The Conductor of the Autonomic Orchestra

Bad bedfellows – autonomic dysfunction, inflammation, and diabetes! Are they related? How? Evidence suggests the activation of inflammatory cytokines like IL-6 and TNFα in newly diagnosed type 2 diabetes and that the inflammatory change correlates with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It occurs in prediabetes, providing opportunities for early intervention. The importance of recognizing autonomic dysfunction as a predictor of morbidity and mortality with intensification of treatment suggests that all patients with type 2 diabetes at onset, and those with type 1 diabetes after 5 years should be screened for autonomic imbalance. These tests can be performed at the bedside with real time output of information – within the scope of the practicing physician – facilitates diagnosis and allows 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. After all, how difficult is it to ask patients “do you have numb feet?” and to determine their heart rate variability – it could be lifesaving. Ultimately methods to reset the hypothalamus and the inflammatory cascade are needed if we are to impact the care of patients with this compendium of conditions

A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet

This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia

Use of Heart Rate Reserve and Rating of Perceived Exertion to Prescribe Exercise Intensity in Diabetic Autonomic Neueropathy

Objective- Individuals with diabetic autonomic neuropathy (DAN) exhibit an increased resting heart rate but depressed maximal heart rate. Thus, the purpose of this study was to examine the validity of using either percent of heart rate reserve (HRR) or a rating of perceived exertion (RPE) scale to prescribe exercise intensity in diabetic individuals both with and without DAN. Research Design and Methods-The subjects consisted of 23 individuals with type 2 diabetes, ages 45-75 years, with (DAN; n=13) or without (No DAN; n=10) clinical signs of DAN, as assessed by heart rate variability using the expiration-to-inspiration ratio of the R-R interval. Peak aerobic capacity was determined using a graded protocol on a cycle ergometer, with RPE, heart rate, and Vo2 values recorded at each Stage. Results-The subjects were similar with the exception of depressed autonomic function in DAN subjects. Peak respiratory exchange ratio values were significantly higher (P\u3c0.05) in the DAN group (1.08 +/- 0.02 vs. 1.02 +/- 0.01 in No DAN subjects), although DAN subjects exhibited a significantly lower (P\u3c0.05) peak exercise heart rate. A similarly highly linear relationship between %HRR and percent Vo2 reserve (Vo2R) existed for both groups (r=0.98). A similar slightly weaker relationship (r=0.94) was found between RPE and %Vo2R. Conclusions-in conclusion, in diabetic individuals, %HRR provides an accurate prediction of %VO2R and can be used to prescribe and monitor exercise intensity, regardless of the presence of DAN. The RPE scale is, also a valid, albeit slightly less accurate, method to monitor exercise intensity in diabetic individuals

Use of somatostatin analog in management of carcinoid syndrome

Carcinoid tumors are the most frequent gut neuroendocrine tumors accounting for more than 50% of all tumors of the gastroenteropancreatic (GEP) axis. These tumors appear to derive from a stem cell line capable of differentiating into a variety of malignant cells that secrete many different peptides and amines. The symptoms of carcinoid tumors are often non-specific, vague abdominal pain that may precede the diagnosis by a median of 9 years. Carcinoid syndrome occurs in <10% of patients. We evaluated the effects of SMS 201-995 in 14 such patients, 12 with diarrhea, 8 with flushing, 3 with wheezing, one with tricuspid valve incompetence, 6 with facial teleangiectasia, 3 with a pellagra type dermatosis and one with myopathy. Diarrhea was abolished or significantly reduced in 83%, flushing in 100%, wheezing in 100%, and myopathy improved in the one patient. Blood serotonin was resistant to change, urine 5HIAA fell in 75%, and most gut neuropeptide hormones apart from somatostatin were suppressed. Tumor growth appeared to be slowed in 2/3 of cases treated for up to 4 years. The analog of somatostatin appears to be a useful addition to the therapeutic armamentarium for carcinoid tumors and the symptom complex .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44412/1/10620_2005_Article_BF01536042.pd

Cardiac Autonomic Imbalance in Newly Diagnosed and Established Diabetes Is Associated with Markers of Adipose Tissue Inflammation

Introduction. Diabetics die from cardiovascular disease at a much greater rate than nondiabetics. Cardiac autonomic imbalance predicts increased cardiovascular risk and mortality. We studied the relationship between cardiac autonomic imbalance and adipose tissue-derived inflammation in newly diagnosed and established type 2 diabetes. Materials and Methods. Non-diabetics, newly diagnosed diabetics, and established diabetics were included. Anthropomorphic and biochemical measurements were obtained, and insulin resistance was approximated. Cardiac autonomic function was assessed using conventional measures and with power spectral analysis of heart rate. Results and Discussion. Heart rate variability was reduced in all diabetics. Interleukin-6 was higher in diabetics, as was the high molecular weight adiponectin-to-leptin ratio. Interleukin-6 correlated negatively with measures of autonomic balance. Ratios of adiponectin to leptin correlated positively with measures of autonomic balance. Cardiac autonomic imbalance and inflammation occur early in diabetes and are interrelated. Conclusions. Cardiac autonomic imbalance correlates with the adipose tissue-derived inflammation seen early in type 2 diabetes

A role for somatostatin in the control of hamster growth

Concentrations of somatostatin-like immunoreactivity (SRIF-LI) were measured in cerebral cortex, hippocampus, septum-POA, median eminence, gastric antrum, fundus and pancreas in adult female hamsters to determine whether changes in somatostatin could be related to increased growth hormone (GH) secretion and somatic growth that follow bilateral transactions of hippocampus (n = 18; 17 controls). In addition, choline acetyltransferase (CAT) activity was measured in the four brain regions in hippocampectomized (n = 10) and control hamsters (n = 10) to gain insight into the relationship between these two neurotransmitters. Hippocampal transections induced: significant acceleration of somatic growth; increased serum GH concentrations; increased concentrations of SRIF-LI in septum-POA and gastric antrum; reduced concentrations of SRIF-LI in hippocampus and pancreas; and reduced CAT activity in the hippocampus. These results suggest that somatostatinergic and cholinergic projections to hippocampus via fornix suppress GH and somatic growth in adult hamsters and that reduced release of SRIF-LI in the gastric antrum may contribute to the acceleration of somatic growth through facilitated nutrient digestion and entry.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25052/1/0000480.pd

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

A Comparison of Screening Tools for the Early Detection of Peripheral Neuropathy in Adults With and Without Type 2 Diabetes

Objective. Examine the effectiveness of the 128 Hz tuning fork, two monofilaments, and Norfolk Quality of Life Diabetic Neuropathy (QOL-DN) questionnaire as tools for the early detection of diabetic peripheral neuropathy (DPN) in overweight, obese, and inactive (OOI) adults or those who have prediabetes (PD) or type 2 diabetes (T2D). Research Design and Methods. Thirty-four adults (mean age 58.4 years +/- 12.1) were divided by glycemia (10 OOI normoglycemic, 13 PD, and 11 T2D). Sural nerves were tested bilaterally with the NC-stat DPNCheck to determine sural nerve amplitude potential (SNAP) and sural nerve conduction velocity (SNCV). All other testing results were compared to SNAP and SNCV. Results. Total 1 g monofilament scores significantly correlated with SNAP values and yielded the highest sensitivity and specificity combinations of tested measures. Total QOL-DN scores negatively correlated with SNAP values, as did QOL-DN symptoms. QOL-DN activities of daily living correlated with the right SNAP, and the QOL-DN small fiber subscore correlated with SNCV. Conclusions. The 1 g monofilament and total QOL-DN are effective, low-cost tools for the early detection of DPN in OOI, PD, and T2D adults. The 128 Hz tuning fork and 10 g monofilament may assist DPN screening as a tandem, but not primary, early DPN detection screening tools

A Comparison of Neuropathy Quality of Life Tools: Norfolk QOL-DN, PN-QOL-97, and NeuroQOL-28

Aims To explore the effectiveness of the Norfolk QOL-DN (QOL-DN), PN-QOL-97, and NeuroQOL-28 as tools for early detection of diabetic peripheral neuropathy in overweight, obese, and inactive (OOI), prediabetes (PD), and type 2 diabetes (T2D) individuals. Methods Thirty-four adults were divided by A1C [(10 OOI, 13 PD, and 11 T2D] and the sural nerves were tested bilaterally via NC-Stat DPN Check, conducting a sural nerve conduction study (NCS). Participants were individually timed, filling out questionnaires (QOL-DN, NeuroQOL-28, and PN-QOL-97) at a self-selected pace. Data were analyzed and compared to NCS findings to determine the best instrument for early neuropathy detection, usability in screening settings, and application for individuals with OOI, PD, and T2D. Results Abnormal NCS results were obtained from 27 individuals, of which 25 were bilateral and symmetrical. Confirmed DSPN criteria were met for 24, and 1 case met criteria for subclinical neuropathy. Normal NCS findings, reported symptoms, and reduced bilateral sensation were found in 7 cases. The QOL-DN and NeuroQOL-28 significantly predict neuropathy criteria in OOI, PD, and T2D subjects. Analyses revealed the QOL-DN as the quickest for completion (M=5.17; SD=1.83), followed by the NeuroQOL-28 (M=5.58; SD=3.56), and the PN-QOL-97 (M=13.23; SD=3.606). Conclusions The QOL-DN and NeuroQOL-28 are valid early screening measures for DPN detection. Time completion studies revealed that the QOL-DN and NeuroQOL-28 may be used as excellent short screening measures, completed in approximately 6 minutes or less, with reasonable scoring for both. The NeuroQOL-28 is a better fit for immediate feedback, time constraints, or limited staff. Future investigations should evaluate these tools for detection in DPN-prone individuals and in subclinical populations screenings