help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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 Eizirik, D. L.
Right arrow Articles by Andersson, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eizirik, D. L.
Right arrow Articles by Andersson, A.
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2660-2663
Copyright © 1997 by The Endocrine Society

Experimental Studies

Mechanisms of Defective Glucose-Induced Insulin Release in Human Pancreatic Islets Transplanted to Diabetic Nude Mice1

Décio L. Eizirik, Leif Jansson, Malin Flodström, Claes Hellerström and Arne Andersson

Department of Medical Cell Biology, Uppsala University, Biomedicum, Uppsala, Sweden

Address all correspondence and requests for reprints to: Dr. Décio L. Eizirik, Department of Metabolism and Endocrinology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. E-mail: deizirik{at}mebo.vub.ac.be


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We have previously observed that human islets, transplanted under the kidney capsule of hyperglycemic nude mice, show a long-lasting impairment in glucose-induced insulin release. To investigate the cause(s) of this phenomenon, we transplanted human islets into normoglycemic or alloxan-diabetic nude mice for a 4- to 6-week period. In a third experimental group, aimed at evaluating reversibility of hyperglycemia effects, diabetic nude mice bearing a human islet graft were cured by a second intrasplenic transplant of mouse islets, and the human islets were exposed to a further 2 weeks of normoglycemia. Four to 6 weeks of hyperglycemia induced a severe impairment of glucose- and arginine-induced insulin release, as demonstrated by perfusion of the graft-bearing kidney. This defective release was not restored by a subsequent 2-week period of normoglycemia, and it was accompanied by normal (pro)insulin biosynthesis, glucose oxidation, and expression of insulin messenger RNA. Taken together with our previous study, these observations indicate that impaired glucose metabolism, depletion of insulin messenger RNA, decreased (pro)insulin biosynthesis, increased glycogen accumulation, and depletion of insulin reserves cannot explain the deleterious effects of the diabetic state on human islet insulin release. This, and the similar inhibition of glucose- and arginine-induced insulin release, suggest that prolonged hyperglycemia may exert its deleterious effect on insulin release at a step distal to closure of ATP-sensitive K-channels.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EXPERIMENTAL DATA suggest that chronic hyperglycemia induces ß-cell dysfunction (reviewed in Refs. 1–3). This deleterious effect of glucose may be of relevance for the defective insulin release observed in noninsulin-dependent diabetes mellitus (non-IDDM) and in the early stages of IDDM. However, the limited access to human islet tissue means that most of the studies reviewed above have been performed in animal models. There are important differences between human and rodent islets regarding glucose transport (4) and mechanisms of ß-cell damage and repair (5, 6). Thus, it is crucial to further characterize hyperglycemia-induced ß-cell dysfunction in human islets. We have previously observed that human islets exposed in vitro to high glucose concentration for 7 days show a defective insulin release in response to glucose or glucose plus theophylline (7). In a subsequent study, we transplanted such islets under the kidney capsule of normoglycemic or diabetic nude mice (8). After 4 weeks of exposure to a diabetic environment, human islet cells showed a marked glycogen accumulation, depletion of insulin reserves, and a lack of insulin release in response to 16.7 mmol/L glucose. When these diabetic mice were cured by a second mouse islet graft, and the human islets consequently exposed to 2-weeks of normoglycemia, a restoration of insulin reserves and disappearance of intracellular glycogen deposits was observed, but the defective glucose-induced insulin release persisted (8).

The aim of the present study was to characterize some of the mechanisms potentially involved in the loss of insulin response to glucose by human islets exposed to a diabetic environment. For this purpose, human islets were grafted into normoglycemic or hyperglycemic nude mice (similar to the groups referred to above) and, after 4–6 weeks in vivo, examined regarding (pro)insulin biosynthesis, insulin messenger RNA (mRNA) content, glucose oxidation, and insulin release in response to both glucose or glucose plus arginine.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Islet isolation, culture, and transplantation

Human islets were isolated from 24 adult heart-beating nondiabetic organ donors at the Central Unit of the ß-Cell Transplant (Medical Campus, Vrije Universiteit Brussel) (9). The mean age of the donors was 43 ± 3 yr (mean ± SEM, range 7–64 yr). Examination by electron microscopy of the islet-enriched fraction after islet isolation showed 7 ± 1% dead cells and 0.6 ± 0.3% acinar cells. Light microscopical characterization of immunohistochemically stained islets (10) indicated the presence of 52 ± 3% insulin-positive cells and 15 ± 2% glucagon-positive cells. The islet insulin content was 1.14 ± 0.13 ng insulin/ng DNA. After isolation, the islets were transported to Uppsala and cultured as previously described (7, 8). The islets were then implanted into athymic male nude mice (C57BL/6 [nu/nu] (Bomholtgaard, Ry, Denmark) weighing 20–25 grams. In some of the mice, diabetes was induced by iv injection of alloxan (80 mg/kg BW; Sigma Chemical Co., St. Louis, MO) 3–5 days before transplantation. For the transplantation procedure, the animals were anesthetized with avertin (11) and the left kidney visualized via a flank incision. Two small incisions were made under the kidney capsule, and around 1.5 µL (circa 150 islets) of human islets were implanted into each incision by means of a braking pipette. The 2 grafts were located, respectively, in the upper and lower kidney poles. The transplantation of 300 human islets is usually not sufficient to restore normoglycemia in alloxan-diabetic nude mice (8). Some diabetic mice also received a second intrasplenic implant of approximately 200 islets from C57BL/6 (ob/ob) mice (8), which, combined with the previously transplanted human islets, is sufficient to restore normoglycemia (8). The experimental groups were as follow: 1) normoglycemic recipients of human islets 4–6 weeks before killing (4N); 2) alloxan-diabetic recipients of human islets 4–6 weeks before killing (4H); 3) alloxan-diabetic recipients transplanted initially with 300 human islets and, after 4 weeks of hyperglycemia, with a second intrasplenic ob/ob mouse islet transplant, which normalized blood glucose during the subsequent 2 weeks (4H + 2N). The function of human islets transplanted into normoglycemic or diabetic mice was similar after 4 or 6 weeks in vivo (data not shown). Thus, data obtained at these 2 time points were pooled and are presented together.

Perfusion of graft-bearing kidneys and graft insulin mRNA content

Graft perfusion was performed as previously described (12). The perfusions started with a 30-min period using Krebs Ringer bicarbonate buffer (KRBH) containing 2.8 mmol/L glucose, followed by 20 min at 16.7 mmol/L glucose, 15 min at 2.8 mmol/L glucose, 10 min at 5.6 mmol/L glucose + 10 mmol/L arginine, and finally, 15 min at 2.8 mmol/L glucose. A 1.0-mL sample of the effluent medium was obtained 14 and 15 min after starting the equilibration period and then every 5 min, with the exception of the first 10 min of perfusion with 16.7 mmol/L glucose or 5.6 mmol/L glucose + 10 mmol/L arginine, when samples were collected after 1–5, 7, and 10 min. The insulin concentration was determined by RIA (13). After perfusion, the human islet grafts were carefully dissected from the surrounding renal tissues (12) and analyzed for insulin mRNA content by Northern blot (14). Total RNA was isolated from 4–5 pooled grafts by using an RNA Isolation Kit (RNAeasy for total RNA extraction, Qiagen, Santa Clarita, CA). After extraction, the RNA samples (5 µg) were electrophoresed on a 1% agarose gel containing formaldehyde. After acridine orange staining of the gel to assure similar sample loading, the RNA was transferred to a nylon membrane and hybridized to a 32P-labeled complementary DNA probe coding for the rat insulin gene (PRI-7; 15 . Hybridization to 18 S ribosomal RNA, using a labeled rat genomic DNA clone (16), was used as internal control.

(Pro)insulin biosynthesis and glucose oxidation

Graft (pro)insulin biosynthesis was determined as previously described (12). Briefly, two grafts, retrieved from the same mouse, were incubated for 2 h at 37 C in 100 µL KRBH containing either 1.7 or 16.7 mmol/L glucose and 100 µCi/mL L-[4,5-3H]leucine (Amersham, Amersham, UK). The tissue was then homogenized and part of the homogenate used for determination of graft DNA content (17) while the newly synthesized (pro)insulin was measured by determination of [3H]leucine incorporation into immunoprecipitated (pro)insulin (18). Total protein biosynthesis was measured after precipitation with trichloroacetic acid. For determination of graft glucose oxidation rates (11, 19), the two dissected grafts were incubated for 90 min in KRBH containing D-[U-14C]glucose and nonradioactive glucose, with a final concentration of 1.7 or 16.7 mmol/L glucose. After the oxidation, the dry weight of the grafts was estimated and the results expressed per µg dry weight (11).

Statistical analysis

Data are presented as means ± SEM, and groups of data were compared by using paired or unpaired Student’s t test or Wilcoxon signed-rank test. When multiple comparisons were performed, the data were evaluated by ANOVA.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The blood glucose concentration of the nonalloxan-treated mice (4N) was 4.1 ± 0.3 mmol/L (n = 14). All alloxan-treated mice in groups 4H and 4H + 2N had blood glucose levels above 15 mmol/L, 4 weeks after the human islet implantation (group 4H, 22.3 ± 0.2 mmol/L; n = 32). Implantation of the additional 200 ob/ob islets in the spleen of 4H + 2N mice normalized blood glucose levels (3.7 ± 0.2 mmol/L; n = 28).

The contribution of (pro)insulin to the total pool of labeled proteins in the human islets was in the range of 5–9%, independent of the glucose concentration used, and in none of the groups studied was there a significant glucose stimulation of (pro)insulin synthesis between 1.7 and 16.7 mmol/L glucose (Table 1Go). Moreover, there were differences neither in (pro)insulin biosynthesis nor in percentage of (pro)insulin over total protein synthesis between human islets grafted into 4N, 4H, or 4H + 2N mice. The apparent trend for higher (pro)insulin synthesis in group 4N (n = 20), as compared with group 4 H (n = 13) (P > 0.1), was not maintained when the corresponding 13 mice (i.e. receiving islet grafts from the same donor) from groups 4N and 4H were compared (data not shown). In line with this lack of difference in (pro)insulin biosynthesis, the expression of insulin mRNA was similar between human islets grafted into 4N or 4H mice (Fig. 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1. (Pro)insulin biosynthesis of human islets transplanted under the renal capsule of normoglycemic or hyperglycemic nude mice

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 1. Northern blot analysis of insulin mRNA expression in human islets grafted under the kidney capsule of normoglycemic (4N) or hyperglycemic (4H) nude mice (4–6 weeks in vivo). Total RNA (5 µg), pooled from human grafts retrieved from five normoglycemic or hyperglycemic mice, were sequentially hybridized with complementary DNAs for insulin (A, the figure is representative of two separate Northern blots) and 18S (not shown). Densitometric analysis of the blots are shown in B (insulin/18S; data as arbitrary units of optical density).

 
Graft glucose oxidation was increased 3–4 x (P < 0.01) in all groups when comparing glucose metabolism at 1.7 and 16.7 mmol/L glucose (Table 2Go). However, the graft glucose oxidation rates did not differ between 4N, 4H, and 4H + 2N mice.


View this table:
[in this window]
[in a new window]
  		Table 2. Glucose oxidation of human islets transplanted under the renal capsule of normoglycemic or hyperglycemic nude mice

 
Grafts in normoglycemic recipients (4N) showed a well-preserved insulin response to glucose or arginine stimulation in the perfusion experiments (Fig. 2Go). Exposure to hyperglycemia for 4–6 weeks (4H) led to total abolition of glucose-induced insulin release and severely decreased the insulin response to arginine. In mice hyperglycemic for 4 weeks, followed by 2 weeks of normoglycemia (4H + 2N), there was still a diminished insulin release in response to both glucose and arginine. Using planimetry, we calculated the total insulin output in the presence of 16.7 mmol/L glucose or 10 mmol/L arginine plus 5.6 mmol/L glucose. Islets grafted into hyperglycemic animals (4H) have a markedly decreased insulin response to both secretagogues, and this was only partially restored by a subsequent 2 weeks of normoglycemia (4H + 2N) (data not shown).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 2. Insulin concentration in the effluent medium collected from human islet graft-bearing kidneys of nude mice 4 or 6 weeks after transplantation. Kidneys were perfused with a medium containing 16.7 mmol/L glucose or 5.6 mmol/L glucose + 10 mmol/L arginine, as indicated in the top of the figure. During the periods before or after stimulation with 16.7 mmol/L glucose or 5.6 mmol/L glucose + 10 mmol/L arginine, the medium contained 2.8 mmol/L glucose. The curves represent data from recipients normoglycemic for 4–6 weeks (4N, open squares; n = 7), hyperglycemic for 4 weeks (4H, filled diamonds; n = 8) or hyperglycemic for 4 weeks followed by normoglycemia for 2 weeks (4H + 2N, filled squares; n = 5).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
There are several hypotheses to explain why ß-cells, chronically exposed to elevated glucose levels, lose their ability to release insulin in response to glucose. Among them, a possible role has been suggested for glycogen accumulation, depletion of insulin reserves, decreased insulin mRNA expression with an associated impaired (pro)insulin biosynthesis, and/or defective glucose transport and oxidation (1, 2, 3, 20, 21). Moreover, there is evidence suggesting that elevated levels of free fatty acids, which often go in parallel with hyperglycemia in decompensated diabetes, contribute to defective islet glucose metabolism and accompanying impaired insulin release (22, 23).

Most of the hypotheses described above are based on data obtained in rodent islets under in vitro conditions. Thus, it is imperative to test these hypotheses in human pancreatic islets, if possible, exposed to long periods of hyperglycemia in vivo. The observations that human islets grafted to normoglycemic nude mice for 4 weeks maintain an elevated insulin release in response to glucose (Ref. 8; present data), well preserved ß-cell ultrastructure (8) and insulin mRNA expression (present data), and a 4-fold increase in glucose oxidation in response to 16.7 mmol/L glucose (present data) indicate that the present model offers an adequate alternative to study these issues. It should be mentioned that reinnervation of islet grafts into renal subcapsular space occurs slowly (24), which may affect both insulin release and synthesis.

Using the above described preparations, we observed that exposure for 4–6 weeks of human islets to hyperglycemia induced a severe impairment of insulin release in response to both glucose and arginine. This defective release was not significantly improved by a subsequent 2-week period of normoglycemia, achieved by transplantation of 200 islets isolated from ob/ob mice. However, it is conceivable that this second transplant, although sufficient to normalize basal glycemia, is not enough to achieve normal glucose tolerance. If that is the case, exaggerated glucose fluctuations over 24 h may contribute to the defective recovery in ß-cell function. The decrease in insulin release in the 4H and 4H + 2N was accompanied neither by a decreased (pro)insulin biosynthesis nor by a decreased expression of the insulin mRNA or by an impaired glucose oxidation. Previous observations in the same model (8) suggested that glucose-induced impairment in insulin release is independent of a depletion of insulin content or glycogen accumulation. These combined observations suggest that impaired glucose metabolism, decreased insulin mRNA expression and (pro)insulin biosynthesis, glycogen accumulation, or depletion of insulin stores (although of possible relevance for hyperglycemia-induced rodent ß-cell dysfunction) cannot explain the prolonged defect in glucose-induced insulin release observed in human islets exposed to a diabetic environment for 4–6 weeks. Of course, these observations do not exclude the possibility that more prolonged exposure of human islets to hyperglycemia may lead to irreversible impairment in insulin gene transcription, as described for a hamster insulinoma cell line (2).

The mechanism by which arginine is supposed to induce insulin release is by electrogenic transport into the ß-cell and direct membrane depolarization, followed by Ca2+ entry and insulin secretion (25, 26). Thus, the present observations that exposure of human ß-cells to a diabetic environment impairs both glucose- and arginine-induced insulin release, without affecting glucose metabolism, suggest a dysfunction located distally to ATP production and closure of ATP-sensitive K-channels, perhaps at the level of the exocytotic process of insulin secretion (for a recent review on these processes, see 27 . The fact that 2 weeks of normoglycemia did not suffice to restore insulin response to glucose suggests that 4–6 weeks of hyperglycemia induces a long-lasting depletion of a crucial component(s) of the insulin exocytotic process. Identification of this component(s) may provide new insights into the mechanisms of human ß-cell dysfunction in non-IDDM and early IDDM.


   Acknowledgments
 
The skilled technical assistance of B. Bodin, M. Engkvist, A. Nordin and I.-B. Hallgren is gratefully acknowledged. We are grateful to Professor D. Pipeleers, Coordinator of the ß-Cell Transplant, for providing the human islet preparations and information on human islet cell composition.


   Footnotes
 
1 This study made use of human islets prepared by the Central Unit of the B-Cell Transplant, supported by a Shared Costs Action of the European Community. It was also supported by grants from the Juvenile Diabetes Foundation International, Swedish Medical Research Council (12X-9237; 12X-109; 12X-9886; 12X-6538; 12P-9287; and 12P-8982), the Swedish Diabetes Association, the Novo-Nordisk Insulin Fund, the Family Ernfors Fund, and the Göran Gustafsson Foundation. Back

Received January 24, 1997.

Accepted April 17, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Leahy JL, Bonner-Weir S, Weir GC. 1992 ß-cell dysfunction induced by chronic hyperglycemia. Diabetes Care. 15:442–455.[Abstract]
  2. Robertson RP, Olson LK, Zhang H-J. 1994 Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes. 43:1085–1089.[Abstract]
  3. Leahy JL. 1996 Impaired ß-cell function with chronic hyperglycemia: "overworked ß-cell" hypothesis. Diabetes Rev. 4:298–319.
  4. De Vos A, Heimberg H, Quartier E, et al. 1995 Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression. J Clin Invest. 96:2489–2495.
  5. Eizirik DL, Pipeleers DG, Ling Z, Welsh N, Hellerström C, Andersson A. 1994 Major species differences between humans and rodents in the susceptibility to pancreatic ß-cell injury. Proc Natl Acad Sci USA. 91:9253–9256.[Abstract/Free Full Text]
  6. Welsh N, Margulis B, Borg LAH, et al. 1995 Differences in the expression of heat shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med. 1:806–820.[Medline]
  7. Eizirik DL, Korbutt GS, Hellerström C. 1992 Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the ß-cell function. J Clin Invest. 90:1263–1268.
  8. Jansson L, Eizirik DL, Pipeleers DG, Borg LAH, Hellerström C, Andersson A. 1995 Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice. J Clin Invest. 96:721–726.
  9. Pipeleers DG. 1994 Treatment of diabetes by islet cell transplantation. In: Baya C, ed. Biomedical and health research. Vol 3. Advances in medical biology. Amsterdam: IOS Press; 185–197.
  10. Pipeleers DG, In’t Veld PA, Van de Winkel M, Maes E, Schuit F, Gepts W. 1985 A new in vitro model for the study of pancreatic A and B cells. Endocrinology. 117:806–816.[Abstract]
  11. Korsgren O, Jansson L, Eizirik DL, Andersson A. 1991 Functional and morphological differentiation of fetal porcine islet-like cell clusters after transplantation into nude mice. Diabetologia. 34:379–386.[CrossRef][Medline]
  12. Korsgren O, Jansson L, Andersson A. 1989 Effects of hyperglycemia on the function of isolated mouse pancreatic islets transplanted under the kidney capsule. Diabetes. 38:510–515.[Abstract]
  13. Heding LG. 1972 Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia. 8:260–266.[CrossRef][Medline]
  14. Eizirik DL, Björklund A, Cagliero E. 1993 Genotoxic agents increase expression of growth arrest and DNA-damage inducible genes gadd 153 and gadd 45 in rat pancreatic islets. Diabetes. 42:738–745.[Abstract]
  15. Chan SJ, Noyes BE, Agarwal KL, Steiner DF. 1979 Construction and selection of recombinant plasmid containing full-length complementary DNAs corresponding to rat insulin I and II. Proc Natl Acad Sci USA. 76:5036–5040.[Abstract/Free Full Text]
  16. Katz RA, Mitsialis SA, Guntovka RV. 1983 Studies on the methylation of avian sarcoma parvovirus in permissive and nonpermissive cells. J Gen Virol. 64:429–435.[Abstract/Free Full Text]
  17. Hinegardner RT. 1971 An improved fluorimetric assay for DNA. Anal Biochem. 39:197–201.[CrossRef][Medline]
  18. Halban PA, Wollheim CB, Blondel B, Renold AE. 1980 Long-term exposure of isolated pancreatic islets to mannoheptulose: evidence for insulin degradation in the ß-cell. Biochem Pharmacol. 29:2625–2633.[CrossRef][Medline]
  19. Andersson A, Sandler S. 1983 Viability tests of cryopreserved endocrine pancreatic cells. Cryobiology. 20:161–168.[CrossRef][Medline]
  20. Malaisse WJ. 1991 Physiology of insulin secretion and its alteration in diabetes: the concept of glucotoxicity. In: Andreani D, Gueriguian JL, Striker GE, eds. Diabetic complications: epidemiology and pathogenetic mechanisms. New York: Raven Press; 3–23.
  21. Malaisse WJ, Maggetto C, Leclerk-Meyer V, Sener A. 1993 Interference of glycogenolysis with glycolysis in pancreatic islets from glucose-infused rats. J Clin Invest. 91:432–436.
  22. Zhou Y-P, Grill VE. 1994 Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest. 93:870–876.
  23. Zhou Y-P, Grill VE. 1995 Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab. 80:1584–1590.[Abstract/Free Full Text]
  24. Korsgren O, Andersson A, Jansson L, Sundler F. 1992 Reinnervation of syngeneic mouse pancreatic islets transplanted into renal subcapsular space. Diabetes. 41:130–135.[Abstract]
  25. Charles S, Tamagawa T, Henquin JC. 1982 A single mechanism for the stimulation of insulin release and Rb efflux from rat islets by cationic amino acids. Biochem J. 208:301–308.[Medline]
  26. Henquin JC. 1992 The biophysical events involved in the stimulation of insulin release by arginine. In: De Deyen PP, Marescau B, Stalon V, Qureshi IA, eds. Guanidino compounds in biology and medicine. John Libbey and Co; 109–116.
  27. Wollheim CB, Lang J, Regazzi R. 1996 The exocytotic process of insulin secretion and its regulation by Ca2+ and G-proteins. Diabetes Rev. 4:276–297.



This article has been cited by other articles:


Home page
 DiabetesHome page
M. Cnop, N. Welsh, J.-C. Jonas, A. Jorns, S. Lenzen, and D. L. Eizirik
Mechanisms of Pancreatic {beta}-Cell Death in Type 1 and Type 2 Diabetes: Many Differences, Few Similarities
Diabetes, December 1, 2005; 54(suppl_2): S97 - S107.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
N. Kaiser, M. Yuli, G. Uckaya, A. I. Oprescu, M.-F. Berthault, C. Kargar, M. Y. Donath, E. Cerasi, and A. Ktorza
Dynamic Changes in {beta}-Cell Mass and Pancreatic Insulin During the Evolution of Nutrition-Dependent Diabetes in Psammomys obesus: Impact of Glycemic Control
Diabetes, January 1, 2005; 54(1): 138 - 145.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. Biarnes, M. Montolio, V. Nacher, M. Raurell, J. Soler, and E. Montanya
{beta}-Cell Death and Mass in Syngeneically Transplanted Islets Exposed to Short- and Long-Term Hyperglycemia
Diabetes, January 1, 2002; 51(1): 66 - 72.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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 Eizirik, D. L.
Right arrow Articles by Andersson, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eizirik, D. L.
Right arrow Articles by Andersson, A.

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