Robert D. Hoeldtke

Treatment of postural tachycardia syndrome: a comparison of octreotide and midodrine

We assessed the potency of octreotide and midodrine, and their combination, in the treatment of the postural tachycardia syndrome (POTS) and orthostatic intolerance (OI). Nine patients with POTS and six patients with OI stood for up to 1xa0hour while their HR and BP were monitored. Patients received on separate days, midodrine 10xa0mg 1xa0hour before testing, octreotide 0.9xa0µg/kg 8xa0minutes before testing or combination therapy. Standing time in the patients with POTS was 41.2xa0±xa08.4xa0minutes and not improved by midodrine or octreotide, but increased to 56.3xa0±xa02.7 (Pxa0<xa00.01) minutes following combination therapy. The standing heart rate in POTS, 114xa0±xa00.7xa0bpm, was suppressed by midodrine 92.8xa0±xa00.7 (Pxa0<xa00.001), octreotide 90.6xa0±xa00.78 (Pxa0<xa00.001), and combination therapy 84.7xa0±xa00.7 (Pxa0<xa00.001). Combination therapy was better than monotherapy (Pxa0<xa00.001) but only for the first 10xa0minutes of standing.Standing time of 36.3 ± 3.5 minutes in the patients with OI improved with midodrine, octreotide and combination therapy (55.5xa0±xa03.1, 56.5xa0±xa03.5, and 56.6xa0±xa03.3, respectively, Pxa0<xa00.05 for each). Standing heart rate in OI was 100xa0±xa0.76xa0bpm; following midodrine it was 80.3xa0±xa0.69 (Pxa0<xa00.05), following octreotide it was 84.8xa0±xa0.86, and following combination therapy it was 71.2xa0±xa0.9 (Pxa0<xa00.01). The RR interval versus time area under the curve (The Orthostatic Index) was 21.1xa0±xa04 in patients with OI. After midodrine it was 41.4xa0±xa03.5 (Pxa0<xa00.01), after octreotide 40.3xa0±xa03.8 (Pxa0<xa00.01) and after the combination it was 47.3xa0±xa04.6 (Pxa0<xa00.001).Midodrine and octreotide suppressed tachycardia in POTS and improved standing times in OI. The two drugs had similar potencies; combination therapy was not significantly better than monotherapy.

Regulation of Metabolism

Publisher Summary Catecholamines activate β-adrenergic receptors (β-ARs) in the liver and stimulate hepatic glucose production by multiple mechanisms. Glycogenolysis and gluconeogenesis are enhanced, whereas glycogen synthesis is inhibited. In addition to stimulating the entry of glucose into the bloodstream, catecholamines decrease plasma glucose clearance by both direct (β)- and indirect (α)-adrenergic mechanisms. These multiple catecholamine effects are synergistic as they all serve to increase plasma glucose concentrations. These mechanisms become physiologically important in the setting of hypoglycemia, the classical stimulus to epinephrine (EPI) secretion by the adrenal medulla. Thus, the autonomic activation associated with hypoglycemia serves the ultimate purpose of mobilizing endogenous substrates for glucose production and increasing glucose concentrations in the bloodstream so that the central nervous systems demand for its obligatory fuel can be met. Catecholamines also act directly on adipose tissue to stimulate fat breakdown. This is a β1-adrenergic effect involving adenyl cyclase-mediated activation of hormone-sensitive triacylglycerol lipase, the enzyme that cleaves triglyceride in the adipose tissue into fatty acids and glycerol. Insulin inhibits catecholamine-induced lipolysis; thus, catecholamine-mediated suppression of insulin secretion is synergistic with the direct catecholamine effects on adipose tissue.

Treatment of orthostatic tachycardia with erythropoietin.

PURPOSEnTo determine whether increasing red blood cell volume with erythropoietin reverses the hemodynamic response to standing in patients with orthostatic tachycardia.nnnPATIENTS AND METHODSnEight 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.nnnRESULTSnErythropoietin 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).nnnCONCLUSIONSnAlthough 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.

Peroxynitrite versus nitric oxide in early diabetes.

BACKGROUNDnPeroxynitrite is a toxic compound formed during the inactivation of nitric oxide (NO) by the superoxide anion. The physiologic significance of this pathway of NO metabolism has never been documented in vivo. Because peroxynitrite provides a pathway for the inactivation of NO we postulated that peroxynitrites correlation with physiologic parameters would be the opposite of those associated with NO, which is a vasodilator and suppresses sudomotor function. We assessed the significance of peroxynitrite by comparing its associations with blood pressure (BP) and sudomotor responses with those of NO.nnnMETHODSnThirty-seven patients with type 1 diabetes enrolled in a longitudinal study of oxidative stress. Nitric oxide was assessed from nitrite and nitrate (collectively NOx) and peroxynitrite was assessed from the nitrotyrosine (nTy) content of protein.nnnMETHODSnnTy was 13.3 +/- 2.0 micromol/L in the control subjects and 26.8 +/- 4.4 micromol/L, 26.1 +/- 4.3 micromol/L, and 32.7 +/- 4.3 micromol/L in the diabetic patients (P <.01) at the time of the first, second, and third evaluations, respectively. Patients with increased nitrotyrosine/tyrosine (nTy/Ty) had higher mean BP than those with low nTy/Ty (81.1 +/- l.9 mm Hg v 75.5 +/- 1.7 at the third evaluation, P <.025). The ratio of nTy/NOx correlated with BP at the first (P <.05), second (P <.05), and third (P <.01) evaluations. Patients with high nTy/Ty had increased sudomotor responses (5.85 +/- 0.75 microL of total sweat) at the third evaluation compared to those with low nTy/Ty (3.32 +/- 0.43 microL, P <.005) and normal controls (3.90 +/- 0.41 microL, P <.05). The associations of nTy with BP and sudomotor responses were the opposite of those with NOx.nnnCONCLUSIONSnThe conversion of NO oxide to peroxynitrite is physiologically significant in humans.

Nitrosative stress in early Type 1 diabetes

Although hyperglycemia has been shown to cause peripheral nerve dysfunction in patients with diabetes, the biochemical mechanisms for this effect are poorly understood. The excessive production of reactive oxygen species and reactive nitrogen species has been proven to be detrimental in experimental diabetes, but there is little evidence that these metabolic events take place clinically and are physiologically important in man. To assess this we measured nitrite and nitrate (indices of nitric oxide production), nitrotyrosine (an index of peroxynitrite), 8-isoprostaglandin F-2 alpha, an isoprostane reflective of oxidative stress and lipid peroxidation, and uric acid, an index of antioxidant defense in patients with recently diagnosed Type 1 diabetes and aged-matched controls. The diabetic patients were followed for three years. We documented the overproduction of nitric oxide and increased lipid peroxidation in early diabetes and showed these changes had detectable adverse effects on peripheral nerve function especially sympathetic sudomotor nerves. We documented the suppression of uric acid and showed this was associated with multiple abnormalities in autonomic function. In addition, we present indirect evidence that overproduction of reactive oxygen species and reactive nitrogen species have adverse effects on beta cell function and blood pressure.

Treatment of autonomic neuropathy, postural tachycardia and orthostatic syncope with octreotide LAR

The purpose of this study was to determine whether autonomic neuropathy and the postural tachycardia syndrome can be treated with octreotide LAR (Long Acting Release). This was an open-label pilot project. Protocol 1 Patients with autonomic neuropathy (n = 4) were given increasing doses of octreotide LAR once a month for three months. Blood pressure was measured in the sitting posture every two weeks. Pretreatment mean blood pressure averaged 83.8 ± 7.1 mm Hg. After four, six and eight weeks of therapy the blood pressures averaged 96.3 ± 6.4, 98.2 ± 6.1 (p < .025), and 104.1 ± 3.1 (p < .025) respectively. Therapy led to a dramatic improvement in symptoms in one patient but another had an unacceptable elevation in supine blood pressure. Protocol 2 Patients with POTS or orthostatic intolerance were given 10, 20, or 30 mg of octreotide LAR over three months. Seven patients entered and five completed the study. After two months treatment, standing time increased from 36.0 ± 9.2 to 59.2 ± .8 minutes (p < .01). Heart rate in the standing position was suppressed from 106 ± .83 to 93.2 ± .8 beats per minute (p < .05). Orthostatic dizziness and chronic fatigue improved. We conclude that octreotide LAR can be used to treat autonomic neuropathy but there is a risk of an excessive pressor response. Octreotide LAR improved standing time and suppressed tachycardia in patients with orthostatic intolerance.

Luminescence experiments involved in the mechanism of streptozotocin diabetes and cataract formation

Streptozotocin (STZ)-induced diabetes is linked to excessive nitric oxide (NO), and possibly peroxynitrite (OONO(-)) and/or other nitrogen oxides, e.g. nitrogen trioxide (N(2)O(3)), which damages DNA of pancreatic beta cells, causing death and loss of insulin. Simultaneous injection of carboxy-PTIO (CPTIO) and STZ prevents diabetes and cataract formation in rats, whereas 4-hydroxy-Tempo (4HT) does not. CPTIO oxidizes nitric oxide to nitrite, which prevents production of the diabetogenic toxin. Peroxynitrite may not be involved, since 4HT (converts O(2)(-) to H(2)O(2)) injected with STZ produces diabetes. All six of the control rats injected with STZ became diabetic and developed cataracts after 3 months. Eight rats injected with STZ and CPTIO were non-diabetic with no cataracts up to a year. This work establishes the idea that excessive nitric oxide is a primary initiator in STZ diabetes. Luminescence experiments using OONO(-) generation from SIN-1 with L-012 indicates that 4HT is an effective inhibitor, while CPTIO is ineffective. Experiments with dilute solutions of nitrogen trioxide added to ladder or plasmid DNA reveal extensive nicking of DNA, thereby raising the possibility that other oxides of nitrogen could be involved with the damage to DNA. It can be concluded that diabetes can be prevented by oxidizing excessive NO from STZ.

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.

Lipid peroxidation in early type 1 diabetes mellitus is unassociated with oxidative damage to DNA

Oxidative stress damages DNA in experimental diabetes, and in vitro studies have suggested that it is linked to lipid peroxidation. The objective of the study was to determine whether lipid peroxidation, as assessed with malondialdehyde excretion in recent-onset type 1 diabetes mellitus, is associated with oxidative damage to DNA, as assessed from 8-hydroxydeoxyguanosine excretion. A 3-year longitudinal study of recent-onset type 1 diabetes mellitus was performed. Age- and sex-matched control subjects were studied once. Patients were studied as inpatients at West Virginia University Hospitals. Thirty-seven patients with recent-onset (2-22 months) type 1 diabetes mellitus (male, 10; female, 27) were enrolled in a longitudinal study of oxidative stress. The mean age of the patients was 20 years. None of the patients had hyperlipidemia or were treated with lipid-lowering drugs. Only 1 patient had hypertension and was being treated with beta-adrenergic blocking therapy. Thirty-six patients completed the study; one withdrew after the second evaluation. Lipid peroxidation was assessed by measuring malondialdehyde excretion. Oxidative damage to DNA was assessed from 8-hydroxydeoxyguanosine excretion. Malondialdehyde excretion was increased in the diabetic patients at the first evaluation (2.43 +/- 0.31 micromol/g creatinine), second evaluation (2.34 +/- 0.24), and third evaluation (1.93 +/- 0.15) compared with control subjects (1.51 +/- 0.11) (P < .005). 8-Hydroxydeoxyguanosine excretion, however, was not increased in the diabetic patients. There was no correlation between malondialdehyde and 8-hydroxydeoxyguanosine excretion. We confirmed the presence of oxidative stress in early diabetes as assessed from malondialdehyde excretion. We were unable, however, to confirm oxidative damage to DNA in this cohort of patients; and there was no evidence of a correlation between lipid peroxidation and DNA damage.

Antibodies to GAD65 and peripheral nerve function in the DCCT

Antibodies to the smaller isoform of glutamic acid decarboxylase (GAD65Ab) have been linked to the presence of neuropathy in Type 1 diabetes in several small studies. We attempted to confirm this association by measuring GAD65Ab, GAD65Ab epitopes and IA-2Ab in 511 patients who participated in the Diabetes Control and Complications Trial (DCCT). We also tested for correlations between these autoantibodies and C-peptide and glycemic control. We only included patients for whom serum was available from the first 4 years of their illness. The presence or absence of neuropathy was determined by electrophysiological studies, autonomic testing and clinical evaluation at baseline and 5 years into the trial or at close out. Samples from controls (patients without neuropathy at 5 years) were selected for patients who had similar C-peptide responses to a standardized meal at baseline. The GAD65Ab index correlated with HgbA(1c) only in the adult participants and only at baseline. The adults initially in poor control (upper tertile for glycemia) had higher GAD65Ab and lower C-peptides. The GAD65Ab index was not significantly different in patients with confirmed clinical neuropathy at 5 years versus controls matched for C-peptide (.248+/-.03 versus .278+/-.03). Epitope analysis, based on the blocking of conformational epitopes by recombinant Fab, revealed that the binding to multiple epitopes was decreased in the patients with neuropathy.