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Endocrinology Vol. 138, No. 2 751-755
Copyright © 1997 by The Endocrine Society

Articles

Two Signaling Pathways, from the Upper Glycolytic Flux and from the Mitochondria, Converge to Potentiate Insulin Release1

Nahoko Asanuma, Toru Aizawa, Yoshihiko Sato, Thomas Schermerhorn, Mitsuhisa Komatsu, Geoffrey W. G. Sharp and Kiyoshi Hashizume

Department of Geriatrics, Endocrinology and Metabolism (N.A., T.A., Y.S., K.H.), Shinshu University School of Medicine, Matsumoto, Nagano-ken, Japan, and Department of Pharmacology (T.S., M.K., G.W.G.S.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401

Address all correspondence and requests for reprints to: Toru Aizawa, M.D., Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, 3–1-1 Asahi, Matsumoto, Nagano-ken, Japan 390.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In the rat pancreatic ß cell, low concentrations of glucose potentiate D-glyceraldehyde (GA)-induced insulin release without any potentiation of the triose-induced elevation of cytosolic free Ca2+ concentration. Namely, 2–3 mM glucose strongly potentiates 5 mM GA-induced insulin release, and the combination of stimulatory concentration of glucose (10 mM) and 5 mM GA elicits far more than additive insulin release: this glucose action is independent of ATP-sensitive K+ channel closure because it can be seen in the presence of diazoxide, an opener of the K+ channel. The triose-induced elevation of cytosolic free Ca2+ concentration was not potentiated by the presence of 3 mM glucose, and oxidation of labeled GA by the islet cells was not enhanced by the presence of glucose. The glucose action can be mimicked by mannose, but not by galactose, and was suppressed by inhibition of glucose phosphorylation with mannoheptulose or 2-deoxyglucose. Glucose also potentiates 2-ketoisocaproate-induced insulin release. In contrast, a combination of GA and 2-ketoisocaproate elicits only additive insulin release. Strikingly, 3 mM glucose does not potentiate insulin release in response to a depolarizing concentration of K+. Therefore, at least two signal pathways, one from upper glycolytic flux and one from mitochondrial metabolism, must converge to provide the potentiation of insulin release. We conclude that the upper glycolytic flux, acting at a site unrelated to the elevation of cytosolic free Ca2+, potentiates insulin release triggered by triose and mitochondrial fuels.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
AN INCREASE in ATP or the ATP/ADP ratio caused by glucose metabolism is regarded as a determinant for glucose stimulation of insulin exocytosis in the ß cell (1). The idea is supported, in part, by the fact that mitochondrial fuels, such as 2-ketoisocaproate (KIC), which bypass the glycolytic pathway, stimulate insulin release in the absence of glucose (2, 3, 4, 5, 6). Accordingly, glycolysis is considered to be funneling sugars to the lower metabolic pathway and not generating metabolic signals for the stimulation of insulin release. However, in an earlier study, the islet ATP content and insulin release did not correlate when mouse islets were stimulated with a combination of glucose and D-glyceraldehyde (GA) or of glucose and the mitochondrial fuel, leucine (7), indicating that the rate of insulin release is not determined simply by that of ATP generation. We report now that glucose amplifies insulin release triggered by GA without any potentiation of GA-induced elevation of Ca2+. The finding provides evidence for a unique functional role of the upper glycolytic flux in the pancreatic ß cell.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Pancreatic islets were obtained from male Wistar rats by collagenase dispersion (8), and insulin release was measured in static incubation and perifusion experiments using Krebs-Ringer bicarbonate buffer (KRBB) containing 0.5% BSA (equilibrated with 5% CO2-95% O2, pH 7.4), as described (9, 10, 11, 12, 13). In static incubation experiments, 5 size-matched islets/tube were incubated with various secretagogues for 30 min: preincubation was with 3 mM glucose for 30 min. When inhibitors were used, they were present during the preincubation and the experimental incubation. In perifusion, 50 islets from a single batch were placed into several columns and all columns were perifused in parallel simultaneously (10). After a 30-min perifusion with 3 mM glucose, test substances were introduced. Insulin was determined by RIA, as described (9, 10, 11, 12, 13).

Because measurement of cytosolic free Ca2+ concentration ([Ca2+]i) was performed (see below) in modified KRBB with HEPES (14) using isolated ß cells, insulin release also was determined under the same condition. For this purpose, approximately 600 freshly isolated islets were dissociated in 200 µl glucose free, Ca2+-omitted KRBB: the islets were gently aspirated and expelled using a 100 µl pipettor for 30–40 times. Immediately thereafter, the cells were resuspended in 500 µl RPMI 1640 (Sigma, St. Louis, MO) supplemented with 10% FBS (Flow Laboratories, North Ryde, New South Wales, Australia) and aliquotted into 14–16 tubes. By this procedure, approximately 2–3 x 104 cells/tube were obtained. Then, the cells were incubated in the RPMI media (1 ml) at 37 C with 5% CO2 for 24 h. For the measurement of insulin release, both preincubation and experimental incubation were carried out, as in the experiments with the islets (see above) using modified KRBB containing 10 mM HEPES and 5 mM NaHCO3.

Oxidation of D-[U-14C]glyceraldehyde (specific activity 55 mCi/mmol, American Radiolabeled Chemicals, St. Louis, MO) was determined, as described (15) using 0.8 µCi/tube: concentration of total (radioactive and nonradioactive, combined) GA was 0.5 mM. Because of the relatively low specific activity of the labeled GA, it was necessary to use a low concentration of total GA in this experiment.

[Ca2+]i was measured using isolated ß cells, as described above (14) using Indo-1 (Molecular Probes, Eugene, OR). The cells were preincubated with 3 mM glucose for 30 min, washed, placed in zero glucose, and then stimulated with 5 mM GA alone or 3 mM glucose and 5 mM GA: determination of [Ca2+]i was carried out for 30 min to critically compare the temporal profiles of insulin secretion and [Ca2+]i. [Ca2+]i was calculated from a standard curve generated from known concentrations of free calcium in KRBB at 37 C using a commercial calibration kit (Molecular Probes).

GA was obtained from Aldrich (Milwaukee, WI); KIC, diazoxide, mannoheptulose, and 2-deoxyglucose from Sigma; and dihydroxyacetone (DHA) from Nacalai Tesque (Kyoto, Japan). Purity of GA, KIC, and DHA was higher than 98%. Statistical analysis was performed by one-way ANOVA with Fisher’s protected least-significant difference test and Wilcoxon’s ranked-sum test. P < 0.05 was considered significant. Data are expressed as means ± SE.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Insulin release induced by 5 mM GA or 12 mM KIC was potentiated by the presence of 3 mM glucose, and the glucose potentiation was selective for the late phase for both GA and KIC (Fig. 1Go). A marked potentiation of the late phase of GA-induced insulin release by glucose was seen also with 3.7 mM GA plus 3 mM glucose, despite the fact that 3.7 mM GA alone caused only marginal insulin release (Fig. 2Go). Glucose potentiation of GA- and KIC-induced insulin release was unequivocally demonstrated with various combinations of glucose and GA or KIC in incubation experiments, as well, and such glucose action was seen at a concentration as low as 2 mM (Table 1Go). In stark contrast, a combination of KIC and GA caused only additive insulin release (Table 1Go). A combination of 5 mM GA and 3 mM glucose elicited significantly greater insulin release than either of the two alone in dispersed islet cells (Table 2Go). However, in the isolated islet cells, the response to 5 mM GA alone was not demonstrable, and the release caused by a combination of the fuels was not significantly greater than the sum of the release by the two agents alone (Table 2Go).



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  		Figure 1. Potentiation of GA (A)- and KIC (B)-induced insulin release by 3 mM glucose. N = 3 for each condition in both figures. The islets were perifused with 3 mM glucose for 30 min. At time 0, the perifusate was changed to 5 mM GA alone (open circles) or 5 mM GA plus 3 mM glucose (closed circles) in Fig. 1AGo. In Fig. 1BGo, the perifusate was changed to 12 mM KIC alone (open circles) or 12 mM KIC plus 3 mM glucose (closed circles). In some experiments, like GA plus glucose in Fig. 1AGo, SE was smaller than the size of the symbol. The conversion factor for immunoreactive insulin to SI units is 0.174 (pg/islet->fmol/islet).

 


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  		Figure 2. Potentiation of GA (3.7 mM)-induced insulin release by 3 mM glucose. N = 3 for each condition in both figures. Exactly the same experiment as in Fig. 1AGo was repeated, except that concentration of GA is 3.7 mM here. See the legend to Fig. 1Go for other details.

 

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  		Table 1. Insulin release by the islets in response to various combinations of fuels and effects of metabolic inhibition

 

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  		Table 2. Insulin release by the isolated islet cells

 
On the other hand, insulin release in response to nonnutrient stimuli, e.g. depolarization by a high concentration of K+, was the same in the presence and absence of 3 mM glucose (Table 3Go). Potentiation of GA-induced insulin release by 3 mM glucose was completely suppressed by inhibition of glucokinase and hexokinase with mannoheptulose (16) and 2-deoxyglucose (17), respectively (Table 1Go). On the other hand, such glucose action was resistant to treatment with 150 µM diazoxide (Table 3Go), an ATP-sensitive K+ (K+ATP) channel activator (18). Oxidation of [U-14C]GA by the islet cells was not significantly different in the presence and absence of 3 mM glucose: GA converted to CO2, 77.8 ± 11.5 and 77.6 ± 4.8 pmoles/20 islets for 60 min, in the presence and absence of glucose, respectively (n = 5 for each condition).


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  		Table 3. Insulin release by the islets in response to various combinations of fuels in the presence of depolarizing concentration of K+

 
Mannose (10 mM) and DHA (up to 20 mM) did not elicit insulin release by themselves. The inability of mannose to significantly stimulate insulin release at this concentration (3) is explained by the fact that mannose is inefficiently metabolized compared with glucose: the apparent Km of the islet glucokinase is 23.7 and 11.3 mM for mannose and glucose, respectively (3). Nevertheless, GA- and KIC-induced insulin release was potentiated by mannose and DHA (Table 1Go). In contrast, galactose, a nonmetabolizable sugar in the ß cell (2, 3), failed to potentiate GA-induced insulin release (data not shown).

GA-induced elevation of [Ca2+]i was both qualitatively (Fig. 3Go) and quantitatively (Table 4Go) unaffected by the presence of 3 mM glucose.



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  		Figure 3. Change in [Ca2+]i upon stimulation with 5 mM GA alone (A), and 5 mM GA and 3 mM glucose (B). After measurement of basal [Ca2+]i for 600 sec, the cells were exposed to the test substances. A representative of five tracings for each condition is shown. Similar results were obtained in cells isolated from four different batches of islets.

 

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  		Table 4. [Ca2+]i upon stimulation with 5 mM GA in the absence and presence of 3 mM glucose

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we showed that glucose potentiates insulin release triggered by nonhexose nutrients, such as GA and KIC. The data obtained with gluco- and hexokinase inhibitors, depolarizing concentrations of K+, and metabolizable and nonmetabolizable sugars lead us to conclude that metabolic signal(s) generated in the upper glycolytic flux, i.e. before the trioses, are potentiating insulin release triggered by the lower metabolic signal, most likely ATP. Potentiation of GA-induced insulin release by glucose cannot be caused simply by generation of ATP from glucose metabolism because addition of a suprathreshold concentration (12 mM) of KIC with GA does not potentiate GA-induced insulin release. Instead, a combination of KIC and GA elicits only additive insulin release. In an earlier study with mouse islets, addition of 5 mM glucose with GA or leucine, a precursor of KIC, did not further increase islet ATP content (7). Nevertheless, insulin release was potentiated dramatically by the addition of glucose (7), a finding that is in good agreement with the current data. It has been reported that addition of GA does not accelerate glucose metabolism by the islet cells (19).

Two molecules of trioses are generated from one glucose molecule; therefore, 3 mM glucose is metabolically equipotent to 6 mM GA. However, the insulinotropic action of GA is much greater than glucose when the two are compared at the metabolically equipotent concentrations (3). For example, 6 mM GA, but not 3 mM glucose, significantly stimulate insulin release by the islets. Accordingly, we did not perform a simple comparison of metabolically equivalent GA and glucose. Instead, we tested a combination of various concentrations of glucose and GA, as shown, and found that glucose at concentrations higher than 2 mM strongly potentiates GA-induced insulin release at all concentrations of GA tested.

The purity of GA used here was confirmed to be higher than 98%, which is most likely purer than that used in the earlier studies. With this level of purity, effects of contaminants of GA, if any, would be practically negligible. Using this preparation, we observed no suppression of insulin release up to 15 mM, and 5 mM GA alone always produces only a small increment in insulin release, as shown in Fig. 1Go and Table 1Go. Because, in previous studies, the effect of GA was usually evaluated in the presence of 3 or 5 mM glucose, it is likely that the insulinotropic effect of GA was already potentiated by glucose, and the potentiation effect unnoticed.

Glucose potentiation of GA-induced insulin release is demonstrable at a glucose concentration as low as 2 mM. Furthermore, it is independent of membrane potential changes because it can be seen in ß cells clamped with high concentrations of K+ and diazoxide, a K+ATP channel opener (18). From such observations, it can be deduced that this is not a potentiation of Ca2+-induced exocytosis or of the [Ca2+]i response itself. To directly verify the idea, [Ca2+]i was measured using isolated islet cells. As we expected, GA-induced elevation of [Ca2+]i was not potentiated by the presence of 3 mM glucose. However, insulin release induced by a combination of 3 mM glucose and 5 mM GA was not significantly greater than the sum of the release by the two agents alone in the isolated islet cells. Therefore, the data on [Ca2+]i should be interpreted with reserve. Direct enhancement of GA metabolism by glucose was ruled out because addition of 3 mM glucose does not significantly increase oxidation of GA.

To explore the mechanism of this newly found glucose action, effects of DHA, which is phosphorylated and enters the glycolytic pathway as DHA phosphate (DHAP), were evaluated. DHA also potentiated GA- and KIC-induced insulin release: the weak effect of DHA on GA-induced insulin release could be caused by the fact that DHA, having a higher affinity for triokinase than GA, may interfere with GA metabolism in the ß cell. Although activation of the glycerol-phosphate shuttle (2, 3) might be responsible for the glucose action described here, replenishment of cytosolic NAD through the glycerol-phosphate shuttle is not likely to be responsible for glucose potentiation of GA-induced insulin release because addition of nicotinamide, which increases cellular NAD (20), caused minimal effect on GA-induced insulin release (data not shown). The other signal arising from DHAP, activation of protein kinase C via conversion of DHAP to diacylglycerol (21), may be a mediator of the glucose action described here because glutamine, which provides the glycerol-3-phosphate backbone for DAG production, strongly potentiates leucine-induced insulin release, as does glucose (22). Phospholipase C is not involved in the glucose action described here because the addition of a low concentration of glucose with a stimulatory concentration of KIC does not further increase phosphoinositide hydrolysis by the islets (23).

Although the glucose-induced rise in ß cell [Ca2+]i is important for its insulinotropic action (24), glucose augmentation of insulin release occurs without any additional increase in [Ca2+]i (5, 25, 26). Augmentation can occur even without any increase in [Ca2+]i (14). Glucose potentiation of insulin release without an additional elevation in [Ca2+]i is unequivocally demonstrated in the present study, as well. The action of glucose described here is distinct from the previously described K+ATP channel-independent glucose actions (5, 10, 12, 13) in the following aspects: 1) this is not a direct potentiation of Ca2+-evoked insulin exocytosis; 2) the potentiation is demonstrable at a glucose concentration as low as 2 mM; and 3) it is dependent upon the nutrients, GA and KIC.

In summary, at least two signals derived from the upper glycolytic pathway of glucose metabolism and from the mitochondria must converge to cause the potentiation of insulin release. They do this by an effect on stimulation-secretion coupling or by supplying substrates in the correct balance to the lower glycolytic pathway, so as to fully activate fuel-responsive effectors for insulin exocytosis. When the ß cell is stimulated with graded concentrations of glucose, the increase in insulin release is greater than the increase in glucose metabolism, as evidenced by a much greater Hill constant for the former than the latter (3). The reason for this apparent discrepancy has been unknown. Now, however, it can, at least in part, be attributed to the potentiation of insulin release by glucose, as shown here.


   Acknowledgments
 
The authors thank Dr. H. Ishida for constructive discussion.


   Footnotes
 
1 This work was supported by a grant-in-aid for scientific research from the Ministry of Education Science and Culture, Japan (to T.A.), and by NIH Grant RO1-DK-42063 (to G.W.G.S). Back

Received June 28, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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