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Increased Pancreatic Islet Blood Flow in 48-Hour Glucose-Infused Rats: Involvement of Central and Autonomic Nervous Systems¹

Laboratoire de Physiopathologie de la Nutrition, CNRS URA 307, Université Paris VII (N.A., M.-C.L., J.-M.N., A.K., L.P.), Paris; and Laboratoire de Neurobiologie, Plasticité Tissulaire et Métabolisme Energétique, UPRESA 5018 Université Paul Sabatier-CNRS, IFR Louis Bugnard, CHU Rangueil (L.P.), Toulouse, France; and Laboratoire des Régulations Physiologiques, Faculté des Sciences Ibn Tofail (N.A., N.M.), Kenitra, Maroc

Address all correspondence and requests for reprints: Dr. L. Pénicaud, Laboratoire de Neurobiologie, Plasticité Tissulaire et Métabolisme Energétique, UPRESA 5018 Université Paul Sabatier-CNRS, 1 avenue Jean Poulhés 31054 Toulouse Cedex, France. E-mail: penicaud{at}rangueil.inserm.fr

	Abstract

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The pancreatic islet blood flow of rats 24 h after a prolonged (48-h) glucose infusion was investigated using a nonradioactive microsphere technique. In the basal state, islet blood flow was significantly increased in previously hyperglycemic rats (HG) compared to that in controls (C). During an iv glucose challenge, both plasma insulin and islet blood flow were increased in the two groups, but these increases were significantly higher in HG than in C rats. Although less pronounced, the results were similar when glucose was injected into the carotid artery toward the brain at a dose that did not modify the peripheral glucose level. The effect of this intracarotid injection was abolished after bilateral subdiaphragmatic vagotomy in both C and HG rats. Furthermore, in the latter group, both plasma insulin concentration and islet blood flow returned to values similar to those observed in the basal state in C rats. After pretreatment with the ₂-adrenoceptor agonist clonidine, the insulin response to the intracarotid glucose load was totally blunted in the two groups of rats. By contrast, whereas such a pretreatment lowered the glucose-induced increase in islet blood flow in C rats, it was without effect in HG rats. These data suggest that a period of hyperglycemia and/or hyperinsulinemia is sufficient to induce a perturbation of pancreatic islet blood flow, which appears to be mainly due to an increased parasympathetic activity, whereas the decrease in sympathetic tone does not play a role. These modifications in autonomic nervous system activity could be due to alterations in some brain areas involved in "glucose sensing."

	Introduction

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FACTORS OF neural origin play an important role in the control of insulin secretion (1, 2). We have previously shown that the autonomic nervous system is involved in the in vivo memory of pancreatic ß-cells to glucose in rats (3). Indeed, chronic hyperglycemia induced by a 48-h glucose infusion induced decreased sympathetic and increased parasympathetic activity, which resulted in the generation of enhanced ß-cell responsiveness to glucose in vivo (3).

On the other hand, although a direct effect of islet blood flow on insulin secretion has not yet been clearly demonstrated, islet blood flow could be involved in the control of plasma insulin kinetics by modulating the amount of nutrients reaching the islets and/or the dispersion of insulin into the blood (4, 5). Indeed, numerous studies have demonstrated that, in normal rats, glucose increased both plasma insulin levels and islet blood flow (5, 6). This effect of glucose appears to be mediated via the central and autonomic nervous systems (4, 7). This idea has been reinforced by data obtained in the obese Zucker rat (5, 8), in which high parasympathetic and low sympathetic tones were paralleled by increased islet blood flow and hyperinsulinemia (9, 10, 11).

We postulated that one of the mechanisms by which the autonomic nervous system could influence insulin secretion in rats submitted to a 48-h glucose infusion could be the alteration of islet blood flow.

The aim of the present work was thus to determine 1) whether islet blood flow was modified in hyperglycemic rats either under basal conditions or after an iv glucose load, and 2) the extent to which the possible changes in islet blood flow were under the influence of the modifications of the nervous system activity previously described in these rats.

	Materials and Methods

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Animals
Eleven- to 12-week-old Wistar female rats (220–240 g) were used. They were housed in cages in an animal quarter in which the temperature was maintained at 22 ± 1 C with lights on from 0700–1900 h. They had free access to water and laboratory chow pellets (UAR, Villemoisson, France; 53% carbohydrates, 5% lipids, and 22% proteins). The technique for long term infusion in unrestrained rats was used as previously described (12). The infusion period started on day 2 after surgery and lasted 2 days. Hypertonic glucose (30%; Chaix & Du Marais, Paris, France) was infused at the initial infusion rate of 50 µl/min to produce hyperglycemia of 20–25 mmol/liter. Plasma glucose was measured in arteriovenous blood collected from the tail vessels five or six times daily using a glucose analyzer (Beckman Instruments, Palo Alto, CA). The glucose infusion rate was modulated throughout the infusion period to maintain glycemia in the desired range. When glycemia was not maintained within the limits mentioned above, the rat was discarded. Control rats were infused with a glucose-free solution.

Blood flow measurements
Blood flow measurements were performed 24 h after the end of glucose infusion. Rats were anesthetized with sodium pentobarbital (50 mg/kg, ip) and heparinized with an iv injection of 200 IU heparin (Roche, Neuilly, France). This time was chosen after preliminary experiments showed that 1) determination of the number of microspheres was not easy 3 h after the end of glucose infusion due to the edematous aspect of the pancreas; and 2) the insulin secretory response to glucose was identically increased in HG rats both 3 and 24 h after the end of glucose infusion (13).

Polyethylene catheters were placed into the lower abdominal aorta to measure arterial blood pressure and into the left ventricle of the heart via the right carotid artery for blood sampling. Body temperature was recorded by a rectal thermistor probe. Mean arterial blood pressure was monitored by a pressure transducer connected to the arterial catheter.

Blood flow measurements were performed as described previously according to the method of Jansson et al. (7, 8, 14, 15). Briefly, 1–1.5 x 10⁵ nonradioactive microspheres (New England Nuclear Corp., Boston, MA) with a diameter of 10 µm were injected via the intracardiac catheter. Simultaneously, an arterial blood sample was withdrawn from the catheter in the abdominal aorta with a peristaltic pump adjusted to a rate of 0.6 ml/min for 90 sec. This reference sample was used to calculate the organ blood flow as described below. Then, immediately after the reference sample, 500 µl blood were quickly sampled and centrifuged, and the plasma was frozen until subsequent determinations of plasma glucose and insulin concentrations.

The rats were killed by cervical dislocation, and the pancreas and both adrenal glands were removed, blotted, and weighed. The organs and the reference sample were further processed and examined for microsphere content, as previously described. Briefly the pancreas and the adrenal glands were treated with a freeze-thawing technique that fragilizes the exocrine tissue and allows vizualization and counting of the microspheres separately in the islets and the exocrine parenchyma (6, 14, 15). The number of microspheres in the reference samples was determined by transferring the sample to glass microfiber filters and counting them in transmitted light.

Blood flow was calculated according to the following formula: Qorg = (Norg x Qref)/Nref, where Qorg is the organ blood flow (milliliters per min), Qref is the withdrawal rate of the reference sample (milliliters per min), Nref is the number of microspheres in the reference sample, and Norg is the number of microspheres in the organ.

The microsphere content of the adrenal gland was used as a measure of the mixing of microspheres with blood. A difference of more than 10% between the two adrenal glands excluded the animal from the study. Likewise, blood pressure and body temperature were continuously monitored, and variations in blood pressure or body temperature exceeding 10% and 0.5 C, respectively, led to exclusion of the animal.

In a set of experiments, rats were injected with glucose (375 mg/kg; 0.5 ml) via the left saphenous vein 5 min before blood flow measurement.

In another series of experiments, glucose (9 mg/kg; 100 µl/30 sec) was infused into the carotid artery in a cranial direction 30 sec before blood flow determination. Some of these rats had been injected with clonidine (12.5 µg/kg), an ₂-adrenergic agonist, 15 min previously. Other rats had been vagotomized 30 min previously. Briefly, a laparotomy was performed, and the two branches of the vagus along the esophagus were cut just under the diaphragm.

Plasma glucose and insulin concentrations were determined using a glucose analyzer (Glucose Analyzer 2, Beckman, Fullerton, CA) and a RIA kit (INSIK 1, CEA, Saclay, France), respectively, and were expressed as picomoles per liter and millimoles per liter, respectively.

Results are expressed as the mean ± SEM. Statistical significance of differences between means were evaluated using the Mann-Whitney U test.

	Results

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Effect of glucose injected in systemic blood
Plasma glucose was significantly lower (P < 0.001) in previously hyperglycemic rats (HG; 4.8 ± 0.3 mmol/liter) than in controls (C; 6.3 ± 0.2 mmol/liter), whereas plasma insulin was similar in the two groups (162 ± 30 and 168 ± 36 pmol/liter, respectively). Pancreatic blood flow was not significantly different in the two groups (Table 1), whereas islet blood flow, expressed as an absolute value as well as a percentage of pancreatic blood flow, was significantly increased in HG rats (Fig. 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Plasma insulin (picomoles per liter)/plasma glucose (millimoles per liter) concentrations and islet blood flow expressed as absolute value or as a percentage of pancreatic blood flow in C and HG rats under basal conditions (open columns) or after an iv glucose load (closed columns). Data are the mean ± SEM of five to eight determinations. Difference statistically significant between control and HG rats: , P < 0.05; , P < 0.01; , P < 0.001; between basal and stimulated conditions: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Effect of a glucose injection toward the brain
The injection toward the brain of a dose of 9 mg/kg glucose via the carotid artery did not significantly alter the plasma glucose concentration in C (6.3 ± 0.2 vs. 6.3 ± 0.1 mmol/liter) and HG (4.8 ± 0.2 vs. 5.1 ± 0.3 mmol/liter) rats. Insulin secretion was increased in both groups, but this increase was larger in HG than in C rats (Fig. 2). Pancreatic blood flow was not significantly affected, although a slight tendency toward an increase was present in C rats (Table 1). In these rats, islet blood flow was significantly increased compared to that in the basal state, whereas this was not the case in HG rats (Fig. 2). However, when expressed as a percentage of the pancreatic blood flow, islet blood flow was increased in the two groups of rats; this increase was larger in HG than in C rats (Fig. 2).

View larger version (22K): [in this window] [in a new window]   Figure 2. Plasma insulin (picomoles per liter)/plasma glucose (millimoles per liter) concentrations and islet blood flow expressed as absolute value or as a percentage of pancreatic blood flow in C or HG rats under basal conditions (open columns) or after an intraarterial glucose load alone (closed columns) or in combination with subdiaphragmatic vagotomy (gray columns) or clonidine pretreatment (hatched columns). Data are the mean ± SEM of 5–11 determinations. Difference statistically significant between C and HG rats: , P < 0.05; , P < 0.001; between basal and experimental conditions: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Effect of clonidine pretreatment
Compared to the basal state or after the injection of glucose, the insulin response to a glucose load was totally blunted by pretreatment with clonidine (Fig. 2).

However, whereas pancreatic blood flow was not significantly altered in HG rats, it was significantly decreased by clonidine in C rats (Table 1). This could be due to the slight increase observed under basal conditions in these rats (Table 1). In contrast, islet blood flow expressed as an absolute value or as a percentage of pancreatic blood flow returned to the basal value in C rats after clonidine injection. In HG rats, islet blood flow was not affected by treatment with the ₂-adrenoceptor agonist (Fig. 2).

	Discussion

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We have previously demonstrated that normal rats subjected to a 48-h hyperglycemia had higher basal and glucose-induced insulin secretion (13, 16, 17). One of the first aims of the present work was to investigate whether this was concomitant with an alteration in islet blood flow. Indeed, it has been repeatedly shown that glucose has a stimulatory effect on the blood perfusion of the pancreatic islets when given acutely (4, 7, 8, 9, 18). The present study demonstrates that this effect is also present 24 h after a 48-h glucose infusion. This is in agreement with the study of Styrud et al. (19). However, in opposition, the increase in islet blood flow paralleled an enhanced plasma insulin concentration. This discrepancy could be due to the different design used for glucose infusion. Thus, whereas the glucose infusion rate was continuously monitored in our study to maintain steady hyperglycemia during 48 h, in the study of Styrud et al., the glucose infusion rate was kept constant, and consequently, both plasma glucose and insulin decreased throughout the infusion period (19). The present results are unlikely to reflect a period of counterregulation, since we demonstrated previously that neither the plasma glucagon level nor glucagon messenger RNA was affected in the period following the end of glucose infusion (20). Furthermore, the data are, with regard to islet blood flow, identical to those reported by Styrud et al. that were obtained during a period of normoglycemia (19).

Our study shows that in response to an iv glucose load performed 24 h after the end of glucose infusion, islet blood flow was much higher in HG rats than in controls. Once again, this was concomitant with a higher glucose-induced insulin secretion. All of these data match the situation described in other models of hyperinsulinemia. Indeed, increased islet blood flow and increased plasma insulin level were observed in the basal state or after an iv glucose load in both genetic (Zucker fa/fa rat) or experimentally induced (Wistar rat after lesion of the ventromedial hypothalamus) obesity (5). Such an increase is also present in the basal state in the GK rat (18), a genetic model of type II diabetes showing postabsorptive hyperinsulinemia (21, 22).

It has been suggested that in normal rats, a change in islet blood flow after an acute glucose load could be mediated by a direct effect of the molecule on brain areas controlling the vagal cholinergic system (5, 7). Our data fit this hypothesis. Thus, glucose injection toward the brain, in an amount not sufficient to modify the systemic plasma glucose level, induced a rapid and transient increase in islet blood flow as well as in plasma insulin. This increase is much more marked in HG than in control rats. This is reminiscent of what was found in obese hyperinsulinemic fa/fa rats, in which the higher increase, compared to that in controls, in islet blood flow induced by glucose was also due at least in part to a direct effect of glucose on the brain (5, 8). Parasympathetic and sympathetic nervous systems were involved in the mediation of this effect (8). In the present study the role of the parasympathetic system was evaluated by performing a bilateral subdiaphragmatic vagotomy that abolished the effect of the glucose load on islet blood flow in both C and HG rats. The level of plasma insulin and islet blood flow in HG rats returned to that observed in C rats before glucose injection. This suggests that the effect of an acute glucose load as well as the effect of a chronic 48-h hyperglycemia are mainly mediated by the vagus nerve. This conclusion is strengthened by previous data showing that in glucose-infused rats, hyperglycemia induces increased parasympathetic activity (3), which participates in the enhanced insulinemia and islet blood flow, as previously demonstrated in obese animals (5, 8).

To investigate the possible sympathetic involvement, we used the ₂-adrenergic agonist clonidine. This compound produced a significant decrease in the plasma insulin concentration and in both pancreatic and islet blood flow in control rats. This is in agreement with data obtained in lean Zucker rats (8) and confirms the influence of the sympathetic nervous system in the regulation of insulin secretion and islet blood flow (5, 8, 23, 24, 25). In contrast, in HG rats, although plasma insulin returned to the basal concentration, islet blood flow was not affected by clonidine. However, its level remained very high compared to that in C rats. These data could be interpreted as follow. The 48-h hyperglycemia leads to a desensitization of the regulatory system, which participates, via the sympathetic nerves, in the control of islet blood flow, but not to that influencing insulin secretion. The dissociation of the effects of clonidine on blood flow and insulin secretion is not totally surprising because clonidine has been shown to have a direct inhibitory effect on insulin secretion in vitro (26, 27).

The association between insulin secretion and islet blood flow is controversial. Under conditions such as after starvation, a low protein diet, partial pancreatectomy, or islet grafts, the two parameters appeared to evolve independently (28, 29, 30, 31). On the contrary, in obese hyperinsulinemic rats, insulin secretion and islet blood flow seemed to be closely associated (5, 8, 11). In our own study, some data argue for an interplay between islet blood flow and insulin release. First, both were persistently increased in HG rats, at least 24 h after the end of glucose infusion. Second, there was a clear stimulation of insulin secretion and an increase in islet blood flow in response to the injection of glucose toward the brain, which were suppressed by vagotomy. However, the fact that insulin release evoked by glucose injection was free of the influence of the sympathetic nervous system, in contrast to islet blood flow, suggests that the brain areas involved in the regulation of islet blood flow and insulin secretion via the sympathetic nervous system are not exactly the same.

However, the data indicate that a 48-h hyperglycemia and/or hyperinsulinemia are sufficient to induce a perturbation in the brain areas involved in "glucose sensing" (32, 33) and, as a consequence, modify insulin secretion and islet blood flow in response to an additional acute glucose load. A change in glucose sensing, reflected in an alteration in glucose utilization in some brain areas, was also observed in conditions associated with hyperglycemia and/or hyperinsulinemia (34, 35, 36, 37).

In summary, this study demonstrates that the high islet blood flow observed in rats infused for 48 h with glucose is mainly due to the increase in parasympathetic activity, whereas the decrease in sympathetic tone does not seem to play a role. The increased parasympathetic tone is probably mediated by a direct effect of glucose on some specific brain areas.

	Footnotes

 
¹ This work was supported by a grant from INSERM (no. 920306).

Received October 22, 1996.

	References

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