Utilizing a quality of life tool to examine the presence of fatigue in subjects with diabetes mellitus.

Introduction: The prevalence of fatigue in patients with diabetes mellitus (DM) can be as high as 50 %. Physical, mental, and psychosocial components of fatigue negatively impact quality of life (QOL), morbidity and mortality. Several tools have been developed to address fatigue, but none specifically for measuring fatigue in DM. The aim of this study was to assess the impact of diabetes and neuropathy on fatigue using the Norfolk QOL-Fatigue (QOL-F) survey. Methods: 605 adult participants from [Anonymous] were recruited (400 subjects with type 1 or type 2 DM and 205 subjects without diabetes (controls)). All subjects completed the Norfolk QOL-F. Demographics, weight, BMI, and duration of diabetes were obtained. The Norfolk QOL-F, a 35-item validated questionnaire, assesses five domains: subjective fatigue, physical and cognitive fatigue, reduced activities, impaired activities of daily living, and depression. Results: Subjects with DM reported significantly higher fatigue total scores (52.63vs33.89, p < 0.0001) and in all five domains when compared to controls. Patients with DM with neuropathy were significantly more fatigued than those without (59.72vs27.83, p < 0.0001). Fatigue scores in patients with DM without neuropathy were similar to controls (27.83vs33.89, p = NS). In multivariate analysis, age, gender, and presence of neuropathy significantly impacted fatigue scores. Conclusions: The Norfolk QOL-F questionnaire can potentially identify the impact of chronic diseases such as diabetes on fatigue. Assessing the different components of fatigue is important for clinicians in improving disease management and outcomes. Further investigations are needed to confirm these observations in specific cohorts with other comorbidities.

Cardiac and Sudomotor Autonomic Function in Subjects with Psoriasis With and Without Metabolic Syndrome.

Purpose: Studies have shown that subjects with psoriasis (PsO) are associated with an increased risk of developing metabolic syndrome (MetS), diabetes, and cardiovascular disease. In addition, MetS and diabetes are associated with autonomic dysfunction (AD). The aim of this study was to investigate cardiac and sudomotor autonomic function in subjects with PsO and without diabetes. Methods: A cross-sectional study was performed in 20 subjects with PsO, compared with age- and sex-matched 21 healthy controls, and 20 subjects with MetS. Subjects underwent skin evaluation by dermatologist, glycated hemoglobin (HbA1c), insulin, glucose, and lipid levels, sudomotor function testing with Sudoscan™ device (Impeto Medical, Paris, France), and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc., Philadelphia, PA). Quality of Life (QOL) and peripheral neurologic function were also assessed. Results: Participants with PsO were significantly more obese, had higher levels of fasting insulin and triglycerides, and were more insulin resistant when compared to controls. Subjects with PsO showed significantly worse cardiac autonomic function when compared to control and MetS groups. Sudomotor function and QOL scores were similar between the groups. Subgroup analysis of PsO subjects without MetS criteria (n = 15) showed persistent significantly deteriorated cardiac autonomic function when compared to the other two groups. Conclusion: This study suggests an association between PsO and cardiac AD, independent of the presence of overt dysglycemia and MetS. Additional larger studies are needed to clarify the significance of these findings and the relationship between PsO, AD, and metabolic disease.

Development and Validation of the Norfolk Quality of Life Fatigue Tool (QOL-F): A New Measure of Perception of Fatigue.

OBJECTIVES: To design a questionnaire to evaluate and distinguish between cognitive and physical aspects of fatigue in different age groups of "nondiseased" people and guide appropriate prevention and interventions for the impact of frailty occurring in normative aging. STUDY DESIGN AND PARTICIPANTS: The Norfolk QOL-Fatigue (QOL-F) with items of cognitive and physical fatigue, anxiety, and depression from validated questionnaires including items from the Patient-Reported Outcomes Measure Information System (PROMIS) databank was developed. The preliminary QOL-F was administered to 409 healthy multiethnic local participants (30-80 years old) in 5 age groups. METHODS: The authors distilled the item pool using exploratory (EFA) and confirmatory factor analysis (CFA). EFA identified 5 latent groups as possible factors related to problems due to fatigue, subjective fatigue, reduced activities, impaired activities of daily living (ADL), and depression. RESULTS: CFA demonstrated good overall fit [χ2(172) = 1094.23, P < .001; Tucker-Lewis index = 0.978; root mean square error of approximation = 0.049] with factor loadings >0.617 and strong interfactor correlations (0.69-0.83), suggesting that fatigue in each domain is closely related to other domains and to the overall scale except for ADL. The 5-factor solution displayed good internal consistency (Cronbach α = 0.78-0.94). Total and domain scores were fairly equivalent in all age groups except for the 40 to 49-year-old group with better overall scores. In addition, 70 to 79-year-olds had better ADL scores. In item response analysis, factor scores in different age groups were similar, so age may not be a significant driver of fatigue scores. Fatigue scores were significantly higher in females than in males (P < .05). CONCLUSIONS AND CLINICAL IMPLICATIONS: The developed Norfolk QOL-F tool demonstrated fatigue as a perceived cognitive phenomenon rather than an objective physical measure, suggesting mandatory inclusion of cognitive as well as physical measures in the evaluation of people as they age. QOL-F is able to distinguish QOL-F domain scores unique to different age groups, proposing clinical benefits from physical, balance, and cognitive interventions tailored to impact frailty occurring in normative aging.

Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events.

Autonomic nervous system (ANS) imbalance manifesting as cardiac autonomic neuropathy in the diabetic population is an important predictor of cardiovascular events. Symptoms and signs of ANS dysfunction, such as resting heart rate elevations, diminished blood pressure responses to standing, and altered time and frequency domain measures of heart rate variability in response to deep breathing, standing, and the Valsalva maneuver, should be elicited from all patients with diabetes and prediabetes. With the recognition of the presence of ANS imbalance or for its prevention, a rigorous regime should be implemented with lifestyle modification, physical activity, and cautious use of medications that lower blood glucose. Rather than intensifying diabetes control, a regimen tailored to the individual risk of autonomic imbalance should be implemented. New agents that may improve autonomic function, such as SGLT2 inhibitors, should be considered and the use of incretins monitored. One of the central mechanisms of dysfunction is disturbance of the hypothalamic cardiac clock, a consequence of dopamine deficiency that leads to sympathetic dominance, insulin resistance, and features of the metabolic syndrome. An improvement in ANS balance may be critical to reducing cardiovascular events, cardiac failure, and early mortality in the diabetic population.

Diabetic Microvascular Disease: An Endocrine Society Scientific Statement.

Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.

Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-Fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes.

OBJECTIVE: The aim was to evaluate the impact of bariatric surgery on cardiac and sudomotor autonomic C-fiber function in obese subjects with and without Type 2 diabetes mellitus (T2DM), using sudorimetry and heart rate variability (HRV) analysis. METHOD: Patients were evaluated at baseline, 4, 12 and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. All subjects were assessed using SudoscanTM to measure electrochemical skin conductance (ESC) of hands and feet, time and frequency domain analysis of HRV, Neurologic Impairment Scores of lower legs (NIS-LL), quantitative sensory tests (QST) and sural nerve conduction studies. RESULTS: Seventy subjects completed up to 24-weeks of follow-up (24 non-T2DM, 29 pre-DM and 17 T2DM). ESC of feet improved significantly towards normal in T2DM subjects (Baseline = 56.71±3.98 vs 12-weeks = 62.69±3.71 vs 24-weeks = 70.13±2.88, p<0.005). HRV improved significantly in T2DM subjects (Baseline sdNN (sample difference of the beat to beat (NN) variability) = 32.53±4.28 vs 12-weeks = 44.94±4.18 vs 24-weeks = 49.71±5.19, p<0,001 and baseline rmsSD (root mean square of the difference of successive R-R intervals) = 23.88±4.67 vs 12-weeks = 38.06±5.39 vs 24-weeks = 43.0±6.25, p<0.0005). Basal heart rate (HR) improved significantly in all groups, as did weight, body mass index (BMI), percent body fat, waist circumference and high-density lipoprotein (HDL). Glycated hemoglobin (HbA1C), insulin and HOMA2-IR (homeostatic model assessment) levels improved significantly in pre-DM and T2DM subjects. On multiple linear regression analysis, feet ESC improvement was independently associated with A1C, insulin and HOMA2-IR levels at baseline, and improvement in A1C at 24 weeks, after adjusting for age, gender and ethnicity. Sudomotor function improvement was not associated with baseline weight, BMI, % body fat or lipid levels. Improvement in basal HR was also independently associated with A1C, insulin and HOMA2-IR levels at baseline. CONCLUSION: This study shows that bariatric surgery can restore both cardiac and sudomotor autonomic C-fiber dysfunction in subjects with diabetes, potentially impacting morbidity and mortality.

The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention.

Sudorimetry technology has evolved dramatically, as a rapid, non-invasive, robust, and accurate biomarker for small fibers that can easily be integrated into clinical practice. Though skin biopsy with quantitation of intraepidermal nerve fiber density is still currently recognized as the gold standard, sudorimetry may yield diagnostic information not only on autonomic dysfunction but also enhance the assessment of the small somatosensory nerves, disease detection, progression, and response to therapy. Sudorimetry can be assessed using Sudoscan™, which measures electrochemical skin conductance (ESC) of hands and feet. It is based on different electrochemical principles (reverse iontophoresis and chronoamperometry) to measure sudomotor function than prior technologies, affording it a much more practical and precise performance profile for routine clinical use with potential as a research tool. Small nerve fiber dysfunction has been found to occur early in metabolic syndrome and diabetes and may also be the only neurological manifestation in small fiber neuropathies, beneath the detection limits of traditional nerve function tests. Test results are robust, accomplished within minutes, require little technical training and no calculations, since established norms have been provided for the effects of age, gender, and ethnicity. Sudomotor testing has been greatly under-utilized in the past, restricted to specialized centers capable of handling the technically demanding and expensive technology. Yet, evaluation of autonomic and somatic nerve function has been shown to be one of the best estimates of cardiovascular risk. Evaluation of sweating has the appeal of quantifiable non-invasive determination of the integrity of the peripheral autonomic nervous system, and can now be accomplished rapidly at point of care clinics with the determination of ESC, allowing intervention for morbid complications prior to permanent structural nerve damage. We review here sudomotor function testing technology, the research evidence accumulated supporting the clinical utility of measuring ESC, the medical applications of sudorimetry now available to physicians with this device, and clinical vignettes illustrating its use in the clinical decision-making process.

Diabetic neuropathy.

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care. The clinical assessment of diabetic peripheral neuropathy and its treatment options are multifactorial. Patients with DN should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications. A review of the clinical assessment and treatment algorithms for diabetic neuropathy, painful neuropathy, and autonomic dysfunction is provided.

Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction.

OBJECTIVE: Sudomotor dysfunction may be an early detectable abnormality in diabetic small fiber neuropathy. The aim of this study was to evaluate the efficacy of Sudoscan™ (Impeto Medical, Paris, France) in detecting diabetic neuropathy (DN), in comparison with other standardized tests, in patients with diabetes mellitus (DM). SUBJECTS AND METHODS: Sudoscan measures electrochemical skin conductance (ESC) of hands and feet through reverse iontophoresis. We evaluated 83 DM patients with and without DN and 210 healthy controls (HCs). Neuropathy Impairment Score-Lower Legs (NIS-LL), quantitative autonomic function testing (QAFT), and quantitative sensory testing (QST) were performed. Symptomatic pain was recorded using a visual analog scale. Receiver-operator characteristic (ROC) curves were calculated to evaluate the efficacy of Sudoscan in detecting DN compared with traditional modalities. RESULTS: Diabetes patients with DN had significantly worse ESCs of feet and hands than DM patients without DN and HCs (respectively, 56.3±3 vs. 75.9±5.5 and 84.4±0.9 [P<0.0001] for feet and 51.9±2.4 vs. 67.5±4.3 and 73.1±0.8 [P<0.0001] for hands). Increasing NIS-LL scores were associated with decreasing ESC values. ESCs correlated significantly with clinical (NIS-LL), somatic (QST), and autonomic (QAFT) measures of neuropathy and with pain scores. ROC curve analysis showed significant results for both hands and feet ESC (area under the curve of 0.86 and 0.88, respectively; P<0.0001) with sensitivity of 78% and specificity of 92% for feet to detect DN. CONCLUSIONS: Sudoscan is a promising, sensitive tool to detect neuropathy in patients with DM. This is a very simple, easy-to-perform test that can be done in the clinical setting in 3-5 min.

Neurovascular function and sudorimetry in health and disease.

In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians.

Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease.

One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy. There is now clear evidence that suggests activation of inflammatory cytokines in diabetic patients and that these correlate with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It also occurs in prediabetes, providing opportunities for early intervention. Simple tests that can be carried out at the bedside with real-time output of information - within the scope of the practicing physician - facilitate diagnosis and allow the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. Several agents have become available for the correction of functional defects in the autonomic nervous system, and restoration of autonomic balance is now possible.

Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin.

Diabetic peripheral neuropathy is a common complication of diabetes. It presents as a variety of syndromes for which there is no universally accepted unique classification. Sensorimotor polyneuropathy is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community. Pain is the reason for 40% of patient visits in a primary care setting, and about 20% of these have had pain for greater than 6 months. Chronic pain may be nociceptive, which occurs as a result of disease or damage to tissue with no abnormality in the nervous system. In contrast, neuropathic pain is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system." Persistent neuropathic pain interferes significantly with quality of life, impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with depression, anxiety, and noncompliance with treatment. Painful diabetic peripheral neuropathy is a difficult-to-manage clinical problem, and patients with this condition are more apt to seek medical attention than those with other types of diabetic neuropathy. Early recognition of psychological problems is critical to the management of pain, and physicians need to go beyond the management of pain per se if they are to achieve success. This evidence-based review of the assessment of the patient with pain in diabetes addresses the state-of-the-art management of pain, recognizing all the conditions that produce pain in diabetes and the evidence in support of a variety of treatments currently available. A search of the full Medline database for the last 10 years was conducted in August 2012 using the terms painful diabetic peripheral neuropathy, painful diabetic peripheral polyneuropathy, painful diabetic neuropathy and pain in diabetes. In addition, recent reviews addressing this issue were adopted as necessary. In particular, reports from the American Academy of Neurology and the Toronto Consensus Panel on Diabetic Neuropathy were included. Unfortunately, the results of evidence-based studies do not necessarily take into account the presence of comorbidities, the cost of treatment, or the role of third-party payers in decision-making. Thus, this review attempts to give a more balanced view of the management of pain in the diabetic patient with neuropathy and in particular the role of pregabalin.

Contact heat-evoked potential stimulation for the evaluation of small nerve fiber function.

BACKGROUND: Small fiber peripheral neuropathy (SFN) is emerging as a common complication in diabetes. Currently there are few, not easily available methods of determining the integrity of small nerve fibers. This study was designed to determine the utility of a noninvasive technique, contact heat-evoked potential stimulation (CHEPS), on the identification of SFN and compare it with standardized measures of diabetic peripheral neuropathy (DPN). SUBJECTS AND METHODS: We evaluated 31 healthy controls and 30 participants with type 2 diabetes and DPN using neurologic examination, nerve conduction studies (NCS), autonomic function tests, quantitative sensory tests (QSTs), and CHEPS. Contact heat was administered to the thenar eminence, volar and dorsal forearms, lower back, and distal lower limb. Evoked potentials were recorded from the skull vertex. Latencies and amplitudes were determined. RESULTS: Intrapeak amplitude (IA) values were significantly reduced in the DPN group at the lower back (44.93±6.5 vs. 23.87±3.36 µV; P<0.01), lower leg (15.87±1.99 vs. 11.68±1.21 µV; P<0.05), and dorsal forearm (29.89±8.86 vs. 14.96±1.61 µV; P<0.05). Pooled data from both groups showed that IA values at different sites significantly correlated with clinical neurologic scores, NCS, QSTs, and autonomic function. Receiver operator characteristic curve analysis, used to evaluate the performance of CHEPS in detecting nerve dysfunction, was most significant for IA at the lower back (area under the curve, 0.778;±SE, 0.06; 95% confidence interval, 0.654-0.875; P<0.0001). CONCLUSIONS: This study suggests that CHEPS is a novel, noninvasive technique able to detect impairment of small nerve fiber function from skin to cerebral cortex, providing an objective measure of C and Aδ nerve dysfunction.

Prevalence of periprosthetic osteolysis after total hip replacement in patients with rheumatic diseases.

Periprosthetic osteolysis (PO) is a frequent complication in patients with joint implants. There are no data regarding the prevalence of PO in patients with rheumatoid arthritis (RA), juvenile chronic arthritis (JCA), ankylosing spondylitis (AS), and osteoarthritis (OA). OBJECTIVES: To evaluate the prevalence of PO in patients with RA, JCA, AS, and OA, who have undergone total hip replacement (THR), and to identify factors associated with its development. METHODS: The study included patients diagnosed with RA (ACR 1987), AS (modified New York criteria), JCA (European 1977 criteria), and osteoarthritis (OA) (ACR 1990 criteria) with unilateral or bilateral THR. Demographic, clinical, and therapeutic data were collected. Panoramic pelvic plain radiographs were performed, to determine the presence of PO at acetabular and femoral levels. Images were read by two independent observers. RESULTS: One hundred twenty-two hip prostheses were analyzed (74 cemented, 30 cementless, and 18 hybrids). The average time from prosthesis implantation to pelvic radiograph was comparable among groups. PO was observed in 72 hips (59%). In 55% of cases, PO was detected on the femoral component, with a lower prevalence in RA (53%) vs AS (64.7%) and JCA (76.5%). Acetabular PO was more frequent in JCA patients (58.8%), compared with RA (11.6%) and OA (28.5%) patients (P = 0.0001 and P = 0.06, respectively). There was no significant association between the presence of PO and clinical, functional, or therapeutic features. CONCLUSION: The prevalence of PO was 59%, being more frequent at the femoral level. Larger studies must be carried out to determine the clinical significance of radiologic PO.

Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2 / Exenatide trials for the treatment of type 2 diabetes

La diabetes mellitus tipo 2 es una enfermedad metabólica crónica, frecuente y progresiva, responsable del 90% de los casos de diabetes a nivel mundial. Aproximadamente el 60% de los individuos que padecen este desorden no alcanzan niveles óptimos de hemoglobina glicosilada, a pesar de la disponibilidad de numerosas alternativas terapéuticas. Los dos objetivos más importantes a cumplir en el manejo actual de la diabetes tipo 2 son la capacidad de los agentes antidiabéticos de exhibir eficacia prolongada y la capacidad de preservar la función de las células beta pancreáticas. El efecto incretina se encuentra reducido en pacientes con diabetes tipo 2. Exenatida pertenece a un nuevo grupo de drogas antidiabéticas que mejoran el control de la glucemia en estos pacientes a través de mecanismos fisiológicos glucorregulatorios que mejoran el efecto incretina. Los ensayos clínicos fase III con exenatida demostraron una reducción media de aproximadamente el 1% en los valores de hemoglobina glicosilada. Los datos a largo plazo de estudios de extensión no controlados indican una mejoría sostenida en los niveles de hemoglobina glicosilada y una reducción progresiva del peso luego de 3 años de tratamiento con esta droga. La droga es generalmente bien tolerada y los efectos adversos más frecuentes son los gastrointestinales, con una intensidad leve a moderada. El objetivo de esta revisión es analizar la evidencia publicada hasta la fecha sobre la eficacia y tolerabilidad del tratamiento con exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

[Exenatide trials for the treatment of type 2 diabetes]. / Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

Clinical manifestations and current treatment options for diabetic neuropathies.

OBJECTIVE: To review the clinical manifestations and current treatment options for diabetic neuropathies, one of the most common complications of diabetes mellitus. METHODS: We performed a MEDLINE search of the English-language literature using a combination of words (diabetic neuropathy, diabetic autonomic neuropathy, diagnosis and treatment) to identify original studies, consensus statements, and reviews on diabetic neuropathies published in the past 25 years. Emphasis was placed on clinical manifestations of distal polyneuropathy and its treatment, especially new therapies. RESULTS: Distal symmetric polyneuropathy, the most common form of diabetic neuropathy, usually involves small and large nerve fibers. Small-nerve fiber neuropathy often presents with pain and loss of intraepidermal nerve fibers, but without objective signs or electrophysiologic evidence of nerve damage. This type of neuropathy is a component of impaired glucose tolerance and the metabolic syndrome. The greatest risk from small-fiber neuropathy is foot ulceration and subsequent gangrene and amputation. Large-nerve fiber neuropathy produces numbness, ataxia, and incoordination, thus impairing activities of daily living and causing falls and fractures. Successfully treating diabetic neuropathy requires addressing the underlying pathogenic mechanisms, treating symptoms to improve quality of life, and preventing progression and complications of diabetes mellitus. Two new drugs, duloxetine hydrochloride and pregabalin, have recently been approved for treatment of neuropathic pain associated with diabetes mellitus. CONCLUSION: Symptomatic therapy has become available and newer and better treatment modalities, based on etiologic factors, are being explored with potential for clinically significant reduction of morbidity and mortality. Preventive strategies and patient and physician education still remain key factors in reducing complication rates and mortality.

A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy.

OBJECTIVE: Diabetes leads to protein kinase C (PKC)-beta overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-beta inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS: Endothelium-dependent and C fiber-mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged > or =18 years; with type 1 or type 2 diabetes and A1C < or =11%) during a randomized, double-masked, single-site, 6-month study. RESULTS: Endothelium-dependent (+78.2%, P < 0.03) and C fiber-mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months -48.3%, P = 0.01; end point -66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point -41.2%, P = 0.01, and -41.0, P = 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo -13.1%; ruboxistaurin -66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo -4.0%; ruboxistaurin -41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies. CONCLUSIONS: In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.