Alpha-adrenergic blockade improves glucose-potentiated insulin secretion in non-insulin-dependent diabetes mellitus.

The impairment of glucose-potentiated insulin secretion present in non-insulin-dependent diabetes mellitus (NIDDM) can be approximated in normal subjects by an epinephrine infusion. Therefore, we sought to determine the role of the endogenous sympathetic nervous system in glucose-potentiated insulin secretion in both NIDDM (n = 6) and normal (n = 6) subjects. Glucose-potentiated insulin secretion was calculated as the slope of the curve relating increasing ambient glucose levels to the acute insulin response to an intravenous pulse of 5 g of L-arginine. Glucose-potentiated insulin secretion was determined on separate days during alpha-, beta-, and combined alpha- plus beta-adrenergic blockade and compared with a saline control. In normal subjects, there was no effect of alpha-, beta-, or alpha- plus beta-blockade on the slope of glucose potentiation. In NIDDM, the initially decreased slope of glucose potentiation (0.25 +/- 0.06 microU X ml-1 X mg-1 X dl, mean +/- SE; P less than .01) was not affected by beta-blockade but increased during alpha-blockade (0.91 +/- 0.22 microU X ml-1 X mg-1 X dl; P less than .05). However, this improvement was abolished by combined alpha- plus beta-blockade (0.32 +/- 0.07 microU X ml-1 X mg-1 X dl). Plasma norepinephrine was increased above basal levels in both normal (+260 +/- 89 pg/ml) and NIDDM (+438 +/- 162 pg/ml) subjects during alpha-blockade (P less than .05 for both). This increase in plasma norepinephrine strongly suggests that there is an increase in synaptic cleft norepinephrine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic influence on cardiovascular performance in diabetic subjects.

PURPOSE: Cardiomyopathy, coronary artery atherosclerosis, or autonomic neuropathy may affect the cardiovascular performance of the diabetic patient. To evaluate the role of parasympathetic nervous system activity on cardiovascular performance, 25 diabetic subjects who lacked symptoms, signs, or objective measurements of ischemia or cardiomyopathy were studied. PATIENTS AND METHODS: Diabetic subjects were classified according to their RR variation, an index of cardiac parasympathetic nervous system activity. Fourteen diabetic subjects had a normal RR variation of greater than 30 (D-NOR), and 11 diabetic patients had an abnormal RR variation of less than 20 (D-ABN). Fifteen age- and weight-matched, healthy, nondiabetic subjects (NOR) constituted the control group. All subjects had oxygen consumption, multigated acquisition determination of cardiac output, and work product measured before and during supine bicycle maximum exercise testing. RESULTS: There was no difference in the resting cardiac output among the groups. Resting work product, however, was greatest in the D-ABN group when compared with performance in the other two groups (D-ABN: 11,500 +/- 800; D-NOR: 9,000 +/- 600; NOR: 8,700 +/- 400; p less than 0.0025). This was due to an increase in both heart rate (p less than 0.025) and systolic blood pressure (p less than 0.015). In the diabetic subjects, there was an inverse relationship between the RR variation and resting work product (r = 0.47, n = 25, p less than 0.005). In response to exercise, the percent increase in cardiac output at matched percent maximum oxygen uptake was greatest in the NOR, D-NOR, and D-ABN groups, respectively (analysis of variance, p less than 0.01). In the diabetic subjects, there was a significant relationship between the RR variation and the maximum percent change in cardiac output (r = 0.41, n = 25, p less than 0.02). Compared with the NOR group, the maximum increase in work product was impaired in diabetic subjects (p less than 0.002) and not different between the D-NOR and D-ABN groups. CONCLUSIONS: The increase in resting work product and the poor cardiac output responses to exercise in the D-ABN group are due to a decrease in cardiac parasympathetic nervous system activity and can be suggested by an abnormal RR variation. This index of parasympathetic nervous system activity can help the physician identify that subset of diabetic patients that may need special consideration when exercise training is prescribed.

Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria.

The primary results of a three-year prospective, double-blind, placebo-controlled trial in non-insulin-dependent diabetic (NIDDM) patients show that an anti-hypertensive regimen, which includes the ACE inhibitor enalapril, preserves renal function to a greater extent than therapy with antihypertensive agents excluding ACE inhibitors (J Am Soc Nephrol 3:335, 1992). The influence of baseline urinary albumin excretion on the renal protective effects of enalapril treatment in these subjects was the objective of this further analysis. Adequate data were available in 121 patients of the 165 hypertensive NIDDM individuals studied [baseline glomerular filtration rate (GFR) 30 to 100 ml/min/1.73 m2]. Twenty-four hour urinary excretion of albumin (UAE), protein, urea nitrogen, creatinine and isotopically determined GFR were measured at baseline and six month intervals. Glycemic control and blood pressure regulation were assessed every three months. The rate of loss of GFR was significantly greater in patients with overt proteinuria at baseline (UAE > 300 mg/24 hr) as compared to patients with baseline sub-clinical proteinuria (UAE < or = 300 mg/24 hr). Antihypertensive treatment with enalapril preserved GFR significantly better (P < 0.01) in the patients with sub-clinical proteinuria at baseline (UAE < or = 300 mg/24 hr) than other antihypertensive treatments which excluded the ACE inhibitor. Furthermore, only 7% of the enalapril-treated group progressed to clinical albuminuria compared to 21% of control treated patients. Although the enalapril-treated group had a lower mean blood pressure during the maintenance period, no correlation between blood pressure (systolic, diastolic or mean arterial) and rate of change of GFR was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group.

The purpose of this clinical study was to determine the efficacy, tolerability, and impact on quality of life of domperidone--a specific peripherally acting dopamine antagonist--in the management of symptoms of gastroparesis, a common and potentially debilitating condition in patients with diabetes mellitus. In the first phase of this multicenter, two-phase withdrawal study, 287 diabetic patients with symptoms of gastroparesis of at least 6 months' duration received domperidone 20 mg QID in a single-masked fashion for 4 weeks. Efficacy was evaluated using a four-point rating scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) for each of the following symptoms: nausea, abdominal distention/bloating, early satiety, vomiting, and abdominal pain. At the end of the first phase, patients with sufficient improvement in their total symptom score (a score < or = 6 and a decrease in score of > or = 5 units from the baseline [selection] visit) were eligible for the 4-week, randomized, placebo-controlled, double-masked withdrawal phase of the study. The impact of domperidone on quality of life was determined using the Medical Outcomes Study Short Form-36 (SF-36). Of 269 patients with data from the single-masked phase, 208 (77%) qualified for entry into the double-masked phase based on a statistically significant improvement in total symptom score, from a mean score of 10.32 at baseline (initial visit) to 3.79 after 4 weeks of single-masked domperidone therapy. During the double-masked phase, patients in the placebo group had significantly greater deterioration in total symptom scores compared with patients in the domperidone group (mean changes of 1.84 and 0.85, respectively). Similar significant differences in favor of domperidone were seen in the secondary efficacy variables (i.e., patients' diary scores and global assessments of symptoms). The tolerability profile of domperidone was similar to that of placebo. Patients who responded to domperidone experienced significant improvements in quality of life, as indicated by the SF-36 physical and mental component summary scores. During the double-masked phase, patients who were randomized to placebo experienced a significant deterioration in the physical component summary score compared with patients in the domperidone group. The results of this study suggest that domperidone 20 mg QID provides significant improvement in the upper gastrointestinal symptoms of diabetic gastroparesis and is well tolerated in patients with this condition.

The effect of an aldose reductase inhibitor on cardiovascular performance in patients with diabetes mellitus.

Because some aldose reductase inhibitor studies have demonstrated clinical improvement in scored neurological signs and symptoms of diabetic neuropathy, a prospective study of the effect on cardiovascular performance of sorbinil 250 mg/day for 12 months was conducted on patients with diabetic autonomic neuropathy who were free of atherosclerotic coronary artery disease and/or cardiomyopathy. After 1 year of treatment, the study group (n = 14) demonstrated significant improvement in both the resting cardiac output (P = 0.02), and the maximal cardiac output (P = 0.03). This observation suggests that the use of an aldose reductase inhibitor may be useful in treating suboptimal cardiovascular performance in patients with diabetic cardiac autonomic neuropathy.

Components of variance for vibratory and thermal threshold testing in normal and diabetic subjects.

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficients of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Myasthenia gravis in conjunction with Graves' disease: a diagnostic challenge.

OBJECTIVE: To describe an association between Graves' disease and myasthenia gravis and discuss the clinical features and laboratory tests that may help distinguish these two diseases. METHODS: The clinical, laboratory, and electrophysiologic findings in a patient with Graves' disease and myasthenia gravis are presented. RESULTS: A 28-year-old African American man was admitted to the University of Louisville Hospital with generalized muscle weakness, exophthalmos, diplopia, weight loss, and mild dysphagia. The diagnosis of Graves' disease with ophthalmologic involvement was suspected clinically and confirmed by an undetectable thyrotropin level (<0.03 mIU/mL), high total thyroxine (20.5 mg/dL), and increased homogeneous 123I thyroid uptake. Because of the generalized muscle weakness and mild dysphagia, assessment was done by a neurology team, and severe thyrotoxic myopathy was diagnosed. He was treated with 131I and b-adrenergic blocking agents and scheduled for follow-up as an outpatient. Two weeks later, the patient presented in acute respiratory failure. The neurology team was reconsulted because of suspected myasthenic crisis. Anti-acetylcholine receptor antibodies were undetectable in the serum, and computed tomography of the chest showed no thymic enlargement. Repetitive nerve stimulation testing, however, showed findings consistent with an abnormality of the neuromuscular junction. The patient responded dramatically to an anticholinesterase agent and corticosteroids. CONCLUSION: The overlapping clinical features may cause diagnostic confusion when myasthenia gravis and Graves' disease coexist, and numerous tests may be needed to distinguish these two conditions, which have differing treatments and prognoses.

Hypoglycemia due to a pharmacy dispensing error.

Drug dispensing error should be considered as a cause of hypoglycemia when the usual initial workup is unrevealing, as in the case described.

Cardiovascular autonomic dysfunction: diagnosis and prognosis.

The symptoms of cardiovascular autonomic dysfunction may be subtle and occur late in the course of diabetes. They include abnormal exercise-induced cardiovascular performance, postural hypotension, and cardiac denervation syndrome. Autonomic nervous system testing involves an evaluation of the responses of complex reflex pathways. Some of the most commonly used and validated cardiovascular autonomic tests are RR-variation, the Valsalva manoeuvre, and postural testing. Sinus arrhythmia during breathing is termed RR-variation. In diabetic patients with autonomic neuropathy the magnitude of the RR-variation is decreased. Abnormal exercise-induced cardiovascular performance has been observed in diabetic subjects with abnormal RR-variation due to autonomic neuropathy. The Valsalva manoeuvre consists of forced expiration against a standardized resistance for a specified period of time. The reflex bradycardia that follows the Valsalva period in normal subjects is lacking in diabetic patients with clinical evidence of autonomic neuropathy. Postural hypotension in diabetics may be due to neuropathy or to a variety of secondary causes. An algorithm is presented to facilitate assessment of diabetic patients with postural symptoms. Treatment of postural hypotension should be directed primarily to the correction of secondary causes, in the absence of which the symptoms can be controlled by mechanical measures, plasma volume expansion, and vasoconstriction. Cardiac denervation syndrome may result in denervation supersensitivity and afferent (pain) nerve dysfunction. The RR-variation is a sensitive indicator of impairment of cardiac autonomic innervation and is a simple method for identifying asymptomatic patients at risk for painless ischaemia. Formal cardiovascular stress testing may be prudent before initiating an exercise programme in such individuals.