cause of the Charcot foot and most patients have a dense neuropathy, but good circulation. Early animal experiments suggested that walking on an insensitive limb could lead to joint destruction. Excessive and repetitive stress to bones leads to microfractures, which render the bone more brittle and could lead to bone and joint destruction. However, the degree of bone destruction often seen in the absence of major injury has suggested an underlying bone abnormality. Diabetic neuropathy leads to an increase in bone blood flow, which may promote osteoclastic activity and bone resorption. Indeed, a small study has demonstrated increased serum markers of osteoclastic action in patients with acute Charcot that was not accompanied by a concomitant increase in markers of osteoblastic activity. Furthermore, lower limb bone mineral 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 usually presents late, the opportunities for further studies are limited. In the early acute stages, when bone turnover is high, treatment involves rest and immobilization of the foot (usually with a total contact cast) in an attempt to reduce the metabolic activity within the bone. There is now some evidence that bisphosphonate drugs given during this acute phase may shorten the duration of the acute phase presumably by reducing the bone turnover directly, and hence slowing down the process which weakens the bone and renders it susceptible to further fracture and fragmentation. Whenever unilateral swelling ofthe foot is present insomeone with diabetic neuropathy, Charcot neuroarthropathy must be considered. Plain X-ray is usually adequate to make or exclude the diagnosis, and while the radiological appearances can be similar to those of osteomyelitis, in the absence of a source of infection (such as an overlying ulcer), neuroarthropathy is nearly always the cause. Conclusion Although the roles of peripheral neuropathy and peripheral vascular dis- ease are now well established as the main aetiological factors in diabetic foot ulceration, there is much work to be done in both the way in which ulcers develop and the interactions of the main risk factors with each other and with all the other risk factors discussed in this chapter. However, this complexity should not deter the clinician, as it is now very clear that simple clinical tests will identify patients at risk of ulceration and amputation, and appropriate, but simple education about footcare can greatly reduce the likelihood of 216Shaw/Boulton developing diabetic foot problems. Foot ulcers can be difficult to heal, but treatment is likely to be successful in the vast majority of cases when pressure is removed, callus and necrotic tissue debrided, infection controlled, and a good 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 217Foot Problems in Diabetes Chapter XVI Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 218–228 Erectile Dysfunction in Diabetes and Its Treatment M. Tagliabue, G.M. Molinatti 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 recog- nized. In the pre-insulin era, impotence was considered one of the commonest symptoms of diabetes, being present in both severe and milder forms of the disease. 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 for the diabetic individual in all his or her complexity. Today, diabetology is no longer satisfied to keep diabetics in reasonably good health, but also addresses everything that may affect the individual’s quality of life and, from this standpoint, sexuality cannot fail to occupy a role of primary importance. In the diabetic male, it is sexuality in the narrowest sense, namely what is conventionally designated ‘potentia coeundi’, that is compromised 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 in the healthy control population. However, the complication is still considered occult since it is often unreported by patients. In the various studies published, the incidence of this dysfunction in diabetics varies from 28 to 59%. The predictive factors are: age, duration of the disease, degree of metabolic com- 218 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 very earliest epidemiological studies showed that the incidence of impotence in diabetic 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 Epidemiologic Study in particular is highly significant (p=0.0001), rising from 1.1% in the 21–30 age group to 47.1% among insulin-dependent diabetics over 43 years old. 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 times more likely to present this complication than those with only a 10- to 14-year history. However, the link between erectile dysfunction and disease duration is not inevitable, since the erectile disorder occasionally appears before the clinical onset of the diabetes. In addition, diabetic erectile dysfunction is also related to HbA 1c levels which indicate the ability to metabolize glucose, the risk of impotence tripling in those worst affected (HbA 1c ?9.8%). That in- creased risk is explained when we consider the treatment needed to control diabetes – restrictive diets and drugs to lower blood sugar and/or insulin – that are most aggressive in the most metabolically compromised patients. Both diabetic retinopathy, especially if severe, and neuropathy, both peripheral and autonomic, are related to a higher incidence of erectile dysfunction which is 5.3 times more likely to occur in such patients. High blood pressure is an additional risk factor especially when treated by certain drugs such as - blockers, methyldopa and particularly diuretics. Finally, excessive drinking and 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: incidence increasing with age, duration of diabetes, severity of failure to metabolize glucose, complexity of diabetic therapy, diabetic complications (angiopathy, retinopathy, kidney disease, neuropathy) as well as cardiovascular disease and the use of certain drugs in its treatment and finally habitual smoking. Apart from erectile dysfunction, diabetes can also produce problems with ejaculation, especially retrograde ejaculation as the so-called ‘dry orgasm’ (a dysfunction of the autonomic and somatic nervous system) which occurs in 1–4% of male diabetics, most particularly in those with the longest history of the 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 commoner among diabetics than in the general population, accounting for 8% of ejacula- tory disorders. By contrast, the incidence of premature ejaculation is almost 219Treatment of Erectile Dysfunction in Diabetes 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 confirms the psychosomatic pathogenesis of that disorder. Be that as it may, the organic character of diabetes and its complications should 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 psy- chogenic and organic components, the latter linked to the failure to metabolize glucose and the related organic complications, not to mention the pathological conditions known to be caused by the drugs used to treat those complications (table 1). However, many studies have confirmed that erectile dysfunction is primarily organic in origin, since the dysfunction is rarely reversible. In mon- itoring the nocturnal erections associated with REM sleep, researchers have found fewer REM sleep-erections in diabetic males, a finding which supports the view that impotence in diabetics is more likely to be organic than psycho- logical in origin. Nevertheless, the role of hormonal abnormalities in the physiopathology of organic erectile dysfunction remains controversial. It is therefore vital to examine the fundamental psychological and organic factors involved in the sexual function of diabetics. The Psychological Factor There is substantial evidence to suggest that erectile dysfunction in dia- betes is often psychological in origin. The main contributory factors are: awareness of suffering from a chronic condition, relationship problems and the fear of failure during sexual intercourse as a result of that situation. It is not clear whether such psychological factors are greater in the diabetics affected than in the general population of people with erectile dysfunctions, though diabetics with theproblem appear more stressed than thoseunaffected. Accord- 220Tagliabue/Molinatti ing to some authors, diabetic patients are more fearful of developing erectile dysfunctions as a complication of their condition than of going blind, but however 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. Pa- tients may recover normal erectile function, as soon as insulin injections to cor- rect their impaired glucose metabolism are started. The impaired delivery of oxygentothe tissue,causedbytheformation ofglycosylatedhaemoglobin which has a greater affinity foroxygen increases vascular permeability,depositinglipo- protein on the vessel wall and this may be the cause of the vascular damage. Vascular Alterations Vascular disorders cause impotence in 18% of diabetic males. Haemo- dynamic disturbances in diabetics may be either arterial (macro- and/or micro- angiopathies) or venous given the direct communication between the two vascular systems. 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 of impotence in diabetics is of vascular origin and atherosclerosis is, in fact, the earliest lesion on the peripheral arteries of the penis. Histological findings of pathological alterations to the small arteries are also reported to occur before any neurological damage. Later, neurological damage caused by the same atherosclerotic 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. Perineural fibrosis may occur without causing any direct damage to the nerve fibres. There is an equally close link between ischaemic heart disease and diabetic erectile dysfunction, both being caused by the ischaemic vasculopathy affecting both areas. Diabetic microangiopathies produce alterations and irregularities in the local microvascular blood flow. Those alterations concern: endothelial cell metabolism and function; the basal membrane of vessel walls, which are thickened; oxygen transportation; the characteristics of blood flow and haemostasis. In the venous system the uncontrolled blood flow and the failure of the arteriovenous 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. 221Treatment of Erectile Dysfunction in Diabetes 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 inter- action of three systems: adrenergic, cholinergic and VIPergic. Other factors like nitric oxide (NO) initially called endothelium-derived relaxing factor (EDRF) and produced by constitutive nitric oxide synthetase (cNOS) which increases the concentration of intracellular cyclic guanosine monophosphate (cGMP) may well be involved in the relaxation of the smooth muscle in the corpus cavernosum. As we know, the earliest studies into NO production by cNOS were carried out on bioptic samples taken from the corpus cavernosum tissue of impotent diabetics who presented reduced acetylcholine vasodilation. The reduced NO production and consequent reduction in intracellular cGMP probably leads to an increase in intracytosolic calcium that is responsible for the contraction in smooth muscle cells. In diabetics there may well also be a reduction in the noradrenaline, VIP and acetylcholine content of the corpus cavernosum and both the cholinergic fibres and their ability to synthesize acetylcholine may be reduced over time, as may the VIPergic pathways. Cho- linergic stimulation is certainly known to increase NO production. This would compromise both the neurogenic and the endothelial mechanisms dependent on the relaxation of the cavernosal smooth muscle. Increased levels of endoth- elin-1, a powerful vasoconstrictor released by the endothelial cells, have also been found in patients with erectile dysfunction, especially those with diabetes. That finding suggests that endothelial dysfunction may contribute to erectile dysfunction and that in the absence of any significant vascular element the increase in plasmatic endothelin-1 may be related to early atherosclerosis. The autocrine role of this peptide, which causes the smooth muscle cells of the corpus cavernosum to proliferate and/or contract, has been confirmed in experimentally induced diabetes mellitus. Somatic and autonomic neuropathy (bladder dysfunction) is often associ- ated with impotence in diabetes and is responsible for 67% of cases, according to recent statistics. The disease causes axonaldegeneration 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 be somewhat improved iftheir glucose metabolism problem is carefully controlled. Researchers have also found a lack of coordination in the electrical activity of the corpus cavernosum in diabetics with a consequent loss 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 and researchers have also documented a diminished response in terms of absolute 222Tagliabue/Molinatti testosterone increases after HCG stimulation. Some reports describe a decrease in the free fraction of testosterone and estradiol, which they attribute to a marked 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. Theevidenceoncirculatinggonadotropinandprolactinisconflicting.Some report an increase in urinary LH among diabetics with primary organic impo- tence, as well as a reduction in levels of free testosterone. Diabetes and obesity often go together and increased aromatization of testerostene in the adipose tissue produces an increase in oestrogen levels thatcontributes to erectile failure. In actual fact, there is increasing doubt about the role of steroids and other hormones in the aetiopathology of sexual disorders in the diabetic male and the variations that may be found do not appear to play a particularly important part in the genesis of this complication. Spermatogenesis The most frequently encountered alteration in spermatogenesis is reduced spermatozoa motility which appears to be closely linked to the metabolic disorders and the presence of autonomic neuropathy. Functional damage to the seminal vesicles is probably a major contributory factor. Studies conducted on rats with streptozotocin-induced diabetes revealed an alteration in the animals’ sexual behaviour and a reduction in the weight of their secondary sex 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 in their 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 system over the penile circulation) while, at least initially, the libido remains unaffected. Anamnesis Anamnesis is the first step. In diabetics, erectile dysfunction usually arises insidiously, evolving slowly but inexorably. Physicians should pay particular 223Treatment of Erectile Dysfunction in Diabetes 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 (office-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 are common) and the drugs they are being treated with, since these often have a negative impact on sexual activity itself. In the case of diabetes mellitus, it is essential to know type, duration and treatment, how far glucose metabolism is compromised and whether or not the patient presents with micro/macroangi- opathic and/or neuropathic complications. In order to obtain a full diagnostic picture, the investigation of organic factors must be accompanied by investigation of learning, intrapsychic, dyadic, systemic and sociocultural factors. The sexual anamnesis will cover aspects like the presence or absence of sexual desire, the presence of spontaneous erections on awakening and/or in response to visual stimuli and/or erotic thoughts and/or physical stimulation by a partner, as well as the quality and frequency of sexual intercourse, the presence of any significant changes in recent months and the description of the sexual intercourse itself. Instrumental Investigations The instrumental investigations indicated include those used to examine the vascular system (ultrasound scans or basal and dynamic Doppler echo- sonography) which usually involves the intracavernosal injection of prosta- glandin (PGE 1 ) and penobrachial plethysmography. Others examine neurological aspects (vibration and heat perception thresholds, autonomic cardiovascular tests, peroneal motor conduction velocity and sural sensitivity tests; possibly also sacral evoked potential tests). Then there are urological tests (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 was assessed using the Rigiscan technique and found to be related to autonomic nerve damage. 224Tagliabue/Molinatti An easy-to-use protocol for the diagnosis of level I erectile dysfunctions in diabetics was proposed by the Italian Diabetology Society’s ‘Diabetic Neu- ropathy’ Study Group in 1996: Anamnestic screening Targeted questionnaire Penile biothesiometry Cardiovascular tests PGE 1 drug stimulation Patients =40 years old: 5 g Patients ?40 years old: 10 g If the erectile response is absent: repeat after 1 week with 10 or 20 g 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, vascu- lar investigations, Rigiscan and audiovisual sexual stimulation precede intra- cavernosal drug stimulation. If there is no erectile response, nocturnal penile erectile tumescence is monitored, which, if found, allows us to label our patient as ‘not suffering from any organic disorder’. Treatment The treatment for erectile dysfunction in diabetics (table 3) is primarily based on rectifying the glucose-metabolizing disorder by diet and/or drug treatment and by persuading the patient to abstain from risk factors like smoking and alcohol abuse. In addition, every possible effort will be made to find substitutes for any drugs with a negative impact on sexual function. Psychological Treatment Psychotherapy can help to minimize anxiety and modify the couple’s sexual 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 with  2 -antagonists (yohimbine) or  1 -antagonists (doxazosin, terazosin, etc.) can enhance penile vasodilation but cannot alone induce and 225Treatment of Erectile Dysfunction in Diabetes [...]... sulphonylureas, according to the American Diabetes Association no restrictions in the use of metformin in combination with sulphonylureas is justified Multifactorial Intervention in Type 2 Diabetes mellitus 231 Insulin Insulin treatment can be given as monotherapy or as combination therapy with insulin and oral hypoglycaemic agents From studies comparing several insulin regimens, bedtime NPH insulin in combination... metformin versus conventional treatment and sulphonylureas or insulin in obese patients was examined Patients randomized to metformin had lower risks for all-cause mortality, strokes and any diabetes- related endpoint than patients on conventional treatment, sulphonylureas or insulin and metformin was found to cause less weight gain and fewer hypoglycaemic attacks than sulphonylureas or insulin In another... metformin twice daily and self-adjustment of insulin dose based on patients’ own fasting blood glucose measurements seems to be an easy and safe way of obtaining optimal glycaemic control This combined insulin and metformin treatment regimen is associated with less weight gain than monotherapy with insulin Whereas hypoglycaemia is frequent in type 1 diabetes mellitus, this is not the case in insulin resistant... multifactorial intervention in patients with type 2 diabetes and microalbuminuria: The Steno Type 2 randomised study Lancet 199 9;353:617–622 Hansson L, Lindholm LH, Niskanen L, et al: Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial Lancet 199 9;353:611–616... Thorgeirsson G: Cholesterol lowering ¨ ¨ ¨ with simvastatin improves prognosis of diabetic patients with coronary heart disease Diabetes Care 199 7;20:614–620 Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M: Long-term stabilizing effect of angiotensinconverting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type 2 diabetic patients Ann Intern Med 199 3;118:577–581 Sacks FM,... insulin-induced weight gain Diabetologia 199 6; 39( suppl 1):A33 Dr Oluf Pedersen, Steno Diabetes Centre, Niels Steensens Vej 2, DK–2820 Copenhagen (Denmark) Tel +45 44 43 90 50, Fax +45 44 43 82 32 Gæde/Pedersen 240 Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment Basel, Karger, 2000, pp 241–252 Chapter XVIII Managing Diabetes and Pregnancy John L Kitzmiller Maternal-Fetal... on extrapolation of results from the original follow-up period to a 5-year period) Trials Hyperglycaemia UKPDS [UKPDS Group, 199 8a] Any diabetes- related endpoint Myocardial infarction (p>0.05) Any microvascular endpoint Hypertension UKPDS [UKPDS Group, 199 8b] Any diabetes- related endpoint Diabetes- related death HOT Study (subgroup analysis) [Hansson et al., 199 8] Major cardiovascular event Cardiovascular... conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 199 8a;352:837–853 UKPDS Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 BMJ 199 8b;317:703–713 Yki-Jarvinen H, Nikkila K, Ryysy L, Tulokas T, Vanamo R, Heikkila M: Comparison of bedtime ¨ ¨ ¨ insulin regimens in NIDDM: Metformin prevents insulin-induced... (eds): New Concepts in Diabetes and Its Treatment Basel, Karger, 2000, pp 2 29 240 Chapter XVII Multifactorial Intervention in Type 2 Diabetes mellitus Peter Gæde, Oluf Pedersen Steno Diabetes Centre, Copenhagen, Denmark Introduction The prevalence of type 2 diabetes mellitus is rapidly increasing Patients with type 2 diabetes suffer from micro- as well as macrovascular complications, the latter causing... [Pyorala et al., 199 7] ¨ ¨ ¨ Major CHD event CARE [Sacks et al., 198 6] Major CHD event (p>0.05) Microalbuminuria Ravid study [Ravid et al., 199 3] Progression to nephropathy Aspirin HOT Study [Hansson et al., 199 8] Major cardiovascular events Myocardial infarction US Male Physicians’ Health Study [Final report, 198 9] Myocardial infarction Multifactorial intervention Steno 2 Study [Gæde et al., 199 9] Any microvascular . Problems in Diabetes Chapter XVI Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment. Basel, Karger, 2000, pp 218–228 Erectile Dysfunction in Diabetes and Its Treatment M per year, in which case insulin treatment must be initiated to maintain satisfactory gly- caemic control. In a substudy in the UKPDS, the effect of metformin versus conventional treatment and sulphonylureas. or insulin in obese patients was examined. Patients randomized to metformin had lower risks for all-cause mortality, strokes and any diabetes- related endpoint than patients on conven- tional treatment,