Diabetic peripheral neuropathy and quality of life.
The quality of life (QOL) of 79 people with type 1 and type 2 diabetes and 37 non-diabetic controls was assessed using the Nottingham Health Profile (NHP). The NHP consists of six domains assessing energy, sleep, pain, physical mobility, emotional reactions and social isolation. Symptomatic diabetic neuropathy was present in 41 of the patients. The neuropathy patients had significantly higher scores (impaired QOL) in 5/6 NHP domains than either the other diabetic patients (p < 0.01) or the non-diabetic (p < 0.001) controls. These were: emotional reaction, energy, pain, physical mobility and sleep. The diabetic patients without neuropathy also had significantly impaired QOL for 4/6 NHP domains compared with the non-diabetic control group (p < 0.05) (energy, pain, physical mobility and sleep). This quantification of the detrimental effect on QOL of diabetes, and in particular of chronic symptomatic peripheral diabetic neuropathy, emphasizes the need for further research into effective management of these patients. (+info)
System identification of closed-loop cardiovascular control mechanisms: diabetic autonomic neuropathy.
We applied cardiovascular system identification (CSI) to characterize closed-loop cardiovascular regulation in patients with diabetic autonomic neuropathy (DAN). The CSI method quantitatively analyzes beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize four physiological coupling mechanisms, two of which are autonomically mediated (the heart rate baroreflex and the coupling of respiration, measured in terms of ILV, to heart rate) and two of which are mechanically mediated (the coupling of ventricular contraction to the generation of the ABP wavelet and the coupling of respiration to ABP). We studied 37 control and 60 diabetic subjects who were classified as having minimal, moderate, or severe DAN on the basis of standard autonomic tests. The autonomically mediated couplings progressively decreased with increasing severity of DAN, whereas the mechanically mediated couplings were essentially unchanged. CSI identified differences between the minimal DAN and control groups, which were indistinguishable based on the standard autonomic tests. CSI may provide a powerful tool for assessing DAN. (+info)
Heterogeneous cardiac sympathetic denervation and decreased myocardial nerve growth factor in streptozotocin-induced diabetic rats: implications for cardiac sympathetic dysinnervation complicating diabetes.
Heterogeneous myocardial sympathetic denervation complicating diabetes has been invoked as a factor contributing to sudden unexplained cardiac death. In subjects with diabetic autonomic neuropathy (DAN), distal left ventricular (LV) denervation contrasts with preservation of islands of proximal innervation, which exhibit impaired vascular responsiveness. The aims of this study were to determine whether this heterogeneous pattern of myocardial sympathetic denervation occurs in a rat model of diabetes and to explore a potential association with regional fluctuations in myocardial nerve growth factor (NGF) protein. Myocardial sympathetic denervation was characterized scintigraphically using the sympathetic neurotransmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial NGF protein abundance and norepinephrine content after 6 and 9 months in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. In ND rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with ND rats, myocardial [11C]HED retention had declined in the proximal segments of STZ-D rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (P < 0.05). Myocardial norepinephrine content was similar in both ND and STZ-D rats. At 6 months, LV myocardial NGF protein content in STZ-D rats decreased by 52% in the proximal myocardial segments (P < 0.01 vs. ND rats) and by 82% distally (P < 0.01 vs. ND rats, P < 0.05 vs. proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the STZ-D rats by 42% (P < 0.01 vs. ND rats), and LV norepinephrine content and NGF protein were decreased in parallel. Therefore, 6 months of STZ-induced diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of LV NGF protein depletion. It is tempting to speculate that regional fluctuations of NGF protein in the diabetic myocardium contribute to heterogeneous cardiac sympathetic denervation complicating diabetes. (+info)
Noninvasive exploration of cardiac autonomic neuropathy. Four reliable methods for diabetes?
OBJECTIVE: The purpose of this work was to assess relevant information that could be provided by various mathematical analyses of spontaneous blood pressure (BP) and heart rate (HR) variabilities in diabetic cardiovascular neuropathy. RESEARCH DESIGN AND METHODS: There were 10 healthy volunteers and 11 diabetic subjects included in the study. Diabetic patients were selected for nonsymptomatic orthostatic hypotension in an assessment of their cardiovascular autonomic impairment. Cardiac autonomic function was scored according to Ewing's methodology adapted to the use of a Finapres device. The spontaneous beat-to-beat BP and HR variabilities were then analyzed on a 1-h recording in supine subjects. The global variabilities were assessed by standard deviation, fractal dimension, and spectral power. The cardiac baroreflex function was estimated by cross-spectral sequences and Z analyses. RESULTS: In diabetic patients, Ewing's scores ranged from 1 to 4.5, confirming cardiovascular autonomic dysfunction. In these diabetic patients, global indices of variabilities were consistently lower than in healthy subjects. Furthermore, some of them (standard deviation and fractal dimension of HR, spectral power of systolic blood pressure and HR) were significantly correlated with the Ewing's scores. The Z methods and the spectral analysis found that the cardiac baroreflex was less effective in diabetic subjects. However, the baroreflex sensitivity could not be reliably assessed in all the patients. The sequence method pointed out a decreased number of baroreflex sequences in diabetic subjects that was correlated to the Ewing's score. CONCLUSIONS: Indices of HR spontaneous beat-to-beat variability are consistently related to the degree of cardiac autonomic dysfunction, according to Ewing's methodology. The Z method and spectral analysis confirmed that the cardiac baroreflex was impaired in diabetic patients. These methods might be clinically relevant for use in detecting incipient neuropathy in diabetic patients. (+info)
Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial.
The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c). (+info)
Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy.
Aberrant neurofilament phosphorylation occurs in many neurodegenerative diseases, and in this study, two animal models of type 1 diabetes--the spontaneously diabetic BB rat and the streptozocin-induced diabetic rat--have been used to determine whether such a phenomenon is involved in the etiology of the symmetrical sensory polyneuropathy commonly associated with diabetes. There was a two- to threefold (P < 0.05) elevation of neurofilament phosphorylation in lumbar dorsal root ganglia (DRG) of diabetic rats that was localized to perikarya of medium to large neurons using immunocytochemistry. Additionally, diabetes enhanced neurofilament M phosphorylation by 2.5-fold (P < 0.001) in sural nerve of BB rats. Neurofilaments are substrates of the mitogen-activated protein kinase (MAPK) family, which includes c-jun NH2-terminal kinase (JNK) or stress-activated protein kinase (SAPK1) and extracellular signal-regulated kinases (ERKs) 1 and 2. Diabetes induced a significant three- to fourfold (P < 0.05) increase in phosphorylation of a 54-kDa isoform of JNK in DRG and sural nerve, and this correlated with elevated c-Jun and neurofilament phosphorylation. In diabetes, ERK phosphorylation was also increased in the DRG, but not in sural nerve. Immunocytochemistry showed that JNK was present in sensory neuron perikarya and axons. Motoneuron perikarya and peroneal nerve of diabetic rats showed no evidence of increased neurofilament phosphorylation and failed to exhibit phosphorylation of JNK. It is hypothesized that in sensory neurons of diabetic rats, aberrant phosphorylation of neurofilament may contribute to the distal sensory axonopathy observed in diabetes. (+info)
Possible sources of discrepancies in the use of the Semmes-Weinstein monofilament. Impact on prevalence of insensate foot and workload requirements.
OBJECTIVE: The purpose of this study was to evaluate the effects of different testing sites and buckling strengths on the sensitivity and specificity of using the Semmes-Weinstein monofilament to detect patients with insensate foot. The impact on workload required to educate and follow up these high-risk individuals was estimated by modeling in our patient population with a documented status of neuropathy. RESEARCH DESIGN AND METHODS: Using the 5.07/10-g monofilament, one observer tested 132 randomly selected subjects with diabetes at five sites on the right foot. The sensitivity and specificity of each site and combinations of sites in detecting vibration perception threshold > 40 was calculated. In addition, two monofilaments, one with a buckling force of 5 g and the other with a force of 15 g, were compared by testing 200 randomly selected patients. An estimate of the prevalence of insensate foot and workload was made by modeling the findings to the 5,270 patients with neuropathy status registered on our computerized database. RESULTS: Specificity of the 5.07/10-g monofilament to detect insensate foot at each of the five sites is high, at approximately 90%, but there is considerably more variation and lower sensitivity, ranging from 44-71%. Data derived from the use of different combinations of sites showed that more stringent criteria are associated with lower sensitivity but higher specificity. If the foot is considered insensate when either of sites 3 and 4 (plantar aspect of the first and fifth metatarsal heads, respectively) cannot feel the monofilament, there is reasonable sensitivity and specificity (80-86%, respectively). By modeling on our diabetes center population, it can be demonstrated that the choice of different methodologies leads to different conclusions about the prevalence of severe neuropathy, ranging from 3.4 to 29.3%. CONCLUSIONS: Using a combination of sites 3 and 4 for monofilament testing gives a reasonable compromise for time, sensitivity, and specificity. Minor changes in sensitivity and specificity can lead to major changes in the prevalence of neuropathy, with implications for workload. (+info)
Antinociceptive effect of Gosha-jinki-gan, a Kampo medicine, in streptozotocin-induced diabetic mice.
We evaluated the antinociceptive effect of Gosha-jinki-gan, a Kampo medicine including processed Aconiti tuber, and its mechanism in streptozotocin-induced diabetic mice. Gosha-jinki-gan (0.1-1.0 g/kg, p.o.) showed a more potent antinociceptive effect in diabetic mice than in non-diabetic mice. The antinociceptive effect of Gosha-jinki-gan (0.3 g/kg, p.o.) in diabetic mice was inhibited by administration of either anti-dynorphin antiserum (5 microg, i.t.) or nor-binaltorphimine (10 mg/kg, s.c.), a kappa-opioid antagonist. The antinociceptive activity of Gosha-jinki-gan (0.3, 1.0 g/kg, p.o.) was decreased by excluding processed Aconiti tuber. Furthermore, the antinociceptive effect of processed Aconiti tuber (0.03, 0.1 g/kg, p.o.) was also shown to be enhanced in diabetic mice. These results suggest that the increased antinociceptive effect of Gosha-jinki-gan in diabetic mice is partly derived from the action of processed Aconiti tuber and that it is based on stimulation of spinal kappa-opioid receptors via dynorphin release. Gosha-jinki-gan was considered useful for treating painful diabetic neuropathy. (+info)