake Oswego, OR). The figures show three point moving averages. Other data are presented as means ± SEM. Differences in secretory rates and frequencies were evaluated with ANOVA.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Insulin release from islets isolated from NOD mice of different ages was measured at basal and stimulatory glucose concentrations. Freshly isolated islets from 5-week-old mice released 18 ± 6 pmol1g-11s-1 insulin in the presence of 3 mM glucose in a pulsatile fashion (0.27 ± 0.01 oscillations/min) (Table 1Go). It should be noted that this secretory pattern is present in Fig. 1Go but not evident due to the scaling of the y-axis. Similar results were obtained after culturing the islets for 7 days in the presence of 11.1 mM glucose. Insulin release increased about 9-fold by augmentation of the amplitude of the insulin pulses in both freshly isolated and cultured islets when the glucose concentration was raised to 11 mM (Fig. 1Go, Table 1Go). The pulsatile insulin release pattern obtained from the islets of the 5-week-old mice is very similar to that obtained from both normal freshly isolated (4) and cultured (19) mouse and rat islets. Furthermore, upon microscopic inspection the NOD mouse islets were devoid of mononuclear cell infiltration and had normal (N) islet morphology and were therefore used as controls.


View this table:
[in this window]
[in a new window]
  		Table 1. Insulin release from NOD islets in the presence of glucose and KIC

 


View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. Insulin release from individual 5-week-old NOD islets in the presence of 3, 11 mM glucose and 5 mM KIC. Insulin release from a freshly isolated islet (A) and an islet cultured at 11.1 mM glucose for 7 days (B). Representative of 4 (A) or 7 (B) experiments.

 
In contrast, freshly isolated islets from 13-week-old mice demonstrated peripheral, periinsular mononuclear cell infiltration (PI) or had insulitis (I) with mononuclear cells infiltrating the islet. Insulin release in the presence of 3 mM glucose from these islets (Fig. 2Go, A and B, Table 1Go) was pulsatile and similar to control. However, there was only a doubling of insulin release when the glucose concentration was increased to 11 mM glucose with a maintained frequency of the oscillations. When islets with insulitis (I) were cultured for 7 days in the presence of either 5.6 or 11.1 mM glucose the mononuclear cell infiltration disappeared with a normalization of the islet morphology (N). Islets cultured at 5.6 mM glucose released significantly less insulin in response to 11 mM glucose compared with islets cultured at 11.1 mM glucose (Table 1Go). Pulsatile insulin release from the latter islets (Fig. 2CGo, Table 1Go) was similar to that observed in control islets.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 2. Insulin release from individual 13-week-old NOD islets in the presence of 3, 11 mM glucose and 5 mM KIC. Insulin release from freshly isolated islets with periinsular mononuclear infiltration (A) and insulitis (B). Insulin release from an islet cultured at 11.1 mM glucose for 7 days (C). Representative of 5 (A), 5 (B), and 8 (C) experiments.

 
Insulin release in the presence of 3 and 11 mM glucose from freshly isolated islets with periinsular infiltration (PI) or insulitis (I) from 25-week-old animals (Fig. 3Go, A and B, Table 1Go) was pulsatile and similar to what was observed in islets from 13-week-old mice. Islets with insulitis (I) were cultured for 7 days in the presence of 5.6 or 11.1 mM glucose, which depleted these islets of the mononuclear cells leaving a few mononuclear cells. A nearly normal (NN) islet morphology was thus observed. Islets cultured at 5.6 mM glucose released significantly less insulin in response to 11 mM glucose compared with islets cultured at 11.1 mM glucose (Table 1Go). Whereas pulsatile insulin release from the latter islets (Fig. 3CGo, Table 1Go) was close to levels observed in control islets, no increase in insulin release was obtained in the islets cultured at 5.6 mM glucose upon raising the glucose concentration (Table 1Go). Indeed, insulin release in the presence of 3 mM glucose from the islets cultured at 5.6 mM glucose was only about 50% of the amount secreted from control islets.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 3. Insulin release from individual 25-week-old NOD islets in the presence of 3, 11 mM glucose and 5 mM KIC. Insulin release from freshly isolated islets with periinsular mononuclear infiltration (A) and insulitis (B). Insulin release from an islet cultured at 11.1 mM glucose for 7 days (C). Representative of 4 (A), 5 (B), and 5 (C) experiments.

 
The effect of KIC on insulin release from NOD islets was evaluated in the absence and presence of 11 mM glucose. In the absence of glucose (Fig. 4Go, Table 2Go), insulin release from freshly isolated and cultured islets from 5-week-old-mice was pulsatile with a frequency and an average secretory rate similar to that observed in the presence of 3 mM glucose (Table 1Go). Addition of 5 mM KIC to the perifusion medium markedly stimulated insulin release in pulses, but with time declining amplitude of the insulin pulses was observed. There was no change in the frequency of the insulin oscillations. Similar secretory patterns in response to 5 mM KIC were recorded both from freshly isolated and cultured islets obtained from 13- and 25-week-old mice (Figs. 5Go and 6Go, Table 2Go).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 4. Insulin release from individual 5 week-old-NOD islets in the absence and presence of 5 mM KIC. Insulin release from a freshly isolated islet (A) and an islet cultured at 11.1 mM glucose for 7 days (B). Representative of 5 (A) or 6 (B) experiments.

 

View this table:
[in this window]
[in a new window]
  		Table 2. Insulin release from NOD islets in the absence or presence of KIC

 


View larger version (14K):
[in this window]
[in a new window]
  		Figure 5. Insulin release from individual 13-week-old NOD islets in the absence and presence of 5 mM KIC. Insulin release from freshly isolated islets with periinsular mononuclear infiltration (A) and insulitis (B). Insulin release from an islet cultured at 11.1 mM glucose for 7 days (C). Representative of 5 (A), 5 (B), and 5 (C) experiments.

 


View larger version (14K):
[in this window]
[in a new window]
  		Figure 6. Insulin release from individual 25-week-old NOD islets in the absence and presence of 5 mM KIC. Insulin release from freshly isolated islets with periinsular mononuclear infiltration (A) and insulitis (B). Insulin release from an islet cultured at 11.1 mM glucose for 7 days (C). Representative of 4 (A), 6 (B), and 7 (C) experiments.

 
In the presence of 11 mM glucose, 5 mM KIC caused a 8- to 9-fold sustained increase in pulsatile insulin release with no change in the frequency in islets isolated from 5-week-old mice (Fig. 1Go, Table 1Go). No decline in the amplitude of the insulin pulses was observed. Similar increases in the secretory rates were obtained from islets isolated from 13-week-old mice (Fig. 2Go, Table 1Go). In freshly isolated islets or islets cultured in the presence of 11.1 mM glucose from 25-week-old mice there was only a 3- to 4-fold increase in the secretory rate (Fig. 3Go, Table 1Go). A mere doubling of the secretory rate was observed from the islets cultured at 5.6 mM glucose (Table 1Go).

The glucose oxidation rate in the presence of 16.7 mM glucose was determined in both freshly isolated islets and islets cultured for 7 days in the presence of 5.6 or 11.1 mM glucose (Table 3Go). The glucose oxidation rate in freshly isolated islets from 5-week-old mice was 264 ± 43 pmol110 islets -11 90 min-1 and was not affected by the culture period. Glucose oxidation was significantly reduced in freshly isolated islets with periinsular infiltration (PI) or insulitis (I) from 13-week-old mice compared with islets that had been cultured for 7 days. The culture period depleted the islets of mononuclear cells and normalized the oxidation rate. In contrast, freshly isolated islets from 25-week-old mice, which predominantly showed insulitis, had a glucose oxidation rate comparable to that of control islets. The oxidation rate was not affected by the 7-day culture period.


View this table:
[in this window]
[in a new window]
  		Table 3. Glucose oxidation from NOD islets

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results in our study are the first dynamic insulin measurements from single isolated islets from an animal model of type I diabetes. They show that the reduced glucose-induced insulin release from islets with insulitis is due to reduction in the amplitude of the insulin pulses, without affecting their frequency. The results provide evidence that the change in the plasma insulin pattern in diabetics may be related to a reduction in the insulin pulse amplitude rather than loss of the regular pulse frequency of the ß-cell.

The proposed loss of pulsatile insulin release from the ß-cell (10) was derived from studies where glucose-induced oscillations in the cytoplasmic Ca2+ concentration ([Ca2+]i) in isolated ß-cells either disappeared after exposure to streptozotocin (20) or became less regular in islets isolated from subjects with impaired glucose tolerance (21). The importance of [Ca2+]i, a key regulator of insulin release (22), in pulsatile insulin release has focused on its possible role as initiator of the secretory pulses (11). Measurements of [Ca2+]i have been used instead of direct measurements of hormonal release from the isolated ß-cell or the islet due to methodological limitations. When it became possible to dynamically monitor insulin release from individual islets (4), the indirect way of monitoring insulin release by [Ca2+]i measurements was strengthened by studies showing synchronous oscillations in [Ca2+]i and insulin release from the isolated islet (19, 23). However, the role of [Ca2+]i as initiator of insulin pulses seemed less plausible when it was found that insulin release from the isolated islet was pulsatile also under conditions when [Ca2+]i was nonoscillatory (24, 25, 26, 27). It can therefore not be excluded that although glucose-induced [Ca2+]i oscillations in ß-cells exposed to streptozotocin disappear (20) or become less regular in ß-cells from glucose intolerant subjects (21) insulin release is still oscillatory. Indeed, when streptozotocin was administered in baboons the plasma insulin oscillations were still present with maintained frequency but with a reduction in the pulse amplitude (28).

It is not likely that the diminished amplitude in insulin secretion is dependent on reduced stores of insulin in the examined islets. We recently measured the insulin content in both freshly isolated and cultured islets isolated from female NOD mice aged 5, 12, 20, and 26 weeks of age (16). When expressed on a per islet basis this was not changed at higher age. On the other hand due to the mononuclear cell infiltration in the islets of the elderly mice the insulin content was much decreased, when the insulin content was expressed per DNA. Moreover, the yield of islets after isolation is low from the older female NOD mice, probably reflecting an ongoing islet loss, and thus a decrease in the whole pancreatic insulin content is likely to exist.

The present reduction in glucose oxidation rate in freshly isolated islets from 13-week-old NOD mice coincides with a decreased glucose-induced insulin release, but a normal secretory response to KIC alone. Provided that the inhibition of insulin release is related to decreased glucose metabolism, our data suggest that the metabolic inhibition should be exerted at a step before mitochondrial metabolism. In this context it should be noted that the cytokine interleukin-1ß, which has been proposed to be involved in the pathogenesis of type I diabetes (29), causes an NO-induced inhibition of the Fe2+-dependent mitochondrial enzyme aconitase in rodent islets (30). Impaired glucose-induced insulin release but normal secretory response to KIC has also been reported from ß-cells from the GK rat (31), which is an animal model for type II diabetes (32). The fact that a decrease in the glucose oxidation rate in the freshly isolated islets from 25-week-old mice was not observed in this study may reflect a selection of islets. At this advanced stage of insulitis the yield of islets upon isolation from the pancreas is much restricted (16), and it is possible that the remaining islets represent a population of islets that is relatively resistant to the suppressive action of the immune system. Furthermore, it can be assumed that glucose oxidation of the mononuclear cells will contribute since they represent more than half of cells based on DNA content at 25 weeks of age (16).

The apparent lack of first phase insulin release in the present study is probably related to the approximately 2-hour exposure period at 3 mM glucose before glucose was raised to 11 mM. Absence of first phase insulin release has previously been observed in normal mouse and rat islets perifused under similar conditions (4). We therefore conclude that the absence of first phase insulin release in NOD islets under the present conditions is probably not specific for this strain. Moreover, the significance of the incubation glucose concentration for pulsatile insulin release before glucose stimulation has been studied specifically (19).

Our findings of a decrease in the amplitude of NOD islet insulin pulses but with maintained frequency is fundamental. The results shift the focus of the investigation of possible lesions in the pancreatic ß-cell causing the deranged plasma insulin pattern during the development of diabetes. It can be envisaged that factors capable of enhancing the amplitude of the insulin pulses could become important for the treatment of diabetes.


   Footnotes
 
1 The study was supported by grants from the Swedish Medical Research Council (12X-8273, 12X-11203, 12P-10739), the Novo Nordisk Foundation, the Swedish Diabetes Association and the Family Ernfors Foundation. Back

Received January 13, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Goodner CJ, Walike BC, Koerker DJ, Ensinck JW, Brown AC, Chideckel EW, Palmer J, Kalnasy L 1977 Insulin, glucagon, and glucose exhibits synchronous, sustained oscillations in fasting monkeys. Science 195:177–179[Abstract/Free Full Text]
  2. Lang DA, Matthews DR, Peto J, Turner RC 1979 Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med 301:1023–1027[Abstract]
  3. Stagner JI, Samols E, Weir GC 1980 Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J Clin Invest 65:939–942
  4. Bergsten P, Hellman B 1993 Glucose-induced amplitude regulation of pulsatile insulin secretion from individual pancreatic islets. Diabetes 42:670–674[Abstract]
  5. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC 1983 Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes 32:617–621[Abstract]
  6. Goodner CJ, Sweet IR, Harrison HC 1988 Rapid reduction and return of surface insulin receptors after exposure to brief pulses of insulin in perifused rat hepatocytes. Diabetes 37:1316–1323[Abstract]
  7. Lang DA, Matthews DR, Burnett M, Turner RC 1981 Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes 30:435–439[Abstract]
  8. O’Rahilly S, Turner RC, Matthews DR 1988 Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med 318:1225–1230[Abstract]
  9. Bingley PJ, Matthews DR, Williams AJ, Bottazzo GF, Gale EA 1992 Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects. Diabetologia 35:32–38[Medline]
  10. Hellman B, Gylfe E, Grapengiesser E, Lund PE, Berts A 1992 Cytoplasmic Ca2+ oscillations in pancreatic ß-cells. Biochim Biophys Acta 1113:295–305[Medline]
  11. Hellman B, Gylfe E, Bergsten P, Grapengiesser E, Lund PE, Saha S, Berts A, Dryselius S, Tengholm A, Liu YJ, Eberhardsson M 1994 Pulsatile Ca2+ signalling and insulin release. In: Flatt PR, Lenzen S (eds) Frontiers of Insulin Secretion and Pancreatic B-cell Research. Smith-Gordon, London, vol 30:221–228
  12. Tochino Y 1987 The NOD mouse as a model of type 1 diabetes. CRC Crit Rev Immunol 8:49–81
  13. Kolb H 1987 Mouse models of insulin-dependent diabetes: low-dose streptozotocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 3:751–778[Medline]
  14. Eisenbarth GS, Connely J, Soeldner JS 1987 The "natural" history of type I diabetes. Diabetes Metab Rev 3:873–891[Medline]
  15. Strandell E, Eizirik DL, Sandler S 1990 Reversal of ß-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J Clin Invest 85:1944–1950
  16. Sternesjö S, Sandler S 1998 Effects of interleukin-12 in vitro on pancreatic islets isolated from normal rodents and from non-obese diabetic mice. J Endocrinol 158:69–75[Abstract]
  17. Keen H, Field JB, Pastan IH 1963 A simple method for in vitro metabolic studies using small volumes of tissue and medium. Metabolism 12:143–174
  18. Andersson A, Sandler S 1983 Viability tests of cryopreserved endocrine pancreatic cells. Cryobiology 20:161–165[CrossRef][Medline]
  19. Bergsten P 1995 Slow and fast oscillations of cytoplasmic Ca2+ in pancreatic islets correspond to pulsatile insulin release. Am J Physiol 268:E282–E287
  20. Grapengiesser E, Gylfe E, Hellman B 1990 Disappearance of glucose-induced oscillations of cytoplasmic Ca2+ in pancreatic ß-cells exposed to streptozotocin or alloxan. Toxicology 63:263–271[CrossRef][Medline]
  21. Kindmark H, Kohler M, Arkhammar P, Efendic S, Larsson O, Linder S, Nilsson T, Berggren PO 1994 Oscillations in cytoplasmic free calcium concentration in human pancreatic islets from subjects with normal and impaired glucose tolerance. Diabetologia 37:1121–1131[Medline]
  22. Hellman B, Gylfe E, Bergsten P, Grapengiesser E, Lund PE, Berts A, Dryselius S, Tengholm A, Liu Y, Eberhardsson M, Chow RH 1994 The role of Ca2+ in the release of pancreatic islet hormones. Diabete Metab 20:123–131[Medline]
  23. Bergsten P, Grapengiesser E, Gylfe E, Tengholm A, Hellman B 1994 Synchronous oscillations of cytoplasmic Ca2+ and insulin release in glucose-stimulated pancreatic islets. J Biol Chem 269:8749–8753[Abstract/Free Full Text]
  24. Westerlund J, Hellman B, Bergsten P 1996 Pulsatile insulin release from mouse islets occurs in the absence of stimulated entry of Ca2+. J Clin Invest 97:1860–1863[Medline]
  25. Westerlund J, Gylfe E, Bergsten P 1997 Pulsatile insulin release from pancreatic islets with nonoscillatory elevation of cytoplasmic Ca2+. J Clin Invest 100:2547–2551[Medline]
  26. Bergsten P 1998 Glucose-induced pulsatile insulin release from single islets at stable and oscillatory cytoplasmic Ca2+. Am J Physiol 274:E796–E800
  27. Bergsten P, Lin J, Westerlund J 1998 Pulsatile insulin release: role of cytoplasmic Ca2+ oscillations. Diabete Metab 24:33–37
  28. Goodner CJ, Koerker DJ, Weigle DS, McCulloch DK 1989 Decreased insulin- and glucagon-pulse amplitude accompanying ß-cell deficiency induced by streptozocin in baboons. Diabetes 38:925–931[Abstract]
  29. Mandrup-Poulsen T 1996 The role of interleukin-1 in the pathogenesis of insulin-dependent diabetes mellitus. Diabetologia 39:1005–1029[Medline]
  30. Welsh N, Eizirik DL, Bendtzen K, Sandler S 1991 Interleukin-1ß-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 129:3167–3173[Abstract/Free Full Text]
  31. Tsuura Y, Ishida H, Okamoto Y, Kato S, Sakamoto K, Horie M, Ikeda H, Okada Y, Seino Y 1993 Glucose sensitivity of ATP-sensitive K+ channels is impaired in ß-cells of the GK rat. A new genetic model of NIDDM. Diabetes 42:1446–1453[Abstract]
  32. Goto Y, Kakizaki M, Masaki N 1975 Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 51:80–85



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
S. M. Katzman, M. A. Messerli, D. T. Barry, A. Grossman, T. Harel, J. D. Wikstrom, B. E. Corkey, P. J. S. Smith, and O. S. Shirihai
Mitochondrial metabolism reveals a functional architecture in intact islets of Langerhans from normal and diabetic Psammomys obesus
Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1090 - E1099.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J.-M. Lin, M. E. Fabregat, R. Gomis, and P. Bergsten
Pulsatile Insulin Release From Islets Isolated From Three Subjects With Type 2 Diabetes
Diabetes, April 1, 2002; 51(4): 988 - 993.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J. Westerlund and P. Bergsten
Glucose Metabolism and Pulsatile Insulin Release From Isolated Islets
Diabetes, August 1, 2001; 50(8): 1785 - 1790.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
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
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, J.-M.
Right arrow Articles by Bergsten, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, J.-M.
Right arrow Articles by Bergsten, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals