The sympathetic skin response (SSR) at the foot to a deep inspiration was measured in 68 randomly selected diabetic patients and 46 age matched normal subjects and compared with other quantitative measures of neurological and sudomotor function. SSR was obtained in all but three diabetic patients. The upper limit of normal for the onset latency was 2202 ms and the lower limit for the amplitude of the first wave 92 uV. Ten diabetic patients had measurable but prolonged latencies, and 11 had measurable but low amplitudes. There were no significant associations between latency, height, and age, but in insulin dependent patients there was a significant diminution of response amplitude with increasing duration of diabetes. Latency was weakly associated with Marstock thermal thresholds, respiratory RR variation, and common peroneal nerve conduction velocity. SSR amplitude was associated with the density of pilocarpine activatable sweatspots in the same region of the foot. Patients with abnormal latencies were significantly older and had reduced thermal sensation than those with normal latencies. Median coefficients of variation for repeat testing in diabetic patients were 90/o for latency and 13% for amplitude. The test is objective and reproducible, but latency measurements reflect conduction in a long multineuronal pathway and are not purely a measure of peripheral C fibre function; amplitude measurements reflect the density of spontaneously activable sweat glands and are therefore a valid measure of peripheral sympathetic activity, though they depend more on temperature than do latencies (mean change over the range 32-34°C; 8-5%°C for amplitude, -2-5%l/°C for latency).
Image-analysis was used to measure nerves immunoreactive to the general neuronal marker protein gene product 9.5 (PGP 9.5-IR) and the neuropeptides calcitonin gene-related peptide and vasoactive intestinal polypeptide in standardised leg skin biopsies of three age-matched groups of young subjects: non-diabetic (n = 14), diabetic patients with normal small fibre function ("non-neuropathic", (n = 11) and diabetic patients with abnormal small fibre function ("neuropathic", n = 11). Depletion of nerves and neuropeptides was most marked in the epidermis, where calcitonin gene-related peptide-immunoreactivity was more frequently absent than PGP 9.5-IR in diabetic patients. Epidermal PGP 9.5-IR nerve area and counts were reduced in neuropathic compared with normal subjects (p less than 0.001), as were epidermal calcitonin gene-related peptide nerve counts (p = 0.003). Sweat gland PGP 9.5 and vasoactive intestinal polypeptide, which may be involved in sweat production, showed no diminution in diabetic patients (area: p = 0.160, p = 0.372 by ANOVA). Two diabetic patients showed elevated sweat gland PGP 9.5-IR and three had increased sweat gland vasoactive intestinal polypeptide; this may represent nerve proliferation. In local sweat tests, acetylcholine-stimulated sweat output was associated with increased immunoreactivity, while the sympathetic skin response showed inverse correlations with immunoreactivity. There were no consistent changes with other commonly-used neurophysiological tests. HbA1 correlated negatively with immunohistochemical measurements. Neuropeptide changes were seen in the absence of macro- and microvascular disease, and epidermal nerve depletion occurred in patients with normal thermal thresholds and cardiac autonomic function.(ABSTRACT TRUNCATED AT 250 WORDS)
Small- and large-fiber function in diabetic neuropathy was studied in 68 patients (mean age 45.4 +/- 12.9 yr; 27 type I and 41 type II diabetics) with psychophysical tests of vibration and thermal sensation and neurophysiological measurements, including the medial plantar sensory action potential (MPSAP). Thermal sensitivity at the dorsolateral aspect of the foot (Pfizer thermal tester) correlated significantly with vibration thresholds (Somedic vibrameter) at three sites in the foot and two in the hand. Forty patients had normal sensory thresholds, but 18 of these lacked an MPSAP. Smaller groups had a single abnormal sensory threshold: 12 (18%) had an abnormal vibration threshold, and 24 (35%) had abnormal thermal sensitivity; 8 of the former group and 17 of the latter group lacked an MPSAP response. Only 8 (12%) had both abnormal vibration and thermal sensation (6 without an MPSAP). Fifteen of the 17 symptomatic patients had lost the MPSAP, but there was no consistent pattern of sensory loss. In this relatively young group of diabetics, more patients showed absent MPSAP responses than an abnormality in either sensory test on its own. The MPSAP is frequently absent in patients with no abnormalities in psychophysical tests of peripheral large-fiber function (vibration sensation) and small-fiber function (thermal sensitivity).
SUMMARY Thermal thresholds can be measured psychophysically using either the method of limits or a forced-choice method. We have compared the two methods in 367 diabetic patients, 128 with symptomatic neuropathy. The Sensortek method was chosen for the forced-choice device, the Somedic modification of the Marstock method for a method of limits. Cooling and heat pain thresholds were also measured using the Marstock method. Somedic thermal thresholds increase with age in normal subjects, but not to a clinically significant degree. Electrophysiology has been the most widely used method for measuring peripheral nerve function in diabetes, but even in its most sophisticated forms,' it assesses function in only the largest and most heavilymyelinated nerve fibres.There is much interest in small fibres particularly in view of their role in the painful symptoms of diabetic neuropathy. Several authors2" have suggested that small-fibre function is affected preferentially in diabetic neuropathy, though there is no definite evidence for this view. At the moment the only peripheral small fibre modality which can be routinely assessed is thermal sensitivity using psychophysical methods. Many devices are now available for testing this modality. One, the Marstock method,5 uses the method of limits, the others a forced-choice method. The latter is generally preferred as it is thought to reduce response bias67 and hence increase reliability and precision. The purpose ofthe study, therefore, was to compare two thermal testing methods, one forced- choice, the other employing a method of limits, in a large number of diabetic subjects. Methods All tests were carried out on the right foot. Thermodes were lightly applied to the skin over the dorsolateral aspect of the foot. Foot temperature was maintained at 30-320C.(1) Forced-choice: Sensortek method8This and some other forced-choice methods measure "static" thermal sensitivity; alternative forms of the apparatus have been described.4 The patient is asked to identify the warmer of two Peltier-controlled elements, differing in temperature by set amounts, by moving his foot from one plate to the other. One of the elements is held at a standard reference temperature (30°C) and the temperature of the other randomly varied above or below this (range 0 1-20'C). The responses are plotted on a graph and the temperature difference altered according to the pattern of correct and incorrect responses, described as the up-down-transformation rule9 (UDTR). Several variants of the UDTR have been described; here the thermal threshold was taken as the mean of six points at which the plot changes either from an up-to-down or a down-to-up direction. In normal and nonneuropathic patients the test takes about 20 minutes, but in neuropathic patients the increased time required to change the temperature of the plates between stimulus pairs can extend the test to 40 minutes. This limitation applies to all thermal threshold methods.
The sensitivity and response to insulin in vitro of (a) the incorporation of U-C-14-glucose into glycogen in the isolated diaphragm muscle, and (b) the oxidation of l-C-14 glucose in the epididymal fat pad and in adipocytes, has been studied in obese hyperglycemic mice fed ad libitum, in obese mice fasted for twenty-four hours and in obese mice maintained on a restricted diet from weaning and in lean mice, at two to four months of age and at six to eight months of age. In both age groups, there was a significant, although reduced, insulin effect in the muscle from obese mice but this was normal in the six to eight-month-old group of obese mice on a restricted diet. The glucose oxidation in the epididymal fat pad of the obese mice fed ad libitum was very reduced in both age groups. Fasting the obese mice for twenty-four hours did not restore glucose oxidation to normal, but it was normal in fat pads from obese mice kept on a restricted diet. There was no insulin effect on the fat pad of obese mice in either age group even after a twenty-four-hour fast. The response and sensitivity of the tissue to insulin was partially restored in the obese mice on a restricted diet. There were only small differences in sensitivity between adipocytes prepared from obese and lean epididymal fat pads. The maximum response to insulin in adipocytes from obese mice was usually lower than that in adipocytes from lean mice at glucose concentrations of 0.03 per cent but equal or higher at glucose concentrations of 0.2 per cent. The clear responses to low concentrations of insulin of the isolated diaphragm muscle and adipocyte suspension from obese mice on a restricted diet and of the adipocytes from obese mice fed ad libitum, suggest that a decreased sensitivity to insulin at the cellular level is not the primary defect in the obese hyperglycemic syndrome.
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