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Endocrinology Vol. 141, No. 1 174-180
Copyright © 2000 by The Endocrine Society

ARTICLES

Glucose Regulates Proinsulin and Prosomatostatin But Not Proglucagon Messenger Ribonucleic Acid Levels in Rat Pancreatic Islets1

Eric Dumonteil, Christophe Magnan, Beate Ritz-Laser, Alain Ktorza, Paolo Meda and Jacques Philippe

Unité de Diabétologie Clinique (E.D., B.R.-L., J.P.), Département de Morphologie (P.M.), CMU, 1211 Geneve 4, Switzerland; and Laboratoire de Physiopathologie de la Nutrition (C.M., A.K.), Groupe Endocrinologie métabolique, Université Paris 7, F-75291 Paris Cedex 05, France

Address all correspondence and requests for reprints to: Jacques Philippe, M.D., Diabetes Unit, Centre Médical Universitaire, 1211 Geneva 4, Switzerland. E-mail: philippe{at}medecine.unige.ch


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Insulin and glucagon are the major hormones involved in the control of fuel metabolism and particularly of glucose homeostasis; in turn, nutrients tightly regulate insulin and glucagon secretion from the islets of Langerhans. Nutrients have clearly been shown to affect insulin secretion, as well as insulin biosynthesis and proinsulin gene expression; by contrast, the effects of nutrients on proglucagon gene expression have not been studied. We have investigated the effect of glucose, arginine, and palmitate on glucagon release, glucagon cell content, and proglucagon messenger RNA (mRNA) levels from isolated rat islets in 24-h incubations. We report here that concentrations of glucose that clearly regulate insulin and somatostatin release as well as proinsulin and prosomatostatin mRNA levels, do not significantly affect glucagon release, glucagon cell content or proglucagon mRNA levels. In addition, though both 10 mM arginine and 1 mM palmitate strongly stimulated glucagon release, they did not affect proglucagon mRNA levels. We conclude that, in contrast to insulin and somatostatin, glucose does not affect glucagon release and proglucagon mRNA levels, and arginine and palmitate do not coordinately regulate glucagon release and proglucagon mRNA levels.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ENDOCRINE PANCREAS plays a central role in the control of fuel metabolism, and particularly of glucose homeostasis. At least four endocrine cell types have been identified in the pancreatic islets: ß-, {alpha}-, {delta}-, and PP cells producing insulin, glucagon, somatostatin, and pancreatic polypeptide, respectively. Insulin and glucagon are the two main hormones controlling antagonistically the balance between glucose storage and consumption. Insulin is secreted in response to nutrients to promote energy storage in target tissues, while glucagon secretion is simultaneously inhibited. In the fasting state, glucagon is released to increase glucose production, thus providing energy to peripheral tissues, whereas insulin secretion falls. The role of local somatostatin is still uncertain, although it has been proposed that this hormone may act indirectly on glucose homeostasis by inhibiting insulin and glucagon secretion (1).

The regulation of insulin secretion and biosynthesis by glucose has been extensively studied both in vivo and in vitro (1, 2, 3, 4). These studies clearly demonstrated that insulin secretion and biosynthesis are stimulated by glucose in a dose-dependent manner. Biosynthesis is modulated at multiple levels, including transcription of the proinsulin gene and translation of insulin messenger RNA (mRNA) (4). Other nutrients, such as the amino acids leucine and arginine, are strong insulin secretagogues, potentiate glucose-induced insulin secretion, and increase insulin biosynthesis and proinsulin gene expression (4, 5, 6, 7). Fatty acids can also modulate insulin secretion and proinsulin gene expression (8, 9, 10). Thus, nutrients coordinately regulate insulin secretion, biosynthesis, and proinsulin gene expression.

By contrast, the regulation of glucagon secretion and biosynthesis by nutrients has not been as intensively investigated. Although glucose is the major physiological regulator of glucagon secretion in vivo, its role as a direct modulator of the 224 cell is still debated (11, 12, 13). For instance, the autonomic nervous system, rather than glucose, may be the main mediator of glucagon secretion in response to hypoglycemia (14, 15). Other nutrients, such as amino acids and fatty acids, may also affect glucagon secretion. Glutamine, alanine, and arginine strongly stimulate glucagon secretion, with arginine being the most potent (11). Free fatty acids, by contrast, result in a marked inhibition of glucagon secretion both in vivo and in vitro (16), although their more chronic effects remain controversial; indeed, palmitate, a saturated fatty acid, acutely inhibits glucagon secretion from isolated islets, while it markedly stimulates glucagon release in 24-h incubations (17, 18). From these studies, however, it is unclear whether nutrients can directly modulate glucagon biosynthesis and proglucagon gene expression. To investigate whether nutrients can affect proglucagon mRNA levels, we have studied the effects of glucose, arginine, and palmitate on glucagon release, glucagon cell content, and proglucagon mRNA levels in primary cultures of rat pancreatic islets. We have found that, over a 24-h period, glucose had no effect on proglucagon mRNA levels, glucagon content, and glucagon release in isolated islets, whereas it increased secretion and cell content of insulin and somatostatin and stimulated both proinsulin and prosomatostatin gene expression. Arginine and palmitate markedly increased glucagon release but did not affect proglucagon mRNA levels. These findings indicate that major nutrients do not affect proglucagon mRNA levels, in contrast to what is observed for the proinsulin and prosomatostatin genes, and that glucagon secretion and proglucagon mRNA levels are not coordinately regulated by these nutrients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Isolation and culture of pancreatic islets
Islets of Langerhans were isolated from rat pancreas by collagenase digestion followed by purification on a Histopaque gradient (19). Batches of 500–700 islets were centrifuged 5 min at 130 g in sterile RPMI-1640 medium supplemented with 10% FCS, 110 U/ml penicillin, 110 µg/ml streptomycin, 250 KIU/ml aprotinin (Sigma, St. Louis, MO), 2 mM glutamine, and 5 mM glucose and were resuspended in the same medium. This washing procedure was repeated twice before plating each islet batch with 4 ml of medium in 60-mm dishes. After 6 h of preincubation at 5 mM glucose, the culture medium was replaced by 4 ml of fresh RPMI-1640 medium containing 2 mM, 5 mM, or 11 mM glucose and was incubated for another 6, 12, or 24 h, as indicated in the text. For some of the experiments, 10 mM arginine (Sigma) or 1 mM palmitate (Sigma) was added to the medium. Stock solutions of palmitate were prepared by binding 12 mM palmitate to a 12.5% solution of free fatty acid-free BSA and was added to the culture medium at a final concentration of 1 mM palmitate/1% BSA (10). The concentration of albumin-bound nonesterified fatty acid was measured using a NEFA C kit (Wako Pure Chemical Industries Ltd., Neuss, Germany). At the end of these incubations, islets and medium were separated by a 5-min centrifugation and frozen rapidly at -80 C for subsequent extraction of total RNA. In all cases, samples collected at the end of the 6-h preincubation period were defined as the t = 0 reference and used for normalization of the results. Preincubation times of 0, 24, and 48 h were also tested in additional experiments. For hormone release and cell content determination, samples of 60 islets were used and incubated similarly, as described above.

Northern blot analyses
Pellets of about 700 pancreatic islets were lysed by sonication in guanidine thiocyanate, and total RNA was extracted by centrifugation through a cesium chloride gradient (20). Then 1–2 µg of total islet RNA were size fractionated on a 1% agarose gel, transferred onto a nylon membrane (Nytran, Schleicher & Schuell, Inc., Keene, NH), and UV-cross-linked. Blots were sequentially hybridized with random-primed complementary DNA (cDNA) probes for rat proglucagon, proinsulin I, prosomatostatin, glyceraldehyde 3-phosphate dehydrogenase, and an 18S ribosomal RNA (rRNA) oligonucleotide probe, respectively. Quantification of the RNA signals was performed by phosphorimaging (Molecular Dynamics, Inc., Sunnyvale, CA), and data were corrected for differences in gel loading using the 18S rRNA signals as standards.

Analytical methods
Immunoreactive insulin, glucagon, and somatostatin in the medium, as well as islet content, were determined by RIAs using kits from CEA [Gif-sur Yvette, France (insulin)], Biodata [Rome, Italy, (glucagon)], and DiaSorin, Inc. [Stillwater, MA (somatostatin)], respectively (10). For hormone cell content determination, islets were washed with PBS buffer; and immunoreactive insulin, glucagon, and somatostatin were measured after acid/ethanol (1.5% HCl, 75% ethanol) extraction (10). The lower limit of the assay was 15 pmol/liter (4 µU/ml) for insulin, 14.5 ng/liter for glucagon, and 8 pg/ml for somatostatin; and the coefficient of variation within and between assays was 6% for the insulin, glucagon, and somatostatin kits.

Presentation of the results and data analysis
Results are presented as mean ± SEM. Statistical analysis of differences between groups were made by ANOVA, followed (when significant) by Scheffé’s test using the ANOVA output.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Glucose does not regulate proglucagon mRNA levels in vitro
To investigate the effects of glucose on proglucagon mRNA levels, we used primary rat islets. Islets were preincubated in RPMI-1640 medium containing 5 mM glucose, for 6 h, to allow for recovery and then incubated for 6–24 h in the presence of either 2, 5, or 11 mM glucose. Cumulative glucagon release in the medium, islet glucagon content, and proglucagon mRNA levels were then measured (Fig. 1Go). Glucagon release remained stable throughout the 24-h period at 11 and 5 mM glucose, whereas it tended to increase at low glucose; however, the difference between 2 mM and 11 mM glucose, which was maximal at 12 h, did not reach statistical significance (P = 0.13). Islet glucagon content slightly and progressively increased at all glucose concentrations studied although not significantly (P = 0.66). Proglucagon mRNA levels also tended to increase with time, irrespective of the glucose concentrations tested, but not significantly (P = 0.88). Interestingly, glyceraldehyde 3-phosphate dehydrogenase could not be used as an internal control in these experiments inasmuch as the mRNA levels were strongly regulated by glucose (data not shown); therefore 18S RNA was chosen as the internal standard.



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  		Figure 1. Effect of glucose on glucagon release, glucagon cell content, and proglucagon gene expression in isolated rat islets. Isolated rat islets were preincubated for 6 h in the presence of 5 mM glucose, then switched during 6, 12, or 24 h to a medium containing 2, 5, or 11 mM glucose. Islets and medium were collected after each time point; medium was used for the measurement of cumulative glucagon release (A) and islets for the determination of glucagon cell content (B) and proglucagon mRNA levels (C and D) with a 32P-labeled rat proglucagon cDNA. Each point represents the mean ± SEM of four experiments. Statistical analyses by ANOVA reveal that glucose has no significant effect on glucagon release (P = 0.13) (A), glucagon content (P = 0.66) (B), and proglucagon mRNA levels (P = 0.88) (C). Northern blot data are expressed relative to the values obtained at time zero and to the level of the 18S rRNA used as internal standard. D, Northern blot illustrating the detected signals for proglucagon, proinsulin, prosomatostatin mRNAs, and 18S rRNA.

 
To test for islet viability and function, we also measured insulin and somatostatin release, islet insulin and somatostatin content, and proinsulin and prosomatostatin mRNA levels under identical experimental conditions (Figs. 1DGo and 2Go). As expected, immunoreactive insulin release was strongly stimulated by glucose, in a dose-dependent manner, with a 10-fold difference between low and high glucose concentrations (P < 0.001). By contrast, islet insulin content remained unchanged under the experimental conditions tested (P = 0.46), suggesting adaptative changes in biosynthesis. Proinsulin mRNA levels were significantly modulated by glucose, after already completing 12 h of culture. After 24 h, the overall difference in proinsulin mRNA levels between 2 and 11 mM glucose was 8.5-fold (P < 0.001). These results indicate that the islet ß-cells in our experiments are functional and do adequately respond to glucose. In the same batches of islets, somatostatin release was also affected by glucose in a manner which was qualitatively similar to that of insulin (Figs. 1DGo and 3Go). Thus, 11 mM glucose stimulated somatostatin release at all time points studied, with maximal effects at 24 h, whereas release was inhibited at 2 mM glucose. Somatostatin content was, however, unchanged under all conditions. Prosomatostatin mRNA levels were also significantly and positively regulated by glucose, with a 2.5-fold difference between low and high glucose at 24 h. To rule out the possibility that {alpha}-cells might require a different preincubation period for recovery after islet isolation, we changed the duration of the preincubation period from 0 to 48 h; the results were unaffected by the length of the preincubation period (data not shown). We conclude from these experiments that glucose does not, by itself, regulate proglucagon mRNA levels, whereas it does so for proinsulin and prosomatostatin mRNAs. Of note, these results were observed despite major changes in insulin and somatostatin release from the islets cultured at high and low glucose during the 24-h incubation period, suggesting that, under these conditions, the levels of insulin and somatostatin released in the medium did not influence proglucagon mRNA levels.



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  		Figure 2. Effect of glucose on insulin release, insulin cell content, and proinsulin gene expression in isolated rat islets. The same experimental protocol as described in Fig. 1Go was used. Insulin release (A) and cell content (B) were measured in the medium and islet extracts, respectively, by RIAs. C, Proinsulin mRNA levels were determined by hybridizing Northern blots with a rat proinsulin I cDNA labeled by random priming as above. Each point represents the mean ± SEM of four experiments. Statistical analyses by ANOVA reveal that the glucose concentrations tested had no significant effects on insulin content (P = 0.45) but markedly affected insulin release (P < 0.001) and insulin mRNA levels (P < 0.0001). *, P < 0.05; +, P < 0.001 for comparisons of individual time points.

 


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  		Figure 3. Effect of glucose on somatostatin release, somatostatin cell content, and prosomatostatin gene expression in isolated rat islets. The same experimental protocol described in Fig. 1Go was used. Somatostatin release (A) and cell content (B) were measured in the medium and islet extracts, respectively, by RIAs; whereas prosomatostatin mRNA levels (C) were determined by hybridizing Northern blots with a 32P-labeled rat prosomatostatin cDNA. Each point represents the mean ± SEM of four experiments. *, P <0.05; +, P <0.001.

 
Effect of other nutrients on proglucagon mRNA levels
To further investigate the effects of other nutrients on proglucagon mRNA levels, we chose amino and fatty acids known to affect glucagon secretion. We thus investigated the effects of arginine (10 mM) and palmitate (1 mM) on islets that were incubated for 24 h in the presence of various glucose concentrations. As shown on Fig. 4Go, glucose did not significantly affect the levels of glucagon released into the medium after 24 h of incubation; glucagon cell content; and, as in the previous set of experiments (Fig. 1Go), the levels of proglucagon mRNA. By contrast, 10 mM arginine induced a marked increase of glucagon release at all glucose concentrations studied, maximal induction being obtained at 11 mM glucose. Glucagon cell content was correspondingly decreased, and 1 mM palmitate had similar effects with marked increases in release and significant decreases in cell content at all glucose concentrations. Despite these effects on glucagon release, neither arginine nor palmitate affected proglucagon mRNA levels (Fig. 4CGo).



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  		Figure 4. Effects of arginine and palmitate on glucagon release, glucagon cell content, and proglucagon gene expression in isolated rat islets. The same experimental protocol described in Fig. 1Go was used. Glucagon release (A), cell content (B), and proglucagon mRNA levels (C) were measured as in. D, Northern blot illustrating the detected signals for proglucagon mRNA and 18S rRNA Fig. 1Go. Release is expressed in pg/10 islets·24 h, because the incubation period lasted 24 h, whereas hormone content is expressed in pg/10 islets, because cells were collected after the 6-h preincubation and 24-h incubation periods. The control group served as control for the incubations performed in the presence of 10 mM arginine, whereas the BSA group (1% BSA) served as control for the incubations performed in the presence of 1 mM palmitate bound to 1% BSA. Each point represents the mean ± SEM of four experiments. *, P < 0.05; +, P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Islet hormones have a major impact in the control of intermediary metabolism; their secretion is, in turn, tightly regulated by nutrients, such as glucose, amino acids, and fatty acids. Glucose is the major regulator of insulin and glucagon secretion in vivo; in addition, glucose regulates both insulin and somatostatin biosynthesis, as well as proinsulin and prosomatostatin gene expression (1, 21, 22, 23). The mechanisms by which glucose affects glucagon secretion are still unclear; glucose could act directly on the {alpha}-cell, through its stimulatory effects on insulin and somatostatin secretion, through GABA A-receptor chloride channels or alternatively by modulating the activity of the autonomic inputs to the {alpha}-cell (11). These mechanisms are not mutually exclusive, because it is likely that more than one mechanism is implicated; in addition, these mechanisms may not have the same relative importance in the inhibition of glucagon secretion by high glucose or its stimulation by low glucose (11, 12, 13, 14, 15).

Our data suggest that glucose does not regulate proglucagon mRNA levels in vitro, in contrast to its clear effect on the levels of proinsulin and prosomatostatin mRNAs. This observation seems to contradict previous in vivo findings. Thus, in normal rats subjected to a 5-day hyperglycemic clamp (200–400 mg/dl), proglucagon mRNA was reduced by 81% (24). Furthermore, during a 4-day fast, resulting in a mean blood glucose of 48 mg/dl, proglucagon mRNA levels more than doubled; such an increase was also observed in rats made hypoglycemic by insulin-producing tumors (25). These results suggest that in vivo proglucagon mRNA levels are modulated by the prevailing glycemia. In our in vitro studies, however, neither high glucose per se, nor the resulting increase in insulin and somatostatin release, significantly affected proglucagon mRNA levels. This observation must be interpreted in the context of the system used in these studies, i.e. culture of isolated islets. Indeed, it has been shown that the characteristics of insulin and glucagon release may differ whether release is studied from the perfused pancreas, perifused or static isolated islets, or dispersed islet cells (26). Whether proglucagon mRNA levels may respond differently to glucose in different systems will have to be examined further. Furthermore, the apparent discrepancy between the in vivo and in vitro findings might be explained, at least partially, by the role of the autonomic system or by some glucose-stimulated humoral factors. Among the autonomic inputs to {alpha}-cells that comprise sympathetic and parasympathetic nerves and the circulating neurohormone epinephrine, several can indeed activate the cAMP second-messenger pathway, which has been shown to activate proglucagon gene transcription (27, 28). Thus, one mechanism by which glucose might affect proglucagon gene expression in vivo is through autonomic mediation. Finally, the concentration of glucose to which {alpha}-cells are exposed between the in vitro and in vivo studies may be different, resulting in different consequences. It is indeed possible that, at the glucose concentration used in our experiments (11 mM), the glucose sensing apparatus of {alpha}-cells is not fully activated, preventing a hypothetical effect on proglucagon mRNA levels to be observed.

Other nutrients, such as amino and fatty acids, have been shown to affect insulin and somatostatin secretion, as well as proinsulin and prosomatostatin gene expression (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 18). Arginine is the amino acid that stimulates glucagon secretion most potently (11). Although arginine markedly stimulated glucagon release from isolated islets over the 24-h period in our studies, it did not increase proglucagon mRNA levels. Also, palmitate, a saturated fatty acid that has been shown to inhibit glucagon secretion acutely and to stimulate it over longer time periods (17, 18), had no effect on proglucagon mRNA levels, whereas it markedly stimulated glucagon release and decreased glucagon cell content. The results suggest that the marked increase in release induced by palmitate and arginine was not compensated for by a corresponding increase in biosynthesis resulting in a decreased glucagon cell content.

We thus conclude that major nutrients that affect glucagon secretion do not modulate proglucagon mRNA levels in vitro. This is in contrast to what is observed for both insulin and somatostatin: that nutrients indeed do regulate their secretion and expression of their cognate gene in a coordinate fashion.


   Acknowledgments
 
We thank C. Ulmer for typing the manuscript and I. Constant for expert technical assistance.


   Footnotes
 
1 This work was supported by the Swiss National Science Foundation [Grants 3200–046816 (to J.P.) and 3100–053720 (to P.M.)] and by the Human Institute of Biochemistry and Genetics, the Berger Foundation, and the Juvenile Diabetes Foundation International [Grant 197124 (to P.M.)]. Back

Received May 19, 1999.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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