Ejaculatory dysfunction in men with diabetes mellitus

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Abstract

Diabetes mellitus (DM) is a metabolic disorder that is characterized by elevated blood glucose levels due to absolute or relative insulin deficiency, in the background of β-cell dysfunction, insulin resistance, or both. Such chronic hyperglycemia is linked to long-term damage to blood vessels, nerves, and various organs. Currently, the worldwide burden of DM and its complications is in increase. Male sexual dysfunction is one of the famous complications of DM, including abnormal orgasmic/ejaculatory functions, desire/libido, and erection. Ejaculatory dysfunction encompasses several disorders related to DM and its complications, such as premature ejaculation, anejaculation (AE), delayed ejaculation, retrograde ejaculation (RE), ejaculatory pain, anesthetic ejaculation, decreased ejaculate volume, and decreased force of ejaculation. The problems linked to ejaculatory dysfunction may extend beyond the poor quality of life in diabetics as both AE and RE are alleged to alter the fertility potential of these patients. However, although both diabetes patients and their physicians are increasingly aware of diabetic ejaculatory dysfunction, this awareness still lags behind that of other diabetes complications. Therefore, all these disorders should be looked for thoroughly during the clinical evaluation of diabetic men. Besides, introducing the suitable option and/or maneuvers to treat these disorders should be tailored according to each case. This review aimed to explore the most important findings regarding ejaculatory dysfunction in diabetes from pre-clinical and clinical perspectives.

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Diagnosis and Classification of Diabetes Mellitus

Vittorio Basevi (2013)

DEFINITION AND DESCRIPTION OF DIABETES MELLITUS Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia. Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome. Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes. The vast majority of cases of diabetes fall into two broad etiopathogenetic categories (discussed in greater detail below). In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In the other, much more prevalent category, type 2 diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load or by A1C. The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process (Fig. 1). A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate glycemic control can be achieved with weight reduction, exercise, and/or oral glucose-lowering agents. These individuals therefore do not require insulin. Other individuals who have some residual insulin secretion but require exogenous insulin for adequate glycemic control can survive without it. Individuals with extensive β-cell destruction and therefore no residual insulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself. Figure 1 Disorders of glycemia: etiologic types and stages. *Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); **in rare instances, patients in these categories (e.g., Vacor toxicity, type 1 diabetes presenting in pregnancy) may require insulin for survival. CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATION Assigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single class. For example, a person diagnosed with gestational diabetes mellitus (GDM) may continue to be hyperglycemic after delivery and may be determined to have, in fact, type 2 diabetes. Alternatively, a person who acquires diabetes because of large doses of exogenous steroids may become normoglycemic once the glucocorticoids are discontinued, but then may develop diabetes many years later after recurrent episodes of pancreatitis. Another example would be a person treated with thiazides who develops diabetes years later. Because thiazides in themselves seldom cause severe hyperglycemia, such individuals probably have type 2 diabetes that is exacerbated by the drug. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) Immune-mediated diabetes. This form of diabetes, which accounts for only 5–10% of those with diabetes, previously encompassed by the terms insulin-dependent diabetes or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to GAD (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. One and usually more of these autoantibodies are present in 85–90% of individuals when fasting hyperglycemia is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. In this form of diabetes, the rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual β-cell function sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life. Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmune disorders such as Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. Idiopathic diabetes. Some forms of type 1 diabetes have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance) This form of diabetes, which accounts for ∼90–95% of those with diabetes, previously referred to as non–insulin-dependent diabetes, type 2 diabetes, or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many different causes of this form of diabetes. Although the specific etiologies are not known, autoimmune destruction of β-cells does not occur, and patients do not have any of the other causes of diabetes listed above or below. Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another illness such as infection. This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications. Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal. The risk of developing this form of diabetes increases with age, obesity, and lack of physical activity. It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidemia, and its frequency varies in different racial/ethnic subgroups. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. However, the genetics of this form of diabetes are complex and not fully defined. Other specific types of diabetes Genetic defects of the β-cell. Several forms of diabetes are associated with monogenetic defects in β-cell function. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturity-onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action. They are inherited in an autosomal dominant pattern. Abnormalities at six genetic loci on different chromosomes have been identified to date. The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α. A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. Glucokinase converts glucose to glucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the β-cell. Thus, glucokinase serves as the “glucose sensor” for the β-cell. Because of defects in the glucokinase gene, increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion. The less common forms result from mutations in other transcription factors, including HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1. Diabetes diagnosed in the first 6 months of life has been shown not to be typical autoimmune type 1 diabetes. This so-called neonatal diabetes can either be transient or permanent. The most common genetic defect causing transient disease is a defect on ZAC/HYAMI imprinting, whereas permanent neonatal diabetes is most commonly a defect in the gene encoding the Kir6.2 subunit of the β-cell KATP channel. Diagnosing the latter has implications, since such children can be well managed with sulfonylureas. Point mutations in mitochondrial DNA have been found to be associated with diabetes and deafness The most common mutation occurs at position 3,243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome); however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion. Genetic abnormalities that result in the inability to convert proinsulin to insulin have been identified in a few families, and such traits are inherited in an autosomal dominant pattern. The resultant glucose intolerance is mild. Similarly, the production of mutant insulin molecules with resultant impaired receptor binding has also been identified in a few families and is associated with an autosomal inheritance and only mildly impaired or even normal glucose metabolism. Genetic defects in insulin action. There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes. Therefore, it is assumed that the lesion(s) must reside in the postreceptor signal transduction pathways. Diseases of the exocrine pancreas. Any process that diffusely injures the pancreas can cause diabetes. Acquired processes include pancreatitis, trauma, infection, pancreatectomy, and pancreatic carcinoma. With the exception of that caused by cancer, damage to the pancreas must be extensive for diabetes to occur; adrenocarcinomas that involve only a small portion of the pancreas have been associated with diabetes. This implies a mechanism other than simple reduction in β-cell mass. If extensive enough, cystic fibrosis and hemochromatosis will also damage β-cells and impair insulin secretion. Fibrocalculous pancreatopathy may be accompanied by abdominal pain radiating to the back and pancreatic calcifications identified on X-ray examination. Pancreatic fibrosis and calcium stones in the exocrine ducts have been found at autopsy. Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, respectively) can cause diabetes. This generally occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is resolved. Somatostatinomas, and aldosteronoma-induced hypokalemia, can cause diabetes, at least in part, by inhibiting insulin secretion. Hyperglycemia generally resolves after successful removal of the tumor. Drug- or chemical-induced diabetes. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate diabetes in individuals with insulin resistance. In such cases, the classification is unclear because the sequence or relative importance of β-cell dysfunction and insulin resistance is unknown. Certain toxins such as Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells. Such drug reactions fortunately are rare. There are also many drugs and hormones that can impair insulin action. Examples include nicotinic acid and glucocorticoids. Patients receiving α-interferon have been reported to develop diabetes associated with islet cell antibodies and, in certain instances, severe insulin deficiency. The list shown in Table 1 is not all-inclusive, but reflects the more commonly recognized drug-, hormone-, or toxin-induced forms of diabetes. Table 1 Etiologic classification of diabetes mellitus Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency) Immune mediated Idiopathic Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) Other specific types Genetic defects of β-cell function MODY 3 (Chromosome 12, HNF-1α) MODY 1 (Chromosome 20, HNF-4α) MODY 2 (Chromosome 7, glucokinase) Other very rare forms of MODY (e.g., MODY 4: Chromosome 13, insulin promoter factor-1; MODY 6: Chromosome 2, NeuroD1; MODY 7: Chromosome 9, carboxyl ester lipase) Transient neonatal diabetes (most commonly ZAC/HYAMI imprinting defect on 6q24) Permanent neonatal diabetes (most commonly KCNJ11 gene encoding Kir6.2 subunit of β-cell KATP channel) Mitochondrial DNA Others Genetic defects in insulin action Type A insulin resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatrophic diabetes Others Diseases of the exocrine pancreas Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Others Endocrinopathies Acromegaly Cushing's syndrome Glucagonoma Pheochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others Drug or chemical induced Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide β-Adrenergic agonists Thiazides Dilantin γ-Interferon Others Infections Congenital rubella Cytomegalovirus Others Uncommon forms of immune-mediated diabetes “Stiff-man” syndrome Anti-insulin receptor antibodies Others Other genetic syndromes sometimes associated with diabetes Down syndrome Klinefelter syndrome Turner syndrome Wolfram syndrome Friedreich ataxia Huntington chorea Laurence-Moon-Biedl syndrome Myotonic dystrophy Porphyria Prader-Willi syndrome Others Gestational diabetes mellitus Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient. Infections. Certain viruses have been associated with β-cell destruction. Diabetes occurs in patients with congenital rubella, although most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of the disease. Uncommon forms of immune-mediated diabetes. In this category, there are two known conditions, and others are likely to occur. The stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness of the axial muscles with painful spasms. Patients usually have high titers of the GAD autoantibodies, and approximately one-third will develop diabetes. Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor, thereby blocking the binding of insulin to its receptor in target tissues. However, in some cases, these antibodies can act as an insulin agonist after binding to the receptor and can thereby cause hypoglycemia. Anti-insulin receptor antibodies are occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases. As in other states of extreme insulin resistance, patients with anti-insulin receptor antibodies often have acanthosis nigricans. In the past, this syndrome was termed type B insulin resistance. Other genetic syndromes sometimes associated with diabetes. Many genetic syndromes are accompanied by an increased incidence of diabetes. These include the chromosomal abnormalities of Down syndrome, Klinefelter syndrome, and Turner syndrome. Wolfram syndrome is an autosomal recessive disorder characterized by insulin-deficient diabetes and the absence of β-cells at autopsy. Additional manifestations include diabetes insipidus, hypogonadism, optic atrophy, and neural deafness. Other syndromes are listed in Table 1. GDM For many years, GDM has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Although most cases resolve with delivery, the definition applied whether or not the condition persisted after pregnancy and did not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but its limitations were recognized for many years. As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2 diabetes has increased. After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including the American Diabetes Association (ADA), recommended that high-risk women found to have diabetes at their initial prenatal visit, using standard criteria (Table 3), receive a diagnosis of overt, not gestational, diabetes. Approximately 7% of all pregnancies (ranging from 1 to 14%, depending on the population studied and the diagnostic tests employed) are complicated by GDM, resulting in more than 200,000 cases annually. CATEGORIES OF INCREASED RISK FOR DIABETES In 1997 and 2003, the Expert Committee on Diagnosis and Classification of Diabetes Mellitus (1,2) recognized an intermediate group of individuals whose glucose levels do not meet criteria for diabetes, yet are higher than those considered normal. These people were defined as having impaired fasting glucose (IFG) [fasting plasma glucose (FPG) levels 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)], or impaired glucose tolerance (IGT) [2-h values in the oral glucose tolerance test (OGTT) of 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)]. Individuals with IFG and/or IGT have been referred to as having prediabetes, indicating the relatively high risk for the future development of diabetes. IFG and IGT should not be viewed as clinical entities in their own right but rather risk factors for diabetes as well as cardiovascular disease. They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. Structured lifestyle intervention, aimed at increasing physical activity and producing 5–10% loss of body weight, and certain pharmacological agents have been demonstrated to prevent or delay the development of diabetes in people with IGT; the potential impact of such interventions to reduce mortality or the incidence of cardiovascular disease has not been demonstrated to date. It should be noted that the 2003 ADA Expert Committee report reduced the lower FPG cut point to define IFG from 110 mg/dl (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), in part to ensure that prevalence of IFG was similar to that of IGT. However, the World Health Organization (WHO) and many other diabetes organizations did not adopt this change in the definition of IFG. As A1C is used more commonly to diagnose diabetes in individuals with risk factors, it will also identify those at higher risk for developing diabetes in the future. When recommending the use of the A1C to diagnose diabetes in its 2009 report, the International Expert Committee (3) stressed the continuum of risk for diabetes with all glycemic measures and did not formally identify an equivalent intermediate category for A1C. The group did note that those with A1C levels above the laboratory “normal” range but below the diagnostic cut point for diabetes (6.0 to <6.5%) are at very high risk of developing diabetes. Indeed, incidence of diabetes in people with A1C levels in this range is more than 10 times that of people with lower levels (4–7). However, the 6.0 to <6.5% range fails to identify a substantial number of patients who have IFG and/or IGT. Prospective studies indicate that people within the A1C range of 5.5–6.0% have a 5-year cumulative incidence of diabetes that ranges from 12 to 25% (4–7), which is appreciably (three- to eightfold) higher than incidence in the U.S. population as a whole (8). Analyses of nationally representative data from the National Health and Nutrition Examination Survey (NHANES) indicate that the A1C value that most accurately identifies people with IFG or IGT falls between 5.5 and 6.0%. In addition, linear regression analyses of these data indicate that among the nondiabetic adult population, an FPG of 110 mg/dl (6.1 mmol/l) corresponds to an A1C of 5.6%, while an FPG of 100 mg/dl (5.6 mmol/l) corresponds to an A1C of 5.4% (R.T. Ackerman, personal communication). Finally, evidence from the Diabetes Prevention Program (DPP), wherein the mean A1C was 5.9% (SD 0.5%), indicates that preventive interventions are effective in groups of people with A1C levels both below and above 5.9% (9). For these reasons, the most appropriate A1C level above which to initiate preventive interventions is likely to be somewhere in the range of 5.5–6%. As was the case with FPG and 2-h PG, defining a lower limit of an intermediate category of A1C is somewhat arbitrary, as the risk of diabetes with any measure or surrogate of glycemia is a continuum, extending well into the normal ranges. To maximize equity and efficiency of preventive interventions, such an A1C cut point should balance the costs of “false negatives” (failing to identify those who are going to develop diabetes) against the costs of “false positives” (falsely identifying and then spending intervention resources on those who were not going to develop diabetes anyway). As is the case with the glucose measures, several prospective studies that used A1C to predict the progression to diabetes demonstrated a strong, continuous association between A1C and subsequent diabetes. In a systematic review of 44,203 individuals from 16 cohort studies with a follow-up interval averaging 5.6 years (range 2.8--12 years), those with an A1C between 5.5 and 6.0% had a substantially increased risk of diabetes with 5-year incidences ranging from 9 to 25%. An A1C range of 6.0--6.5% had a 5-year risk of developing diabetes between 25 and 50% and relative risk 20 times higher compared with an A1C of 5.0% (10). In a community-based study of black and white adults without diabetes, baseline A1C was a stronger predictor of subsequent diabetes and cardiovascular events than was fasting glucose (11). Other analyses suggest that an A1C of 5.7% is associated with similar diabetes risk to the high-risk participants in the DPP (12). Hence, it is reasonable to consider an A1C range of 5.7--6.4% as identifying individuals with high risk for future diabetes, to whom the term prediabetes may be applied. Individuals with an A1C of 5.7–6.4% should be informed of their increased risk for diabetes as well as cardiovascular disease and counseled about effective strategies, such as weight loss and physical activity, to lower their risks. As with glucose measurements, the continuum of risk is curvilinear, so that as A1C rises, the risk of diabetes rises disproportionately. Accordingly, interventions should be most intensive and follow-up should be particularly vigilant for those with A1C levels above 6.0%, who should be considered to be at very high risk. However, just as an individual with a fasting glucose of 98 mg/dl (5.4 mmol/l) may not be at negligible risk for diabetes, individuals with A1C levels below 5.7% may still be at risk, depending on level of A1C and presence of other risk factors, such as obesity and family history. Table 2 summarizes the categories of increased risk for diabetes. Evaluation of patients at risk should incorporate a global risk factor assessment for both diabetes and cardiovascular disease. Screening for and counseling about risk of diabetes should always be in the pragmatic context of the patient's comorbidities, life expectancy, personal capacity to engage in lifestyle change, and overall health goals. Table 2 Categories of increased risk for diabetes (prediabetes)* FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) [IFG] 2-h PG in the 75-g OGTT 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) [IGT] A1C 5.7–6.4% *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range. DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS For decades, the diagnosis of diabetes has been based on glucose criteria, either the FPG or the 75-g OGTT. In 1997, the first Expert Committee on the Diagnosis and Classification of Diabetes Mellitus revised the diagnostic criteria, using the observed association between FPG levels and presence of retinopathy as the key factor with which to identify threshold glucose level. The Committee examined data from three cross-sectional epidemiologic studies that assessed retinopathy with fundus photography or direct ophthalmoscopy and measured glycemia as FPG, 2-h PG, and A1C. These studies demonstrated glycemic levels below which there was little prevalent retinopathy and above which the prevalence of retinopathy increased in an apparently linear fashion. The deciles of the three measures at which retinopathy began to increase were the same for each measure within each population. Moreover, the glycemic values above which retinopathy increased were similar among the populations. These analyses confirmed the long-standing diagnostic 2-h PG value of ≥200 mg/dl (11.1 mmol/l). However, the older FPG diagnostic cut point of 140 mg/dl (7.8 mmol/l) was noted to identify far fewer individuals with diabetes than the 2-h PG cut point. The FPG diagnostic cut point was reduced to ≥126 mg/dl (7.0 mmol/l). A1C is a widely used marker of chronic glycemia, reflecting average blood glucose levels over a 2- to 3-month period of time. The test plays a critical role in the management of the patient with diabetes, since it correlates well with both microvascular and, to a lesser extent, macrovascular complications and is widely used as the standard biomarker for the adequacy of glycemic management. Prior Expert Committees have not recommended use of the A1C for diagnosis of diabetes, in part due to lack of standardization of the assay. However, A1C assays are now highly standardized so that their results can be uniformly applied both temporally and across populations. In their recent report (3), an International Expert Committee, after an extensive review of both established and emerging epidemiological evidence, recommended the use of the A1C test to diagnose diabetes, with a threshold of ≥6.5%, and ADA affirms this decision. The diagnostic A1C cut point of 6.5% is associated with an inflection point for retinopathy prevalence, as are the diagnostic thresholds for FPG and 2-h PG (3). The diagnostic test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial reference assay. Point-of-care A1C assays are not sufficiently accurate at this time to use for diagnostic purposes. There is an inherent logic to using a more chronic versus an acute marker of dysglycemia, particularly since the A1C is already widely familiar to clinicians as a marker of glycemic control. Moreover, the A1C has several advantages to the FPG, including greater convenience, since fasting is not required, evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness. These advantages, however, must be balanced by greater cost, the limited availability of A1C testing in certain regions of the developing world, and the incomplete correlation between A1C and average glucose in certain individuals. In addition, the A1C can be misleading in patients with certain forms of anemia and hemoglobinopathies, which may also have unique ethnic or geographic distributions. For patients with a hemoglobinopathy but normal red cell turnover, such as sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used (an updated list is available at http://www.ngsp.org/interf.asp). For conditions with abnormal red cell turnover, such as anemias from hemolysis and iron deficiency, the diagnosis of diabetes must employ glucose criteria exclusively. The established glucose criteria for the diagnosis of diabetes remain valid. These include the FPG and 2-h PG. Additionally, patients with severe hyperglycemia such as those who present with severe classic hyperglycemic symptoms or hyperglycemic crisis can continue to be diagnosed when a random (or casual) plasma glucose of ≥200 mg/dl (11.1 mmol/l) is found. It is likely that in such cases the health care professional would also measure an A1C test as part of the initial assessment of the severity of the diabetes and that it would (in most cases) be above the diagnostic cut point for diabetes. However, in rapidly evolving diabetes, such as the development of type 1 diabetes in some children, A1C may not be significantly elevated despite frank diabetes. Just as there is less than 100% concordance between the FPG and 2-h PG tests, there is not full concordance between A1C and either glucose-based test. Analyses of NHANES data indicate that, assuming universal screening of the undiagnosed, the A1C cut point of ≥6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of ≥126 mg/dl (7.0 mmol/l) (www.cdc.gov/diabetes/pubs/factsheet11/tables1_2.htm). However, in practice, a large portion of the population with type 2 diabetes remains unaware of their condition. Thus, it is conceivable that the lower sensitivity of A1C at the designated cut point will be offset by the test's greater practicality, and that wider application of a more convenient test (A1C) may actually increase the number of diagnoses made. Further research is needed to better characterize those patients whose glycemic status might be categorized differently by two different tests (e.g., FPG and A1C), obtained in close temporal approximation. Such discordance may arise from measurement variability, change over time, or because A1C, FPG, and postchallenge glucose each measure different physiological processes. In the setting of an elevated A1C but “nondiabetic” FPG, the likelihood of greater postprandial glucose levels or increased glycation rates for a given degree of hyperglycemia may be present. In the opposite scenario (high FPG yet A1C below the diabetes cut point), augmented hepatic glucose production or reduced glycation rates may be present. As with most diagnostic tests, a test result diagnostic of diabetes should be repeated to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such as a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, there are scenarios in which results of two different tests (e.g., FPG and A1C) are available for the same patient. In this situation, if the two different tests are both above the diagnostic thresholds, the diagnosis of diabetes is confirmed. On the other hand, when two different tests are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the FPG (<126 mg/dl or 7.0 mmol/l), or vice versa, that person should be considered to have diabetes. Admittedly, in most circumstance the “nondiabetic” test is likely to be in a range very close to the threshold that defines diabetes. Since there is preanalytic and analytic variability of all the tests, it is also possible that when a test whose result was above the diagnostic threshold is repeated, the second value will be below the diagnostic cut point. This is least likely for A1C, somewhat more likely for FPG, and most likely for the 2-h PG. Barring a laboratory error, such patients are likely to have test results near the margins of the threshold for a diagnosis. The healthcare professional might opt to follow the patient closely and repeat the testing in 3–6 months. The decision about which test to use to assess a specific patient for diabetes should be at the discretion of the health care professional, taking into account the availability and practicality of testing an individual patient or groups of patients. Perhaps more important than which diagnostic test is used, is that the testing for diabetes be performed when indicated. There is discouraging evidence indicating that many at-risk patients still do not receive adequate testing and counseling for this increasingly common disease, or for its frequently accompanying cardiovascular risk factors. The current diagnostic criteria for diabetes are summarized in Table 3. Table 3 Criteria for the diagnosis of diabetes Diagnosis of GDM GDM carries risks for the mother and neonate. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (13), a large-scale (∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. After deliberations in 2008–2009, the IADPSG, an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM. The group recommended that all women not known to have diabetes undergo a 75-g OGTT at 24–28 weeks of gestation. Additionally, the group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with women with mean glucose levels in the HAPO study. Current screening and diagnostic strategies, based on the IADPSG statement (14), are outlined in Table 4. Table 4 Screening for and diagnosis of GDM Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24–28 weeks of gestation in women not previously diagnosed with overt diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are exceeded: Fasting: ≥92 mg/dl (5.1 mmol/l) 1 h: ≥180 mg/dl (10.0 mmol/l) 2 h: ≥153 mg/dl (8.5 mmol/l) These new criteria will significantly increase the prevalence of GDM, primarily because only one abnormal value, not two, is sufficient to make the diagnosis. The ADA recognizes the anticipated significant increase in the incidence of GDM to be diagnosed by these criteria and is sensitive to concerns about the “medicalization” of pregnancies previously categorized as normal. These diagnostic criteria changes are being made in the context of worrisome worldwide increases in obesity and diabetes rates, with the intent of optimizing gestational outcomes for women and their babies. Admittedly, there are few data from randomized clinical trials regarding therapeutic interventions in women who will now be diagnosed with GDM based on only one blood glucose value above the specified cut points (in contrast to the older criteria that stipulated at least two abnormal values). Expected benefits to their pregnancies and offspring is inferred from intervention trials that focused on women with more mild hyperglycemia than identified using older GDM diagnostic criteria and that found modest benefits (15,16). The frequency of their follow-up and blood glucose monitoring is not yet clear but likely to be less intensive than women diagnosed by the older criteria. Additional well-designed clinical studies are needed to determine the optimal intensity of monitoring and treatment of women with GDM diagnosed by the new criteria (that would not have met the prior definition of GDM). It is important to note that 80–90% of women in both of the mild GDM studies (whose glucose values overlapped with the thresholds recommended herein) could be managed with lifestyle therapy alone.

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Diabetic Neuropathy: A Position Statement by the American Diabetes Association

Rodica Pop-Busui, Andrew J.M. Boulton, Eva Feldman … (2016)

Introduction Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. A number of treatment options exist for symptomatic diabetic neuropathy. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies. Table 1 Classification for diabetic neuropathies Diabetic neuropathies A. Diffuse neuropathy DSPN • Primarily small-fiber neuropathy • Primarily large-fiber neuropathy • Mixed small- and large-fiber neuropathy (most common) Autonomic Cardiovascular • Reduced HRV • Resting tachycardia • Orthostatic hypotension • Sudden death (malignant arrhythmia) Gastrointestinal • Diabetic gastroparesis (gastropathy) • Diabetic enteropathy (diarrhea) • Colonic hypomotility (constipation) Urogenital • Diabetic cystopathy (neurogenic bladder) • Erectile dysfunction • Female sexual dysfunction Sudomotor dysfunction • Distal hypohydrosis/anhidrosis, • Gustatory sweating Hypoglycemia unawareness Abnormal pupillary function B. Mononeuropathy (mononeuritis multiplex) (atypical forms) Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal) Mononeuritis multiplex (if confluent may resemble polyneuropathy) C. Radiculopathy or polyradiculopathy (atypical forms) Radiculoplexus neuropathy (a.k.a. lumbosacral polyradiculopathy, proximal motor amyotrophy) Thoracic radiculopathy Nondiabetic neuropathies common in diabetes Pressure palsies Chronic inflammatory demyelinating polyneuropathy Radiculoplexus neuropathy Acute painful small-fiber neuropathies (treatment-induced) Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion and relevant references to the literature (3,4,11–16). PREVENTION Prevention of diabetic neuropathies focuses on glucose control and lifestyle modifications. Available evidence pertains only to DSPN and CAN, and most of the large trials that have evaluated the effect of glucose control on the risk of complications have included DSPN and CAN as secondary outcomes or as post hoc analyses rather than as primary outcomes. In addition, in some of these trials, the outcome measures used to evaluate neuropathy may have limited ability to detect a benefit, if present. Recommendations Optimize glucose control as early as possible to prevent or delay the development of distal symmetric polyneuropathy and cardiovascular autonomic neuropathy in people with type 1 diabetes. A Optimize glucose control to prevent or slow the progression of distal symmetric polyneuropathy in people with type 2 diabetes. B Consider a multifactorial approach targeting glycemia among other risk factors to prevent cardiovascular autonomic neuropathy in people with type 2 diabetes. C Glucose Control Enhanced glucose control in people with type 1 diabetes dramatically reduces the incidence of DSPN (78% relative risk reduction) (17–19). In contrast, enhanced glucose control in people with type 2 diabetes reduces the risk of developing DSPN modestly (5%–9% relative risk reduction) (20,21). In a small trial of Japanese patients with early type 2 diabetes, intensive insulin treatment was associated with improvement in selected DSPN measures (22), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial reported a modest but significant DSPN risk reduction with the glycemia intervention in individuals with type 2 diabetes after 5 years of follow-up (21). Yet, no effects are observed in other large trials (20,23–25). This discrepancy highlights the differences between type 1 and type 2 diabetes and emphasizes the point that many people with type 2 diabetes develop DSPN despite adequate glucose control (20,25). The presence of multiple comorbidities, polypharmacy, hypoglycemia, and weight gain might have attenuated the effects of glucose control in these trials and contributed to inconsistent findings (25). Specific glucose-lowering strategies may also contribute to the discrepancy. For example, participants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) study treated with insulin sensitizers had a lower incidence of DSPN over 4 years than those treated with insulin/sulfonylurea (26). This outcome may be a result of less weight gain and less hypoglycemia (26). Last, the fact that many patients have had asymptomatic hyperglycemia for many years prior to the diagnosis of type 2 diabetes may also explain the limited benefit in these patients. Similar to the findings in DSPN, the most robust evidence for CAN prevention was reported in type 1 diabetes. Intensive glucose control designed to achieve near-normal glycemia reduced the risk of incident CAN during the Diabetes Control and Complications Trial (DCCT) by 45% and by 31% in its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study (27). The highly reproducible and sensitive testing protocol, the robust definitions used for CAN, and the large sample size in DCCT/EDIC enhance the validity of the results and support the rationale for implementing and maintaining tight glucose control as early as possible in the course of type 1 diabetes. In contrast, glycemic control in type 2 diabetes has not consistently lowered the risk of CAN (25). However, a multifactorial intervention, including a lifestyle component, targeting glucose and cardiovascular disease risk factors reduced the risk of CAN by 60% in people with type 2 diabetes (28). Lifestyle Modifications The best models to date regarding parameters for an evidence-based, intensive lifestyle intervention come from the Diabetes Prevention Program (DPP) (29), the Steno-2 Study (28), the Italian supervised treadmill study (30), and the University of Utah type 2 diabetes study (31). The latter study recently reported nerve fiber regeneration in patients with type 2 diabetes engaged in an exercise program compared with loss of nerve fibers in those who only followed standard of care. Overall, such an approach focuses on either exercise alone (supervised aerobic and/or resistance training) (30,31) or combined dietary modification and exercise. There is no consensus regarding dietary regimens, and although the DPP used a low-calorie, low-fat diet, others have championed a Mediterranean diet that is moderately lower in carbohydrate (45%) and higher in fat (35%–40%), with less than 10% of saturated fat. Although the DPP (32) and the Impaired Glucose Tolerance Neuropathy (IGTN) study (33) reported benefits of lifestyle interventions on measures of CAN and DSPN, respectively, these trials did not include subjects with established diabetes. In addition, in the DPP, indices of CAN improved with the lifestyle intervention and did not change in the other arms (32). DSPN Most common among diabetic neuropathies is chronic DSPN, accounting for about 75% of the diabetic neuropathies (1,3). A simple definition of DSPN for clinical practice is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. Experimental studies suggest a multifactorial pathogenesis of DSPN (Fig. 1), but the causes remain unknown (34–37). A prevailing view of the pathogenesis is that oxidative and inflammatory stress may, in the context of metabolic dysfunction, damage nerve cells (34–37). Figure 1 Mechanisms of diabetic neuropathy. Factors linked to type 1 diabetes (yellow), type 2 diabetes (blue), and both (green) cause DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction, cellular injury, and irreversible damage. The relative importance of the pathways in this network will vary with cell type, disease profile, and time. ER, endoplasmic reticulum; FFA, free fatty acids; PI3-K, phosphatidylinositol-3 kinase; RNS, reactive nitrogen species; ROS, reactive oxygen species. Adapted and reprinted from Callaghan et al. (20), with permission from Elsevier. Estimates of the incidence and prevalence of DSPN vary greatly (25,38–40), but evidence from several large observational cohorts (41,42) and the DCCT/EDIC (27,43) suggests that DSPN occurs in at least 20% of people with type 1 diabetes after 20 years of disease duration. DSPN may be present in at least 10%–15% of newly diagnosed patients with type 2 diabetes (44,45), with rates increasing to 50% after 10 years of disease duration (25,26). Rates in youth with type 1 and type 2 diabetes approach those observed in adult populations (46). DSPN has been associated with glycemia (14,33–35), height (47) (perhaps as a proxy for nerve length), smoking (48), blood pressure, weight, and lipid measures (49,50). There is emerging evidence that DSPN, especially the painful small-fiber neuropathy subtype, may be present in 10%–30% of subjects with impaired glucose tolerance, also known as prediabetes (5–10) or metabolic syndrome (51). DSPN is the most important cause of foot ulceration, and it is also a prerequisite in the development of Charcot neuroarthropathy (CN) (52). The reader is referred to several other reviews that cover this topic (52,53). Foot ulceration and CN are both recognized as late complications of DSPN (52,54). These late complications drive amputation risk and economic costs of diabetic neuropathy and are also predictors of mortality. DSPN is also a major contributor to falls and fractures (55–57), through more advanced small- and large-fiber dysfunction, with loss of sensory, proprioception, temperature discrimination, and pain, all ultimately leading to unsteadiness, recurrent minor injuries, and an increased risk of falls. These recurrent minor injuries may further contribute to the pathogenesis of CN (58). Screening and Diagnosis Recommendations All patients should be assessed for distal symmetric polyneuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. B Consider screening patients with prediabetes who have symptoms of peripheral neuropathy. B Assessment should include a careful history and either temperature or pinprick sensation (small-fiber function) and vibration sensation using a 128-Hz tuning fork (large-fiber function). All patients should have an annual 10-g monofilament testing to assess for feet at risk for ulceration and amputation. B Electrophysiological testing or referral to a neurologist is rarely needed for screening, except in situations where the clinical features are atypical, the diagnosis is unclear, or a different etiology is suspected. Atypical features include motor greater than sensory neuropathy, rapid onset, or asymmetrical presentation. B Patients with type 1 diabetes for 5 or more years and all patients with type 2 diabetes should be assessed annually for DSPN using medical history and simple clinical tests. Up to 50% of patients may experience symptoms of DSPN (Table 2), whereas the rest are asymptomatic. Patients may not volunteer symptoms but on inquiry may reveal that they are experiencing numbness or other positive symptoms of DSPN. Table 2 Symptoms and signs of DSPN Large myelinated nerve fibers Small myelinated nerve fibers Function Pressure, balance Nociception, protective sensation Symptoms§ Numbness, tingling, poor balance Pain: burning, electric shocks, stabbing Examination (clinically diagnostic)** Ankle reflexes: reduced/absent Vibration perception: reduced/absent 10-g monofilament: reduced/absent Proprioception: reduced/absent Thermal (cold/hot) discrimination: reduced/absent** Pinprick sensation: reduced/absent** §To document the presence of symptoms for diagnosis; **Documented in symmetrical, distal to proximal pattern. Symptoms vary according to the class of sensory fibers involved. The most common early symptoms are induced by the involvement of small fibers and include pain and dysesthesias (unpleasant sensations of burning) (1,4,59,60). Neuropathic pain may be the first symptom that prompts patients to seek medical care and is present in up to 25% of individuals with DSPN (61–63). Characteristically, the pain is burning, lancinating, tingling, or shooting (electric shock–like); occurs with paresthesias; presents in varying combinations; and is typically worse at night. Neuropathic pain may be accompanied by an exaggerated response to painful stimuli (hyperalgesia) and pain evoked by contact, e.g., with socks, shoes, and bedclothes (allodynia). Neuropathic pain can lead to interference with daily activities, disability, psychosocial impairment, and reduced health-related quality of life (64–66). The direct and indirect economic burden associated with neuropathic pain is substantial (67–69). The involvement of large fibers may cause numbness, tingling without pain, and loss of protective sensation. Loss of protective sensation indicates the presence of DSPN and is a risk factor for diabetic foot ulceration. Patients can also initially present with an insensate, numb foot due to the loss of large fibers. Patients frequently state that their feet feel like they are wrapped in wool or they are walking on thick socks. It is the loss of the “gift of pain” that permits patients with plantar neuropathic ulcers to walk on the lesions, inducing chronicity, frequently complicated by infection (70). The following clinical tests may be used to assess small- and large-fiber function distal to proximal (Table 2): Small-fiber function: pinprick and temperature sensation Large-fiber function: vibration perception, proprioception, 10-g monofilament, and ankle reflexes A 128-Hz tuning fork can be used for the assessment of vibration perception. Assessment of light-touch perception using a 10-g monofilament should include evaluation on the dorsal aspect of the great toe bilaterally as previously validated by Perkins et al. (71). The 10-g monofilament is a useful clinical tool mainly for detecting more advanced neuropathy and identifying patients at increased risk of ulceration and amputation (72). Assessments should follow the typical DSPN pattern, starting distally (the dorsal aspect of the hallux) on both sides and move proximally until a sensory threshold is identified (72). Combining at least two examinations will increase the sensitivity and specificity of detecting DSPN, as demonstrated in several cohorts of patients with type 1 and type 2 diabetes including children and adolescents (26,46,73–79). The diagnosis of DSPN is principally a clinical one (Table 2). A combination of typical symptomatology and symmetrical distal sensory loss or typical signs in the absence of symptoms in a patient with diabetes is highly suggestive of DSPN and may not require additional evaluation or referral. As up to half of the patients may be asymptomatic, a diagnosis may only be made on examination or, in some cases, when the patient presents with a painless foot ulcer. Clinicians should note that the 10-g monofilament test included for the annual DSPN screening and diagnosis is different than the diagnosis of the “high-risk foot” for ulceration, a late DSPN complication that requires that four sites (first, third, and fifth metatarsal heads and plantar surface of distal hallux) be tested on each foot (80). Consider excluding neuropathy with causes other than diabetes (Table 3) by undertaking a family and medication history and performing relevant investigations (e.g., serum B12, folic acid, thyroid function, complete blood count, metabolic panel, and a serum protein immunoelectrophoresis) (81). Table 3 Differential diagnosis of diabetic neuropathies Metabolic disease Thyroid disease (common) Renal disease Systemic disease Systemic vasculitis Nonsystemic vasculitis Paraproteinemia (common) Amyloidosis Infectious HIV Hepatitis B Lyme Inflammatory Chronic inflammatory demyelinating polyradiculoneuropathy Nutritional B12 * Postgastroplasty Pyridoxine Thiamine Tocopherol Industrial agents, drugs, and metals Industrial agents Acrylamide Organophosphorous agents Drugs Alcohol Amiodarone Colchicine Dapsone Vinka alkaloids Platinum Taxol Metals Arsenic Mercury Hereditary Hereditary motor, sensory, and autonomic neuropathies *B12 deficiency is more commonly associated with malabsorption rather than nutritional deficiency. Electrophysiological testing or referral to a neurologist is rarely needed for diagnosis, except in situations where the clinical features are atypical, the diagnosis is unclear, or a different etiology is suspected (2,38,40,80). Atypical features that warrant referral include motor greater than sensory neuropathy, asymmetry of symptoms and signs, and rapid progression. Foot Complications The simple yet comprehensive clinical exam is principally designed to identify those at risk for the late complications who need education on preventative foot self-care and regular podiatric foot care. Recently an even simpler foot exam, the “3-minute diabetic foot exam,” has been proposed (82). This is intended not only for physicians but also for other health care professionals who may only have 15 min for the entire diabetes annual review; it requires no equipment and provides simple advice on education on preventative foot self-care. Management Recommendations Tight glucose control targeting near-normal glycemia in patients with type 1 diabetes dramatically reduces the incidence of distal symmetric polyneuropathy and is recommended for distal symmetric polyneuropathy prevention in type 1 diabetes. A In patients with type 2 diabetes with more advanced disease and multiple risk factors and comorbidities, intensive glucose control alone is modestly effective in preventing distal symmetric polyneuropathy and patient-centered goals should be targeted. B Lifestyle interventions are recommended for distal symmetric polyneuropathy prevention in patients with prediabetes/metabolic syndrome and type 2 diabetes. B Prevention Please refer to Prevention on page 136. Pathogenetic Therapies Despite the recent major advances in elucidating the pathogenesis of diabetic neuropathy, there remains a lack of treatment options that effectively target the natural history of DSPN (83) or reverse DSPN once established. Several pathogenetic pharmacotherapies have been investigated (36), but evidence from randomized clinical trials is very limited (81,83,84). Advances in DSPN disease modification need to be confirmed with further robust evidence from clinical trials, together with a better understanding of the mechanisms of action of promising treatments (83). Pain Management Recommendations Consider either pregabalin or duloxetine as the initial approach in the symptomatic treatment for neuropathic pain in diabetes. A Gabapentin may also be used as an effective initial approach, taking into account patients’ socioeconomic status, comorbidities, and potential drug interactions. B Although not approved by the U.S. Food and Drug Administration, tricyclic antidepressants are also effective for neuropathic pain in diabetes but should be used with caution given the higher risk of serious side effects. B Given the high risks of addiction and other complications, the use of opioids, including tapentadol or tramadol, is not recommended as first- or second-line agents for treating the pain associated with DSPN. E No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or prediabetes (33,85), which leaves only pharmaceutical interventions. At present, pregabalin and duloxetine have received regulatory approval for the treatment of neuropathic pain in diabetes by the U.S. Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency. The opioid, tapentadol, has regulatory approval in the U.S. and Canada, but the evidence of its use is weaker (15). A large evidence base supports pharmacological treatment of neuropathic pain in diabetic neuropathy using other agents of different classes, as documented by several recent guidelines and systematic reviews (15,16,20,86,87). It is important to mention that only a few trials that targeted pain in peripheral neuropathic pain were carried out in DSPN alone. However, the results of studies performed on peripheral nondiabetic neuropathic pain or mixed neuropathic pain may be applicable to patients with neuropathic pain due to DSPN. Although there are broad general agreements among the recommendations, there are some inconsistencies that are, in part, a consequence of whether the guidelines are specific for painful DSPN or whether they address neuropathic pain due to all causes (15,16,20,86,87). Below we summarize the available evidence on the most effective agents for DSPN pain starting with the currently approved drugs and continuing with the other agents based on mechanism of action and strength of evidence. Evidence levels are assigned based on the strength of the published clinical evidence for the efficacy and safety of the agents for the treatment of DSPN pain, which should be considered in clinical decision making. However, a certain degree of publication bias should be considered, given that many negative trials may not have been published (15). Additional information on dose titration, adverse effects, number needed to treat, and safety is presented in Table 4. Table 4 Treatment for pain associated with DSPN (15,16,20,86,87) Drug class Agent Dose NNT range 30–50% improvement** Common adverse events Major adverse events Initial Effective Anticonvulsants Pregabalin* (15,86,88–94) 25–75 mg, 1–3×/day 300–600 mg/day 3.3–8.3 • Somnolence • Angioedema • Dizziness • Hepatotoxicity • Peripheral edema • Rhabdomyolysis • Headache • Suicidal thoughts and behavior • Ataxia • Seizures after rapid discontinuation • Fatigue • Thrombocytopenia • Xerostomia • Weight gain Gabapentin (15,86,96,105–111) 100–300 mg, 1–3×/day 900–3,600 mg/day 3.3–7.2 • Somnolence • Stevens-Johnson syndrome • Dizziness • Suicidal thoughts and behavior • Ataxia • Seizures after rapid discontinuation • Fatigue Antidepressants Serotonin-norepinephrine reuptake inhibitors Duloxetine* (15,86,94,96,98–101) 20–30 mg/day 60–120 mg/day 3.8–11 • Nausea • Stevens-Johnson syndrome • Somnolence • Hepatotoxicity • Dizziness • Hypertensive crisis • Constipation • Gastrointestinal hemorrhage • Dyspepsia • Delirium • Diarrhea • Myocardial infarction • Xerostomia • Cardiac arrhythmias • Anorexia • Glaucoma • Headache • Suicidal thoughts and behavior • Diaphoresis • Shift to mania in patients with bipolar disorder • Insomnia • Seizures • Fatigue • Severe hyponatremia • Decreased libido • Fragility bone fractures • Serotonin syndrome • Neuroleptic malignant syndrome Venlafaxine (15,16,20,86,87,126,127) 37.5 mg/day 75–225 mg/day 5.2–8.4 • Nausea • Same as duloxetine • Somnolence • Dizziness • Constipation • Dyspepsia • Diarrhea • Xerostomia • Anorexia • Headache • Diaphoresis • Insomnia • Fatigue • Decreased libido Tricyclic antidepressants Amitriptyline (16,110,112–116) 10–25 mg/day 25–100 mg/day 2.1–4.2 • Xerostomia • Delirium • Somnolence • Cardiac arrhythmias • Fatigue • Conduction abnormalities • Headache • Myocardial infarction • Dizziness • Heart failure exacerbation • Insomnia • Stroke • Orthostatic hypotension • Seizures • Anorexia • Hepatotoxicity • Nausea • Bone marrow suppression • Urinary retention • Suicidal thoughts and behavior • Constipation • Shift to mania in bipolar disorder • Blurred vision • Neuroleptic malignant syndrome • Accommodation • Serotonin syndrome • Disturbance • Severe hyponatremia • Mydriasis • Fragility bone fractures • Weight gain Desipramine (113,118–121,122) • Same as above • Same as above Nortriptyline (15,16,86,87,113,114,120,121,123) • Same as above • Same as above Opioids Tramadol (15,16,86,87,109,130) 50 mg, 1–2×/day 210 mg/day 3.1–6.4 • Somnolence • Confusion • Nausea • Seizures • Vomiting • Cardiac arrhythmias • Constipation • Hypertension • Light-headedness • Hypersensitivity reactions • Dizziness • Stevens-Johnson syndrome • Headache Tapentadol* (103,104,135) Immediate release:50–100 mg, 4–6×/day Immediate-release: day 1: 700 mg; after day 1, 60 mg/day N/A • Somnolence • Respiratory depression • Nausea • Serotonin syndrome Extended release:50 mg, 2×/day Extended release:50 mg, 2×/day • Vomiting • Seizures • Constipation • Hypertension • Dizziness • Neonatal opioid withdrawal syndrome NNT, number needed to treat. *FDA approved. **FDA considers 30–50% improvement to be significant. Approved Medications Pregabalin and duloxetine have received regulatory approval for the treatment of neuropathic pain in diabetes in the U.S., Europe, and Canada. Pregabalin, a calcium channel α2-δ subunit ligand, is an effective treatment for neuropathic pain associated with DSPN. It is the most extensively studied drug by far in DSPN, with the majority of studies being positive regarding the proportion of responders with at least 30%–50% improvement in pain (15,86,88–94). There is also some evidence suggesting a dose response, with a weaker effect with 300 vs. 600 mg/day (88). However, not all trials with pregabalin have been positive (15,86,95,96), especially when treating advanced refractory patients (93). Pregabalin, in contrast to gabapentin (see below), has a linear, dose-proportional absorption in the therapeutic dose range (150–600 mg/day) (88). In addition, pregabalin has a more rapid onset of action and more limited dosage range that requires minimal titration. Adverse effects may be more severe in older patients (97) and may be attenuated by lower starting doses and more gradual titration. Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor. Doses of 60 and 120 mg/day showed efficacy in the treatment of pain associated with DSPN in multicenter randomized trials, although some of these had a rather high drop-out rate (15,86,94,96,98–101). Duloxetine was also suggested to induce improvement in neuropathy-related quality of life (100). In longer-term studies, a small increase in A1C was reported in people with diabetes treated with duloxetine compared with placebo (102). Adverse events may again be more severe in older people but may be attenuated with lower doses and progressive titrations of duloxetine. Tapentadol extended release is a novel centrally acting opioid analgesic that exerts its analgesic effects through both μ-opioid receptor agonism and noradrenaline reuptake inhibition. Extended-release tapentadol was approved by the FDA for the treatment of neuropathic pain associated with diabetes based on data from two multicenter randomized withdrawal, placebo-controlled phase 3 trials (103,104). However, both used an enriched design and therefore are not generalizable, and a recent systematic review and meta-analysis by the International Association for the Study of Pain Special Interest Group on Neuropathic Pain (NeuPSIG) found the evidence of the effectiveness of tapentadol in reducing neuropathic pain inconclusive (15). Therefore, given the high risk for addiction and safety concerns compared with the relatively modest pain reduction, the use of tapentadol extended release is not recommended as first- or second-line treatment. Anticonvulsants Gabapentin, like pregabalin, also binds the calcium channel α2-δ subunit and has shown efficacy in a number of clinical trials for treating the pain associated with DSPN (15,86,96,105–111). However, not all painful DSPN studies, some of which are unpublished, have been positive (15,107). Given its pharmacokinetic profile, gabapentin requires gradual titration and doses up to 1,800–3,600 mg are generally needed to be clinically effective (96,105–107). Adverse effects may be more severe in older patients (97). Monoamine Reuptake Inhibitors The monoamine reuptake inhibitors—tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine and serotonin reuptake inhibitors—increase synaptic monoamine levels and directly influence the activity of the descending neurons. Amitriptyline, although not FDA approved, is the most used of the tricyclic agents. Many previous guidelines recommend the medication as a first-line treatment based on few randomized, blinded, placebo-controlled clinical trials that reported significant improvement in neuropathic pain (110,112–116). The effectiveness appeared unrelated to the antidepressant effect (112). A recent Cochrane Review questioned the quality of evidence on amitriptyline by raising concerns for bias given the small sample size in most and concluded that in fact there is no clear evidence for a beneficial effect for amitriptyline on DSPN pain, especially when balanced against spectrum of side effects (117). However, there was no good evidence of a lack of effect either (117). The secondary amines, nortriptyline and desipramine, have a less troublesome side effect profile than the tertiary amines, amitriptyline and imipramine, although fewer randomized controlled trials were performed with these agents, and the potential for bias was high given the small size (113,118–123). The use of these agents is preferable, particularly in older and side effect–prone patients (113,118–121). Several studies have suggested that there is an increased risk of myocardial ischemia and arrhythmogenesis associated with tricyclic agents (124,125). Because of concerns of possible cardiotoxicity, tricyclic antidepressants should be used with caution in patients with known or suspected cardiac disease. Venlafaxine, a selective norepinephrine and serotonin reuptake inhibitor, in doses between 150 and 225 mg/day has shown some effectiveness in the treatment of painful DSPN (126,127). Both venlafaxine and duloxetine (see above) inhibit the reuptake of serotonin and norepinephrine without the muscarinic, histaminic, and adrenergic side effects that accompany the use of the tricyclic agents (98–100,102). However, the level of evidence for pain reduction associated with DSPN is higher with duloxetine (see above). Venlafaxine may lower the seizure threshold, and gradual tapering is recommended to avoid the emergence of adverse events upon discontinuation (126,127). Opioid and Atypical Opioid Analgesics Tramadol is a centrally acting analgesic with pain relief mediated by a weak μ-opioid receptor agonist activity and inhibition of norepinephrine and serotonin reuptake (128,129). It is an effective agent in the treatment of painful diabetic peripheral neuropathy compared with placebo as demonstrated by two large multicenter trials (129,130), and it appears to have long-term effects (131). Although tramadol has a lower potential for abuse compared with other opioids, given these safety concerns, it is not recommended for use as first- or second-line agent. Controlled-release oxycodone improved pain scores in two single-center trials in patients with painful diabetic neuropathy, one of which had a small sample size (132,133). It may provide additional analgesia for patients on α2-δ ligand treatment (134). As with all opioids, it is not recommended for use as first-, second-, or third-line agent. Warnings on All Opioids Despite the demonstrated effectiveness of opioids in the treatment of neuropathic pain (15,132,134,135), there is a high risk of addiction, abuse, sedation, and other complications and psychosocial issues even with short-term opioid use. For these reasons, opioids are not recommended in the treatment of painful DSPN before failure of other agents that do not have these associated concerns (136–138). Although add-on therapy with strong opioids may be required in some patients who do not respond to all other combinations, referral to specialized pain clinics is recommended in these cases to avoid risks. Additional Considerations for Pain Management Combination therapy, including combinations with opioids, may provide effective treatment for diabetic neuropathic pain at lower doses (94,139). A detailed approach for pain management is amply covered in other literature (15,109), and a simple algorithm for clinical practice use is shown in Fig. 2. Figure 2 Algorithm for management of the patient with pain because of DSPN. AE, adverse events.*Pregabalin is FDA approved for painful DSPN, whereas gabapentin is not. Pharmacokinetic profile, spectrum of AEs, drug interactions, comorbidities, and costs to be considered in selecting the agent of choice. **Duloxetine is FDA approved for painful DSPN, whereas venlafaxine is not. Pharmacokinetic profile, spectrum of AEs, drug interactions, comorbidities, and costs to be considered in selecting the agent of choice. #None is FDA approved for painful DSPN. Spectrum of AEs, drug interactions, and comorbidities need be considered if selecting these agents. Treatment of Foot Complications Detailed treatment of foot ulceration and CN is beyond the scope of this statement, and the reader is referred to a relevant review (54). Effective off-loading that prevents patients with plantar neuropathic ulcers to walk on the lesions is the key to successful management (52,54). Off-loading, usually with casting, and careful follow-up and repeated investigations are also key components for the management of CN (52,54). Ongoing education and regular podiatry follow-up can reduce the incidence of foot complications in those found to be at “high risk.” Early intervention for foot lesions and CN or suspected CN can slow or reverse progression. Fall Prevention Recommendation Tests assessing gait and balance may be considered in people with distal symmetric polyneuropathy to evaluate the risk of falls. E DSPN may also compromise balance in daily activities (58). For instance, progressive loss of proprioception (diminished sensation) and later weakness, superimposed on age-related functional impairments, lead to imbalance and unsteadiness in gait, with increased likelihood of a fall (55,58). A decline in cognitive function, polypharmacy, and neuropathic pain may further contribute. In addition, treatment of neuropathic pain often requires dosages and drug combinations that may further increase the fall risk due to cognitive impairment, drowsiness, dizziness, blurred vision, and gait disturbances (97,109). Older patients are the most susceptible (97,109). Therefore, tests assessing gait and balance may be considered in clinical practice to evaluate risk of falls in patients at risk (55,58). Psychosocial Factors Recommendations Consider treatment with duloxetine, pregabalin, and gabapentin to improve quality of life in patients with neuropathic pain. C Assess the effects of distal symmetric polyneuropathy on quality of life to improve adherence and response to neuropathic pain treatment. E Assessing the effects of DSPN on a patient’s quality of life is emerging as a component of patient care and may play an important part in the adherence and the response to therapies in patients with neuropathic pain (140). Some studies report an improvement in quality of life in people with painful DSPN treated with duloxetine (100), pregabalin (141), and gabapentin (106,142). A longitudinal study has shown that DSPN is a risk factor for depression and the strongest symptom associated with depression was unsteadiness. Pain with DSPN may also give rise to symptoms of anxiety (143). Two research tools that can be used to assess quality of life that are neuropathy specific are the Neuro-QoL (Quality of Life in Neurological Disorders) (144) and QOL-DN (Norfolk Quality of Life-Diabetic Neuropathy) instruments (145). Diabetic Autonomic Neuropathies Autonomic neuropathies affect the autonomic neurons (parasympathetic, sympathetic, or both) and are associated with a variety of site-specific symptoms. The symptoms and signs of autonomic dysfunction should be elicited carefully during the medical history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. Although CAN is the most studied and clinically relevant of the diabetic autonomic neuropathies, gastrointestinal, genitourinary, and sudomotor dysfunction should be considered in the optimal care of patients with diabetes. CAN Although CAN prevalence is very low in newly diagnosed patients with type 1 diabetes (146), CAN prevalence increases substantially with diabetes duration (13,25), and prevalence rates of at least 30% were observed in the DCCT/EDIC cohort after 20 years of diabetes duration (27,147). In type 2 diabetes, the prevalence of CAN also increases with diabetes duration and may be present in up to 60% of patients with type 2 diabetes after 15 years (13,148,149). CAN may affect youth, especially young women and those with elevated A1C levels, with prevalence rates of at least 20% reported in youth with type 1 or type 2 diabetes (150). In addition, CAN is present in patients with impaired glucose tolerance, insulin resistance, or metabolic syndrome (10,32,151). A timely diagnosis of CAN may have important clinical implications, as CAN is an independent risk factor for cardiovascular mortality, arrhythmia, silent ischemia, any major cardiovascular event, and myocardial dysfunction (152–157). Data from two large cardiovascular outcomes trials that included 31,531 patients with stable heart disease and/or diabetes followed for a median of 5 years reported that heart rate, an indirect measure of CAN, analyzed as either categorical (baseline heart rate >70 vs. ≤70 bpm) or across heart rate quintile, was independently associated with significant increases in cardiovascular disease (CVD) events and all-cause death (158). CAN may also be associated with hemodynamic instability or cardiorespiratory arrest (159). CAN was the strongest risk factor for mortality in a large cohort of patients with type 1 diabetes participating in the EURODIAB Prospective Cohort Study (160), and a meta-analysis of several trials reported higher mortality risk with worse measures of CAN (152). Conclusive evidence that supports CAN as an independent predictor of mortality was confirmed in more than 8,000 participants with type 2 diabetes in the ACCORD trial (154). Hazard ratios for all-cause and CVD mortality in those with CAN were as high as 2.14 after adjusting for all traditional CVD risk factors and many other risk factors, including use of various classes of medication use (154). It was also suggested that intensification of glucose and blood pressure management may increase the risk of a cardiovascular event in people with signs of CAN (161–165). Similarly, emerging evidence demonstrates an association between CAN and glucose variability, especially in the hypoglycemic range (150,164). In addition, CAN independently predicts the progression of diabetic nephropathy and chronic kidney disease in diabetes (13,166–168). Screening and Diagnosis Recommendations Symptoms and signs of autonomic neuropathy should be assessed in patients with microvascular and neuropathic complications. E In the presence of symptoms or signs of cardiovascular autonomic neuropathy, tests excluding other comorbidities or drug effects/interactions that could mimic cardiovascular autonomic neuropathy should be performed. E Consider assessing symptoms and signs of cardiovascular autonomic neuropathy in patients with hypoglycemia unawareness. C The most common symptoms of CAN occur upon standing and include light-headedness, weakness, palpitations, faintness, and syncope (13,169,170) (Table 5). The patient should be asked about these symptoms when a medical history is taken in the office, although the correlation of symptoms with overall autonomic deficits is weak (149,171). However, these symptoms may occur quite late in the disease course (25,27,147,149). It may be appropriate to screen patients with hypoglycemia unawareness, as this may be associated with CAN (81). Table 5 Symptoms and signs associated with diabetic autonomic neuropathy CAN Gastrointestinal Urogenital Sudomotor Resting tachycardia Gastroparesis (Gastropathy) Bladder dysfunction Dry skin Abnormal blood pressure regulation Nondipping Reverse dipping Nausea Bloating Loss of appetite Early satiety Postprandial vomiting Brittle diabetes Frequency Urgency Nocturia Hesitancy Weak stream Dribbling Urinary incontinence Urinary retention Anhidrosis Gustatory sweating Orthostatic hypotension (all with standing) Esophageal dysfunction Male sexual dysfunction Light-headedness Weakness Faintness Visual impairment Syncope Heartburn Dysphagia for solids Erectile dysfunction Decreased libido Abnormal ejaculation Orthostatic tachycardia or bradycardia and chronotropic incompetence (all with standing) Diabetic diarrhea Female sexual dysfunction Light-headedness Weakness Faintness Dizziness Visual impairment Syncope Profuse and watery diarrhea Fecal incontinence May alternate with constipation Decreased sexual desire Increased pain during intercourse Decreased sexual arousal Inadequate lubrication Exercise intolerance Constipation May alternate with explosive diarrhea In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability (HRV) with deep breathing (13,169,170). Testing HRV may be done in the office by either 1) taking an electrocardiogram recording as a patient begins to rise from a seated position or 2) taking an electrocardiogram recording during 1–2 min of deep breathing with calculation of HRV (11,81,170). In more advanced cases, patients may present with resting tachycardia (>100 bpm) and exercise intolerance (13,170). Advanced disease may also be associated with orthostatic hypotension (a fall in systolic or diastolic blood pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate) (172). Orthostatic hypotension is usually easy to document in the office. In most cases of CAN, there is no compensatory increase in the heart rate, despite hypotension (173). The diagnosis includes documentation of symptoms (Table 5) and signs of CAN, which include impaired HRV, higher resting heart rate, and presence of orthostatic hypotension. In a symptomatic patient presenting with resting tachycardia, with a history of poor glucose control, or when the diagnosis of CAN is likely, clinicians may not need to perform additional tests given costs and burden. Exclusion of other comorbidities or drug effects/interactions that may present with the symptoms or signs of CAN and that mimic CAN may be needed (81,174) (Table 6). In addition, polypharmacy may also directly or indirectly impact CAN. Table 6 Diagnostic algorithm for CAN Symptoms Signs/diagnostic tests Differential workup Resting tachycardia Palpitations Clinical exam: resting heart rate >100 bpm • Anemia Could be asymptomatic • Hypothyroidism • Fever • CVD (atrial fibrillation, flutter, other) • Dehydration • Adrenal insufficiency • Medications • Sympathomimetic agents (asthma) • Over-the-counter cold agents containing ephedrine or pseudoephedrine • Dietary supplements (e.g., ephedra alkaloids) • Smoking, alcohol, caffeine • Recreational drugs (cocaine, amphetamines, methamphetamine, mephedrone) Orthostatic hypotension Light-headedness Clinical exam: a reduction of >20 mmHg in the systolic blood pressure or >10 mmHg in diastolic blood pressure • Adrenal insufficiency Weakness • Intravascular volume depletion Faintness • Blood loss/acute anemia Visual impairment • Dehydration Syncope • Pregnancy/postpartum • CVD • Arrhythmias • Heart failure • Myocarditis • Pericarditis • Valvular heart disease • Alcohol • Medication • Antiadrenergics • Antianginals • Antiarrhythmics • Anticholinergics • Diuretics • ACE inhibitors/angiotensin receptor blocker • Narcotics • Neuroleptics • Sedatives Treatment Prevention. Please refer to Prevention on page 136. Recommendations Optimize glucose control as early as possible to prevent or delay the development of cardiovascular autonomic neuropathy in people with type 1 diabetes. A Consider a multifactorial approach targeting glycemia among other risk factors to prevent cardiovascular autonomic neuropathy in people with type 2 diabetes. C Consider lifestyle modifications to improve cardiovascular autonomic neuropathy in patients with prediabetes. C As with DSPN, multiple other therapies targeting various pathogenetic mechanisms have failed to reverse established CAN. CAN treatment is generally focused on alleviating symptoms and should be targeted to the specific clinical manifestation. Symptomatic Treatment of Orthostatic Hypotension. Treatment for orthostatic hypotension is challenging and usually involves both pharmacological and nonpharmacological interventions. Physical activity and exercise should be encouraged to avoid deconditioning, which is known to exacerbate orthostatic intolerance. Volume repletion with fluids and salt is central to the management of orthostatic hypotension. Low-dose fludrocortisone may be beneficial in supplementing volume repletion in some patients, although there are growing concerns on risk of supine hypertension. As neurogenic orthostatic hypotension is in large part a consequence of the failure of norepinephrine release from sympathetic neurons, the administration of sympathomimetic medications is central to the care of patients whose symptoms are not controlled with other measures (173). Midodrine, a peripheral, selective, direct α1-adrenoreceptor agonist, is an FDA-approved drug for the treatment of orthostatic hypotension (175). Midodrine should be titrated gradually to efficacy. It should be used only when patients intend to be upright or seated to minimize supine hypertension (173). Recently, droxidopa was approved by the FDA for the treatment of neurogenic orthostatic hypotension but not specifically for patients with orthostatic hypotension due to diabetes (176). Gastrointestinal Neuropathies Gastrointestinal neuropathies may involve any portion of the gastrointestinal tract with manifestations including esophageal dysmotility, gastroparesis (delayed gastric emptying), constipation, diarrhea, and fecal incontinence. The prevalence data on gastroparesis are limited, as most reports were from selected case series rather than larger populations, and there was inconsistency in the outcome measures used (177). In the only community-based study, the cumulative incidence of gastroparesis over 10 years was higher in type 1 diabetes (5%) than in type 2 diabetes (1%) and in control subjects (1%) (178). Gastroparesis may directly affect glycemic management (e.g., insulin dose or other antidiabetes agents) and may be a cause of glucose variability and unexplained hypoglycemia due to the dissociation between food absorption and the pharmacokinetic profiles of insulin and other agents (12,179–182). Gastroparesis is mainly found in patients with long-standing diabetes (183). Screening and Diagnosis Recommendations Evaluate for gastroparesis in people with diabetic neuropathy, retinopathy, and/or nephropathy by assessing for symptoms of unexpected glycemic variability, early satiety, bloating, nausea, and vomiting. C Exclusion of other causes documented to alter gastric emptying, such as use of opioids or glucagon-like peptide 1 receptor agonists and organic gastric outlet obstruction, is needed before performing specialized testing for gastroparesis. C To test for gastroparesis, either measure gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake or use a 13C-octanoic acid breath test. B Gastroparesis may manifest with a broad spectrum of symptoms and signs (12,177,179,181). As part of a medical history, providers are encouraged to document symptoms of gastroparesis, such as early satiety, fullness, bloating, nausea, vomiting, dyspepsia, and abdominal pain. However, gastroparesis may be clinically silent in the majority of cases, and symptoms do not necessarily correspond with severity of gastroparesis and are poorly associated with abnormal gastric emptying (184,185). Symptoms such as anorexia, nausea, vomiting, and dyspepsia are nonspecific and resemble many other conditions (186) and may just be associated with the presence of diabetes (181). Importantly, hyperglycemia, hypoglycemia, and acute changes in blood glucose are well documented to alter gastric emptying (182,187,188), as are some medications, especially opioids, other pain management agents, and glucagon-like peptide 1 receptor agonists (189,190). Therefore, all these factors known to affect gastric emptying should always be considered before a firm diagnosis is established. Exclusion of organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering specialized testing for gastroparesis. The diagnostic gold standard is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake; the use of 13C-octanoic acid breath test is emerging as a viable alternative (12,179). Optimization of glucose levels prior to scanning is needed (182,186–188) to avoid false-positive results. Treatment Recommendation Consider short-term metoclopramide in the treatment of diabetic gastroparesis. E Treatment for diabetic gastroparesis may be very challenging. Dietary changes may be useful, such as eating multiple small meals and decreasing dietary fat and fiber intake. Withdrawing drugs with effects on gastrointestinal motility, such as opioids, anticholinergics, tricyclic antidepressants, glucagon-like peptide 1 receptor agonists, pramlintide, and possibly dipeptidyl peptidase 4 inhibitors, may also improve intestinal motility (180,191). In cases of severe gastroparesis, pharmacological interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of metoclopramide for the management of gastroparesis is weak, and given the risk for serious adverse effects (extrapyramidal symptoms, such as acute dystonic reactions; drug-induced parkinsonism; akathisia; and tardive dyskinesia), its use in the treatment of gastroparesis beyond 5 days is no longer recommended by the FDA and the European Medicines Agency. It should be reserved for severe cases that are unresponsive to other therapies (191). Urogenital Neuropathies Diabetic autonomic neuropathy may also cause genitourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction (ED) and/or retrograde ejaculation. ED is three times more common in men with diabetes than those without the disease (192–194). Sexual dysfunction is also more common in women with diabetes (195–199). Recommendations Consider screening men with other forms of diabetic neuropathy annually for erectile dysfunction with simple questions about a patient’s libido and ability to reach and maintain an erection. C Consider screening patients with other forms of diabetic neuropathy for lower urinary tract symptoms and female sexual dysfunction in the presence of recurrent urinary tract infections using targeted questioning regarding symptoms, such as nocturia, pain during intercourse, and others. E ED ED may be a consequence of autonomic neuropathy, as autonomic neurotransmission controls the cavernosal and detrusor smooth muscle tone and function (200). The etiology, however, is multifactorial, and clinicians should also evaluate other vascular risk factors such as hypertension, hyperlipidemia, obesity, endothelial dysfunction, smoking, CVD, concomitant medication, and psychogenic factors (12). There is evidence of associations between ED and other diabetes complications, including CAN (201–203). A diagnosis should be made after establishing the signs and symptoms of ED and after excluding alternate causes. Clinicians should consider performing hormonal evaluation (luteinizing hormone, testosterone, free testosterone, prolactin) to rule out hypogonadism. In addition, a variety of medications and organic causes should be excluded (12). Glucose control was associated with a lower incidence of erectile dysfunction in men with type 1 diabetes (204,205). Evidence is less strong for type 2 diabetes. Control of other risk factors such as hypertension and hyperlipidemia may also improve the condition (12). Pharmacological treatment includes phosphodiesterase type 5 inhibitors as first-line therapy and transurethral prostaglandins, intracavernosal injections, vacuum devices, and penile prosthesis in more advanced cases. Lower Urinary Tract Symptoms and Female Sexual Dysfunction Lower urinary tract symptoms manifest as urinary incontinence and bladder dysfunction (nocturia, frequent urination, urination urgency, weak urinary stream) and is linked to the presence of diabetic neuropathy in both men and women (12,206). Female sexual dysfunction occurs more frequently in women with diabetes than in those without diabetes (196,207) and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication. Evaluation of bladder function should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. The medical history should include simple questions to unveil symptoms of lower urinary tract symptoms and female sexual dysfunction (196,207,208). Sudomotor Dysfunction Sudomotor dysfunction may manifest as dry skin, anhidrosis, or heat intolerance (209,210). A rare form of sudomotor dysfunction is gustatory sweating that comprises excessive sweating limited exclusively to the head and neck region triggered by food consumption or, in some cases, the smell of food. Originally described as being solely due to autonomic neuropathy, gustatory sweating is also described in patients with diabetic nephropathy on dialysis (211). On the basis of the available evidence, the routine screening for sudomotor dysfunction in clinical practice is not recommended at this time. The efficacy of the topical antimuscarinic agent glycopyrrolate in the treatment of gustatory sweating was confirmed in a randomized controlled trial, and daily application attenuates this complication in most patients for at least 24 h (212). ATYPICAL NEUROPATHIES Mononeuropathies Mononeuropathies occur more commonly in patients with diabetes than in those without diabetes (1) and can occur as a result of involvement of the median, ulnar, radial, and common peroneal nerves (213). Cranial neuropathies present acutely and are rare; primarily involve cranial nerves III, IV, VI, and VII; and usually resolve spontaneously over several months (213). Electrophysiological studies are most helpful in identifying nerve conduction slowing or conduction block at the site of nerve entrapment. Nerve entrapments may require surgical decompression. The improvement in symptom severity and functional status score is no different between patients with and without diabetes (213). Diabetic Radiculoplexus Neuropathy Diabetic radiculoplexus neuropathy, a.k.a. diabetic amyotrophy or diabetic polyradiculoneuropathy, typically involves the lumbosacral plexus (214–216). The complication occurs mostly in men with type 2 diabetes. People with the condition routinely present with extreme unilateral thigh pain and weight loss, followed by motor weakness. Electrophysiological assessment is required to document the extent of disease and alternative etiologies, including degenerative disc disease or neoplastic, infectious, and inflammatory spinal disease (215,216). The disorder is usually self-limiting, and patients improve over time with medical management and physical therapy (214,215). There is presently no evidence from randomized trials to support any recommendation on the use of any immunotherapy treatment in this condition (217). Treatment-Induced Neuropathy Treatment-induced neuropathy in diabetes (also referred to as insulin neuritis) is considered a rare iatrogenic small-fiber neuropathy caused by an abrupt improvement in glycemic control in the setting of chronic hyperglycemia, especially in patients with very poor glucose control (218). The prevalence and risk factors of this disorder are not known but are currently under study. Neuropathy End Points for Research and Clinical Trials There are currently no approved disease-modifying therapies for DSPN, CAN, or other forms of diabetic neuropathy, and multiple clinical trials for these conditions have failed. Important contributing factors include a lack of agreement and uniformity in the use of the most sensitive DSPN measures that capture the natural history of the disease and detect repair in the specific nerve fiber populations, as well as the inclusion of appropriate patient populations. Thus, a valid and careful diagnosis for DSPN in clinical research is critical for correctly identifying the appropriate patient population targeted for either a specific intervention or for prognostic implications. The use of validated clinical instruments such as the Michigan Neuropathy Screening Instrument (MNSI) (most widely used in large cohorts of patients with type 1 and type 2 diabetes) (21,26,27,46,74,75), the modified Toronto Clinical Neuropathy Scale (mTCNS) (73), the Utah Early Neuropathy Scale (UENS) (77), or the Neuropathy Disability Score (NDS) (44) are recommended. These may be combined with electrophysiology; measures of small-fiber damage and repair, such as intraepidermal nerve fiber density (219–221) or corneal confocal microscopy (222); and objective measures of patient function in the design of DSPN trials. The recommended CAN measures for clinical trials targeting either a specific intervention or for prognostic implications include 1) standardized cardiovascular autonomic reflex tests that are simple, sensitive, specific, reproducible, and assess the changes in the R-R interval on electrocardiogram recordings in response to simple clinical maneuvers (deep breathing, Valsalva, and standing) (13,81,191,223); 2) indices of HRV (see above) (11,151,169); and 3) resting heart rate and QTc (154,156,157). Other methods such as baroreflex sensitivity, cardiac sympathetic imaging, and microneurography require sophisticated infrastructure and highly trained personnel and are quite expensive and time-consuming (11,13,224).

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The neural control of micturition.

Timothy D. Griffiths, Randal Fowler, Henrica de Vet (2008)

Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

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Taymour Mostafa

Ibrahim A Abdel-Hamid

Journal

Journal ID (nlm-ta): World J Diabetes

Journal ID (publisher-id): WJD

Title: World Journal of Diabetes

Publisher: Baishideng Publishing Group Inc

ISSN (Electronic): 1948-9358

Publication date (Print): 15 July 2021

Publication date (Electronic): 15 July 2021

Volume: 12

Issue: 7

Pages: 954-974

Affiliations

Department of Andrology & Sexology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt. taymour1155@ 123456link.net

Department of Andrology, Mansoura Faculty of Medicine, Mansoura 35516, Egypt

Author notes

Author contributions: Mostafa T and Abdel-Hamid IA contributed equally to this work in all its aspects.

Corresponding author: Taymour Mostafa, PhD, Professor, Department of Andrology & Sexology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt. taymour1155@ 123456link.net

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Other ID: jWJD.v12.i7.pg954

DOI: 10.4239/wjd.v12.i7.954

PMC ID: 8311479

PubMed ID: 34326948

SO-VID: 2794db9a-bb28-4567-9296-72957eb43bf5

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This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

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Date received : 30 January 2021

Date revision received : 6 May 2021

Date accepted : 15 June 2021

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Ejaculatory dysfunction in men with diabetes mellitus

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The neural control of micturition.

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