Redistribution of sudomotor responses is an early sign of sympathetic dysfunction in type 1 diabetes.

Patients with diabetic neuropathy typically have decreased sweating in the feet but excessive sweating in the upper body. Previous studies of sudomotor function in diabetes have included patients with longstanding disease. The present study was designed to test for the early presence of sudomotor dysfunction and to characterize its relation to glycemic control and other aspects of peripheral nerve function. A total of 37 patients (10 males, 27 females) enrolled in a longitudinal study, in which autonomic function was evaluated annually for 3 years. Patients enrolled 2-22 months after the diagnosis of type 1 diabetes. Forty-one age- and sex-matched healthy control subjects were also studied. Sweat production in response to acetylcholine stimulation was dramatically increased in the forearm at the time of the first evaluation (1.67 +/- 0.24 micro/cm2 in the diabetic patients vs. 1.04 +/- 0.14 microl/cm2 in the control subjects, P < 0.05). Likewise, the ratio of sweating in the forearm to sweating below the waist was higher in the diabetic patients (0.553 +/- 0.07 microl/cm2) than in the control subjects (0.385 +/- 0.04 microl/cm2, P < 0.05). Forearm sweat was negatively associated with the renin-toprorenin ratio and vanillylmandelic acid (VMA) excretion (P < 0.025), tests of sympathetic nerve function. The ratio of sweating in the forearm to sweating in the foot was likewise increased in diabetic patients with poor glycemic control. We interpret this redistribution of sudomotor responses to be indicative of sympathetic nerve injury and conclude 1) that the sympathetic nervous system is especially vulnerable to the adverse effects of chronic hyperglycemia and 2) that sympathetic dysfunction can be detected very early in type 1 diabetes.

Antibodies to glutamic acid decarboxylase and peripheral nerve function in type 1 diabetes.

Autoimmune mechanisms have been implicated in the pathophysiology of diabetic neuropathy. We studied the association between glutamic acid decarboxylase (GAD65) and islet cell (IA-2) autoantibodies as well as autoantibodies to the autonomic nervous system and peripheral nerve function in recent onset type 1 diabetes. Thirty-seven patients (27 females and 10 males) enrolled 2-22 months after diagnosis. Humoral factors, glycemic control, and peripheral nerve function were measured annually for 3 yr. Patients with high GAD65Ab had worse glycemic control and higher insulin requirements. Patients with high GAD65Ab had slower motor nerve conduction velocities in the median, ulnar, and peroneal nerves (P < 0.025 for each nerve). The mean motor nerve conduction velocity Z scores at the time of the third evaluation was 0.341 +/- 0.25 for the low GAD65Ab patients and -0.600 +/- 0.25 for the high GAD65Ab patients (P < 0.01). Similar differences between the low and high GAD65Ab groups were observed for F wave latencies, thermal threshold detection, and cardiovascular autonomic function. The composite peripheral nerve function Z scores in the low GAD65Ab patients were 0.62 +/- 11, 0.71 +/- 0.19, and 0.21 +/- 0.14 at the first, second, and third evaluations, significantly different from those in the high GAD65Ab patients in whom they were -0.35 +/- 0.15, -0.46 +/- 0.18, and -0.42 +/- 0.16 (P < 0.001). In summary, GAD65Ab in patients with recent onset type 1 diabetes are associated with worse glycemic control and slightly worse peripheral nerve function. Although the latter remained within normal limits and none of the patients had clinical neuropathy, the GAD65Ab-related differences in composite peripheral nerve function were highly significant (P < 0.001) and could not be attributed to GAD65Ab-related differences in glycemic control.

Decreased prorenin processing develops before autonomic dysfunction in type 1 diabetes.

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598-1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied. PRA in the diabetic patients at the time of the second and third evaluations was 1.71 +/- 0.24 ng angiotensin I/mL x h and 1.67 +/- 0.24 ng angiotensin I/mL x h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 +/- 0.38 ng angiotensin I/mL x h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 +/- 0.03, 0.235 +/- 0.05, and 0.227 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 +/- 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04-0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15-0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01). We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.

Treatment of orthostatic hypotension with midodrine and octreotide.

The purpose of this study was to compare two treatments for orthostatic hypotension, midodrine (an alpha adrenergic agonist), and octreotide (an SRIH analogue) to each other and to combination therapy. Sixteen patients participated. Our hypothesis was that the 2 drugs together would be more effective than either drug alone. The effect of the drugs on the hemodynamic response to food ingestion was evaluated while patients were sitting. Midodrine (5 mg orally, 30 min before breakfast) increased mean blood pressure slightly (5-10 mm Hg, over 30 min) before the patients started eating, but it only partially reversed the hypotensive effect of food ingestion. The nadir in postprandial blood pressure after midodrine was 69 +/- 4 mm Hg, not different from placebo (63 +/- 5). Nevertheless, midodrine accentuated the response to sc octreotide (0.5 microgram/kg). Fifteen minutes after octreotide administration to midodrine-pretreated patients, the average mean blood pressure was 115 +/- 9 mm Hg, higher (P = .0095) than after octreotide given alone (102 +/- 7). Drug effects on orthostatic hypotension were assessed by measuring standing time (minutes before symptoms of hypotension or definite hypotension). In the absence of treatment, standing time was 3.5 +/- 7 min; 1 h after 10 mg midodrine, 8.4 +/- 2.7 min (P = .11); after 1.0 microgram/kg octreotide, 13.2 +/- 3.9 min (P = .0034 vs. no treatment); and after both drugs, 21.2 +/- 5.5 min (P = .0002 vs. no treatment, P = .036 vs. octreotide only). The combination of midodrine and octreotide is more potent than either drug alone.

Antibodies to GAD and glycemic control in recent-onset IDDM.

OBJECTIVE: To analyze the effect of antibodies to glutamic acid decarboxylase (GAD65Ab) and islet cells (ICA512Ab) on glycemic control early in IDDM. RESEARCH DESIGN AND METHODS: GAD65Ab and ICA512Ab were measured twice in 35 patients (10 male, 25 female; age 10-40 years) initially within 2 years of diagnosis and again 1 year later. The glycosylated hemoglobin was measured one to four times each year, and the average glycosylated hemoglobin for the preceding year was calculated each time the antibodies were measured. RESULTS: The mean HbA1 at the time of the initial evaluation was 8.04 +/- 0.30 (reference range 4.7-7.3% for nondiabetic patients), the average GAD65Ab index was 0.735 +/- 0.306, and the mean ICA512Ab index was 1.94 +/- 0.65. The GAD65Ab index correlated with HbA1 (r = 0.41, P < 0.025), whereas the ICA512Ab index did not (r = 0.13). One year later, the mean GAD65Ab index was 0.94 +/- 0.34, the mean ICA512Ab index was 1.04 +/- 0.40, and the mean HbA1 was 9.03 +/- 0.30. The GAD65Ab index correlated with HbA1 (r = 0.61 P < 0.001), whereas the ICA512Ab index did not (r = -0.06). Stratification of patients into tertiles according to the average GAD65 index revealed, at the follow-up evaluation, that the better glycemic control in the lowest GAD65Ab tertile was accomplished with significantly less insulin (0.43 +/- 0.08 U/kg for the lowest tertile vs. 0.71 +/- 0.09 and 0.64 +/- 0.09 for the middle and highest tertiles, respectively; P < 0.05). CONCLUSIONS: In summary, patients with IDDM and low GAD65Ab have better glycemic control even though they require less insulin. The ICA512Ab index, however, fails to correlate with glycemia.

Treatment of orthostatic tachycardia with erythropoietin.

PURPOSE: To determine whether increasing red blood cell volume with erythropoietin reverses the hemodynamic response to standing in patients with orthostatic tachycardia. PATIENTS AND METHODS: Eight patients (2 men, 6 women) with orthostatic tachycardia were administered erythropoietin (50 U/kg body weight 3 times a week for 6 to 12 weeks) in order to reverse their red blood cell volume deficit. Six of the patients also received fludrocortisone (0.1 mg/d). Plasma and red blood cell volumes as well as the hemodynamic response to orthostatic stress were measured before and after erythropoietin therapy. RESULTS: Erythropoietin therapy increased the mean +/- hematocrit from 37.6 +/- 1.0 to 46.4 +/- 1.4 (+/- standard error) (P < 0.01) and increased the red blood cell volume from 17.7 +/- 1.1 to 24.6 +/- 2.0 mL/kg (P < 0.01). Treatment increased supine mean blood pressure (from 87 +/- 4 to 93 +/- 5 mm Hg, P < 0.025) and standing mean blood pressure (from 87 +/- 4 to 94 +/- 5 mm Hg, P < 0.025). Erythropoietin therapy, however, failed to reverse orthostatic tachycardia. Following treatment, the mean heart rate after 5 minutes standing was 129 +/- 7 bpm, not significantly different from the pretreatment standing heart rate (134 +/- 5 bpm). CONCLUSIONS: Although patients with the orthostatic tachycardia syndrome have a deficit in red blood cell volume, this is not the cause of their abnormal hemodynamic response to standing. Erythropoietin therapy fails to reverse orthostatic tachycardia.