Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance.

To study the mechanism of the diabetogenic action of ethanol, ethanol (0.75 g/kg over 30 min) and then glucose (0.5 g/kg over 5 min) were infused intravenously into six normal males. During the 4-h study, 21.8 +/- 2.1 g of ethanol was metabolized and oxidized to CO2 and H2O. Ethanol decreased total body fat oxidation by 79% and protein oxidation by 39%, and almost completely abolished the 249% rise in carbohydrate (CHO) oxidation seen in controls after glucose infusion. Ethanol decreased the basal rate of glucose appearance (GRa) by 30% and the basal rate of glucose disappearance (GRd) by 38%, potentiated glucose-stimulated insulin release by 54%, and had no effect on glucose tolerance. In hyperinsulinemic-euglycemic clamp studies, ethanol caused a 36% decrease in glucose disposal. We conclude that ethanol was a preferred fuel preventing fat, and to lesser degrees, CHO and protein, from being oxidized. It also caused acute insulin resistance which was compensated for by hypersecretion of insulin.

Acetone metabolism in humans during diabetic ketoacidosis.

Plasma acetone turnover rates were measured with the primed continuous infusion of 2-[14C]acetone in patients with moderate to severe diabetic ketoacidosis. Plasma acetone turnover rates ranged from 1.52 to 15.9 mumol X kg-1 X min-1 (108-1038 mumol X 1.73 m-2 X min-1) and were directly related to the plasma acetone concentrations that ranged from 0.47 to 7.61 mM. The average acetone turnover rate was 6.45 mumol X kg-1 X min-1 (533 mumol X 1.73 m-2 X min-1), a value twice that obtained in a similar group of diabetic ketoacidotic patients via the single-injection technique of 2-[14C]acetone administration. Degradation of urine glucose revealed that 14C from administered 2-[14C )acetone was principally located in carbons 1, 2, 5, and 6 of the glucose molecule in five of six patients. This distribution is similar to that expected from 2-[14C]pyruvate, suggesting that acetone was converted to glucose through pyruvate. In one patient, label was located predominantly in glucose carbons 3 and 4, indicating that acetone metabolism may be different in some patients. Acetol (1-hydroxyacetone) and 1,2-propanediol (PPD), two possible metabolites of acetone, were detected in plasma of the patients. The concentrations of Acetol ranged from 0 to 0.48 mM and of PPD ranged from 0 to 0.53 mM. The concentrations of each metabolite were directly related to the plasma acetone concentrations. During the continuous infusion of 2-[14C]acetone, the specific activities of plasma glucose and PPD rose continuously but did not reach constant values. Estimates of the minimal percent plasma glucose and PPD derived from plasma acetone averaged 2.1 and 74%, respectively.

Counterregulatory hormone release and glucose recovery after hypoglycemia in non-insulin-dependent diabetic patients.

An increasing number of patients with non-insulin-dependent diabetes mellitus (NIDDM) is presently being treated with insulin, some aggressively with intensified treatment schedules. However, there is little information on the ability of these patients to recover from insulin-induced hypoglycemia. We have, therefore, determined glucose recovery and counterregulatory hormone secretion in response to insulin-induced hypoglycemia in 10 NIDDM patients without autonomic neuropathy and in 6 age- and weight-matched normal controls. Recovery of plasma glucose concentration and hypoglycemia-induced increments of plasma concentrations of glucagon, epinephrine, norepinephrine, and HGH were similar in the NIDDM patients and the age- and weight-matched nondiabetic controls. It appears likely, therefore, that these NIDDM patients, if treated aggressively with insulin, may be at lesser risk for severe and prolonged hypoglycemia than insulin-dependent diabetic patients, particularly those with autonomic neuropathy or those treated with beta-adrenergic antagonists.

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.

Acetone metabolism during diabetic ketoacidosis.

The presence and the importance of acetone and its metabolism in diabetic ketoacidosis has largely been ignored. Therefore, we studied acetone metabolism in nine diabetic patients in moderate to severe ketoacidosis. The concentration of acetone in plasma, urine, and breath, and the rates of acetone production and elimination in breath and urine were determined and the rates of vivo metabolism were calculated. Plasma acetone concentrations (1.55-8.91 mM) were directly related and were generally greater than acetoacetate concentrations (1.16-6.08 mM). The rates of acetone production ranged from 68 to 581 mumol/min/1.73 m2, indicating the heterogeneous nature of the patients studied. The average acetone production rate was 265 mumol/min/1.73 m2 and accounted for about 52% of the estimated acetoacetate production rate. Urinary excretion of acetone remained constant and accounted for about 7% of the acetone production rate in all patients. There was a positive linear relationship between the percentage of the acetone production rate accounted for by excretion in breath and the plasma acetone concentration. At low plasma acetone concentrations, approximately 20%, and at high plasma acetone concentrations, approximately 80% of the production rate was accounted for by breath acetone. In contrast, there was a negative linear relationship between the percentage of acetone production rate undergoing in vivo metabolism and plasma acetone concentration. At low plasma acetone concentrations, approximately 75%, and at high concentrations, approximately 20% of acetone production rate was accounted for by in vivo metabolism. Radioactivity from 2-[14C]-acetone was variably present in plasma acetone, glucose, lipids and proteins. No radioactivity was found in plasma acetoacetate, beta-hydroxy butyrate or free fatty acids or other anionic compounds. Exchange rates of acetone into other metabolites could not be estimated because of non-steady-state precursor product relationships in these patients.

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.

Effects of aging on catecholamine metabolism.

To determine the cause of the high plasma norepinephrine (NE) concentrations in elderly subjects, we measured apparent NE secretion, NE plasma clearance, and NE production in 14 young and 13 elderly normal subjects. Apparent NE secretion, estimated by isotope dilution analysis, was higher (P less than 0.01) in the elderly subjects [3.08 +/- 0.45 (+/- SEM) nmol/m2 X min] than in the young subjects (1.84 +/- 0.12 nmol/m2 X min). Plasma clearance of NE did not differ between the young (1470 +/- 120 ml/m2 X min) and the elderly (1295 +/- 153) subjects. NE production, estimated from NE metabolite excretion, was 9.66 +/- 0.8 nmol/m2 X min in the elderly subjects, not significantly different from that in the young subjects, who produced NE at a rate of 11.7 +/- 1.1 nmol/m2 X min. Excretion of the O-methyl derivative of NE normetanephrine was increased (P less than 0.01) in the aged, whereas excretion of the deaminated metabolites vanillylmandelic acid and dihydroxmandelic acid was decreased. Our data indicate that the rate at which NE enters the circulation is increased in the elderly, but NE production is normal. Taken together, these results suggest that in aging, there is an alteration in the local disposition of sympathetic neuronal NE.

Treatment of orthostatic hypotension with octreotide.

The purpose of this study was to evaluate the therapeutic potential of the somatostatin analog octreotide in patients with orthostatic hypotension. Octreotide was administered sc, and its pressor effect was assessed while the patients were semirecumbent and on the tilt table. We also studied the effect of octreotide on blood pressure while patients walked. The efficacy of therapy was assessed by measuring the duration of walking (walking time) before the onset of hypotension. Low doses of octreotide (0.2-0.4 micrograms/kg) had a pressor effect in all patients with progressive autonomic failure (n = 7), multiple system atrophy (n = 7), and diabetic autonomic neuropathy (n = 8), but not in patients with sympathotonic orthostatic hypotension (n = 6). Larger doses (0.4-1.6 micrograms/kg) resulted in a sustained (greater than or equal to 50 min) increase in blood pressure during walking in four of six patients with progressive autonomic failure and in one of six patients with multiple system atrophy. Some patients in whom octreotide failed to stabilize upright blood pressure had a satisfactory response to the drug after pretreatment with dihydroergotamine (10 micrograms/kg, sc). Patients with diabetic autonomic neuropathy, although sensitive to the pressor effect of octreotide, often developed nausea or abdominal cramps after moderate doses (greater than 1.0 micrograms/kg). These results indicate that the pressor effect of octreotide is sufficiently potent to prevent orthostatic hypotension in some patients with autonomic neuropathy. Others require treatment with both dihydroergotamine and octreotide to achieve a stable upright blood pressure.

The orthostatic tachycardia syndrome: evaluation of autonomic function and treatment with octreotide and ergot alkaloids.

Orthostatic tachycardia is a poorly understood syndrome in which patients develop dizziness, diaphoresis, or palpitations upon shifting from the supine to the upright posture. The present study was performed to determine whether autonomic neuropathy might be present in these patients, and whether the abnormal hemodynamic response to standing might be the result of failure of reflex vasoconstriction. We measured autonomic function in 9 patients with idiopathic orthostatic tachycardia and 2 patients with orthostatic tachycardia and insulin-dependent diabetes mellitus and compared them to 33 age-matched controls. Although most patients with orthostatic tachycardia had normal vasomotor reflexes and normal surface potential amplitudes, the latency of the autonomic response, a measure of sympathetic nerve conduction velocity, was prolonged in the soles (2.44 +/- 0.08 s in patients with idiopathic orthostatic tachycardia vs. 2.12 +/- 0.04 s in controls; P less than 0.005). In 6 of 9 patients, however, the latencies were within the normal range. Autonomic surface potentials were absent in 1 diabetic patient with orthostatic tachycardia; the latency of the response in the feet was greatly prolonged (2.95 s) in the second patient. We also assessed the response of orthostatic tachycardia patients to octreotide and dihydroergotamine, which are known to have a pressor effect in patients with recognized forms of autonomic neuropathy. These agents, in combination, suppressed orthostatic tachycardia (from 116 +/- 7 to 89 +/- 6 beats/min; P less than 0.001) in patients with this syndrome. In summary, our data indicate that evidence of autonomic dysfunction is present in only a minority of patients with orthostatic tachycardia. Nevertheless, administration of the vasoconstrictor drugs dihydroergotamine and octreotide can prevent the abnormal hemodynamic response to the upright posture shown by patients with this syndrome.

Norepinephrine secretion and production in diabetic autonomic neuropathy.

Orthostatic hypotension (OH) in patients with diabetic autonomic neuropathy may result from sympathetic neuronal dysfunction and inadequate norepinephrine (NE) release as patients shift from the supine to an upright posture. The biochemical basis for this physiological abnormality is not understood. We measured basal supine NE secretion and production in 10 diabetic patients with OH, 9 diabetic patients without OH, and in 13 age-matched normal subjects. Apparent NE secretion, the rate at which NE enters the bloodstream, was 1.22 +/- 0.24 (SEM) nmol/m2 X min in the diabetic patients with OH, significantly lower than in the diabetic patients without OH and normal subjects in whom apparent NE secretion rates were 2.27 +/- 0.48 and 1.86 +/- 0.12 nmol/m2 X min, respectively. NE production, estimated from integrated NE metabolite excretion, was 10.2 +/- 0.85 nmol/mg creatinine in the diabetic patients with OH, which was significantly lower (P less than 0.01) than that in the diabetic patients without OH and normal subjects in whom NE production was 14.8 +/- 1.8 and 16.9 +/- 1.2 nmol/mg creatinine, respectively. These data demonstrate that supine basal apparent NE secretion and NE production are decreased in patients with OH secondary to diabetic autonomic neuropathy.

An in vivo tritium release assay of human dopamine beta-hydroxylase.

A non-invasive method is described for estimating dopamine beta-hydroxylase (DBH) activity in sympathetic neurons. Our assay is based on the measurement of the in vivo rate of tritiated water (THO) release from dopamine specifically labeled in the beta-position ([beta-3H]DA). In validation of this method, we have establsihed in human subjects that 1) THO release from [beta-3H]DA correlates with [beta-3H]norepinephrine metabolite excretion, and 2) partial inhibition of DBH with disulfiram (5.5 mg/kg for 4 days) causes parallel decreases in these two indices of dopamine beta-hydroxylation. Since there is a strong correlation (r = 0.89; P < 0.05) between the effect of disulfiram on THO release and the effect of the drug on [3H]-norepinephrine metabolite excretion, our data indicate that the rate at which THO is liberated from [beta-3H]DA into the total body water can be used as an in vivo index of DBH activity.

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.

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.

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.

DL-Threo-3,4-dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension.

DL-Threo-3,4-dihydroxyphenylserine (DL-DOPS) was given to six subjects with severe orthostatic hypotension (OH). On separate days each subject took either 600 or 800 mg DL-DOPS or placebo. DL-DOPS increased norepinephrine (NE) excretion 10,000% and urinary normetanephrine and dihydroxyphenylglycol excretion 400%. DL-DOPS, however, led to only slight increases in excretion of the major NE metabolites 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid. Only approximately 2.2% +/- 0.5% (range 0.65% to 3.8%) of the L-stereoisomer (L-DOPS), when given as DL-DOPS, is converted to NE in vivo over 24 hr. DL-DOPS did not affect either supine or upright blood pressure in our subjects. Our findings do not support reports that DL-DOPS may be therapeutically useful in OH.

Sympathotonic orthostatic hypotension: a report of four cases.

We describe four patients with sympathotonic orthostatic hypotension, a syndrome in which the decrease in blood pressure associated with standing is accompanied by tachycardia. The patients in this series had experienced either a viral infection or rapid weight loss prior to the onset of their orthostatic intolerance. Vasomotor reflexes and norepinephrine production were normal, and analysis of palmar autonomic surface potentials indicated that the sympathetic innervation of the upper extremities was intact. The amplitudes of the plantar autonomic surface potentials, however, were decreased although still within the normal range. The latencies of plantar autonomic surface potentials were slightly prolonged. Although most autonomic function tests are normal in sympathotonic orthostatic hypotension, mild abnormalities in the plantar autonomic surface potentials may indicate a neuropathy that primarily affects low thoracic or lumbar sympathetic neurons.

Treatment of postprandial hypotension with a somatostatin analogue (SMS 201-995).

A somatostatin analogue, compound SMS 201-995, was used to treat postprandial hypotension in a patient with autonomic neuropathy. Prior to treatment, the patient's mean blood pressure decreased 50 to 80 mm Hg after each meal, resulting in frequent loss of consciousness. Subcutaneous administration of low doses of compound SMS 201-995 (12 to 16 micrograms) prevented the postprandial hypotension. The therapeutic benefits of SMS 201-995 dissipated after a few hours, however, which made it necessary to administer the drug with each meal. No adverse effects of this agent were noted over a nine-month treatment period. Compound SMS 201-995 provided safe and effective therapy for postprandial hypotension.

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.

Effect of the somatostatin analogue SMS-201-995 on the adrenergic response to glucose ingestion in patients with postprandial hypotension.

PURPOSE: The somatostatin analogue SMS-201-995 has recently been introduced as a new therapy for postprandial hypotension in patients with autonomic neuropathy. The present study was performed to determine the effect of SMS-201-995 on the adrenergic response to glucose ingestion in patients with this disorder. PATIENTS AND METHODS: Eleven patients with postprandial hypotension were studied: six with central autonomic dysfunction (multiple system atrophy) and five with peripheral sympathetic dysfunction (progressive autonomic failure). Patients received either a subcutaneous injection of SMS-201-995 or a placebo injection, immediately before administration of a 50-g glucose drink. Each treatment was given on separate, consecutive days in a randomized fashion. RESULTS: Glucose ingestion caused a decrease in blood pressure (from 82 +/- 6 mm Hg to 66 +/- 7 mm Hg, p less than 0.01) and an increase in plasma norepinephrine level (165 +/- 20 pg/mL to 305 +/- 85 pg/mL, p less than 0.01) in five patients with progressive autonomic failure. Administration of SMS-201-995 prevented both the decline in blood pressure and the increase in norepinephrine. By contrast, glucose ingestion elicited no increase in plasma norepinephrine levels despite profound hypotension (average postprandial mean blood pressure, 55 +/- 3 mm Hg) in six patients with multiple system atrophy. Administration of SMS-201-995 prevented postprandial hypotension in these patients, but had no effect on plasma norepinephrine. CONCLUSION: Our data indicate that the pressor effect of SMS-201-995 is independent of the sympathetic nervous system in patients with multiple system atrophy, but may suppress the adrenergic response to glucose ingestion in patients with progressive autonomic failure.

Are there two types of diabetic foot ulcers?

Neurological function was determined in diabetic patients with peripheral vascular disease and foot ulcers (n = 13). This was compared to that of diabetic patients without foot ulcers with (n = 23) and without (n = 13) symptoms of neuropathy. Diabetic patients with typical neuropathic ulcers (n = 13) and age-matched healthy controls (n = 20) were also studied. The beat-to-beat variation with deep breathing was 6.1 +/- 1.0 beats/min in those with peripheral vascular disease and foot ulcers, less than 50% of that of diabetic patients without foot ulcers (p < 0.01) or normal controls (p < 0.005). Autonomic surface potentials in the soles were greatly diminished or absent in nearly all the patients with peripheral vascular disease and ulcers. Quantitative sensory testing revealed profound abnormalities in small fiber (heat and cold sensation) and large fiber (vibration sensation) function in diabetic patients with peripheral vascular disease and foot ulcers. Our results document the presence of advanced autonomic and somatosensory neuropathy in nearly all diabetic patients with peripheral vascular disease and foot ulcers.