Diabetic neuropathy and cardiovascular disease -
Thus, a recent study reported that exposure to hypoglycemia leads to impaired CAN function in healthy volunteers In a meta-analysis of 12 published studies, Vinik et al.
In the Detection of Ischemia in Asymptomatic Diabetics DIAD study of 1, patients with type 2 diabetes, CAN was a strong predictor of silent ischemia and subsequent cardiovascular events The association between CAN and silent ischemia has important implications, as reduced appreciation for ischemic pain impairs timely recognition of myocardial ischemia or infarction, thereby delaying appropriate therapy.
The presence of CAN was also linked to the development of diabetic cardiomyopathy in type 1 diabetes because in these patients LV dysfunction often precedes or occurs in the absence of significant coronary artery disease or hypertension. We have identified diastolic dysfunction early in the course of type 1 diabetes that correlated with abnormal cardiac sympathetic imaging Further studies are needed to clarify the complex interactions between CAN, silent myocardial ischemia, and cardiomyopathy in diabetes.
Observations in diabetic patients undergoing general anesthesia reported that individuals with CAN required vasopressor support more often than those without CAN Individuals with CAN may experience a greater decline in heart rate and blood pressure during induction of anesthesia and more severe intraoperative hypothermia resulting in decreased drug metabolism and impaired wound healing A recent study in 1, patients with type 2 diabetes reported that presence of CAN, assessed by standard HRV testing, was one of the strongest predictors of ischemic stroke in this cohort together with age and hypertension Earlier reports showed similar associations The Epidemiology of Diabetes Interventions and Complications EDIC study, the prospective observational study of the DCCT cohort, has shown persistent beneficial effects of past glucose control on microvascular complications despite the loss of glycemic separation Recently we evaluated CAN in 1, well-characterized EDIC participants during the 13th and 14th year of EDIC follow-up.
We found that during EDIC CAN progressed substantially in both treatment groups, but the prevalence and incidence of CAN remained significantly lower in the former intensive group than in the former conventional group, despite similar levels of glycemic control in the EDIC study Treatment group differences in the mean A1C level during the DCCT and the EDIC study explained virtually all of the beneficial effects of intensive versus conventional therapy on risk of incident CAN, supporting the concept that intensive treatment of type 1 diabetes should be initiated as early as is safely possible In type 2 diabetes, the effects of glycemic control are less conclusive.
The VA Cooperative Study demonstrated no difference in the prevalence of autonomic neuropathy in type 2 diabetic patients after 2 years of tight glycemic control compared with those without tight control On the other hand, the Steno-2 Trial reported that a targeted, intensive intervention involving glucose control and multiple cardiovascular risk factors reduced the prevalence of CAN among patients with type 2 diabetes and microalbuminuria Data regarding the impact of lifestyle interventions in preventing progression of CAN are emerging.
Strictly supervised endurance training combined with dietary changes was associated with weight loss and improved HRV in patients with minimal abnormalities In the Diabetes Prevention Program, indexes of CAN improved most in the lifestyle modification arm compared with the metformin or placebo arm.
ACE inhibitors, angiotensin receptor blockers, or aldose reductase inhibitors appear promising but are yet to be validated The treatment of orthostatic hypotension is challenging. Nonpharmacological treatments include avoidance of sudden changes in body posture to the head-up position; avoiding medications that aggravate hypotension, such as tricyclic antidepressants and phenothiazines; eating small, frequent meals to avoid postprandial hypotension; and avoiding activities that involve straining, since increased intra-abdominal and intra-thoracic pressure decrease venous return Several physical counter maneuvers, such as leg crossing, squatting, and muscle pumping can help maintain blood pressure during daily activities by inducing increased cardiac filling pressures and stroke volume.
Midodrine, a peripheral-selective α 1 -adrenoreceptor agonist is the only Food and Drug Administration—approved agent for the treatment of orthostatic hypotension in doses of 2. Several double-blind, placebo-controlled studies have documented its efficacy in the treatment of orthostatic hypotension 7.
It does not cross the blood-brain barrier, resulting in fewer central side effects. The main adverse effects are piloerection, pruritis, paresthesias, urinary retention, and supine hypertension.
Fludrocortisone acetate, a synthetic mineralocorticoid with a long duration of action, induces plasma expansion and may enhance the sensitivity of blood vessels to circulating catecholamines The effects usually occur over a 1- to 2-week period.
Supine hypertension, hypokalemia, and hypomagnesemia may occur. Caution must be used, particularly in patients with congestive heart failure, to avoid fluid overload. Treatment with fludrocortisone should begin with 0. Doses up to 0. Erythropoietin may improve orthostatic hypotension, but the mechanism of action for this pressor effect is still unresolved.
Possibilities include the increase in red cell mass and central blood volume, correction of the normochromic normocytic anemia that frequently accompanies severe CAN, and direct or indirect neurohumoral effects on the vascular wall and vascular tone regulation mediated by the interaction between hemoglobin and the vasodilator nitric oxide Nonselective β-blockers, particularly those with intrinsic sympathomimetic activity, may have a limited role in the treatment of orthostatic hypotension The suggested mechanism of action of these agents is the blockade of vasodilating β-2 receptors allowing unopposed α-adrenoreceptor—mediated vasoconstriction.
To date there is no clear efficacy evidence in diabetic CAN. Clonidine, an α-2 antagonist, produces a central sympatholytic effect and a consequent decrease in blood pressure.
Patients with severe CAN have little central sympathetic efferent activity, and the use of clonidine 0. Its use is limited by the inconsistent hypertensive effect and serious side effects. However, severe cases of hypertension were reported with their use in patients with diabetic CAN Pyridostigmine bromide, a cholinesterase inhibitor, was recently shown to ameliorate orthostatic hypotension by enhancing ganglionic transmission without worsening supine hypertension CAN is a serious chronic complication of diabetes and an independent predictor of cardiovascular disease mortality.
As illustrated by the case vignette and by the evidence presented in this review, CAN is associated with a poor prognosis and poor quality of life. Conclusive clinical evidence from randomized prospective trials supports a central role for hyperglycemia in the pathogenesis of CAN, although other metabolic and vascular factors contribute to the disease state.
The clinical presentation of CAN comprises a broad constellation of symptoms and deficits. Assessment of HRV is an easily available tool to document the presence of CAN. Cardiac scintigraphic imaging with sympathetic analogs offers more sensitive diagnostic alternatives for research use.
The treatment of CAN is challenging. Recent clinical evidence continues to prove the benefits of glycemic control, while the benefits of lifestyle interventions are emerging. The costs of publication of this article were defrayed in part by the payment of page charges.
Section solely to indicate this fact. is supported by American Diabetes Association Grant CR, Juvenile Diabetes Research Foundation JDRF Grant , and JDRF for the Study of Complications of Diabetes Grant acknowledges the work of Dr.
David Raffel, Department of Radiology, University of Michigan, for assistance in generating the polar map of [ 11 C]HED retention.
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Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 33, Issue 2. Previous Article Next Article. CLINICAL SIGNS. Article Navigation. Review February 01 Cardiac Autonomic Neuropathy in Diabetes : A clinical perspective Rodica Pop-Busui, MD, PHD Rodica Pop-Busui, MD, PHD.
From the Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan. Corresponding author: Rodica Pop-Busui, rpbusui umich. This Site. Google Scholar. Diabetes Care ;33 2 — Article history Received:.
Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1. View large Download slide. Figure 2. No potential conflicts of interest relevant to this article were reported. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial DCCT.
Search ADS. Neuropathy profile of diabetic patients in a pancreas transplantation program. This can be easily performed in the office by utilizing an electrocardiogram recording during either 1—2 min of deep breathing, or as the subject begins to rise from a seated position, with calculation of HRV indices Pop-Busui et al.
TABLE 1. Diagnostic tests for cardiovascular autonomic neuropathy adapted from Brownlee et al. ADA recommendations regarding screening and diagnosis of CAN are as follows Pop-Busui et al. The Toronto Consensus Panel, the European Society of Cardiology, the North American Society of Pacing and Electrophysiology, and the ADA Position Statement on Diabetic Neuropathy recommend the following regarding CAN assessments for clinical trials measuring a targeted intervention or for prognostication Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, ; Bernardi et al.
Cardiovascular autonomic reflex tests assess cardiovascular autonomic function through time-domain HR response to deep breathing, Valsalva maneuver and postural change, and by measuring the consequent changes in HR and BP.
Although indirect autonomic measures, the following CARTs are considered the gold standard in autonomic testing: HR response to deep breathing E:I ratio , standing ratio and Valsalva maneuver, and BP response to standing. The presence of one abnormal cardiovagal test result identifies possible or early CAN, to be confirmed over time.
At least two abnormal cardiovagal results are required for a definite or confirmed diagnosis of CAN. The time-domain HR tests and the BP response to postural change have the reproducibility necessary for clinical trials. Analysis of time-domain measures under resting conditions offers an accurate assessment of the sympathetic and parasympathetic regulation of the heart beat the R—R interval on an electrocardiogram documented at baseline conditions and during deep breathing, Valsalva, and standing from a sitting position maneuvers.
The sdNN is an evaluation of both sympathetic and parasympathetic activity on HRV, and the rMSSD is a primary indicator of parasympathetic activity. Postural ratio is evaluated at beats 15 and 30 after standing up and is regarded as reflective of sympathetic response and baroreflex function. Convertino demonstrated that cardiac parasympathetic withdrawal mediated by the carotid cardiac baroreflex is the principal trigger for tachycardia within milliseconds of a postural change, while sympathetic adrenergic control sustains tachycardia during extended periods of orthostasis.
The Valsalva ratio is calculated by the longest R—R interval during the procedure to the shortest R—R interval throughout the duration or immediately following the maneuver. This reaction is facilitated by the interspersed activity of parasympathetic and sympathetic nerve fibers.
Frequency-domain analysis can identify underlying periodicities in HR patterns. Rfa also termed HF power is calculated as the area under the HR spectral curve over a frequency range fixed on the fundamental Rfa 0. LF is computed as the area under the HR spectral curve over the frequency range from 0.
Despite its use in research for decades, the concept that LF and HF bands fully reflect separate influences of the sympathetic and parasympathetic branches has been recently under debate Heathers and Goodwin, , mainly due to their simultaneous action in the LF power Valenza et al.
Therefore, there has been increasing interest in using non-linear analyses of HRV, as these may be clinically more relevant by providing a better interpretation of the pathophysiological behavior of HRV under various conditions and by enhancing its prognostic value de Godoy, Non-linear analysis methods do not assess the magnitude of variability but rather the quality, scaling, and correlation properties of the signals; these analyses allow a more subtle characterization of autonomic balance and have been shown to be more reliable markers of morbidity and mortality in patients with CVD.
A number of studies have shown that abnormal non-linear HRV indices are associated with diabetes or an elevated risk of developing diabetes Roy and Ghatak, ; Silva-E-Oliveira et al. The technical complexity of these analyses, however, has made interpretation and understanding of variability challenging for common clinical use.
Further research is needed to demonstrate conclusively that these refinements in the analysis enhance the sensitivity for prediction of cardiovascular events Sassi et al. Sudomotor nerves are thin unmyelinated C-fibers, with largely cholinergic neurotransmission, where the ganglion neurotransmitter is acetylcholine, the primary parasympathetic nervous system neurotransmitter.
However, epinephrine, norepinephrine, vasoactive intestinal peptide VIP , atrial natriuretic peptide, calcitonin gene related polypeptide CGRP , galanin, ATP, and substance P have been identified in periglandular nerves and thus may be contributing to the electrical response.
The addition of sudomotor function assessments, combined with CART, may present a more precise and well-defined early diagnosis of ANS dysfunction. Although quantitation of intraepidermal nerve fiber density on skin biopsies remains the gold standard and is the most recognized technique to diagnose small nerve fiber dysfunction, sudorimetry has the ability to produce diagnostic information on the evaluation of the small somatosensory nerves, detection and progression of disease, and responsiveness to therapeutic intervention.
Sudorimetry technology has advanced rapidly as a non-invasive and precise tool to assess small fibers that can potentially be incorporated into clinical practice.
Current sudorimetry assessments can be performed using Sudoscan TM , which measures electrochemical skin conductance ESC of hands and feet. This technology is founded on the electrochemical theories of reverse iontophoresis and chronoamperometry to measure sudomotor function, which makes it an affordable, practical, and precise tool generating accurate profiles for routine clinical use and a viable research tool on the integrity of this complex system of control.
This testing has assumed greater significance now that there are medications that can prevent the development or progression of ANS dysfunction. The American Association of Clinical Endocrinologists AACE endorses the use of current procedural technology CPT code for simplified sudomotor testing and the code for evaluation of cardiac autonomic function testing.
AACE would urge that sudomotor function testing be authorized for all practitioners seeing patients with diabetes, including primary care, endocrinology, and podiatry.
Cardiac autonomic neuropathy therapies are typically focused on mitigating symptoms and should be directed to specified clinical manifestations. Exercise, volume repletion, low dose fludrocortisone and midodrine are among the most frequently used therapies.
Recommendations for the treatment of CAN include the following Pop-Busui et al. Most recently there has been great interest in the action and effects of the sodium-glucose cotransporter-2 SGLT2 inhibitors on reducing cardiovascular events.
Empaglifozin is a highly selective inhibitor of the SGLT2 in the kidney. Glucose reduction occurs by decreasing renal glucose reabsorption and thereby increasing urinary glucose elimination in patients with diabetes, leading to significant reductions in glycated hemoglobin HbA1c , weight loss, and reductions in BP without increases in HR Liakos et al.
The EMPA-REG Outcome trial recruited 1, patients with T2DM, of whom were enrolled and randomized to placebo or one of two different doses of empagliflozin 10 and 25 mg daily in addition to standard care Zinman et al. Empagliflozin was similar to other oral antihyperglycemic agents in HbA1c reduction 0.
placebo, slightly greater weight loss at 52 weeks, modest BP reduction of 2—7 mmHg vs. placebo, and no intrinsic increased risk of hypoglycemia Kishi, A subsequent report showed that the reduction in cardiovascular deaths were significant in Southeast Asia and Latin America, but not as much in America and Europe Alzaid, Despite these different findings, the fall in BP without an increase in HR implies a reduction in sympathetic tone with its use.
Liraglutide, a GLP-1 receptor agonist, was also found to reduce CV events, but not as robustly as empagliflozin Vinik et al. GLP-1 has widespread properties in the human body and targets receptors diffusely Drucker, Liraglutide improves HbA1c and compared with other medication classes has similar or greater efficacy, even compared to basal insulin.
Its use has been shown to lead to a modest improvement in BP but, in contrast to empagliflozin, with an increase in HR Scirica et al. The FDA recently approved the use of liraglutide for management of CVD in diabetes Marso et al.
The actions of liraglutide on HRV and daily variation of HR in newly diagnosed, overweight patients with T2DM and stable CAD have been investigated. Diurnal HR fluctuations and sympathovagal balance evaluated by rMSSD in NN intervals and HF and LF power were assessed.
Liraglutide decreased sdNN in some subjects; decreased rMSSD; and increased mean, daytime, and nighttime HR compared to placebo. Thus, in overweight patients with CAD and newly diagnosed T2DM, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters; the increase in nightly HR and decrease in parameters of parasympathetic activity rMSSD and HF power suggest that this medication may negatively affect sympathovagal balance Kumarathurai et al.
The authors hypothesize that the chronotropic effect of liraglutide, which may be mediated through the GLP-1 receptor on the sinoatrial node, cannot explain the worsening of HRV measures; instead, the impaired HRV may be due to a direct influence on sympathovagal balance, as reflected by the increase in night-time HR in conjunction with the significant decrease in sdNN and rMSSD suggesting an impairment of parasympathetic activity.
The addition of a cholinergic agent to a GLP-1 analog might recapture the loss of cholinergic activity induced by a GLP-1 analog. This might even be a useful strategy to further enhance the cardiac protection afforded by the SGLT-2 inhibitors.
A number of researchers have demonstrated that autonomic balance can be restored using simple lifestyle interventions, potentially reversing CAN. Motooka et al. Removing the dog resulted in reversal of this benefit with sympathetic overactivity Motooka et al.
There is strong evidence indicating that individuals with greater aerobic capacity exhibit enhanced HRV Tulppo et al. Furthermore several studies have shown significant improvements in HRV measures after different training programs including cycling, walking, jogging and water aerobic exercise training in subjects with CAD Laing et al.
We have documented that falls and fractures in older diabetics were often the result of loss of organized variability, strength, and reaction times. Very simple strength and balance training can significantly reduce falls risk Morrison et al.
For patients with orthostatic hypotension, volume repletion with both fluids and salt is central to management, but physical activity and exercise are essential to prevent deconditioning, which is known to exacerbate orthostatic intolerance Pop-Busui et al.
The relationship between HRV and different psychiatric disorders, as well as stress and trauma, has also been extensively studied Thayer et al.
Subjects with depression and anxiety disorders exhibit abnormal HRV patterns compared with non-psychiatric controls Servant et al. Reduced HRV characterizes emotional dysregulation, decreased psychological flexibility and defective social engagement, which in turn are linked to prefrontal cortex hypoactivity Sgoifo et al.
High occupational stress has also been associated with lowered HRV, specifically with reduced parasympathetic activation. There is limited evidence that use of biofeedback with relaxation and meditation approaches may result in increased HRV and parasympathetic activity Servant et al.
A more detailed review on this topic is beyond the scope of this article and the reader can refer to recent reviews on the subject.
Prevention of CAN should be a primary focus of lifestyle and other clinical interventions. Intense glycemic control The Diabetes Control and Complications Trial Research Group, utilizing a step-by-step progressive lowering of hyperglycemia, lipids, and BP, in addition to the use of antioxidants Ziegler and Gries, and ACE inhibitors Athyros et al.
CAN progressed in both treatment groups during the EDIC follow-up, but the prevalence and incidence continued to be decreased in the previous intensive group compared to the standard group despite comparable levels of glycemic control. To diminish the development of CAN, intense glucose control of T1DM ought to be started as soon as possible Pop-Busui et al.
However, in patients with established CAN, glycemic control may need to be less stringent to avoid hypoglycemia and adverse drug effects Inzucchi et al. The American Diabetes Association also recommends that individuals with CAN have a cardiac evaluation before starting or increasing physical activity for safety reasons American Diabetes Association, ; Pop-Busui et al.
Pathogenesis-oriented interventions may promote some degree of reversal of established CAN Vinik et al. Lifestyle interventions, increased physical activity, β-adrenergic blockers, aldose reductase inhibitors, ACE inhibitors, ARBs, and potent antioxidants such as α-lipoic acid have all been shown to restore autonomic balance.
Enhanced glycemic control with a reduced HbA1c from 9. The Veterans Administration Cooperative Study showed no impact on the occurrence of CAN after 2 years of intense glycemic control in patients with T2DM Azad et al.
Although glucose-lowering agents exerted the least benefit in comparison with antihypertensive treatments, lipid-lowering agents, aspirin, and vitamin-mineral supplements Gaede et al. Early identification of CAN also may allow for the well-timed initiation of antioxidant alpha-lipoic acid therapies that slow or reverse advancement of CAN Ziegler and Gries, Certain medications hold promise for the prevention and reversal of CAN.
Early therapeutic intervention with ACE inhibition or ARBs improved both CAN and left ventricular diastolic dysfunction after 1 year of treatment in patients with no symptoms and long-term diabetes. The combined therapies were slightly superior to monotherapies, auguring well for patients with established CAN Didangelos et al.
Treatment with fluvastatin improves cardiac sympathetic neuropathy in the diabetic rat heart in relation to attenuation of increased cardiac oxidative stress Matsuki et al. Alternatively, selective inactivation of cyclooxygenase-2 COX-2 guards against sympathetic denervation in experimental diabetes by decreasing intramyocardial oxidative stress and inflammation Kellogg et al.
Consequently, statins and COX-2 inactivation may assist in attenuating cardiac sympathetic dysfunction. Successful pancreas transplantation showed improvements in epinephrine response and normalized hypoglycemia symptom awareness in patients with established diabetes Burger et al.
Weight loss and weight-reducing surgeries may also potentially reduce CAN. ANS dysfunction and increased sympathetic activity have been directly correlated with obesity Piestrzeniewicz et al. et al. Moreover, weight reduction significantly improves HRV and reduces ANS imbalances Karason et al.
To evaluate the ability to reverse autonomic imbalance, we examined sudomotor function and HRV measurements in obese patients undergoing bariatric surgery. Patients were assessed at baseline, 4, 12, and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass.
Seventy subjects completed at least weeks of follow-up. Sudorimetry results of ESC of feet improved significantly trending toward normal in T2DM patients. HRV improved significantly, as did many other metabolic parameters.
Improvements in feet ESC were shown to be independently associated with HbA1c, insulin, and HOMA2-IR levels at baseline, as well as HbA1c at 24 weeks. Additionally, improvement in basal HR had an independent association with HbA1C, insulin and HOMA2-IR levels.
These positive results suggest that bariatric surgery can return both cardiac and sudomotor autonomic C-fiber dysfunction in those with diabetes to normal, possibly positively influencing morbidity and mortality Casellini et al.
The host of targets that are potential candidates for reduction of cardiovascular risk have been addressed in the previous paragraphs. For years we were confronted with glycemic control as the only measure by the glucocentric majority and those who believed in the lipid hypothesis who have now carried this to the extreme of need for even lower LDL-C in high risk patients.
The entry of SGLT2 inhibitors and the incretins shed new light on the challenge armed with new ammunition and also created an avenue of adventure for those interested in novel pathways. However the initial inroad into reduction of CV events was a discovery of the power of resetting a biologic clock and targeting the brain rather than other members of the dreadful dektet!
It has been established that there is a brain dopamine deficiency in obese diabetic patients present in the early hours of the morning Cincotta et al.
The working hypothesis is that in early morning, decreased dopaminergic tone in the hypothalamus unbridles sympathetic activation with all its consequences, as illustrated in Figure 1.
Restoring the morning peak in dopaminergic activity by dopamine D2 receptor-mediated activities may, therefore, restore ANS balance. FIGURE 1. Schematic of dopamine — clock interactions in the regulation of fuel metabolism. Figure illustrates the hypothalamic clock with decreased suprachiasmic nuclear SCN early morning peak of dopamine activity and enhanced activity of the paraventricular nucleus PVN , which increase autonomic tone and the paraventricular nucleus to raise levels of corticotrophin releasing hormone CRH.
The consequences include activation of the sympathetic nervous system SNS hypothalamic and glucose sensitization reducing parasympathetic vagal drive to the liver and resistance to both leptin and insulin. CRH, corticotrophin releasing hormone; eNOS, endothelial nitric oxide synthase; FFAs, free fatty acids; NPY, neuropeptide Y; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SNS, sympathetic nervous system; TGs, triglycerides; VMH, ventromedial hypothalamus Raskin and Cincotta, It may also be possible to reset the biologic hypothalamic clock and ANS function using bromocriptine QR to restore morning dopaminergic activity.
It sensitizes the body to insulin and reduces sympathetic tone thereby reducing HR Raskin and Cincotta, Bromocriptine QR has also demonstrated a favorable effect on CV outcomes in clinical trials Figure 1 and Table 2 Gaziano et al. Our current quest is to determine if any of the novel discoveries in cardiovascular outcome studies CVOTs are indeed working through rebalancing the ANS thereby creating a wonderful opportunity for taking a fork in the road.
TABLE 2. Impact of bromocriptine-QR on CV death-inclusive composite cardiovascular endpoint and individual components of the composite as well as the MACE endpoint. An improvement in ANS balance may be critical to reducing cardiovascular events and early mortality.
Symptoms and signs of autonomic dysfunction, including resting HR, BP responses to standing, and time and frequency measures of HRV in response to deep breathing, standing and Valsalva maneuver, should be elicited from all patients with diabetes to allow for early detection and intervention.
Rather than intensifying diabetes blood glucose management, a regimen tailored to the individual risk of ANS dysfunction should be constructed.
The advent of new agents that may have the potential to improve ANS function, such as the SGLT2 inhibitors and the GLP-1 agonists, should be considered. However, it is not clear how these compounds work and what the mechanism of reduction of major adverse cardiovascular events is.
An overlooked mechanism is a resetting of the biologic clock with correction of the dopamine deficiencies in the brainstem of obese people with diabetes, restoring the functioning of the ANS with its potential for significant reduction of cardiovascular events.
AV conceived of the presented idea and took the lead in writing the manuscript. CC and HP assisted in theory development, background research, and critical revisions to incorporate important intellectual content. SC participated in the manuscript development in the following ways: a substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; b drafting the work or revising it critically for important intellectual content; c final approval of the version to be published; d agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
M-LN critical review and manuscript editing. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
ACCORD, action to control cardiovascular risk in diabetes; ACE inhibitors, angiotensin-converting enzyme inhibitors; AN, autonomic neuropathy; ANS, autonomic nervous system; ARBs, angiotensin receptor blockers; BP, blood pressure; CAD, coronary artery disease; CAN, cardiac autonomic neuropathy; CARTs, cardiovascular autonomic reflex tests; COX-2, cyclooxygenase-2; CVD, cardiovascular disease; DCCT, diabetic control and complications trial; DM, diabetes mellitus; DN, diabetic neuropathy; DPN, diabetic peripheral neuropathy; EDIC, epidemiology of diabetes interventions and complications; GLP-1, glucagon-like peptide-1; HF, high frequency; HR, heart rate; HRV, heart rate variability; LF, low frequency; Lfa, low frequency area; MI, myocardial ischemia; Rfa, respiratory frequency area; rMSSD, root-mean-square of the difference of successive R—R interval; sdNN, standard deviation of all normal R—R intervals; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Alzaid, A. Diabetes Technol. doi: PubMed Abstract CrossRef Full Text Google Scholar. American Diabetes Association Standards of medical care in diabetes - Diabetes Care 40 Suppl.
Google Scholar. The QSART involves iontophoresis of a cholinergic agonist to measure axon reflex-medicated sudomotor responses quantitatively to evaluate postganglionic sudomotor function.
Four sites are used and studied simultaneously with the patient supine. The test is not generally available and requires the purchase of expensive specialized equipment.
A sweat imprint may be formed by the secretion of active sweat glands into a plastic or silicone mold in response to iontophoresis of a cholinergic agonist.
This test can be used to determine sweat gland density, sweat droplet size, and sweat volume per area. The TST assesses both central and peripheral aspects of the efferent sympathetic nervous system, from the hypothalamus to the sweat glands.
It is a well-standardized test and evaluates the distribution of sweat by a change in color of an indicator powder on the skin after exposure to infrared light. The TST is semiquantitative percentage of anterior body anhidrosis and has a high sensitivity.
The specificity is low, however, because it is not able to differentiate between pre- and postganglionic causes of anhidrosis. In combination with QSART, the specificity of the TST for delineating the lesion site is significantly increased.
The sympathetic skin response or peripheral autonomic surface potential is generated by the sweat glands and overlying epidermis. This response may occur spontaneously or can be evoked by stimuli such as respiration and startle.
The sympathetic skin response can be measured with surface electrodes connected to a standard electromyogram instrument. The response habituates with repeated stimuli and is subject to variability. Delivering stimuli at irregular intervals may minimize habituation.
Concordance between the sympathetic skin response and sudomotor function has been shown in some but not all studies. Smooth muscle microvasculature in the periphery reacts sympathetically to a number of stressor tasks.
These may be divided into those dependent on the integrity of the central nervous system orienting response and mental arithmetic and those dependent on the distal sympathetic axon handgrip and cold pressor tests :. Orienting response. Orienting response is the vasoconstriction and resulting drop in peripheral index finger, pulp surface skin blood flow when a subject engages in speech after several minutes of relaxation with music.
Mental arithmetic. There is no response in the presence of either a proximal or distal ANS lesion. Hand grip. Cold pressor. In some individuals, this response becomes biphasic after prolonged exposure 30 s to such intense cold because it is extremely uncomfortable. There is a predominately peripheral component, but pain generates a centrally mediated response.
Heating and gravity. Heating the limb to 44°C and dropping it below the level of the heart results in a marked increase in blood flow in normal subjects. The response is a measure of autonomic microvascular integrity and is markedly depressed in patients with AN. Patients with DAN show delayed or absent reflex response to light and diminished hippus due to decreased sympathetic activity and reduced resting pupillary diameter 7.
Pupillary measurements are usually only performed in a research setting. Several worldwide consensus meetings have been convened since the s to evaluate the growing evidence concerning tests for the assessment of diabetic neuropathy.
Two of the meetings the San Antonio Conference on Diabetic Neuropathy held in and a second conference in were jointly sponsored by the American Diabetes Association and AAN. The consensus statement published by the expert panel at the San Antonio Conference was a synthesis of reviewed research efforts to date in the clinical assessment of neuropathies and offered recommendations for the testing of diabetic neuropathy including autonomic neuropathy in clinical studies.
The selection of standardized measurement techniques based on reliability and precision studies was encouraged. The expressed purpose was to recommend common inter-study methodologies that would facilitate the comparison of results from one clinical investigation to another. Specifically concerning the assessment of CAN, the panel recognized strong evidence for three tests of heart rate control mainly tests of parasympathetic control.
The three tests recommended were heart rate response to 1 deep breathing, 2 standing, and 3 the Valsalva maneuver. Two tests of blood pressure control were also recommended: blood pressure response to 1 standing or passive tilting and 2 sustained handgrip.
These tests were judged suitable for both routine screening and monitoring the progress of autonomic neuropathy 3. No tests of sweating, sympathetic skin responses, pupillary reflexes, or genitourinary or GI function were considered to be sufficiently well standardized for routine clinical use.
Results from earlier research suggested that using a battery of cardiovascular tests some indicating parasympathetic involvement and others indicating possible sympathetic involvement would make it possible to follow the progression of autonomic function over time The San Antonio consensus panel further extended the utility of tests of cardiovascular autonomic function by suggesting that a battery of tests could be used to stage patients with autonomic neuropathy.
A three-stage model was proposed as follows:. The San Antonio Consensus Panel also made several general recommendations regarding the need to fully classify DAN:. Symptoms possibly reflecting autonomic neuropathy should not, by themselves, be considered markers for its presence.
Noninvasive validated measures of autonomic neural reflexes should be used as specific markers of autonomic neuropathy if end-organ failure is carefully ruled out and other important factors such as concomitant illness, drug use, and age are taken into account.
An abnormality on more than one test on more than one occasion is desirable to establish the presence of autonomic dysfunction. A battery of quantitative measures of autonomic reflexes should be used to monitor improvement or deterioration of autonomic nerve function.
In , a second jointly sponsored conference was convened to review the state-of-the-art of diabetic neuropathy measures used in epidemiological and clinical studies including cross-sectional, longitudinal, and therapeutic trials. While recognizing the importance of clinical measures such as medical and neurological history and physical examination, conference participants also recognized the subjective nature of such measures and emphasized the importance of objective measures, including autonomic function tests in the case of autonomic neuropathy.
The panel in also revised its recommendation to include three tests for the longitudinal testing of the cardiovascular ANS: 1 heart rate response during deep breathing, 2 Valsalva maneuver, and 3 postural blood pressure testing It is important to note that tests that specifically evaluate cardiovascular autonomic function are part of the consensus guidelines.
Although there is an association between the presence of peripheral somatic neuropathy and DAN, researchers have reported that the appearance of parasympathetic dysfunction may be independent of peripheral neuropathy Weinberg and Pfeifer have also shown that reduced HRV may be predictive of the development of symptomatic somatic neuropathy, although these results require follow-up in a larger study cohort.
Therefore, assessment modalities that are used to measure other forms of diabetic peripheral neuropathy, such as tests of sensory or motor nerve fiber function e. Thus, tests for other forms of diabetic peripheral neuropathy should not be substituted for tests of cardiovascular autonomic dysfunction.
An expert panel from the AAN reviewed a number of standardized measures and found that noninvasive autonomic tests were found to have a high value-to-risk ratio Some tests do, however, carry a small risk for an adverse event.
The Valsalva maneuver transiently increases intrathoracic, intraocular, and intracranial pressure, creating, for example, a small theoretical risk of intraocular hemorrhage and lens dislocation In practical terms, the risk is minimal because comparable intrathoracic pressures occur in the performance of daily activities.
In the published literature of over studies, there have been no reports of deaths during testing and no reports of adverse events after completion of the tests attributable to the procedures. The Diabetes Control and Complications Trial DCCT , one of the largest trials to use cardiovascular autonomic function tests, evaluated 1, patients with type 1 diabetes in 29 centers over a mean duration of 6.
When used by properly trained individuals, autonomic function tests are a safe and effective diagnostic tool. Patient cooperation is required for performing autonomic function tests. Thus, children may pose some challenges related to performance such as the attainment of the expiration pressure target required for the Valsalva maneuver and the performance of metronomic breathing and the cooperation and attention requirements of the test situation.
These same challenges may also apply to elderly patients, where deterioration of physiological response is of concern, and to developmentally and cognitively disabled individuals.
Autonomic function tests based on changes in heart rate variation and blood pressure regulation can detect cardiovascular complications at early stages of involvement in asymptomatic patients. Because late stages of CAN are indicators of poor prognosis in diabetic patients, early prognostic capabilities offer a significant contribution to diagnosis and subsequent therapy.
Evidence from clinical literature can be found that support recommendations for various subpopulations. They include the following. Long-term poor glycemic control can only increase the risk of developing advanced diabetic neuropathy, although long-term follow-up studies are lacking Mustonen et al.
The DCCT provided extensive clinical evidence that good metabolic control reduces diabetic complications. Specifically with regard to cardiovascular autonomic function, the DCCT showed that intensive glycemic control prevented the development of abnormal heart rate variation and slowed the deterioration of autonomic dysfunction over time for individuals with type 1 diabetes Unfortunately, however, one cannot predict what the metabolic control will be or has been over a long period of time by looking at current HbA 1c results.
Poor glycemic control may also be a consequence of DAN e. Treatment of GI dysfunction often improves glycemic control.
Primary prevention of diabetes is the absolute goal. Unfortunately, that goal has not yet been obtained. However, it has been shown that lifestyle intervention can reduce the incidence of type 2 diabetes Individuals that do develop diabetes, however, are likely to suffer from its complications.
In fact, researchers have confirmed the presence of autonomic neuropathy at presentation Some manifestations of autonomic neuropathy may even precede the diagnosis of diabetes by several years In its entirety, the evidence supports the contention that all patients with diabetes, regardless of metabolic control, are at risk for autonomic complications.
Given that CAN may be life-threatening and the assessment for its presence can be easily performed, testing for cardiovascular autonomic dysfunction is suggested for individuals with diabetes. This includes testing to identify children and adolescents with autonomic neuropathy.
Massin et al. With regard to whether either sex is more likely to develop autonomic dysfunction, the literature has revealed conflicting reports. For example, in the DCCT, the presence of autonomic neuropathy correlated with male sex along with age and duration Jaffe et al.
However, in another study of type 1 diabetic individuals, females along with other parameters e. May et al. Identifying individuals at risk is only the first step in managing patients and ultimately affecting outcomes. After identification, effective management must be provided.
Proactive measures are required, because if those patients at high risk or those shown to be in early stages are not treated until advanced symptomatology is present, little has been achieved. Unfortunately, information presented at the fifth Regenstrief conference on the intensive management of type 2 diabetes indicated that physicians may feel that screening is not of value because treatment options for identified complications are limited Such a view does not take into account the clinical research advances that have been made in the treatment of diabetes.
Tests that provide evidence of further health consequences may bring patients to medical attention before other signs of diabetic end-organ injury emerge, making proactive treatment, particularly the establishment of intensive diabetes care, possible.
The results of autonomic function testing can contribute to good patient management in the following ways. Early observations by researchers that near-normal glycemic control seems to be the most effective way to delay the onset of CAN in type 1 diabetes has been confirmed by evidence from the DCCT Intensive insulin therapy has been shown to be effective at preventing multiple complications in patients with type 1 diabetes and is postulated to be effective for patients with type 2 diabetes, although clinical studies are underway in the latter.
In its earliest stages, there has been some clinical demonstration that autonomic dysfunction may be influenced within a few days to a few weeks with effective treatment 44 , Delay in instituting appropriate interventions can only increase the likelihood of developing advanced neuropathies.
Stabilization of the neuropathies generally considered to be any delays in further progression through tight glycemic control seems possible, whereas reversal of the condition may be less likely 44 , Again, the results from the DCCT show that intensive glycemic treatment can prevent the development of abnormal heart rate variation and slow the deterioration of autonomic dysfunction over time for individuals with type 1 diabetes Although the relationship between features of autonomic neuropathy and hypoglycemic unawareness is complex and there is overlap, it is recognized that autonomic neuropathy may cause or contribute to the development of hypoglycemic unawareness.
In most individuals with hypoglycemic unawareness, raising the target may be necessary to prevent repeat episodes. Thus, emphasizing tight control for individuals with autonomic dysfunction should also include increased vigilance in glycemic monitoring and reeducation of the patient with regard to hypoglycemia.
Several different factors have been implicated in the potential metabolic-vascular pathogenic process of diabetic neuropathy e. Thus, timely identification of autonomic dysfunction in diabetic patients may expedite end-organ prophylaxis such as the use of ACE inhibitors and aspirin and the use of pharmacological and nonpharmacological interventions to improve blood pressure and lipid control.
Improved nutrition and reduced alcohol and tobacco consumption are additional options available to patients with diabetes who are identified with autonomic nerve dysfunction. Interventions to modulate reduced heart rate variation currently being studied in clinical trials are based on theories of the pathogenesis of CAN.
Evidence from clinical trials evaluating the use of antioxidants is promising. Early identification of CAN permits timely initiation of therapy with the antioxidant α-lipoic acid thioctic acid , which appears to slow or reverse progression of neuropathies in some studies , but further testing is necessary.
Other antioxidants such as vitamin E have been shown to improve the ratio of cardiac sympathetic to parasympathetic tone in type 2 diabetic individuals with CAN but may mitigate the effects of statins and niacin in treating or preventing macrovascular disease.
Studies using ACE inhibitors as a means to improve heart rate variation have resulted in conflicting results. Whereas quinapril significantly increased parasympathetic activity after 3 months of treatment , cardiovascular autonomic function did not change significantly after 12 months of treatment with trandolapril The use of cardioselective e.
By opposing the sympathetic stimulus, they may restore the parasympathetic-sympathetic balance. Recently, the administration of metoprolol to ramipril-treated type 1 diabetic patients with abnormal albuminuria has been shown to improve autonomic dysfunction Although the benefit of currently available agents in treating neuropathies is unproven, the investment in research time, labor, and money attests to the potential for treatment of detected neuropathies.
Because the pathogenesis of CAN is most likely a multifactorial process, a combination of therapies directed simultaneously at different parts of the pathogenic pathway may be needed. In addition, the goal of these interventions should be directed at the prevention of further deterioration of cardiovascular autonomic dysfunction rather than expecting to realize improved function.
It is again emphasized that lifestyle interventions e. Recently, a report indicated that impaired glucose tolerance may be associated with the development of diabetic neuropathy i. Should this be confirmed in large prospective studies coupled with evidence that primary intervention would prevent the development of neuropathy, this would put even greater emphasis on the importance of lifestyle interventions and screening at or soon after diagnosis.
Motivation to adhere and remain compliant with nonpharmacological interventions is difficult. Current research suggests that preventive measures glycemic control, diet, and exercise introduced to the general diabetic population are difficult to sustain and consequently less than effective.
This is due, in part, to the long-term commitment that must be made to the practice of preventive measures. Although individuals with diabetes are faced with the immediate pressures of disease management on a day-to-day basis, it is the long-term risks of micro- and macrovascular complications that pose the most serious risks The ability to determine early stages of autonomic dysfunction could intensify the salience of measures such as diet and exercise that directly affect efforts to establish tight glycemic control and delay the development of autonomic dysfunction.
Colloquial patient management strategies could be introduced to a now potentially motivated patient. As mentioned previously, clinicians must be careful when giving recommendations with regard to exercise for individuals with CAN.
This does not mean, however, that exercise is inappropriate for individuals with CAN. In fact, Howorka et al. Thus, careful testing to evaluate cardiovascular autonomic function and its degree of development is extremely important.
Clinicians working together with the patient can develop an appropriate exercise program that will yield a plan for reaping maximum benefits. Autonomic dysfunction is a prevalent and serious complication for individuals with diabetes. The clinical manifestations of autonomic dysfunction can affect daily activities e.
The economic impact of the recommendation to use autonomic function testing is minimal compared with the economic impact of the catastrophic events related to advanced cardiovascular, cerebrovascular, and renal complications. The relative cost of testing will always be less than the incremental costs of treating either a detected complication or the more catastrophic event that could eventually occur.
Despite research evidence that clinical observations whether they be symptoms or routine vital signs should not be the sole basis for the diagnosis of cardiovascular autonomic dysfunction, screening for abnormalities is infrequently done.
This is also despite the fact that office-based commercially available instrumentation for detection is readily available. Given the clinical and economic impact of this complication, testing of diabetic individuals for cardiovascular autonomic dysfunction should be part of their standard of care.
Such a recommendation does not diminish the importance of clinical evaluation and patient observation; rather, it enhances the clinical assessment of the diabetic patient by providing an objective, quantifiable, and reproducible measure of autonomic function.
The portion of the nervous system that regulates individual organ function and homeostasis not under voluntary control. An efferent and afferent system, the ANS transmits impulses from the central nervous system to peripheral organ systems. This results in control of heart rate and force of contraction, constriction and dilatation of blood vessels, contraction and relaxation of smooth muscle in various organs, visual accommodation, pupillary size, and secretions from exocrine and endocrine glands.
The ANS is also responsible for conveying visceral sensation. The ANS is typically divided into two divisions: the parasympathetic and the sympathetic systems on the basis of anatomical and functional differences.
A number of simple objective tests of cardiovascular autonomic function and reflexes to aid in the diagnosis of cardiovascular autonomic neuropathy.
This disorder results from damage to the fibers of the ANS with associated abnormalities of heart rate control and vascular dynamics. A neuropathic disorder associated with diabetes that includes manifestations in the peripheral components of the ANS.
DAN affects sensory, motor, and vasomotor fibers innervating a large number of organs. DAN may thus affect a number of different organ systems e. The magnitude of heart rate fluctuations R-R interval around the mean heart rate that are modulated by the ANS.
HRV is considered the earliest indicator and most frequent finding in symptomatic cardiovascular autonomic dysfunction. The portion of the ANS concerned with conservation and restoration of energy. It causes a reduction in heart rate and blood pressure, facilitates the digestion and absorption of nutrients, and facilitates the excretion of waste products from the body.
The portion of the ANS that enables the body to be prepared for fear, flight, or fight. Sympathetic responses include increases in heart rate, blood pressure, and cardiac output and diversion of blood flow from the skin and splanchnic vessels to those supplying skeletal muscle.
The important criteria for appraising clinical tests of autonomic function include reliability, reproducibility, general correlation with each other and with tests of peripheral somatic nerve function, well-established normal values, and demonstrated prognostic value.
Three tests of cardiovascular autonomic nerve function that fulfill these criteria are 1 the E:I ratio obtained from R-R variations , 2 the Valsalva ratio, and 3 the standing ratio. These tests use deep breathing, the Valsalva maneuver, and standing from a supine position, respectively, as provocative stimuli.
For purposes of reimbursement, the three tests are grouped together under Current Procedural Terminology code At least two of these three tests should be performed to provide adequate diagnostic information and to support reimbursement claims. An abnormal result for each test is defined as HRV below that of the 5th percentile of the normal age-matched population.
Abnormal HRV in one test is indicative of early autonomic neuropathy. Because of the technical requirements for these tests, they should be performed at the point-of-care office or in a clinical laboratory setting.
The tests are not currently appropriate for nonclinical screening venues. These currently unpublished data from A. and Risk were based on standardized testing of normal subjects and 3, patients with type 1 or type 2 diabetes from 42 centers. The time intervals between R-waves of the QRS complexes are measured in milliseconds.
This measurement should be obtained using the deep respiration test and the results evaluated by determining the E:I ratio. To perform the test, the subject remains supine and breathes deeply at the rate of one breath per 10 s i.
The E:I is the ratio of the mean of the longest R-R intervals during deep expirations to the mean of the shortest R-R intervals during deep inspirations. The E:I ratio is significantly affected by shifting of the heart rate and regularity of the respiratory cycling. HRV decreases with increasing respiration rate, with the greatest variation occurring at a respiratory rate of six breaths per minute.
Respiration should therefore be standardized at six breaths per minute to optimize test results. E:I ratios are based on the fact that inspiration shortens R-R intervals while expiration lengthens them.
The complex effect of the Valsalva maneuver on cardiovascular function is the basis of its usefulness as a measure of autonomic function. In the standard Valsalva maneuver, the supine patient, connected to an ECG monitor, forcibly exhales for 15 s against a fixed resistance with an open glottis. The patient should maintain constant pressure at 40 ml over the s interval.
This causes a sudden transient increase in intrathoracic and intra-abdominal pressure and a consequent hemodynamic response. Healthy patients develop tachycardia and peripheral vasoconstriction during the strain and an overshoot in blood pressure and bradycardia on release.
However, in patients with autonomic damage from diabetes, the reflex pathways are damaged, resulting in a slow and steady decline in blood pressure during strain, followed by gradual return to normal after release. Heart rate responses are often unchanged in this situation.
The Valsalva ratio is the longest R-R divided by the shortest R-R occurring within 45 s of peak heart rate and is indicative of overall condition of the parasympathetic and sympathetic fibers.
To test the heart rate response to standing, the patient is connected to the heart rate monitor while in the supine position. The patient then stands to a full upright position, and the ECG is monitored for an additional period while standing.
Standing causes an immediate rapid increase in heart rate with the maximum rate generally found at or around the 15th beat after standing. The heart rate slows at or around the 30th beat. The heart rate tracing is used to calculate the ratio of the longest R-R interval about beat 30 after the stand to the shortest R-R interval about beat This measure, called the ratio, reflects the overall condition of the parasympathetic fibers.
Normal ranges are age dependent. Association of CAN and silent myocardial infarction SMI in 12 studies. A : Association of CAN and mortality in 15 studies. B : Log relative risks from the 15 studies. Evaluation of diabetic patients with ED NPT, nocturnal peniletumescence.
BP, blood pressure; CAD, coronary artery disease; dBP, diastolic blood pressure; sBP, systolic blood pressure; SMI, silent myocardial ischemia.
Adapted from Maser et al. Duration of diabetes, retinopathy, and smoking were not found to be significant predictors of death. Address correspondence and reprint requests to Aaron I.
Vinik, MD, PhD, Director, Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, W. Brambleton Ave. E-mail: vinikai evms. This paper was peer-reviewed, modified, and approved by the Professional Practice Committee, January A table elsewhere in this issue shows conventional and Système International SI units and conversion factors for many substances.
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WHO IS A CANDIDATE FOR TESTING? Article Navigation. Diabetic Autonomic Neuropathy Aaron I. Vinik, MD, PHD ; Aaron I. Vinik, MD, PHD. This Site. Google Scholar.
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toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Resting tachycardia Exercise intolerance Orthostatic hypotension Silent myocardial ischemia. Esophageal dysmotility Gastroparesis diabeticorum Constipation Diarrhea Fecal incontinence.
Neurogenic bladder diabetic cystopathy Erectile dysfunction Retrograde ejaculation Female sexual dysfunction e. Hypoglycemia unawareness Hypoglycemia-associated autonomic failure. Anhidrosis Heat intolerance Gustatory sweating Dry skin. Pupillomotor function impairment e.
The differential diagnosis of DAN involves excluding the following conditions:. Even with consensus regarding these general observations, much remains unclear:. Type 1 and type 2 diabetes may have different progression paths. Tests for the diagnosis and assessment of constipation might include the following:.
Anorectal manometry for evaluating sphincter tone and the rectal anal inhibitory reflex to distinguish colonic hypomotility from rectosigmoid dysfunction causing outlet obstructive symptoms Assessment of colonic segmental transit time.
Pelvic examination, with careful bimanual examination for women Three stools tested for occult blood which, if present, requires that a complete blood count, iron count, TIBG, proctosigmoidoscopy and barium enema, or full colonoscopy be performed.
Most of these procedures will typically be performed by a specialist. Assessment of diarrhea in patients with diabetes might include the following:. History to rule out diarrhea secondary to ingestion of lactose, nonabsorbable hexitols, or medication especially biguanides, α-glucosidase inhibitors, and tetrahydrolipostatin History to rule out other causes, especially iatrogenic ones Travel and sexual histories and questioning regarding similar illnesses among both household members and coworkers History of prior ethanol consumption History of pancreatitis and biliary stone diseases Examination for enteric pathogens and ova and parasites Patients with large-volume diarrhea or fecal fat should be further studied with a h fecal fat collection: the d-xylose test is an appropriate screen for small bowel malabsorptive disorders.
Autonomic neuropathy testing e. Hormonal evaluation luteinizing hormone, testosterone, free testosterone, prolactin Psychological evaluation Minnesota Multiphasic Personality Inventory [MMPI]. Assessment of renal function Urinary culture Postvoid ultrasound to assess residual volume and upper-urinary tract dilation Cystometry and voiding cystometrogram to measure bladder sensation and volume pressure changes associated with bladder filling with known volumes of water and voiding.
Early stage: abnormality of heart rate response during deep breathing alone Intermediate stage: an abnormality of Valsalva response Severe stage: the presence of postural hypotension. Independent tests of both parasympathetic and sympathetic function should be performed.
Figure 1—. View large Download slide. Figure 2—. Figure 3—. Table 1— Reported prevalence of CAN. Date of publication. Diabetes type. Subjects n. Test s used. Sharpey-Schafer and Taylor 26 Valsalva maneuver 21 Ewing et al.
BP, blood pressure; MCR, mean circular resultant. View Large. Table 2— Studies of CAN and silent myocardial ischemia. Tests of autonomic function. Definition of CAN. Table 3— Studies of CAN and mortality.
Follow-up years. Sampson et al. Jermendy et al. Deceased subjects were older and had more complications at baseline. Hathaway et al. Control subjects survived 2—5 years posttransplant. Sawicki et al.
Toyry et al. Subjects were newly diagnosed with diabetes. Veglio et al. Gerritsen et al. Table 4— Discriminant analysis of 5-year survival in type 1 diabetic patients.
Digestive health support Pop-Busui; Cardiac Pancreas health Neuropathy in Diabetes : A clinical perspective. Diqbetic Care Conditioning for team sports February Diabetid 33 Dental technology advancements : cardipvascular This review covers the Conditioning for team sports, pathophysiology, clinical presentation, and diagnosis neutopathy cardiac Diabettic neuropathy CAN in diabetes and discusses caddiovascular evidence on approaches to prevention and treatment of CAN. She had a year history of poor diabetes control presenting with wide blood glucose fluctuations, recurrent episodes of severe hypoglycemia, and hypoglycemia unawareness. Over time she developed persistent orthostatic hypotension with daily falls in systolic blood pressure ranging from 30—60 mmHg. These episodes had significant impact on her daily activities and required intermittent therapy with the α-1 agonist midodrine. Other complications included severe gastroparesis, refractory diarrhea, and painful diabetic peripheral neuropathy.Video
Diabetes Complication and Pathophysiology of the complication Autonomic nervous system ANS imbalance manifesting as cardiac Diabetic neuropathy and cardiovascular disease neuropathy in Diabetic neuropathy and cardiovascular disease diabetic population is fisease important predictor of cardiovascular events. Symptoms and signs cardiobascular ANS dysfunction, such cardivascular resting heart rate elevations, diminished xisease pressure cardioovascular to standing, and altered Senior athlete nutrition and neuropayhy domain measures of heart rate variability in Conditioning for team sports to deep breathing, cardiovascilar, and Digestive health support Valsalva maneuver, should be elicited from cardipvascular 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.
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