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Endocrinology Vol. 139, No. 7 3143-3147
Copyright © 1998 by The Endocrine Society

ARTICLES

Improvement of Erectile Function in Diabetic Rats by Insulin: Possible Role of the Insulin-Like Growth Factor System1

Tarek M. Abdelbaky, Gerald B. Brock and Hung Huynh

Lady Davis Research Institute of the Jewish General Hospital, Departments of Surgery (T.M.A., G.B.B.) and Medicine (H.H.), McGill University, Montréal, Québec, Canada H3T 1E2

Address all correspondence and requests for reprints to: Hung Huynh, Lady Davis Research Institute, McGill University, 3755 Cote Ste Catherine Road, Montréal, Québec, Canada H3T 1E2. E-mail: hhuynh{at}ldi.jgh.mcgill.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Erectile dysfunction is commonly experienced in men with diabetes mellitus. We report that the intracavernous pressure (ICP) rise in diabetic rats was 55% of the control and returned to normal following insulin (I) or insulin plus free oxygen scavenger (I + S) treatment. Insulin-like growth factor (IGF) binding protein (IGFBP) -3, -4, and -5 messenger RNA (mRNA) levels in the major pelvic ganglia (MPG) of diabetic rats were elevated by 2-fold, 2.6-fold, and 2.5-fold, respectively. Both I and I + S returned IGFBP-4 and 5 mRNA levels to normal, whereas IGFBP-3 gene expression was severely inhibited. IGFBP-2 gene expression was greatly inhibited by diabetes and was unresponsive to treatment. In the penis of diabetic rats, IGFBP-2 and -4 mRNA levels were low, whereas IGFBP-3 mRNA levels were elevated 10-fold. These effects were reversed by I and I + S. I and I + S also corrected the IGFBP-3 expression pattern. IGF-I gene expression in the penis and MPG was not significantly increased (P < 0.05) by diabetes and returned to normal levels following I or I + S treatment. Because IGFs are potent regulatory factors in vascular tone, this newly described activity of insulin may play an important role in the improvement of erectile function seen clinically and in animal models.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NORMAL erectile function requires timely coordinated action of signaling pathways and delicate penile vasculature. Diabetic men represent the largest cohort of patients with erectile dysfunction (ED) believed to be of a neurovascular basis. The underlying molecular cause remains poorly defined and inadequately studied.

ED is a common problem affecting millions of North American men (1). There is evidence that insulin inhibits contraction in renal artery, femoral, aortic, and rat tail vasculature (2, 3, 4), thereby contributing to the regulation of vascular tone (5). Insulin and insulin-like growth factor (IGF)-I share similar receptors (6, 7). IGF-I appears to function like insulin in human skeletal muscle blood vessels (8, 9, 10, 11, 12). Systemic infusion of either insulin or IGF-I can elicit vasodilation (13). Unlike insulin, IGF-I is produced locally (14) and therefore may potentially be a more important regulator of regional blood flow.

Both IGF-I and IGF-II bind with high affinity to specific IGF binding proteins (IGFBPs), which modulate their bioactivity. At least seven IGFBPs have been described (15, 16). The expression of genes encoding the various IGFBPs has been observed in many tissues and is subjected to intricate physiological regulation (17, 18). We recently reported that penile IGF-I and IGFBP gene expression is controlled by androgens, and there is a positive correlation between erectile function and IGF-I bioavailability (19).

Described mechanisms of insulin action include inhibition of agonists and voltage-induced vascular smooth muscle cells intracellular calcium ([Ca2+]i) (20, 21, 22), attenuation of [Ca2+]i by selective antagonism of {alpha}2 receptors (23), decrease in ß adrenergic receptor binding, and down-regulation of ß2 receptor activity via phosphorylation (24). The effect of insulin however, on the endothelium-derived relaxing factor, nitric oxide (NO), is believed to be an important mediator of both insulin- and IGF-induced vascular relaxation (9, 10, 11, 25).

Free radicals and other reactive oxygen metabolites (ROMs) have been implicated in diabetes. Research into the precise mechanism of injury and the therapeutic effects of antioxidant treatment has not yet been performed in animal models of erection. Reactive radicals use several common pathways to achieve their devastating physiological effects. Loss of membrane integrity, alteration of protein stability, and injury to the nucleic acid structures within the cell are fundamentally what is seen following exposure to these ubiquitous offenders. The relationship between ROMs and diabetes has driven investigators to examine whether a cause and effect relationship exists. Persistent elevation of glucose produces an environment high in ROMs. Several potential pathways exist: 1) autooxidation of glucose; 2) increased polyol pathway activity; 3) impaired myo-inositol metabolism; 4) impaired essential fatty acid metabolism; 5) deficits in neurotrophic factors; and 6) nonenzymatic protein glycosylation with diabetes. Nerves exposed to ROMs show slow conduction velocity, altered vascular reactivity, and histological changes similar to those reported among diabetic animals (26, 27, 28, 29).

In this report, we demonstrate that 8 weeks following streptozotocin (STZ)-induced diabetes in the rat model, the intracavernous pressure (ICP) rise decreased greatly. In the major pelvic ganglia (MPG) of diabetic rats, IGFBP-3, -4, and -5 gene expression increased, whereas IGFBP-2 gene expression was almost abolished. In the penis, IGFBP-3 messenger RNA (mRNA) levels were elevated, whereas IGFBP-2 and -5 gene expression were depressed. Administration of insulin (I) or insulin plus free oxygen scavengers (I + S) resulted in a down-regulation of IGFBP-3 gene expression in both the MPG and penis. IGFBP-5 and IGFBP-4, but not IGFBP-2 in the MPG returned to normal levels following I or I + S treatment, whereas IGFBP-4 in the penis was stimulated. IGF-I and IGF-IR gene expression was not significantly affected by either diabetes or insulin replacement.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Animals were maintained and treated according to the guidelines of the Canadian Council on Animal Care. The experimental protocol was approved by the local Animal Care Committee. To induce diabetes, sexually experienced, male Sprague-Dawley rats (n = 60) weighing 300–400 g were injected with 50 mg of STZ ip per kg body weight (BW) in citrate phosphate buffer, pH 4.5. Control rats were given only vehicle. The development of diabetes was confirmed by determining blood glucose levels 1 week after STZ administration. Diabetic rats were divided into three groups. Rats in group 1 were left untreated. Rats in group 2 were treated daily with 1 U/100 g BW sc of human recombinant insulin. Rats in group 3 were given 1 U/100 g BW sc of human recombinant insulin with free radical scavengers (3 mg vitamin C, 0.8 mg deferoxamine mesylate and 2 mg triethylene-tetramine dihydrochloride per 100 g BW by gavage) daily throughout the 8-week study period.

Sample collection
Rats were anesthetized with pentobarbital (45 mg/kg BW ip), and the lower pelvis was exposed. The MPG were excised and frozen in liquid nitrogen. The penis was dissected from the integument, and the urethra was isolated and excluded from the samples. The penile samples were cut into 4–5 pieces and frozen in liquid nitrogen.

Blood glucose determination
The development of diabetes and the efficacy of insulin therapy were assessed weekly by measuring the blood glucose levels in serum samples obtained from the tail vein of the rats. STZ-treated rats not given insulin were excluded from the study if their serum glucose levels were below 15 mmol/liter.

Electrophysiologic study of erection
After 8 weeks, five rats per group were anesthetized with pentobarbital (45 mg/kg BW ip). The right carotid artery was catheterized with a PE-50 tube for systemic blood pressure monitoring. Through a low abdominal midline incision, the latero-prostatic space was dissected, and the MPG was identified. The cavernous nerve has a constant course from the MPG on the dorsolateral prostatic surface and is covered by a thin film of semitransparent fascia. The nerve was isolated and hooked by a bipolar steel electrode 2 mm distal to the MPG. Through a transverse perineal incision, the penile crus was exposed by spreading the overlying ischiocavernosus muscle. A 23-gauge needle filled with 250 U/ml of heparin and connected to PE-50 tubing was inserted into the penile crus. The systemic and ICP rise were measured and recorded using a Labview 2 program software (National Instruments Co., Austin, TX). Electro-stimulation with rectangular pulses was delivered from a computer program. The pulse width was fixed at 0.2 msec, frequency at 20 pulses per second, and the current at 2 mA. The duration of stimulation was 40 sec. Each animal was stimulated four times at 10-min intervals.

Northern blotting
Total RNA was isolated from penile tissue, and the MPG using the RNAzol B method (Teltest, Friendswood, TX) as described (30). Total RNA was fractionated on 1% agarose gels and hybridized with IGF-I (31), IGF-IR (ATCC) (American Type Culture Collection, Rockville, MD), and IGFBP (from 2–5) (32) complementary DNA (cDNA) probes. mRNA levels were quantitated by densitometric scanning of autoradiograms. The statistical significance of IGF-I, IGF-IR, and IGFBP differences were determined by Wilcoxon test.

Significant differences in body weight, blood glucose levels, and ICP rise were determined by the Student t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
STZ treatment caused a 6-fold increase in blood glucose levels and a 25% decrease in body weight (Fig. 1Go, A and B). There was no statistically significant difference between control, I-treated and I + S-treated rats. These data support the beneficial effect of the two treatment arms evaluated.



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  		Figure 1. Effects of diabetes, insulin and insulin plus scavenger treatments on ICP rise. Diabetic rats were created and treated with I or I + S as described in Materials and Methods. Means (n = 5) of blood glucose levels (A), body weight (B), and ICP rise (C) of control nondiabetic (lane 1), diabetic (lane 2), diabetic insulin-treated (lane 3), and diabetic insulin plus scavenger-treated (lane 4) rats are shown. Diabetes caused a significant elevation in blood glucose levels (P < 0.01), and significant decreases in body weight (P < 0.05) and ICP rise (P < 0.01) compared with control nondiabetic rats. There was no difference in ICP rise, blood glucose levels, and body weight among control nondiabetic, I and I + S-treated groups. Means SEM of triplicate experiments are plotted.

 
The physiologic erectile response was tested using cavernous nerve direct stimulation. This model permits evaluation of the impact of disease and metabolic changes on the function of both the penile structure (cavernous smooth muscle, intrapenile vasculature, and competence of the veno-occlusive mechanism), and the peripheral nervous system. EFS of the cavernous nerve in diabetic rats showed that the ICP rise decreased significantly (P < 0.01) compared with controls (Fig. 1CGo, lane 2). This impairment was corrected by either I or I + S replacement (Fig. 1CGo, lanes 2 and 3).

Because insulin and IGF-I can induce vascular relaxation, changes in the expression of the IGF system in the penile tissue and MPG under different physiological conditions were investigated. IGF-I but not IGF-IR gene expression in the penis and MPG increased nonsignificantly (P < 0.05) in diabetic conditions (Fig. 2Go, lane 2). IGF-I returned to normal levels following either I or I + S replacement (Fig. 2Go, lanes 3 and 4).



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  		Figure 2. Effects of diabetes, insulin, and insulin plus scavenger treatments on MPG and penile IGF-I and IGF-IR gene expression. Diabetic rats were created and treated with I or I + S as described in Materials and Methods. Total RNA from whole penis or MPG was extracted and Northern blotting performed as described in Materials and Methods. Representative autoradiograms of blots hybridized with IGF-IR (A and D), IGF-I (B and E) and ß-actin (C and F) cDNAs are shown. Treatments are control nondiabetic (lane 1), diabetic (lane 2), diabetic insulin-treated (lane 3), and diabetic insulin scavenger-treated (lane 4). There were no significant differences in IGF-I and IGF-IR mRNA levels among all groups.

 
As shown in Fig. 3Go, IGFBP-3, -4, and -5 gene expression in the MPG tissue of diabetic rats increased significantly (P < 0.01) by 2-fold, 2.6-fold, and 2.5-fold, respectively, whereas IGFBP-2 mRNA levels were barely detected (Fig. 3Go, lanes 2). Both I and I + S effectively brought IGFBP-4 and 5, but not IGFBP-2 mRNA levels back to normal (Fig. 3Go, lane 3 and 4). IGFBP-3 gene expression was significantly inhibited (P < 0.01) by I and I + S treatments with mRNA levels reduced to one sixth and one eighth of control and diabetic MPG.



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  		Figure 3. Effects of diabetes, insulin, and insulin plus scavenger treatments on IGFBP gene expression in the MPG. Diabetic rats were created and treated with In or I + S as described in Materials and Methods. Total RNA from the MPG was extracted and Northern blotting performed as described in Materials and Methods. Representative autoradiograms of blots hybridized with IGFBP-2, 4 and 5 (A), IGFBP-3 (B), and ß-actin (C) cDNAs are shown. A densitometric scanning of the IGFBP-3, -4, and -5 mRNAs is shown in D. Treatments are control nondiabetic (lane 1), diabetic (lane 2), diabetic insulin-treated (lane 3), and diabetic insulin plus scavenger-treated (lane 4). Diabetes caused a significant increase in IGFBP-3, -4, and -5 (P < 0.01) and a significant decrease in IGFBP-2 mRNA levels (P < 0.01) compared with control nondiabetic rats. There was a significant difference in IGFBP-2 but not in IGFBP-4 and -5 among control nondiabetic, I and I + S-treated groups. Means SEM of triplicate experiments are plotted.

 
In the penis, IGFBP-2 and 4 mRNA levels significantly decreased (P < 0.01) in diabetic conditions (Fig. 4Go). An approximate 10-fold increase (P < 0.01) in IGFBP-3 mRNA levels was observed in the penis of diabetic rats (Fig. 4Go). Three IGFBP-3 transcripts of approximately 3, 2.6, and 1.5 kb were detected in the penis of diabetic rats but not in the controls (Fig. 4Go, lane 2). Diabetes-induced abnormal penile IGFBP-3 gene expression was corrected by either I or I + S treatment (Fig. 4Go, lanes 3 and 4). An inverse correlation between ICP rise and IGFBP-3 mRNA levels in MPG and penile tissues was observed. Insulin significantly enhanced IGFBP-4 gene expression (P < 0.01), whereas IGFBP-2 and IGFBP-5 mRNA levels were unaffected (Fig. 4Go, lane 3).



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  		Figure 4. Effects of diabetes, insulin, and insulin plus scavenger treatments on IGFBP gene expression in the penis. Diabetic rats were created and treated with I or I + S as described in Materials and Methods. Total RNA from whole penis was extracted and Northern blotting performed as described in Materials and Methods. Representative autoradiograms of blots hybridized with IGFBP-2, -4, and 5(A), IGFBP-3 (B), and 8-actin (C) cDNAs are shown. A densitometric scanning of the IGFBP-2, -3, and -4 mRNAs is shown in D. Treatments are control nondiabetic (lane 1), diabetic (lane 2), diabetic insulin-treated (lane 3), and diabetic insulin scavenger-treated (lane 4). Diabetes caused a significant decrease in IGFBP-4 and 2 (P < 0.05) and a significant increase in IGFBP-3 mRNA levels (P < 0.01) compared with control nondiabetic rats. There was no significant difference in IGFBP-5 mRNA levels among all groups. IGFBP-3 mRNA levels in control nondiabetic rats were significantly lower than I and I + S-treated groups (P < 0.05). Means SEM of triplicate experiments are plotted.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Progress in the field of ED over the past decade has led to improved diagnostic tests and therapeutic options for couples suffering from sexual difficulties. The largest group of patients experiencing sexual dysfunction is diabetic (33, 34, 35). Several physiological pathways leading to erection in the penis have been reported to be impaired in diabetic rats (33, 34, 36, 37). The mechanisms by which insulin regulates the IGF system in the penis and MPG have not previously been investigated.

In this study, we have shown that the mRNAs encoding IGF-I, IGF-IR, and IGFBP-2, -3, -4, and -5 are present in the rat MPG and penis. Expression of these genes is tightly regulated by insulin. The mRNA encoding IGFBP-2 is barely detectable in the MPG and greatly reduced in the penis of diabetic rats compared with controls. IGFBP-3 gene expression in the penis is not only elevated, but also abnormally expressed under diabetic conditions where three IGFBP-3 transcripts are detected. Insulin not only effectively blocks diabetes-induced IGFBP-3 gene expression, but also corrects IGFBP-3 mRNA patterns. The IGFBP-4 gene in the MPG is expressed at high levels during diabetes and returns to normal after insulin treatment. In contrast to MPG, penile IGFBP-4 gene expression is inhibited by diabetes and is stimulated by insulin. IGFBP-5 gene expression in the MPG is up-regulated by diabetes and is corrected by insulin. IGF-I mRNA levels in both the MPG and penis are slightly elevated compared with controls and return to normal levels with insulin therapy. IGF-IR mRNA levels appear to be unaffected by diabetic conditions. These results demonstrate that diabetes has an effect on IGF physiology in the penis and MPG, producing an unfavorable microenvironment for the activity of IGF-responsive cells. Impairment of erection seen in diabetic rats may be related to the presence of high levels of IGFBPs, which reduce IGF bioavailability in the penis and MPG.

The relative importance of the regulation of genes involved in IGF physiology by I and I + S cannot be determined from our present data. In view of our findings, however, it is possible that elevated levels of IGFBPs, known to play an important role in inhibiting IGF action, may contribute toward the frequent ED seen in diabetes. It is possible that low levels of insulin may trigger local IGFBP expression to trap IGF-I. Because the regulation of vascular tone by IGF-I is believed to be mediated in part by the endothelium-derived relaxing factor, NO (5, 8, 9, 11, 12, 20, 25, 38, 39), we hypothesize that increases in IGFBP expression due to diabetes would attenuate the cellular response to IGF-I through the high affinity binding of IGF-I to IGFBPs. This would result in decreased availability of IGF-I for the receptor and thus would interfere with the release of NO.

Interestingly, in vitro studies have shown that IGFBP-3 inhibits DNA synthesis in several cell types (15). Our present study shows that IGFBP-3 mRNA levels in the penis and MPG of diabetic rats strongly correlate with ED. IGFBP-3 mRNA levels almost return to normal following insulin therapy, suggesting a role of IGFBP-3 in the vascular relaxation process and implying that suppression of IGFBP-3 gene expression may be important for normal erectile function. This novel finding provides the first evidence that, in vivo, IGFBP-3 may participate in the mechanisms of erectile function. The mechanism of IGFBP-3 gene activation in the penis and MPG is unknown.

Correlation of the intracorporal pressure with the measured changes in IGF-I, IGF-IR, and binding proteins demonstrate an important physiological role for IGFBP-3 in erection. Up-regulation of IGFBP-3 in the diabetic rat penis and MPG was associated with a significant loss of erectile function. Insulin therapy and insulin plus scavenger treatment restored IGFBP-3 in the penile and MPG samples to near normal levels. The physiological erectile function as measured by the rise in the intracavernous pressure was also restored. Binding proteins 4 and 5 within the MPG also showed marked elevations with diabetes (associated with a loss of erectile function) and returned to normal levels with insulin and insulin plus scavengers, resulting in an improved physiological erectile response. No such relationship for binding proteins 2, 4, and 5 in the penis were found.

IGFBP-4 gene expression in the penis increases following insulin treatment, but decreases in the MPG. The relevance of up-regulating penile IGFBP-4 gene expression following insulin treatment is unknown. Nerves exposed to reactive oxygen species show slow conduction velocity, altered vascular reactivity, and histological changes similar to those reported among diabetic animals (28); therefore, the use of reactive radical scavengers to mitigate the effects of oxidative stress have been proposed (28, 40). Treatment of diabetic rats with insulin supplemented with free radical scavengers does not appear to be superior to insulin alone in monitoring the IGF system and improvement of erectile function.

ED represents an important clinical problem for millions of North American men. New treatment strategies in the next decade will likely depend on an improved understanding of the molecular biology that causes the dysfunction. This study is to our knowledge the first to report altered regulation of the IGF system within the penile tissue and MPG in a diabetic animal model.

Up-regulation of vasocontricting binding protein and down-regulation of vasodilation binding protein create an environment where erections are inhibited. Development of specific agonists and antagonists to the IGF system seem like promising new avenues for treatment of ED for millions of affected men.


   Acknowledgments
 
We thank Dr. L. Murphy for rat IGF-I cDNA, Dr. Shimasaki for rat IGFBP cDNAs, and Alexis Codrington for manuscript preparation.


   Footnotes
 
1 This work was supported by grants from the Cancer Research Society (Grant 778) to Hung Huynh, and from the FRSQ and the Canadian Diabetes Association to Gerald B. Brock. Back

Received January 13, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals