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Endocrinology Vol. 139, No. 3 822-826
Copyright © 1998 by The Endocrine Society

ARTICLES

Inhibition of Insulin Secretion by Leptin in Normal Rodent Islets of Langerhans

Vincent Poitout, Christine Rouault, Michèle Guerre-Millo, Isabelle Briaud and Gérard Reach

INSERM U341, Service de Diabétologie (V.P., C.R., I.B., G.R.); and INSERM U465, Institut Biomédical des Cordeliers (M.G-M.), Paris, France

Address all correspondence and requests for reprints to: Vincent Poitout, INSERM U341, Service de Diabétologie, Hôtel-Dieu, 1 Place du Parvis Notre Dame, 75004 Paris, France. E-mail: poitout{at}infobiogen.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The recently discovered adipose cell-specific hormone called leptin decreases food intake and increases energy expenditure in rodents through a pathway involving hypothalamic leptin receptors, OB-R. In addition, leptin decreases insulin circulating levels independent of the reduction in food intake. Whether or not the hormone has a direct effect on pancreatic ß-cells is not clear, because previous in vitro studies have led to controversial results depending on the animal model used. The present study was designed to investigate the effects of leptin in islets of Langerhans isolated from normal rodents. Three isoforms of the leptin receptor, OB-Ra, b, and f, were detected by RT-PCR analysis of total RNA from rat islets. In static incubations, leptin (10 ng/ml) did not alter basal insulin secretion nor insulin secretion stimulated by glucose alone, potassium chloride, or ketoisocaproic acid. In contrast, insulin secretion stimulated by glucose + 3-isobutyl 1-methylxanthine (IBMX) was inhibited by 34 ± 15% (n = 4, P < 0.05). This was further substantiated in perifusion experiments, in which leptin decreased by 31 ± 3% (n = 5, P < 0.01) glucose + IBMX-stimulated insulin release. Similarly, in mouse islets a significant inhibitory effect of leptin (-31 ± 4%, n = 6, P < 0.05) was observed only on glucose + IBMX-stimulated insulin secretion, with no effect of the hormone on basal nor glucose-stimulated secretion. Finally, leptin was totally inefficient in islets isolated from obese fa/fa rats, which bear a mutation in OB-R. These results suggest that, in normal rodent islets, leptin specifically inhibits IBMX-potentiated glucose-induced insulin secretion, through a direct effect involving at least one of the three isoforms of OB-R expressed in islets.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ob gene product leptin, secreted by the adipocytes, decreases food intake and increases energy expenditure in rodents. Leptin acts through a specific receptor, OB-R, belonging to the class I cytokine receptor family. In ob/ob mice, mutations in the ob gene result in the absence of functional leptin, massive obesity, and noninsulin-dependent diabetes mellitus (1). db/db mice and fa/fa rats, on the other hand, have similar phenotypes in the presence of elevated levels of circulating leptin. The genetic alterations underlying the obese phenotype in the latter models are mutations in the OB-R gene, resulting in defective leptin signaling (2, 3, 4, 5, 6). Several alternatively spliced OB-R variants, differing in the length of the intracellular domain, have been cloned in rats, mice, and humans (3, 7, 8). The long isoform OB-Rb, containing the potential Janus kinase (JAK) binding domains box 1 and box 2, activates the JAK-signal transducers and activators of transcription (STAT) pathway in reconstituted cell systems (9, 10, 11, 12). Less documented are the signaling capabilities of the isoforms with shorter cytoplasmic domains (13). The various isoforms of OB-R are widely expressed in a tissue-specific manner (3, 7, 8, 14, 15, 16). Hypothalamus, which expresses the highest ratio of long vs. short isoforms (11), is a major target for leptin. In vivo experiments have demonstrated that leptin induces STAT activation in the hypothalamus of ob/ob mice, but not in any other tissue tested (17). The physiological significance of OB-R in a large variety of peripheral tissues remains therefore unclear.

Several observations suggest that leptin can modulate pancreatic ß-cell function. Administration of exogenous leptin in ob/ob mice decreases circulating insulin levels, independent of the reduction in food intake elicited by the hormone (18, 19, 20). This was also observed in normal rats under adenovirus-mediated leptin administration, in which insulinemia is markedly decreased compared with pair-fed controls (21). Furthermore, the recent demonstration that OB-Rb messenger RNA (mRNA) and protein are expressed in rat pancreatic ß-cells (22), indicates that leptin may directly regulate insulin secretion. Several groups have addressed this question, leading to controversial results. Leclercq-Meyer et al. (23) and Leclercq-Meyer and Malaisse (24) did not find any effect of leptin neither on basal nor on glucose-induced insulin secretion from the perfused rat pancreas. Other groups have reported suppression of basal (25) or glucose-stimulated (26) insulin secretion, or increased basal release (27), from normal rat isolated islets. Using islets from ob/ob mice and high doses of leptin (>=100 ng/ml), Emilsson et al. (28) and Kieffer et al. (22) demonstrated that leptin inhibits both basal and glucose-induced insulin secretion. In contrast, the results of Chen et al. (29) indicate a specific inhibition of phospholipase C-potentiated insulin secretion, with no effect on basal nor glucose-stimulated release. The reasons for such discrepancies are unclear. The observations in ob/ob mouse islets might not be representative of the effect of the hormone in normal mice. Indeed, islets from ob/ob mice have never been previously exposed to leptin, and are characterized by alterations in the regulation of insulin secretion by glucose and other secretagogues (30, 31, 32). On the other hand, the discrepancy between the in vitro effects of leptin in rats and mice could be accounted for by species-related differences in the islet sensitivity to leptin.

This prompted us to assess the effects of physiological doses of leptin on basal and stimulated insulin secretion in islets isolated from normal rats and mice. In addition, we investigated the expression of three isoforms of OB-R in isolated rat islets. Finally, the specificity of leptin effects was verified by using islets isolated from Zucker fa/fa rats, homozygous for the fa mutation in OB-R.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Normal Wistar rats and CD1 mice were purchased from Charles River France (Cléon, France). Obese fa/fa Zucker rats and their lean Fa/fa littermates were bred at U465 from pairs originally provided by the Harriet G. Bird Memorial Hospital (Stow, MA). Animals were housed on a 12 h light/ 12 h dark cycle with free access to water and standard laboratory chow (usine alimentation rationnelle, Epinay sur Orge, France).

Islet isolation
Pancreas were digested by intraductal injection of collagenase type XI (Sigma, Saint-Quentin Fallavier, France) (0.5 mg/ml) and stationary incubation as described (33). Islets were purified by double-hand picking under a dissecting microscope and cultured for 1 h in RPMI 1640 (Sigma) containing 11.1 mM glucose and supplemented with 10% FBS (GIBCO BRL, Cergy-Pontoise, France) and 1% penicillin/streptomycin (GIBCO BRL) before secretion studies.

Identification of leptin receptor mRNA in isolated islets
Total RNA was extracted from isolated rat islets according to Chomczynski and Sacchi (34). Five hundred nanograms of total RNA were reverse transcribed by random priming using avian myeloblastosis virus reverse transcriptase (first-strand DNA synthesis, Amersham Life Sciences, Les Ulis, France) according to the manufacturer’s instructions. Control samples were run in the absence of reverse transcriptase. Fragments of ObR-a, ObRb and ObR-f complementary DNA (cDNA) of 487, 370, and 390 bp, respectively, were PCR-amplified by Taq Polymerase (GIBCO BRL) using a primer from the transmembrane region common to all three isoforms and three isoform-specific primers from C-terminal regions (8). PCR reactions were run at 94 C for 5 min, 50 C for 30 sec, and then 72 C for 1 min 30 sec, followed by 48 cycles at 94 C for 45 sec, 50 C for 30 sec, and then 72 C for 1 min 30 sec, and a last cycle with a 7-min final extension in a Crocodile III thermocycler (Appligène Oncor, Illkirch, France). Five-microliter aliquots of the PCR reaction were run for 20 min on a 2% agarose gel at 100 V. Gels were stained with ethidium bromide to visualize the products.

Static incubations
Isolated islets were washed in Krebs buffer (KRBB: 118.5 mM NaCl, 2.54 mM CaCl2.2H2O, 1.19 mM KH2PO4, 4.74 mM potassium chloride (KCl), 25 mM NaHCO3, 1.19 mM MgSO4.7H2O, 10 mM HEPES, 0.1% BSA, 5 mM glutamic acid, 5 mM fumaric acid, 5 mM pyruvic acid, pH 7.4) containing 2.8 mM glucose for 15 min at 37 C, then incubated for 60 min in the presence of various secretagogues, as indicated in the figure legends, with 0, 0.1, 1, or 10 ng/ml recombinant murine leptin (Tebu, Le Perray en Yvelines, France). In some experiments, recombinant leptin from another source (a kind gift of M. Chiesi, Novartis, Basel, Switzerland) was used. Leptin from both sources were equally potent (data not shown). Each incubation tube contained 10 islets, and each condition was run in triplicate.

Insulin was assayed in the supernatant by RIA (Sanofi Diagnostic Pasteur, Marnes la Coquette, France) using rat insulin as standard.

Perifusions
Batches of 50 rat islets were placed in Swinnex chambers (Millipore, Molsheim, France) kept at 37 C and perifused for 1 h with KRBB containing 2.8 mM glucose. Islets were then challenged with KRBB containing 16.7 mM glucose + 0.1 mM 3-isobutyl 1-methylxanthine (IBMX) (Sigma) for 60 min, followed by a 20-min perifusion with basal buffer. The effect of leptin on stimulated insulin secretion was tested by adding 10 ng/ml murine leptin to the perifusate, starting 5 min before the switch to the 16.7 mM glucose + 0.1 mM IBMX buffer. Effluent perifusate was collected over an 80-min period at the times indicated in Fig. 3Go. Each condition was run in duplicate chambers.



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  		Figure 3. Effect of leptin on insulin secretion from isolated Wistar rat islets in perifusions. Batches of 50 islets were perifused for 1 h with KRBB containing 2.8 mM glucose, then for 1 h with KRBB containing 16.7 mM glucose + 0.1 mM IBMX, starting at time 0. In experimental groups, leptin (10 ng/ml) was added to perifusion buffer 5 min before beginning of stimulation. Leptin significantly inhibited stimulated insulin release (n = 5, P < 0.01 vs. control).

 
Expression of data and statistics
Data are presented as mean ± SE. Statistical analysis of insulin secretion in perifusions was performed by comparing the areas under the curves between leptin-treated and control islets after subtraction of the basal level. Intergroup comparisons were performed by Student’s t test or by Dunnett’s t test for multiple comparisons, when appropriate. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of OB-R isoforms in isolated rat islets
Expression of three isoforms of OB-R was investigated by RT-PCR. Using specific pairs of primers for OB-Ra, OB-Rb, and OB-Rf, three cDNA fragments were amplified from rat islet total cDNA with expected mol wts of 487, 370, and 390 bp, respectively (Fig. 1Go). OB-Ra and OB-Rf were easily detected, whereas the signal corresponding to OB-Rb was much less abundant.



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  		Figure 1. RT-PCR analysis of OB-Ra, OB-Rb, and OBR-f expression in isolated Wistar rat islets. Total RNA from isolated islets was reverse transcribed and PCR amplified as described in Materials and Methods. Amplified products were resolved on a 2%-agarose gel and stained with ethidium bromide.

 
Effect of leptin on insulin secretion in islets from normal Wistar rats
Batches of 10 islets isolated from normal Wistar rats were incubated in either basal (2.8 mM glucose) or stimulating (16.7 mM glucose + 0.1 mM IBMX) buffer for 60 min in the presence of increasing concentrations of leptin. The presence of leptin in the incubation buffer did not significantly change the amount of released insulin under basal conditions [139 ± 50 (n = 6), 89 ± 36 (n = 3), 142 ± 94 (n = 3), and 131 ± 66 (n = 4) µU/islet at 0, 0.1, 1, and 10 ng/ml, respectively]. In contrast, leptin inhibited insulin secretion stimulated by glucose + IBMX with a maximal and statistically significant effect observed at 10 ng/ml (Fig. 2Go). At this concentration of leptin, insulin secretion was 66 ± 15% of control (269 ± 61 vs. 404 ± 64 µU/islet, P < 0.05, n = 4).



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  		Figure 2. Effect of leptin on insulin secretion from isolated Wistar rat islets in static incubations. Batches of 10 islets were incubated for 60 min in KRBB containing 2.8 or 16.7 mM glucose + 0.1 mM IBMX in the presence of increasing leptin concentrations. Leptin was added to buffer at beginning of incubation. Data are presented as mean ± SEM of (n) individual experiments. *, P < 0,05 vs. insulin secretion in response to 16.7 mM glucose in absence of leptin.

 
To further substantiate these observations, Wistar rat islets were perifused in the absence or in the presence of 10 ng/ml leptin (Fig. 3Go). When islets were perifused with 16.7 mM glucose + 0.1 mM IBMX, the area under the curve was 1122 ± 164 µU•islets-1•h. In the presence of leptin, phasic insulin release in response to glucose + IBMX was decreased to 69 ± 3% of control (769 ± 100 µU · islets-1•h, n = 5, P < 0.01).

Finally, as shown in Fig. 4Go, leptin (10 ng/ml) failed to inhibit insulin release in response to 16.7 mM glucose alone [321 ± 53 vs. 316 ± 55 µU/islet, n = 4, not significant (NS)], 20 mM KCl (93 ± 28 vs. 92 ± 26, n = 4, NS), or 10 mM ketoisocaproic acid (KIC) (152 ± 26 vs. 143 ± 34, n = 4, NS) in static incubations.



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  		Figure 4. Effect of leptin on insulin secretion from isolated Wistar rat islets in static incubations. Batches of 10 islets were incubated for 60 min in presence of 2.8 mM glucose, 16.7 mM glucose, 20 mM KCl, or 10 mM KIC, with or without 10 ng/ml leptin added to buffer at beginning of incubation. Data are presented as mean ± SEM of four experiments.

 
Effect of leptin on insulin secretion in islets from normal CD1 mice
To determine whether species-related differences could account for the variable effects of leptin reported in the literature, we investigated the effect of leptin on insulin secretion in islets isolated from normal mice in static incubations (Fig. 5Go). As observed in rat islets, the presence of 10 ng/ml leptin in the incubation buffer had no effect on basal nor glucose alone-induced insulin secretion. In contrast, leptin inhibited insulin secretion stimulated by 16.7 mM glucose + 0.1 mM IBMX by 31 ± 4% (382 ± 24 vs. 563 ± 52 µU/islet, n = 6, P < 0.05).



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  		Figure 5. Effect of leptin on insulin secretion from isolated CD1 mouse islets in static incubations. Batches of 10 islets were incubated for 60 min in KRBB containing 2.8 mM glucose, 16.7 mM glucose, or 16.7 mM glucose + 0.1 mM IBMX, in presence or absence of 10 ng/ml leptin added to buffer at beginning of incubation. Data are presented as mean ± SEM of six experiments. *, P < 0,05 vs. insulin secretion in absence of leptin.

 
Effect of leptin on insulin secretion in islets from Zucker rats
To verify the specificity of the inhibitory effect of leptin, islets isolated from obese fa/fa and lean Fa/fa Zucker rats were incubated in the presence or absence of 10 ng/ml leptin. Glucose + IBMX-induced insulin secretion in the presence of leptin was 70 ± 19% of control in islets from Zucker Fa/fa rats (P < 0.01, n = 4, Table 1Go), an effect of similar magnitude of that observed in Wistar rats. In contrast, no effect of leptin was observed in islets isolated from Zucker fa/fa rats (NS, n = 4, Table 1Go).


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  		Table 1. Effect of leptin on glucose-induced insulin secretion in islets of lean (Fa/fa) or obese (fa/fa) Zucker rats

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study was designed to investigate a direct effect of leptin on insulin secretion in islets of Langerhans isolated from normal rodents. We demonstrate that acute exposure of both rat and mouse islets to concentrations of leptin within the physiological range (10 ng/ml) does not alter basal insulin secretion nor insulin secretion stimulated by glucose alone. These data are in agreement with the observations of Leclercq-Meyer et al. (23) and Leclercq-Meyer and Malaisse (24). In contrast, an inhibitory effect of leptin was reported in islets from ob/ob mice (22, 28). This could first be due to the higher concentrations of leptin used in these studies. Alternatively, a different mechanism of regulation of insulin secretion by leptin could occur in the mutant vs. normal mice. Kieffer et al. (22) showed that the effect of leptin in islets from ob/ob mice is mediated through activation of the ATP-sensitive potassium channel of the ß-cell. Our data, showing no effect of leptin on insulin secretion stimulated by glucose or KIC, do not support this mechanism of action in normal rodents, although we cannot exclude that KIC acts through a K-ATP channel-independent pathway (35), or that the inhibitory effect of leptin is overpowered by this nonglucose secretagogue. We show that leptin specifically inhibits glucose + IBMX-stimulated insulin release. Given the well-known effect of IBMX, which inhibits islet phoshodiesterases, our observations suggest that the hormone decreases either the intracellular levels of cAMP or its downstream effect on insulin secretion. This, together with the lack of effect of leptin on KCl-stimulated secretion, suggests that in normal rodents leptin does not act on the main pathway of coupling between glucose and insulin release in the ß-cell, involving activation of ATP-sensitive potassium channels, membrane depolarization, and calcium entry through voltage-sensitive calcium channels. Rather, we hypothesize that leptin decreases either the intracellular levels of cAMP or its potentiating effect on this pathway. Further studies are required to identify the molecular mechanisms of leptin action. The lack of effect of leptin in islets from fa/fa rats supports the hypothesis that functional OB-Rs are required.

Our results indicate that OB-Ra and OB-Rb mRNAs are expressed in isolated rat islets, in agreement with previous observations (22, 23). In addition, we demonstrate for the first time that pancreatic rat islets also express OB-Rf mRNA. However, the relative levels of expression of the three isoforms of OB-R were not measured in the present study. Which isoform of OB-R mediates leptin effects on ß-cells is presently unknown. The lack of response in islets from Zucker fa/fa does not allow for discriminating the respective roles of these three isoforms, because the fa mutation affects the extracellular domain common to all known OB-Rs (4, 5, 6). OB-Ra and OB-Rf are two isoforms with short intracellular domains, whereas OB-Rb is the long isoform thought to transduce leptin signal through the JAK/STAT pathway. OB-Ra is commonly thought to be devoid of a significant role in leptin signaling because it lacks the intracellular domain responsible for signal transduction by OB-Rb through the JAK/STAT pathway. However, the possibility that short isoforms of OB-R could have signal transduction capacities through different pathways cannot be excluded. Indeed, it was recently demonstrated that leptin induces the expression of early genes in Chinese hamster ovary (CHO) cells overexpressing OB-Ra (13). Furthermore, mutational analysis of the cytoplasmic domain of OB-Rb indicates that a truncated receptor is still able, although less efficient, to activate STAT 5 (36). These observations support the notion that the leptin receptors with short intracellular domains, which are expressed in rat islets, are capable of signal transduction. Finally, a modulatory effect of OB-Ra on OB-Rb function was recently demonstrated (36), suggesting that the relative expression of OB-R isoforms may be important for leptin signaling in islets.

In summary, this study uniquely demonstrates that leptin inhibits glucose-induced insulin secretion potentiated by IBMX in islets isolated from normal rodents. It is noteworthy that this was observed at concentrations in the range of circulating leptin levels. Assuming that circulating levels of leptin reflect the local concentration in the pancreas, this finding strongly suggests that our in vitro observations are physiologically relevant. Based on the results obtained in ob/ob mice islets, Kieffer et al. (22) hypothesized that leptin acts as a tonic inhibitor of basal insulin release, and that this effect can be overcome after a meal, when insulin secretion is potentiated by incretins. In contrast, our results obtained in normal animals lead us to speculate that the slight inhibitory effect of leptin on stimulated insulin secretion under conditions of increased cAMP intracellular levels may represent a brake avoiding insulin hypersecretion in response to meals. This effect would be enhanced in overweight individuals with increased plasma levels of leptin. It could therefore participate in the physiological mechanisms preventing the development of frank obesity, before the occurrence of confonding alterations, such as a putative resistance to leptin.


   Acknowledgments
 
We thank Dr. M. Chiesi for the gift of recombinant murine leptin, and Drs. M. Sharon and P. Ferré for fruitful comments.

Received September 22, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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D. K. Hagman, M. G. Latour, S. K. Chakrabarti, G. Fontes, J. Amyot, C. Tremblay, M. Semache, J. A. Lausier, V. Roskens, R. G. Mirmira, et al.
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M. G. Latour, T. Alquier, E. Oseid, C. Tremblay, T. L. Jetton, J. Luo, D. C.-H. Lin, and V. Poitout
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M. Jackerott, A. Moldrup, P. Thams, E. D. Galsgaard, J. Knudsen, Y. C. Lee, and J. H. Nielsen
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M. H. Vickers, P. D. Gluckman, A. H. Coveny, P. L. Hofman, W. S. Cutfield, A. Gertler, B. H. Breier, and M. Harris
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M. Amstalden, M.R. Garcia, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, and G.L. Williams
Central Infusion of Recombinant Ovine Leptin Normalizes Plasma Insulin and Stimulates a Novel Hypersecretion of Luteinizing Hormone after Short-Term Fasting in Mature Beef Cows
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M. Guerre-Millo, C. Rouault, P. Poulain, J. Andre, V. Poitout, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, G. Reach, and B. Staels
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S. E. Kahn
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M. J. Holness and M. C. Sugden
Dexamethasone during Late Gestation Exacerbates Peripheral Insulin Resistance and Selectively Targets Glucose-Sensitive Functions in {beta} Cell and Liver
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H. Yamashita, J. Shao, T. Ishizuka, P. J. Klepcyk, P. Muhlenkamp, L. Qiao, N. Hoggard, and J. E. Friedman
Leptin Administration Prevents Spontaneous Gestational Diabetes in Heterozygous Leprdb/+ Mice: Effects on Placental Leptin and Fetal Growth
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J. A. Cases, I. Gabriely, X. H. Ma, X. M. Yang, T. Michaeli, N. Fleischer, L. Rossetti, and N. Barzilai
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G. A. Brockmann, J. Kratzsch, C. S. Haley, U. Renne, M. Schwerin, and S. Karle
Single QTL Effects, Epistasis, and Pleiotropy Account for Two-thirds of the Phenotypic F2 Variance of Growth and Obesity in DU6i x DBA/2 Mice
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res.</