New Concepts in Diabetes and Its Treatment - part 9 pdf

Conclusion Although the roles of peripheral neuropathy and peripheral vascular ease are now well established as the main aetiological factors in diabetic footulceration, there is much wo

cause of the Charcot foot and most patients have a dense neuropathy, butgood circulation Early animal experiments suggested that walking on aninsensitive limb could lead to joint destruction Excessive and repetitive stress

to bones leads to microfractures, which render the bone more brittle and couldlead to bone and joint destruction However, the degree of bone destructionoften seen in the absence of major injury has suggested an underlying boneabnormality Diabetic neuropathy leads to an increase in bone blood flow,which may promote osteoclastic activity and bone resorption Indeed, a smallstudy has demonstrated increased serum markers of osteoclastic action inpatients with acute Charcot that was not accompanied by a concomitantincrease in markers of osteoblastic activity Furthermore, lower limb bonemineral density has been found to be lower in patients with a Charcot foot,when compared to neuropathic controls A full understanding of the patho-logical process leading to the often dramatic and progressive destruction seen

in this condition has not yet been arrived at, and as it is rare and usuallypresents late, the opportunities for further studies are limited

In the early acute stages, when bone turnover is high, treatment involvesrest and immobilization of the foot (usually with a total contact cast) in anattempt to reduce the metabolic activity within the bone There is now someevidence that bisphosphonate drugs given during this acute phase may shortenthe duration of the acute phase presumably by reducing the bone turnoverdirectly, and hence slowing down the process which weakens the bone andrenders it susceptible to further fracture and fragmentation

Whenever unilateral swelling of the foot is present in someone with diabeticneuropathy, Charcot neuroarthropathy must be considered Plain X-ray isusually adequate to make or exclude the diagnosis, and while the radiologicalappearances can be similar to those of osteomyelitis, in the absence of a source

of infection (such as an overlying ulcer), neuroarthropathy is nearly alwaysthe cause

Conclusion

Although the roles of peripheral neuropathy and peripheral vascular ease are now well established as the main aetiological factors in diabetic footulceration, there is much work to be done in both the way in which ulcersdevelop and the interactions of the main risk factors with each other and withall the other risk factors discussed in this chapter However, this complexityshould not deter the clinician, as it is now very clear that simple clinical testswill identify patients at risk of ulceration and amputation, and appropriate,but simple education about footcare can greatly reduce the likelihood of

dis-developing diabetic foot problems Foot ulcers can be difficult to heal, buttreatment is likely to be successful in the vast majority of cases when pressure

is removed, callus and necrotic tissue debrided, infection controlled, and agood circulation is maintained

Suggested Reading

Boulton AJM, Connor H, Cavanagh PR (eds): The Foot in Diabetes, ed 2 Chichester, Wiley, 1994 Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW: Assessment and management of foot disease in patients with diabetes N Engl J Med 1994;331:854–860.

Schapper NC, Bakker K (eds): The diabetic foot Diabet Med 1996;13(suppl 1):1–64.

Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: An overview Diabetes 1997;46(suppl 2): 58–61.

Dr J Shaw, Department of Medicine (M7), Manchester Royal Infirmary,

Manchester M13 9WL (UK)

Tel +44 161 276 4452, Fax +44 161 274 4740, E-Mail jshotham@hotmail.com

Dipartimento di Medicina Interna, Universita` degli Studi di Torino,

Ospedale Molinette, Torino, Italy

Introduction

The existence of sexual disorders in diabetes mellitus has long been nized In the pre-insulin era, impotence was considered one of the commonestsymptoms of diabetes, being present in both severe and milder forms of thedisease However, only now are sexual function problems receiving their right-ful attention, as the medical professional has moved from a mere ‘survivalist’approach to diabetes and its more invalidating complications towards care forthe diabetic individual in all his or her complexity

recog-Today, diabetology is no longer satisfied to keep diabetics in reasonablygood health, but also addresses everything that may affect the individual’squality of life and, from this standpoint, sexuality cannot fail to occupy arole of primary importance In the diabetic male, it is sexuality in the narrowestsense, namely what is conventionally designated ‘potentia coeundi’, that iscompromised and it is precisely in relation to that situation that a comprehen-sive overview of this condition can provide the diabetic patient with the answer

he seeks

Epidemiology

Erectile dysfunction is 3 times more common among diabetics than inthe healthy control population However, the complication is still consideredoccult since it is often unreported by patients In the various studies published,the incidence of this dysfunction in diabetics varies from 28 to 59% Thepredictive factors are: age, duration of the disease, degree of metabolic com-

pensation, the presence of microvascular complications (especially retinopathy)and neuropathy, high blood pressure and the drugs taken for that condition,smoking and alcohol abuse The age factor is particularly important The veryearliest epidemiological studies showed that the incidence of impotence indiabetic males rose from 1.5% in the under-40s to 25% in the 40–60 age group.More recently, others have reported incidences rising from 15% in the under-

40 group to 55% at 60 The trend revealed by the Wisconsin EpidemiologicStudy in particular is highly significant (p=0.0001), rising from 1.1% in the21–30 age group to 47.1% among insulin-dependent diabetics over 43 yearsold Klein himself confirms that significance when he analyses the duration

of diabetes: men with a more than 35-year history of the disease are 7.2 timesmore likely to present this complication than those with only a 10- to 14-yearhistory However, the link between erectile dysfunction and disease duration

is not inevitable, since the erectile disorder occasionally appears before theclinical onset of the diabetes In addition, diabetic erectile dysfunction is alsorelated to HbA1c levels which indicate the ability to metabolize glucose, therisk of impotence tripling in those worst affected (HbA1c ?9.8%) That in-creased risk is explained when we consider the treatment needed to controldiabetes – restrictive diets and drugs to lower blood sugar and/or insulin –that are most aggressive in the most metabolically compromised patients Bothdiabetic retinopathy, especially if severe, and neuropathy, both peripheral andautonomic, are related to a higher incidence of erectile dysfunction which is5.3 times more likely to occur in such patients High blood pressure is anadditional risk factor especially when treated by certain drugs such as b-blockers, methyldopa and particularly diuretics Finally, excessive drinkingand smoking intensify the risk of erectile dysfunction in diabetics

A recent Italian study of 9,868 diabetic patients reported a 35.8% incidence

of erectile dysfunction and confirms the reported literature data: incidenceincreasing with age, duration of diabetes, severity of failure to metabolizeglucose, complexity of diabetic therapy, diabetic complications (angiopathy,retinopathy, kidney disease, neuropathy) as well as cardiovascular disease andthe use of certain drugs in its treatment and finally habitual smoking.Apart from erectile dysfunction, diabetes can also produce problems withejaculation, especially retrograde ejaculation as the so-called ‘dry orgasm’ (adysfunction of the autonomic and somatic nervous system) which occurs in1–4% of male diabetics, most particularly in those with the longest history ofthe disease and those who are most metabolically compromised

Ejaculation without orgasm and indeed failure to achieve ejaculation(reflecting a compromised sympathetic nervous system) are also commoneramong diabetics than in the general population, accounting for 8% of ejacula-tory disorders By contrast, the incidence of premature ejaculation is almost

Table 1 Possible causes of erectile dysfunctions in diabetics

Psychological causes

Poor glycaemic control

Vascular alterations (macro-/microangiopathies and venous)

Autonomic neuropathy

Endothelial alterations (reduced NO secretion)

Concomitant pathologies and related drugs

identical in the diabetic and the healthy populations, a finding that confirmsthe psychosomatic pathogenesis of that disorder

Be that as it may, the organic character of diabetes and its complicationsshould not lead us to forget the influence of psychological factors which may

at times be preponderant

Etiopathogenesis

Diabetic erectile dysfunction is often a complex problem given its chogenic and organic components, the latter linked to the failure to metabolizeglucose and the related organic complications, not to mention the pathologicalconditions known to be caused by the drugs used to treat those complications(table 1) However, many studies have confirmed that erectile dysfunction isprimarily organic in origin, since the dysfunction is rarely reversible In mon-itoring the nocturnal erections associated with REM sleep, researchers havefound fewer REM sleep-erections in diabetic males, a finding which supportsthe view that impotence in diabetics is more likely to be organic than psycho-logical in origin Nevertheless, the role of hormonal abnormalities in thephysiopathology of organic erectile dysfunction remains controversial It istherefore vital to examine the fundamental psychological and organic factorsinvolved in the sexual function of diabetics

psy-The Psychological Factor

There is substantial evidence to suggest that erectile dysfunction in betes is often psychological in origin The main contributory factors are:awareness of suffering from a chronic condition, relationship problems andthe fear of failure during sexual intercourse as a result of that situation It isnot clear whether such psychological factors are greater in the diabetics affectedthan in the general population of people with erectile dysfunctions, thoughdiabetics with the problem appear more stressed than those unaffected Accord-

dia-ing to some authors, diabetic patients are more fearful of developdia-ing erectiledysfunctions as a complication of their condition than of going blind, buthowever great their concern, they are unlikely to discuss it with their doctor.

In fact only 50% of erectile dysfunction sufferers report it to their physician

Impaired Glucose Metabolism

It is important for the correct management of diabetic erectile dysfunction

to repair any severe metabolic disorder the patient may be suffering from tients may recover normal erectile function, as soon as insulin injections to cor-rect their impaired glucose metabolism are started The impaired delivery ofoxygen to the tissue, caused by the formation of glycosylated haemoglobin whichhas a greater affinity for oxygen increases vascular permeability, depositing lipo-protein on the vessel wall and this may be the cause of the vascular damage

Pa-Vascular Alterations

Vascular disorders cause impotence in 18% of diabetic males dynamic disturbances in diabetics may be either arterial (macro- and/or micro-angiopathies) or venous given the direct communication between the twovascular systems

Haemo-Macroangiopathy causes major arterosclerotic obstructions of the large,medium-sized and small arterial blood vessels which cut off the blood flow

to the corpora cavernosa Many authors claim that the primary cause ofimpotence in diabetics is of vascular origin and atherosclerosis is, in fact, theearliest lesion on the peripheral arteries of the penis Histological findings ofpathological alterations to the small arteries are also reported to occur beforeany neurological damage Later, neurological damage caused by the sameatherosclerotic processes appears on the vasa nervorum Such vascular altera-tions are the result of proliferating endothelial and intimal cells, fragmentation

of the endothelium, calcium deposits, and perivascular fibrosis Perineuralfibrosis may occur without causing any direct damage to the nerve fibres.There is an equally close link between ischaemic heart disease and diabeticerectile dysfunction, both being caused by the ischaemic vasculopathy affectingboth areas Diabetic microangiopathies produce alterations and irregularities

in the local microvascular blood flow Those alterations concern: endothelialcell metabolism and function; the basal membrane of vessel walls, whichare thickened; oxygen transportation; the characteristics of blood flow andhaemostasis

In the venous system the uncontrolled blood flow and the failure of thearteriovenous anastomoses may also contribute to the erectile dysfunction.Finally, venous occlusions in diabetes may be due to a structural alteration

in the fibroelastic components of the trabeculae

Neurological and Endothelial Alterations

The penile nerve system is both autonomic and somatic and the relaxation

of the smooth muscle tissue of the corpus cavernosum results from the action of three systems: adrenergic, cholinergic and VIPergic Other factorslike nitric oxide (NO) initially called endothelium-derived relaxing factor(EDRF) and produced by constitutive nitric oxide synthetase (cNOS) whichincreases the concentration of intracellular cyclic guanosine monophosphate(cGMP) may well be involved in the relaxation of the smooth muscle in thecorpus cavernosum As we know, the earliest studies into NO production bycNOS were carried out on bioptic samples taken from the corpus cavernosumtissue of impotent diabetics who presented reduced acetylcholine vasodilation.The reduced NO production and consequent reduction in intracellular cGMPprobably leads to an increase in intracytosolic calcium that is responsible forthe contraction in smooth muscle cells In diabetics there may well also be areduction in the noradrenaline, VIP and acetylcholine content of the corpuscavernosum and both the cholinergic fibres and their ability to synthesizeacetylcholine may be reduced over time, as may the VIPergic pathways Cho-linergic stimulation is certainly known to increase NO production This wouldcompromise both the neurogenic and the endothelial mechanisms dependent

inter-on the relaxatiinter-on of the cavernosal smooth muscle Increased levels of elin-1, a powerful vasoconstrictor released by the endothelial cells, have alsobeen found in patients with erectile dysfunction, especially those with diabetes.That finding suggests that endothelial dysfunction may contribute to erectiledysfunction and that in the absence of any significant vascular element theincrease in plasmatic endothelin-1 may be related to early atherosclerosis Theautocrine role of this peptide, which causes the smooth muscle cells of thecorpus cavernosum to proliferate and/or contract, has been confirmed inexperimentally induced diabetes mellitus

endoth-Somatic and autonomic neuropathy (bladder dysfunction) is often ated with impotence in diabetes and is responsible for 67% of cases, according torecent statistics The disease causes axonal degeneration of the nerves in the penis(and other parts of the body) together with thickening of the basal membrane.The biochemical abnormalities encountered in diabetic patients can besomewhat improved if their glucose metabolism problem is carefully controlled.Researchers have also found a lack of coordination in the electrical activity

associ-of the corpus cavernosum in diabetics with a consequent loss associ-of the diminished

or absent activity that is normal in the tumescent or erectile phase

Hormonal Alterations

Total basal testosterone levels have been found to be normal or low andresearchers have also documented a diminished response in terms of absolute

testosterone increases after HCG stimulation Some reports describe a decrease

in the free fraction of testosterone and estradiol, which they attribute to amarked increase and/or enhanced binding capacity in SHBG and/or inappro-priate gonadotropin secretion In addition, there also appears to be an altera-tion in gonadic response to tropine stimulation with a tendential rise in basal

LH and a more protracted increase after GnRH stimulation

The evidence on circulating gonadotropin and prolactin is conflicting Somereport an increase in urinary LH among diabetics with primary organic impo-tence, as well as a reduction in levels of free testosterone Diabetes and obesityoften go together and increased aromatization of testerostene in the adiposetissue produces an increase in oestrogen levels that contributes to erectile failure

In actual fact, there is increasing doubt about the role of steroids andother hormones in the aetiopathology of sexual disorders in the diabetic maleand the variations that may be found do not appear to play a particularlyimportant part in the genesis of this complication

Spermatogenesis

The most frequently encountered alteration in spermatogenesis is reducedspermatozoa motility which appears to be closely linked to the metabolicdisorders and the presence of autonomic neuropathy Functional damage tothe seminal vesicles is probably a major contributory factor Studies conducted

on rats with streptozotocin-induced diabetes revealed an alteration in theanimals’ sexual behaviour and a reduction in the weight of their secondarysex glands, in their production of androgens and in spermatogenesis as a result

of altered gonadotropin pulsatility

Diagnosis

Erectile dysfunction is diagnosed in diabetics in much the same way as intheir healthy counterparts and diagnosis therefore includes anamnestic assess-ment, objective examination, laboratory tests and instrumental investigation(table 2) Both the rigidity and the duration of penile erections are affected (re-duced arterial blood flow and altered control of the autonomic nervous systemover the penile circulation) while, at least initially, the libido remains unaffected

Anamnesis

Anamnesis is the first step In diabetics, erectile dysfunction usually arisesinsidiously, evolving slowly but inexorably Physicians should pay particular

Table 2 Main diagnostic procedures for erectile dysfunction in diabetics

Anamnesis (physiology, pathology, pharmacology, sexual)

Clinical examination

Blood chemical analyses (HbA 1c , T, PRL, TSH)

Instrumental investigations (penile biothesiometry and cardiovascular tests)

Vascular evaluation (o ffice-intracavernosal injection test)

attention to their patient’s smoking and drinking habits and to the presence

of any concomitant pathologies (high blood pressure and dyslipidaemias arecommon) and the drugs they are being treated with, since these often have anegative impact on sexual activity itself In the case of diabetes mellitus, it isessential to know type, duration and treatment, how far glucose metabolism

is compromised and whether or not the patient presents with opathic and/or neuropathic complications

micro/macroangi-In order to obtain a full diagnostic picture, the investigation of organicfactors must be accompanied by investigation of learning, intrapsychic, dyadic,systemic and sociocultural factors

The sexual anamnesis will cover aspects like the presence or absence ofsexual desire, the presence of spontaneous erections on awakening and/or inresponse to visual stimuli and/or erotic thoughts and/or physical stimulation

by a partner, as well as the quality and frequency of sexual intercourse, thepresence of any significant changes in recent months and the description ofthe sexual intercourse itself

Instrumental Investigations

The instrumental investigations indicated include those used to examinethe vascular system (ultrasound scans or basal and dynamic Doppler echo-sonography) which usually involves the intracavernosal injection of prosta-glandin (PGE1) and penobrachial plethysmography Others examineneurological aspects (vibration and heat perception thresholds, autonomiccardiovascular tests, peroneal motor conduction velocity and sural sensitivitytests; possibly also sacral evoked potential tests) Then there are urologicaltests (cavernosography, cavernosometry, bulbocavernosus reflex) A new min-imally invasive test has recently been proposed and has been tested on type

2 diabetics with no vascular disease in whom basal penile tumescence wasassessed using the Rigiscan technique and found to be related to autonomicnerve damage

An easy-to-use protocol for the diagnosis of level I erectile dysfunctions

in diabetics was proposed by the Italian Diabetology Society’s ‘Diabetic ropathy’ Study Group in 1996:

Neu-Anamnestic screening

Targeted questionnaire

Penile biothesiometry

Cardiovascular tests

PGE 1 drug stimulation

Patients =40 years old: 5 lg

Patients ?40 years old: 10 lg

If the erectile response is

absent: repeat after 1 week with 10 or 20lg PGE 1

persistently absent: refer to your andrology unit for further investigation

(Rigiscan, Ultrasound, Doppler ultrasonography, invasive vascular tests)

If the erectile response is

present: oral and/or intracavernosal and/or psychological treatment.

The protocol proposed by Japanese authors is more complex In it, lar investigations, Rigiscan and audiovisual sexual stimulation precede intra-cavernosal drug stimulation If there is no erectile response, nocturnal penileerectile tumescence is monitored, which, if found, allows us to label our patient

vascu-as ‘not suffering from any organic disorder’

Treatment

The treatment for erectile dysfunction in diabetics (table 3) is primarilybased on rectifying the glucose-metabolizing disorder by diet and/or drugtreatment and by persuading the patient to abstain from risk factors likesmoking and alcohol abuse In addition, every possible effort will be made tofind substitutes for any drugs with a negative impact on sexual function.Psychological Treatment

Psychotherapy can help to minimize anxiety and modify the couple’ssexual habits in a helpful fashion Even so, ‘psychological problems’ appear

to be no more common among diabetics than among the general population

Drug Treatment

Treatment witha2-antagonists (yohimbine) ora1-antagonists (doxazosin,terazosin, etc.) can enhance penile vasodilation but cannot alone induce and

Table 3 Treatment of erectile

dysfunction Psycho- or behavioural therapy

Drug treatment Yohimbine

a 1 -antagonists Local nitroderivatives Sildenafil

Endourethral alprostadil Intracavernosal injection Papaverine

Alprostadil Phentolamine Moxisylyte External mechanical support Vacuum device

Revascularization surgery Venous

Arterial Penile prosthesis

maintain erection These drugs are indicated in patients with high bloodpressure and certain prostate pathologies Moderate success has been obtainedwith topical nitroderivatives that are rapidly absorbed through the skin (nitro-glycerin) These act directly by stimulating the release of the adenylase cyclasewhich relaxes the smooth muscle tissue

Sildenafil, a selective inhibitor of type V cyclic phosphodiesterase in thecorpus cavernosus, prevents the breakdown of cGMP and therefore acts onthe NO mechanism (NO/cGMP) that plays a dominant part in the relaxation

of smooth muscle tissue and hence penile erection This is a rapidly absorbeddrug that is taken 60 min before intercourse and has an effect lasting about

4 h It does not trigger erection as such but improves its quality by promotingthe smooth muscle relaxation initiated by NO release It is important toremember that Sildenafil is contraindicated in men taking nitrates, given therisk of significant reductions in blood pressure caused by intensification ofthe vasodilatory effects of such drugs Caution must also be exercised in anumber of other clinical conditions (kidney or liver problems) and/or whenthe patient is taking other drugs which might interfere with absorption kinetics

In doses of 25–100 mg, Sildenafil has proved effective in 59% of diabeticpatients with erectile dysfunction (placebo 15%) It is well tolerated and the

side effects reported in this population are: headache, dyspepsia and flushing.Other side effects described are temporary and relate to the perception ofcolours, sensitivity to light and fuzzy vision.

Alprostadil (a synthetic preparation of PGE1), also appears as a compoundthat is incorporated into pellets for intraurethral application (MUSE: MedicalUrethral System for Erection) Patients have to be taught how to use theapplicator which delivers a microsuppository into the urethra at an averagedose of 500–1,000lg The side effects are penile pain, stranguria and slightbleeding MUSE is contraindicated without the use of a condom in intercoursewith a partner who is pregnant or liable to conceive It is not widely used

in Italy and may be contraindicated in diabetics with their greater risk ofinfections

Intracavernosal Injection

Intracavernosal pharmacoprosthesis is currently one of the most widelyused treatments and enjoys good patient compliance, especially among dia-betics who get a satisfactory response in 66% of cases compared to only 23%

in nondiabetics with erectile dysfunction Vasodilatory substances either alone

or in combination (papaverine, alprostadil, phentolamine and atropine) areinoculated directly into the corpus cavernosum The patient has to be trained

in the inoculation procedure and doses must be carefully selected in order toavoid prolonged erections or priapism Erection occurs about 10 min afterinoculation of the substance The incidence of complications depends on thetype of drug used Pain on the inoculation site is rare, but penile fibrosis orpriapism may develop over time The most commonly used drug is alprostadilbecause of its minimal side effects and the dose varies from 5 to 20 lg Thisprostaglandin produces cAMP which acts with cGMP to relax the smoothmusculature Both are metabolized by the type V phosphodiesterase found inboth the penile smooth muscle tissue and the eyes Moxisylyte is a selective

a1drug used in 10- to 20-lg doses Its minimal side effects include penile painand prolonged erections Vasointestinal peptide combined with phentolamine

is now in the advanced research stage Its side effects are flushing and dia and, rarely, penile pain

tachycar-External Mechanical Support

A patient who prefers not to use drugs can employ a so-called ‘vacuumdevice’ This is a cylinder into which the penis is inserted The cylinder ispressed against the abdominal wall and a mechanical or electric pump isactivated to create a vacuum which draws blood into the corpus cavernosumthereby producing a penile erection The erection is maintained by a rubberring around the base of the penis for as long as the ring remains in situ

Patient compliance with this system is generally good However the deviceshould not be used for more than 30 min at a time, since it can create a feeling

of chill in the penis Furthermore, ejaculation is generally impeded and thismay make for a less satisfying orgasm The vacuum device can be used topotentiate the effect of drug treatment

Dunsmuir WD, Holmes SAV: The aetiology and management of erectile, ejaculatory, and fertility problems

in men with diabetes mellitus Diabet Med 1996;13:700–708.

Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB: Impotence and its medical and psychosocial correlates: Results of the Massachusetts male aging study J Urol 1994;151:54–61 Klein R, Klein BEK, Lee KE, Moss SE, Cruickshanks KJ: Prevalence of self-reported erectile dysfunction

in people with long-term IDDM Diabetes Care 1996;19:135–141.

Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA: Impaired neurogenic and mediated relaxation of penile smooth muscle from diabetic men with impotence N Engl J Med 1989;320:1025–1030.

endothelium-Takanami M, Nagao K, Ishii N, Miura K, Shirai M: Is diabetic neuropathy responsible for diabetic impotence? Urol Int 1997;58:181–185.

Prof G.M Molinatti, Dipartimento di Medicina Interna, Universita` degli Studi di Torino, Ospedale Molinette, I–10126 Torino (Italy)

Tel +39 (0)11 6635318, Fax +39 (0)11 6634751, E-Mail molinatti@molinette.unito.it