The autonomic nervous system (ANS) supplies all organs in the body and consists of an afferent and an efferent system, with long efferents in the vagus (cholinergic) and short postganglionic unmyelinated fibers in the sympathetic system (adrenergic). A third component is the neuropeptidergic system with its neurotransmitters substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP) amongst others. Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes but remains among the least recognized and understood. Diabetic autonomic neuropathy (DAN) can cause dysfunction of every part of the body, and has a significant negative impact on survival and quality of life (143). The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the pupils, sweat glands, genitourinary system, gastrointestinal tract, adrenal medullary system, and the cardiovascular system (Table 1). Clinical symptoms generally do not appear until long after the onset of diabetes. However, subclinical autonomic dysfunction can occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1 diabetes patients (144).

Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, hand grip and heating (145). The defect is associated with a reduction in the amplitude of vasomotion (146) and resembles premature aging (145). There are differences in the glabrous and hairy skin circulations. In hairy skin a functional defect is found prior to the development of neuropathy (147) and is correctable with antioxidants (148). The clinical counterpart is a dry cold skin, loss of sweating, develops of fissures and cracks that are portals of entry for organisms leading to infectious ulcers and gangrenes. Silent myocardial infarction, respiratory failure, amputations and sudden death are hazards for the diabetic patients with cardiac autonomic neuropathy (149,150). Therefore, it is vitally important to make this diagnosis early so that appropriate intervention can be instituted (151).

Disturbances in autonomic nervous system may be functional e.g. gastroparesis with hyperglycemia and ketoacidosis, or organic wherein nerve fibers are actually lost. This creates inordinate difficulties in diagnosing, treating and prognosticating as well as establishing true prevalence rates. Tests of autonomic function generally stimulate entire reflex pathways. Furthermore, autonomic control for each organ system is usually divided between opposing sympathetic and parasympathetic innervation, so that heart rate acceleration, for example, may reflect either decreased parasympathetic or increased sympathetic nervous system stimulation. Since many conditions affect the autonomic nervous system and AN is not unique to diabetes, the diagnosis of diabetic autonomic neuropathy rests with establishing the diagnosis and excluding other causes. The best studied methods, and for which there are large databases and evidence to support their use in clinical practice, relate to the evaluation of cardiovascular reflexes. In addition the evaluation of orthostasis is fairly straightforward and is readily done in clinical practice, as is the establishment of the cause of gastrointestinal symptoms and erectile dysfunction. The evaluation of pupillary abnormalities, hypoglycemia unawareness and unresponsiveness, neurovascular dysfunction and sweating disturbances are for the most part done only in research laboratories, require specialized equipment and familiarity with the diagnostic procedures, and are best left in the hands of those who have a special interest in the area. Table 2 below presents the diagnostic tests that would be applicable to the diagnosis of cardiovascular autonomic neuropathy. These tests can be used as a surrogate for the diagnosis of AN of any system since it is generally rare to find involvement (although it does occur) of any other division of the ANS in the absence of cardiovascular autonomic dysfunction. For example if one entertains the possibility that the patient has erectile dysfunction due to AN, then prior to embarking upon a sophisticated and expensive evaluation of erectile status a measure of heart rate and its variability in response to deep breathing would if normal exclude the likelihood that the erectile dysfunction is a consequence of disease of the autonomic nervous system. The cause thereof would have to be sought elsewhere. Similarly it is extremely unusual to find gastroparesis secondary to AN in a patient with normal cardiovascular autonomic reflexes.

The role of over-activation of the autonomic nervous system is illustrated in Figure-9 (152).

There are few data on the longitudinal trends in small fiber dysfunction. Much remains to be learned of the natural history of diabetic autonomic neuropathy. Recently, Karamitsos et al (153) reported that the progression of diabetic autonomic neuropathy is significant during the 2 years subsequent to its discovery.

The mortality for diabetic autonomic neuropathy has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy (10). In a meta analysis, the Mantel-Haenszel estimates for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53 to 2.51 (p<0.001; n = 1,468 total subjects). Thus, a consistent association between CAN and the presence of silent myocardial ischemia was shown (152) in figure-10.

It has now become clear that strict glycemic control (20) and a stepwise progressive management of hyperglycemia, lipids, blood pressure and use of antioxidants (155) and ACE inhibitors (156) reduce the odds ratio for autonomic neuropathy to 0.32 (157). It has also been shown that early mortality is a function of loss of beat to beat variability with MI. This can be reduced by 33% with acute administration of insulin (158). Kendall et al (159) reported that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long standing diabetes and established autonomic neuropathy. Burger et al (160) showed that a reversible metabolic component of CAN exists in patients with early CAN.

The syndrome of postural hypotension is posture-related dizziness and syncope. Patients who have Type 2 diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension (161). Postural hypotension in the patient with diabetic autonomic neuropathy can present a difficult management problem. Elevating the blood pressure in the standing position must be balanced against preventing hypertension in the supine position.

Supportive Garments: Whenever possible, attempts should be made to increase venous return from the periphery using total body stockings. But leg compression alone is less effective, presumably reflecting the large capacity of the abdomen relative to the legs (162). Patients should be instructed to put them on while lying down and to not remove them until returning to the supine position.

Drug Therapy: Some patients with postural hypotension may benefit from treatment with 9-flurohydrocortisone. Unfortunately, symptoms do not improve until edema occurs, and there is a significant risk of developing congestive heart failure and hypertension. If fluorohydrocortisone does not work satisfactorily, various adrenergic agonists and antagonists may be used. If the adrenergic receptor status is known, then therapy can be guided to the appropriate agent. Metoclopramide may be helpful in patients with dopamine excess or increased sensitivity to dopaminergic stimulation. Patients with α2-adrenergic receptor excess may respond to the α2-antagonist yohimbine. Those few patients in whom ß-receptors are increased may be helped with propranolol. α2-adrenergic receptor deficiency can be treated with the α2-agonist, clonidine, which in this setting may paradoxically increase blood pressure. One should start with small doses and gradually increase the dose. If the preceding measures fail, midodrine, an α1-adrenergic agonist or dihydroergotamine in combination with caffeine may help. A particularly refractory form of postural hypotension occurs in some patients post-prandially and may respond to therapy with octreotide given subcutaneously in the mornings.

During sleep, increased sympathetic drive is a result of repetitive episodes of hypoxia, hypercapnia and obstructive apnea acting through chemoreceptor reflexes. Increased sympathetic drive has been implicated in increased blood pressure variability with repetitive sympathetic activation and blood pressure surges impairing baroreflex and cardiovascular reflex functions (152). A direct relationship between the severity of OSA and the increase in blood pressure has been noted. Furthermore, the use of continuous positive airway pressure (CPAP) for the treatment of OSA has been shown to lower blood pressure and improve cardiovascular autonomic nerve fiber function for individuals with OSA , Withdrawal of CPAP for even a short period (i.e., 1 week) has been shown to result in a marked increase in sympathetic activity(152).

Gastrointestinal motor disorders are frequent and widespread in type 2 diabetic patients, regardless of symptoms (163) and there is a poor correlation between symptoms and objective evidence of a functional or organic defects. The first step in management of diabetic gastroparesis consists of multiple, small feedings. The amount of fat should be decreased, as it tends to delay gastric emptying. Maintenance of glycemic control is important (164,165). Metoclopramide may be used. Cisapride and domperidone (166,167) has been shown to be effective in some patients, although probably no more so than metoclopramide. Cisapride has however been withdrawn from the market. Erythromycin given as either a liquid or suppository also may be helpful. Erythromycin acts on the motilin receptor, "the sweeper of the gut," and shortens gastric emptying time (168). If medications fail and severe gastroparesis persists, jejunostomy placement into normally functioning bowel may be needed. Different treatment modalities for gastroparesis includes dietary modifications, prokinetic and antiemetic medications, measures to control pain and address psychological issues, and endoscopic or surgical options in selected instances (169).

Enteropathy involving the small bowel and colon can produce both chronic constipation and explosive diabetic diarrhea, making treatment of this particular complication difficult.

Antibiotics: Stasis of bowel contents with bacterial overgrowth may contribute to the diarrhea. Treatment with broad-spectrum antibiotics is the mainstay of therapy, including tetracycline or trimethoprim and sulfamethoxazole. Metronidazole appears to be the most effective and should be continued for at least 3 weeks.

Cholestyramine: Retention of bile may occur and can be highly irritating to the gut. Chelation of bile salts with cholestyramine 4g tid mixed with fluid may offer relief of symptoms.

Diphenoxylate plus Atropine: Diphenoxylate plus atropine may help to control the diarrhea, however, toxic megacolon can occur, and extreme care should be used.

Diet: Patients with poor digestion may benefit from a gluten-free diet. Beware of certain fibers in the neuropathic patient that can lead to bezoar formation because of bowel stasis in gastroparetic or constipated patients.

Patients with neurogenic bladder should be instructed to palpate their bladders and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver to start the flow of urine. Parasympathomimetics such as bethanechol are sometimes helpful, although frequently they do not help to fully empty the bladder. Extended sphincter relaxation can be achieved with an α-1-blocker, such as doxazosin (29). Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.

Erectile dysfunction (ED) occurs in 50-75% of diabetic men, and it tends to occur at an earlier age than in the general population. The incidence of ED in diabetic men aged 20-29 years is 9% and increases to 95% by age 70. It may be the presenting symptom of diabetes. More than 50% notice the onset of ED within 10 years of the diagnosis, but it may precede the other complications of diabetes. The etiology of ED in diabetes is multifactorial. Neuropathy, vascular disease, diabetes control, nutrition, endocrine disorders, psychogenic factors as well as drugs used in the treatment of diabetes and its complications play a role (170) (171). The diagnosis of the cause of ED is made by a logical stepwise progression (170) (171) in all instances. An approach to therapy has recently been presented to which the reader is referred; figure below shows flow chart modified from Vinik et. al., 1998. (170).

A thorough work-up for impotence will include: medical and sexual history; physical and psychological evaluations; blood test for diabetes and a check of levels of testosterone, prolactin, and thyroid hormones; test for nocturnal erections; tests to assess penile, pelvic, and spinal nerve function; and test to assess penile blood supply and blood pressure. The flow chart provided is intended as a guide to assist in defining problem.

The healthcare provider should initiate questions that will help distinguish the various forms of organic erectile dysfunction from those that are psychogenic in origin. Physical examination must include an evaluation of the autonomic nervous system, vascular supply, and the hypothalamic-pituitary-gonadal axis.

Autonomic neuropathy causing ED is almost always accompanied by loss of ankle jerks and absence or reduction of vibration sense over the large toes. More direct evidence of impairment of penile autonomic function can be obtained by demonstrating normal perianal sensation, assessing the tone of the anal sphincter during a rectal exam, and ascertaining the presence of an anal wink when the area of the skin adjacent to the anus is stroked or contraction of the anus when the glans penis is squeezed, i.e., the bulbo-cavernosus reflex. These measurements are easily and quickly done at the bedside and reflect the integrity of sacral parasympathetic divisions.

Vascular disease is usually manifested by buttock claudication but may be due to stenosis of the internal pudendal artery. A penile/brachial index of <0.7 indicates diminished blood supply. A venous leak manifests as unresponsiveness to vasodilators and needs to be evaluated by penile Doppler sonography.

In order to, distinguish psychogenic from organic erectile dysfunction, nocturnal penile tumescence (NPT) measurement can be done. Normal NPT defines psychogenic ED, and a negative response to vasodilators implies vascular insufficiency. Application of NPT is not so simple. It is much like having a sphygmomanometer cuff inflate over the penis many times during the night while one is trying to have a normal night's sleep and the REM sleep associated with erections. The individual may have to take home the device and become familiar with it over several nights before one has a reliable estimate of the failure of NPT.

A number of treatment modalities are available and each treatment has positive and negative effects; therefore patients must be made aware of both aspects before a therapeutic decision is made. Before considering any form of treatment, every effort should be made to have the patient withdraw from alcohol and eliminate smoking. First and foremost, the patient should be removed, if possible, from drugs that are known to cause erectile dysfunction. Metabolic control should be optimized.

According to more recent research, relaxation of the corpus cavernosus smooth-muscle cells is caused by NO and cGMP, and the ability to have and maintain an erection depends on NO and cGMP. Sildenafil (Viagra) exerts its effect by transiently increasing NO and cGMP levels. Sildenafil is a GMP type-5 phospodiesterase inhibitor that enhances blood flow to the corpora cavernosae with sexual stimulation. A 50 mg tablet taken orally is the usual starting dose, 60 minutes before sexual activity. Lower doses should be considered in patients with renal failure and hepatic dysfunction. The duration of the drug effect is 4 hours. Before it is prescribed, it is important to exclude ischemic heart disease. It is absolutely contraindicated in patients being treated with nitroglycerine or other nitrate-containing drugs. Severe hypotension and fatal cardiac events can occur (172). Sildenafil was well tolerated, effective and increased the number of succesful attempts of intercourse. Sildenafil should be considered as first line treatment for erectile dysfunction in men with Type 2 diabetes mellitus (173). Tadalafil at 10 and 20 mg improved erectile function irrespective of the type of diabetes, presence of microvascular complications, or type of diabetes treatment (174) Vardenafil statistically improved erectile function and was generally well tolerated in diabetic patients with ED. Vardenafil treatment was effective in increasing intercourse success rates at all levels of baseline ED severity, at each level of plasma HbA1c, and for type 1 and 2 diabetes. Treatment-emergent adverse events were primarily mild to moderate headache, flushing, and rhinitis (175)

Direct injection of prostacylin into the corpus cavernosum will induce satisfactory erections in a significant number of men. Also, surgical implantation of a penile prosthesis may be appropriate. The less expensive type of prosthesis is a semirigid, permanently erect type that may be embarrassing and uncomfortable for some patients. The inflatable type is three times more expensive and subject to mechanical failure, but it avoids the embarrassment caused by other devices.

Women with diabetes mellitus may experience decreased sexual desire and more pain on sexual intercourse, but they are at risk of decreased sexual arousal, with inadequate lubrication (176). Diagnosis of female sexual dysfunction using vaginal plethysmography to measure lubrication and vaginal flushing has not been well established.

In diabetic autonomic neuropathy, the motor function of the bladder is unimpaired, but afferent fiber damage results in diminished bladder sensation. The urinary bladder can be enlarged to more than three times its normal size. Patients are seen with bladders filled to their umbilicus, yet they feel no discomfort. Loss of bladder sensation occurs with diminished voiding frequency, and the patient is no longer able to void completely. Consequently, dribbling and overflow incontinence are common complaints. A postvoiding residual of greater than 150 cc is diagnostic of cystopathy. Cystopathy may put the patients at risk for urinary infections.

Patients with cystopathy should be instructed to palpate their bladder and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver (massage or pressure on the lower portion of abdomen just above the pubic bone) to start the flow of urine. The principal aim of the treatment should be to improve bladder emptying and to reduce the risk of urinary tract infection. Parasympathomimetics such as bethanechol are sometimes helpful, although frequently they do not help to fully empty the bladder. Extended sphincter relaxation can be achieved with an alpha-1-blocker, such as doxazosin . Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.