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Biology of Reproduction 62, 1256-1261 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Article

Central Action of Insulin Regulates Pulsatile Luteinizing Hormone Secretion in the Diabetic Sheep Model1

Tomomi Tanakaa, Shoji Nagatanib, David C. Bucholtzb,e, Satoshi Ohkurac, Hiroko Tsukamurad, Kei-Ichiro Maedad, and Douglas L. Foster2,,b,f,g

a Laboratory of Veterinary Reproduction, Tokyo University of Agriculture and Technology, Tokyo, Japan b Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109-0404 c Primate Research Institute, Kyoto University, Inuyama, Japan d Laboratory of Animal Reproduction, Nagoya University, Nagoya, Japan e Departments of Physiology, f Obstetrics & Gynecology, g and Biology, University of Michigan, Ann Arbor, Michigan 48109-0404


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study tested the hypothesis that central mechanisms regulating luteinizing hormone (LH) secretion are responsive to insulin. Our approach was to infuse insulin into the lateral ventricle of six streptozotocin-induced diabetic sheep in an amount that is normally present in the CSF when LH secretion is maintained by peripheral insulin administration. In the first experiment, we monitored cerebrospinal fluid (CSF) insulin concentrations every 3–5 h in four diabetic sheep given insulin by peripheral injection (30 IU). The insulin concentration in the CSF was increased after insulin injection, and there was a positive relationship between CSF and plasma concentrations of insulin (r = 0.80, P < 0.01). In the second experiment, peripheral insulin administration was discontinued, and the sheep received either an intracerebroventricular (i.c.v.) infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5 days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated to approximate the increase in CSF insulin concentration found after peripheral insulin treatment. To monitor LH secretory patterns, blood samples were collected by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days after the start of i.c.v. insulin infusion. To monitor the increase in CSF insulin concentrations, a single CSF sample was collected one and four days after the start of the central infusion. The i.c.v. insulin infusion increased CSF insulin concentrations above those in saline-treated animals (P < 0.05) and maintained them at or above the peak levels achieved after peripheral insulin treatment. Central insulin infusion did not affect peripheral (plasma) insulin or glucose concentrations. LH pulse frequency in insulin-treated animals was greater than that in saline-treated animals (3.5 ± 0.2 vs. 2.3 ± 0.3 pulses/4 h, P < 0.01), but it was less than that during peripheral insulin treatment (4.8 ± 0.2 pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central insulin supplementation are able to increase pulsatile LH secretion in diabetic sheep with low peripheral insulin. These results are consistent with the notion that central insulin plays a role in regulating pulsatile GnRH secretion.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Level of nutrition is a key modulator of neuroendocrine mechanisms governing GnRH secretion. For example, dietary restriction slows growth, reduces peripheral glucose concentrations, and delays the onset of high frequency GnRH pulses in the lamb [1]. However, the specific metabolic signal(s) or metabolite(s) that relate information about nutritional status to mechanisms governing GnRH secretion have not yet been determined. Insulin is a likely candidate for such a metabolic signal, because several studies have found that peripheral concentrations of insulin are associated positively with an individual's nutritional state [2–5]. In our companion study [6], we have determined that peripheral insulin treatment influences LH pulse frequency when endogenous secretion of insulin is compromised. In that study using the developing diabetic sheep, pulsatile LH secretion was decreased acutely by insulin withdrawal and, likewise, restored acutely by insulin re-supplementation. Despite evidence for an association between insulin and LH secretion, such results do not uncover the site of insulin action. In this regard, several lines of investigation suggest that insulin may act directly within the central nervous system. First, entry of circulating insulin into the central nervous system has been documented in dogs [7], rats [8], and baboons [9]. Second, neurons express high concentrations of insulin receptors in brain regions known to participate in the regulation of feeding and reproduction. Third insulin has been reported to depress food intake following its central [10] and peripheral [9] administration. However, there are few studies that have addressed the role of intracerebral insulin in the regulation of GnRH secretion. Hileman et al. [11] reported that central injection of insulin (lateral cerebral ventricle) did not increase LH secretion in their model system, the growth-restricted, hypogonadotropic lamb. By contrast, Miller et al. [12] found that the infusion of insulin into the third ventricle stimulated pulsatile LH secretion in adult male sheep. Thus, the central action of insulin regulating GnRH secretion remains controversial. In the present study, we used the diabetic sheep as a model to test the hypothesis that hypoinsulinemic suppression of LH(GnRH) results from a deficiency of insulin in the brain.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

Six gonadectomized, diabetic male sheep of predominantly Suffolk breeding were studied at 1 yr of age. They were selected at random from the nine sheep used in our previous study [6], which had been made diabetic by streptozotocin. At the time of the present study, the beef/pork insulin was no longer available commercially. Therefore, in the present study, the sheep were continuously maintained on twice-daily subcutaneous (s.c.) injections (30 IU) of a long-acting human recombinant insulin (Novolin-L; Novo Nordisk Pharmaceuticals Inc., Princeton, NJ), except for brief periods of withdrawal (see Experiments, below). Human recombinant insulin was biologically active in our diabetic sheep model (minimized diabetes-induced hyperglycemia and maintained normal growth). Glycemic concentrations found after recombinant insulin treatment were comparable to those found after beef/pork insulin treatment in our diabetic sheep model (data not shown). Likewise, in comparative studies conducted in human beings [13, 14], the biopotency of recombinant insulin was similar to that of beef/pork insulin. For central infusion, a readily soluble noncrystalline form of human recombinant insulin was used (Sigma Chemical, Inc., St. Louis, MO). The animals were housed at the Reproductive Sciences Sheep Research Facility at the University of Michigan in Ann Arbor under natural lighting, and fed a diet of alfalfa hay designed to maintain body weight. Water and supplemental vitamins and minerals were provided at all times. All procedures were approved by the University Committee for the Use and Care of Animals at the University of Michigan.

Cerebroventricular Cannulation

Two cannulae, one for collecting cerebrospinal fluid (CSF) and one for the infusion of insulin, were stereotaxically implanted bilaterally into the lateral cerebral ventricles under general anesthesia. The outer guide cannula was lowered just dorsal to the roof of the lateral ventricle (to a depth at which a 21-gauge inner cannula could penetrate the lateral ventricle) and then fixed to the skull with dental acrylic and stainless steel screws. CSF samples were obtained from conscious animals by inserting an inner cannula down the guide cannula at each CSF sampling. For infusions, a 21-mm x 20-gauge stainless steel cannula was lowered until CSF could be aspirated from the lateral ventricle. At least 2 wk were allowed to elapse between surgery and the experiments.

Experiment 1: Determination of CSF insulin values after peripheral insulin treatment This experiment determined the pattern and concentration of insulin in the CSF after an s.c. insulin injection known to sustain LH pulse frequency under diabetic conditions [6]. CSF (500 µl) and blood samples (2.5 ml) were simultaneously collected from four diabetic sheep for determination of insulin concentrations at or immediately before the s.c. insulin injection, and then at 3- to 5-h intervals until 12 h after insulin injection. CSF samples were collected from the lateral ventricle as described above, and blood samples were collected by jugular venipuncture.

Experiment 2: Effect of central insulin treatment on LH secretion This experiment determined if central insulin supplementation alone could increase LH secretion under peripherally diabetic conditions. The dose and infusion rate of insulin (based on the study of Miller et al. [12]) was formulated to meet or exceed the peak CSF concentration that occurred after s.c. insulin injection in experiment 1. The sheep (n = 6) were allocated to a series of crossover infusion treatments so that each animal received each treatment. After the first treatment, the animals were maintained on twice-daily s.c. insulin injections again until the second crossover treatment (at least 2 wk later). On Day 0, peripheral insulin administration was stopped, and the animals were infused with saline (control) or insulin solution (5000 µU/ml) into the lateral ventricle at a rate of 100 µl/h for 5 days with a programmable, battery-powered, backpack infusion pump (model ASBH; Travenol Laboratories, Inc., Hooksett, NH). This central dose of insulin was only 1/5000 of the dose given systemically. The 5-day period of i.c.v. infusion was based on our previous study in which LH pulse frequency was significantly suppressed after 96 h of insulin withdrawal in diabetic sheep [6]. To determine peripheral concentrations of LH, insulin, and glucose, jugular blood samples were collected by venipuncture at 10-min intervals for 4 h on Day -1 and on Day 5; to determine insulin and glucose concentrations in the CSF, a single CSF sample was collected on Day 1 and on Day 4.

Hormone Assays

Plasma LH was measured in duplicate 50- to 200-µl aliquots of plasma using a modified RIA developed by Niswender et al. [15]. Assay sensitivity averaged 0.74 ng/ml (n = 4 assays) for 200 µl plasma expressed relative to NIH LH-S12. The intraassay coefficient of variation (CV), determined from a serum pool that bound at 50% averaged 2.5%; the interassay CV averaged 3.0%. For a serum pool that bound at 20%, the intraassay CV averaged 3.5%, and the interassay CV averaged 4.0%.

Insulin concentrations were determined by an RIA kit (ICN Pharmaceuticals, Inc., Costa Mesa, CA) validated for use in the sheep [16]. Assay sensitivity averaged 2.4 µU/ml, and intra- and interassay CV were 7.8% and 6.0%, respectively.

Glucose was quantified by the glucose oxidase method (Sigma diagnostics; Sigma). Intraassay CV was 1.4%.

Statistical Analysis

For the identification of LH pulses in the samples collected at 10-min intervals, Cluster analysis, developed by Veldhuis and Johnson [17], was used. The nadir and peak clusters were 2/1 points; the t statistics for significant increases and decreases were 1.5/1.5. The number of identified LH pulses per unit of time (4 h) was compared with or without insulin supplementation. To determine differences, means for each period were subjected to analysis by ANOVA or a paired t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiment 1: Central Insulin Measurement

Figure 1 illustrates changes in insulin concentrations in plasma and CSF after an s.c. insulin injection in a representative sheep. Similar changes were documented in three other animals. Plasma and CSF concentrations of insulin increased (P < 0.05) relative to those before treatment. Both achieved peak concentrations within 5 h after peripheral insulin treatment (plasma = 73.1 ± 15.4 µU/ml; CSF = 19.7 ± 9.0 µU/ml). CSF concentrations of insulin were positively related to plasma concentrations of insulin (Fig. 1., inset; r = 0.80, P < 0.01).



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  		FIG. 1. Changes in CSF and plasma insulin concentration after s.c. insulin injection (30 IU/animal) at Hour 0 in a representative sheep. Inset: Correlation between the CSF and plasma insulin concentration (n = 4 animals) collected at 3- to 5-h intervals for 12 h after s.c. insulin injection (30 IU/animal). Dotted line indicates assay sensitivity

Experiment 2: Central Insulin Infusion

Figure 2 presents insulin and glucose concentrations in CSF and in plasma on Day 4 of the central insulin infusion in peripherally diabetic sheep. These concentrations were similar to those on Day 1. CSF insulin concentrations were increased (P < 0.01) by the intracerebral insulin infusion as compared with those during saline treatment. There was no difference in plasma insulin concentration or in plasma/CSF glucose concentrations between the central insulin- and saline-treatments (P > 0.1).



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  		FIG. 2. Insulin (top) and glucose (bottom) concentrations in plasma (open bars) and CSF (hatched bars) 4 days after the start of i.c.v. infusion of saline or insulin. Values are mean ± SEM (n = 4). **P < 0.01 vs. saline-treated controls

Representative patterns of circulating LH and mean results are presented in Figure 3. LH pulse frequency on Day 5 was significantly greater in insulin-infused animals compared to saline-infused (3.5 ± 0.2 vs. 2.3 ± 0.3 pulses/4 h, P < 0.01), but lower than during peripheral insulin treatment (4.8 ± 0.3 pulses/4 h, P < 0.01). Mean LH concentrations and LH pulse amplitude did not differ between individuals infused centrally with insulin or saline vehicle.



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  		FIG. 3. Top) Secretory profiles of LH in 3 representative sheep for 4 h on Day -1 (s.c. systemic insulin treatment) and Day 5 after the start of i.c.v. infusion of saline or insulin. Bottom) Mean ± SEM pulse frequencies before and after i.c.v. infusion with saline (n = 6) or insulin (n = 6). Columns with different letters are different, P < 0.05 (by ANOVA with repeated measures)


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In our companion study [6], we found that developing diabetic sheep with hypoinsulinemia had reduced LH secretion and that systemic insulin treatment could restore high frequency LH secretion. Using the same model, the present study determined that central insulin supplementation could also increase LH pulse frequency in the diabetic individual. Continuous infusion of insulin into the lateral ventricle maintained levels of insulin in CSF that met or exceeded those produced by s.c. insulin injection. It is unlikely that the infused insulin spilled over from the CSF into the peripheral circulation because plasma insulin concentrations in centrally insulin-treated animals remained low, i.e., at the same concentrations as those in saline-treated animals. These results indicate that intracerebral insulin plays a role in maintaining pulsatile GnRH secretion in the diabetic sheep, and are consistent with findings in non-diabetic sheep that central insulin influences LH secretion [12]. However, they do not agree with the findings of Hileman et al. [11], in which insulin treatment was unable to stimulate LH secretion in nutritionally growth-restricted lambs. The reason for the disagreement between these latter findings and our present results is unclear, although it may be related to differences in the experimental model (diabetic vs. growth-retarded) or the method of insulin administration (chronic infusion vs. acute injection).

It is possible that a central deficiency of insulin is a contributing factor in the etiology of diabetic hypogonadotropism based on our present findings, which clearly demonstrate that insulin is able to cross the blood-brain barrier and enter the CSF (brain). Interestingly, central insulin infusion into the hypoinsulinemic diabetic individual was not able to sustain LH pulse frequency at the same level as systemic insulin treatment. This finding was not due to an insufficient dose of insulin during i.c.v. infusion, as CSF insulin concentrations exceeded peak levels achieved during systemic insulin treatment. Some explanations for this finding may be considered. First, changes in other peripheral metabolic signal(s) (serum metabolites or metabolic hormones) may also provide information for the reduced GnRH secretion in diabetes mellitus. In the present study, which experimentally maintained central insulin (by infusion), the body remained insulin deficient because plasma insulin concentrations remained depressed while plasma glucose levels were high (typical of uncontrolled diabetes). This systemic hypoinsulinemia (despite optimal central insulin concentrations) was likely accompanied by an increase in plasma concentrations of cortisol, non-esterified fatty acids and ketones based upon findings from our previous study [6]. Although leptin concentrations were not measured in the present experiment (no leptin assay is currently available for use in the sheep), they were found to be depressed in the diabetic rat in the absence of peripheral insulin replacement therapy [18]. Such peripheral metabolic disturbances, e.g., decreased leptin, could explain why central insulin alone could not restore LH pulse frequency to levels found during peripheral insulin supplementation. In this regard, we ([19]) and others [20–22] have determined that peripheral leptin levels modulate neuroendocrine mechanisms controlling LH pulse frequency in the rodent, sheep, and monkey. A second possibility is that insulin and/or insulin-responsive glucose detectors regulating GnRH secretion may exist in the periphery. For example, glucosensors in the liver have been identified [23]. Insulin is known to play a role in the modulation of glucose utilization in hepatocytes by regulating the production of glucokinase, an essential enzyme of glucose metabolism [24, 25]. Previous investigations of the control of food intake indicate that a hepatic glucose sensor can mediate feeding behavior [26–28]. Such findings lead to the speculation that despite high concentrations of insulin centrally (insulin infusion), a peripheral insulin deficiency could decrease glucose utilization in the liver, which in turn, through the vagal neural pathway, might suppress the activity of the hypothalamic GnRH pulse generator. Although there does not appear to be an important hepatic glucose sensor in sheep that provides information for the central control of GnRH secretion [29], we cannot rule out the possibility that other peripheral glucose sensors exist that provide such information. A third possibility is that our central infusion dosage was supraphysiologic. Compared to peak CSF concentrations found after s.c. insulin treatment, our central infusion paradigm achieved levels that were approximately 50% higher. Moreover, CSF insulin concentrations attained during central insulin infusion in the present study were 10-fold higher than normal CSF levels reported elsewhere in non-diabetic sheep [12]. We did not obtain CSF insulin measurements from non-diabetic animals during the course of this study. However, previous findings in the sheep suggest that the effect of central insulin treatment on LH secretion is dose-dependent. Although the pharmacologic mechanism was not determined, low-dose central insulin infusion increased LH pulse frequency [12]; doses of insulin that were approximately 100-fold higher decreased LH pulse frequency [11]. Such reports in non-diabetic sheep provide a possible explanation why LH pulse frequency was not completely restored by a "high-dose" of insulin (i.c.v.) in our diabetic sheep model.

An important question is whether central insulin effects on GnRH secretion is due to the direct action of insulin or to an indirect action of insulin upon glucose availability. A direct, central action of insulin is possible, as insulin receptors are widely distributed in the brain including sites that are important in the control of GnRH secretion, i.e., the arcuate nucleus and the median eminence within the medial basal hypothalamus [30, 31]. Insulin inhibits uptake of norepinephrine in dissociated rat brain cells [32] and alters catecholamine kinetics in the hypothalamus [33]. Moreover, insulin receptors are present on catecholaminergic terminals in the hypothalamus [34], at sites where such neurotransmitters are known to regulate GnRH secretion in sheep [35]. Central insulin could therefore influence GnRH secretion by its neuromodulatory effect on catecholamine neurotransmission. Alternatively, other investigations suggest that the action of insulin may be indirect, and that the regulation of GnRH secretion by insulin is associated with insulin-dependent changes in central glucose availability. Both in vitro and in vivo studies have determined that insulin in the brain potently affects neuronal glucose metabolism [36, 37] via the mitochondrial citric acid cycle [38]. A recent immunohistochemical study by our group localized pancreatic glucokinase (a key element of a glucose sensing mechanism in pancreatic beta cells) in the rat brain [39]. In addition, GLUT4, the insulin-responsive glucose transporter, mRNA and/or protein has been found in the rat brain [40–43]. One possible mechanism is that changes in insulin-dependent glucose availability are detected by central glucodetectors, and then this information is transduced into neural signals modulating GnRH secretion. In this regard, we determined that central glucoprivation by lateral ventricular 2DG injection suppressed pulsatile LH secretion in the sheep [44]. More specifically, local delivery of 2DG into the fourth ventricle produces the same result both in the rat [45] and sheep (unpublished). This hindbrain region contains a circumventricular organ, the area postrema, that has been implicated as a chemosensor mediating the effect of a variety of blood-borne substances on central-visceral functions, including appetite [46]. Insulin specifically binds to neurons of the area postrema in the rat [47]. Most importantly, this brain region has recently been implicated as a neural center regulating reproductive activity. In the Syrian hamster, lesions of the area postrema disrupt the capacity of 2DG-induced glucoprivation to block ovulatory cycles [48].

In view of all of the foregoing considerations, our results suggest that insulin acts within the brain to regulate GnRH secretion in the diabetic sheep model. Perhaps such a model can be used to resolve in non-diabetic individuals, whether insulin has a central and/or peripheral site of action to regulate GnRH secretion, and if insulin acts directly or indirectly through modulation of glucose availability.


   ACKNOWLEDGMENTS
 
We are grateful to Douglas D. Doop for animal technical services; Ms. Juanita Pelt for technical advice and laboratory assistance; Dr. Gordon D. Niswender, Colorado State University, and Dr. Leo E. Reichert, Jr., Albany Medical College, for providing reagents used in the LH assay. Important contributions were made by members of various Core Facilities of the Center for the Study of Reproduction (NIH P30 HD 18258): Gary R. McCalla of the Sheep Research Core Facility for conscientious animal care; the staff of the Assays and Reagents Core Facility for standardization of hormone radioimmunoassay reagents; the staff of the Administrative Core Facility for administrative and computer assistance.


   FOOTNOTES
 
First decision: 30 September 1999.

1 This study was supported by travel grants from the Japanese Ministry of Education, Science, Culture and Sports (9-Y-40); by JSPS-NSF Cooperative Science Program (NSF INT-9603310); and research grants from NIH (HD-18394 and HD-18258). A preliminary report of this work was presented at the 28th Annual Meeting of the Society for Neuroscience, Los Angeles, CA, November, 1998 (Abstract #110.2). Back

2 Correspondence: Douglas L. Foster, Room 1138, 300 North Ingalls Building, University of Michigan, Ann Arbor, MI 48109-0404. FAX: 734 936 8620; dlfoster{at}umich.edu Back

Accepted: January 18, 2000.

Received: August 11, 1999.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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