High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease.

AIMS/HYPOTHESIS: To assess thiamine status by analysis of plasma, erythrocytes and urine in type 1 and type 2 diabetic patients and links to markers of vascular dysfunction. METHODS: Diabetic patients (26 type 1 and 48 type 2) with and without microalbuminuria and 20 normal healthy control volunteers were recruited. Erythrocyte activity of transketolase, the concentrations of thiamine and related phosphorylated metabolites in plasma, erythrocytes and urine, and markers of metabolic control and vascular dysfunction were determined. RESULTS: Plasma thiamine concentration was decreased 76% in type 1 diabetic patients and 75% in type 2 diabetic patients: normal volunteers 64.1 (95% CI 58.5-69.7) nmol/l, type 1 diabetes 15.3 (95% CI 11.5-19.1) nmol/l, p < 0.001, and type 2 diabetes 16.3 (95% CI 13.0-9.6) nmol/l, p < 0.001. Renal clearance of thiamine was increased 24-fold in type 1 diabetic patients and 16-fold in type 2 diabetic patients. Plasma thiamine concentration correlated negatively with renal clearance of thiamine (r = -0.531, p < 0.001) and fractional excretion of thiamine (r = -0.616, p < 0.001). Erythrocyte transketolase activity correlated negatively with urinary albumin excretion (r = -0.232, p < 0.05). Thiamine transporter protein contents of erythrocyte membranes of type 1 and type 2 diabetic patients were increased. Plasma thiamine concentration and urinary excretion of thiamine correlated negatively with soluble vascular adhesion molecule-1 (r = -0.246, p < 0.05, and -0.311, p < 0.01, respectively). CONCLUSIONS/INTERPRETATION: Low plasma thiamine concentration is prevalent in patients with type 1 and type 2 diabetes, associated with increased thiamine clearance. The conventional assessment of thiamine status was masked by increased thiamine transporter content of erythrocytes.

Hand vein responses to noradrenaline in normotensive patients with insulin-dependent diabetes mellitus and microalbuminuria: effects of alpha-adrenoceptor blockade with doxazosin.

Nephropathy commonly develops in patients with insulin-dependent (type 1) diabetes. Administration of an antihypertensive agent to type 1 diabetes patients with microalbuminuria, the first clinically detectable stage of nephropathy, can help slow renal deterioration. It is postulated that the exaggerated vasoconstrictor response to noradrenaline seen in these patients may be relevant in the development of microalbuminuria. This open, non-comparative pilot study was designed to investigate the effects of the alpha-adrenoceptor antagonist doxazosin on noradrenaline-induced hand vein vasoconstriction and on albumin excretion in 14 normotensive type 1 diabetes patients with microalbuminuria. After a three-week placebo run-in period, patients received doxazosin (1, 2, and then 4 mg once-daily, at two-week intervals) for six weeks, followed by a two-week placebo washout period. Vasoconstrictor responses to noradrenaline were measured in dorsal hand veins at the end of each two-week period. Hand vein vasoconstrictor responses to noradrenaline decreased significantly, compared with placebo, at 4 mg/day doxazosin (p = 0.006). The mean albumin excretion rate was lower than baseline at all doses of doxazosin, but changes did not reach statistical significance. Doxazosin was generally well-tolerated; four patients (29%) reported mild-to-moderate treatment-related adverse events. This study indicates that alpha 1-adrenoceptor blockade can blunt the exaggerated vascular reactivity to noradrenaline in normotensive type 1 diabetes patients with microalbuminuria, and supports further research into a potential role for doxazosin in preventing the development of diabetic nephropathy.

Development of a questionnaire identifying factors responsible for successful self-management of insulin-treated diabetes.

Education and psychosocial factors are widely believed to contribute to diabetes control. However, there is no systematic way of measuring or recording these factors, or for transfer of information to future care-givers. We developed a 41-question questionnaire to measure the skills and contributory factors to self-management in diabetes, and examined the relationship between these factors and glycaemic control. The questionnaire was assessed for construct validity, and for content validity by independent diabetes health professionals, and easily completed by 128 insulin-treated diabetic patients (mean age 42 +/- 13 (SD) yr, diabetes duration 17 +/- 9 yr, HbA, 10.5 +/- 1.8%). Principle Components Factor analysis revealed nine factors explaining 63% of variance (Eigen values 1.2-5.8). Five of these were significantly related to HbA1. These were: practical self-management skills, p < 0.001; emotional adjustment, p < 0.002; perceived goals, p < 0.01; perceived self-efficacy, p < 0.005; and costs-benefit analysis, p < 0.01. Multiple regression revealed that these five predictor variables (factors) explain 21% of variance in HbA1, combined r = 0.46. The questionnaire also distinguished between patients with good and poor control (HbA1 8.2 vs 13.4%, p < 0.001), p for differences in question responses, 0.014-0.001. Four factors (lifestyle, influence of other people, diet concerns, and weight concerns) were unrelated to HbA1. In conclusion, we have developed a single, patient-completed questionnaire of high content and construct validity, which identifies alterable factors (in contrast to fixed demographic variables) which may be specifically targeted in individual patients on the one hand to improve glycaemic control and, on the other, to enable more satisfactory adjustment to life with diabetes. It may be used in day-to-day practice to identify patient needs, and their barriers to effective self-management, and to transfer this information to future care-givers.

Vascular reactivity to noradrenaline and neuropeptide Y in the streptozotocin-induced diabetic rat.

The study aimed to assess vascular reactivity to noradrenaline with and without neuropeptide Y in diabetic rats, and to determine whether any abnormality could be attributed to insulin deficiency or to hyperglycaemia per se. The authors compared non-diabetic rats (n = 9) and rats with streptozotocin-induced diabetes that were either untreated (n = 10), or treated with insulin (n = 9) or food restriction (n = 8) to restore near-normoglycaemia. After 4 weeks of diabetes, contractile responses to noradrenaline (0.24-48 mumol L-1), without and with neuropeptide Y (0.1 mumol L-1), were assessed using an isometric myograph in two mesenteric arteries from each rat. Vessels from untreated diabetic rats were significantly more reactive to noradrenaline than the control vessels when tested without (P < 0.0001) but not with (P = NS) neuropeptide Y. Diabetic rats rendered nearly normoglycaemic through food restriction showed dose-response curves that were very similar to the untreated diabetic group (P = NS). By contrast, insulin-treated diabetic vessels showed reduced sensitivity to noradrenaline, with and without neuropeptide Y, compared with both the diet-restricted and untreated vessels (both P < 0.0001). The authors conclude that vascular sensitivity to noradrenaline, without or with neuropeptide Y, is reduced over a wide dose range in vessels taken from rats treated in vivo with insulin; furthermore, vessels taken from diabetic rats not treated with insulin (hypoinsulinaemic) tended to be more reactive than either control vessels or those taken from the insulin-treated rats. The latter group of rats were probably hyperinsulinaemic for much of the time; the results may therefore support the hypothesis that insulin acts as a vasodilator.

Effects of quinagolide (CV 205-502), a selective D2-agonist, on vascular reactivity in patients with a prolactin-secreting adenoma.

BACKGROUND: Quinagolide (CV 205 502) is a dopamine D2-receptor agonist which has proved effective in the treatment of prolactinomas, reducing both serum PRL and tumour size. Some of its D2-receptor effects are mediated via alpha-adrenoceptors, which have a major influence on the control of vascular tone. The aim of this study was to examine the influence of quinagolide on in-vivo dorsal hand vein vascular responses to noradrenaline in patients with a prolactinoma. DESIGN AND PATIENTS: Seven female patients with prolactinomas (age 37 (28-46) years), intolerant of bromocriptine, were studied before and after 3 months treatment with quinagolide (0.75-1.5 mg/day). Patients were otherwise disease free, were taking no other medication, and had been on no other medication (including bromocriptine) for at least 3 months prior to enrollment into the study. MEASUREMENTS: Vascular responses to locally infused noradrenaline were measured in dorsal hand veins using an established technique. PRL, oestradiol, FSH, LH, blood pressure and body mass index were also measured before and after 3 months treatment. RESULTS: Quinagolide significantly reduced PRL in all 7 patients (1795 (696-4680) (mean (range)) vs 488 (290-868) mU/l, P = 0.001), with no effect on the other parameters, including mean arterial pressure (88 (2) vs 87 (4) mmHg, P = 0.6). Vascular reactivity to noradrenaline was significantly increased after 3 months therapy: log10 dose estimated to cause 50% vasoconstriction (ED50) 1.37 (0.12) vs 0.85 (0.12) ng/min (P = 0.003; a lower ED50 indicates less noradrenaline is required to constrict the vein by 50%). CONCLUSIONS: Vasoconstrictor responses to noradrenaline were increased in all patients after 3 months treatment with quinagolide. Peripheral veins carry alpha-adrenoceptors analogous to those of systemic resistance vessels. If this increased vasoconstrictor response in patients with prolactinomas was occurring in hypophyseal vessels, it would lead to reduced tumour blood supply. Quinagolide may therefore reduce tumour blood flow, which may be one factor responsible for its effectiveness in these patients.

Selective enhancement of alpha 2-adrenoceptor-mediated vasoconstriction in insulin-dependent diabetic patients with microalbuminuria.

1. Microalbuminuria, the earliest clinical marker of microvascular disease, is an important predictor of early death in insulin-dependent diabetes, and abnormal vascular reactivity may contribute to microvascular disease. We have previously found that vasoconstrictive responses to noradrenaline are exaggerated in insulin-dependent diabetic patients with microalbuminuria as compared with both normoalbuminuric insulin-dependent diabetic patients and non-diabetic control subjects. 2. To determine whether this is due to increased sensitivity at alpha 1- or alpha 2-adrenergic receptors, we compared vascular responses to the alpha 1-adrenergic agonist phenylephrine and the alpha 2-adrenergic agonist clonidine. 3. We studied 15 insulin-dependent diabetic patients with microalbuminuria, 15 insulin-dependent diabetic patients with normal urinary albumin excretion and 14 non-diabetic subjects. Vascular constrictive responses were measured in dorsal hand veins. 4. No difference in vasoreactivity to phenylephrine was demonstrated between any of the three groups. However, enhanced vascular responsitivity to clonidine at infusion rates of 16-2048 ng/min (analysis of variance, P < 0.001) was found in insulin-dependent diabetic patients with microalbuminuria as compared with both non-diabetic control subjects and normoalbuminuric insulin-dependent diabetic patients. There were no significant differences between the dose-response curves of the diabetic group with normal urinary albumin excretion and the non-diabetic group. 5. Vasoconstriction mediated by alpha 2-adrenergic receptors is therefore enhanced in normotensive insulin-dependent diabetic patients with microalbuminuria. If also present at the level of the peripheral resistance arterioles or the efferent glomerular arterioles, this could lead to systemic and intraglomerular hypertension, factors which may contribute to the development of diabetic nephropathy.

Asymptomatic peripheral nerve dysfunction and vascular reactivity in IDDM patients with and without microalbuminuria.

Abnormal vascular reactivity has been implicated in the aetiology of diabetic microvascular disease and we have previously demonstrated enhanced contractility of hand veins to noradrenaline in insulin-dependent diabetic (IDDM) patients with microalbuminuria. We have now assessed the possible contribution of subclinical peripheral nerve dysfunction to exaggerated vascular reactivity in micro-albuminuric patients. Twenty-five IDDM patients (15 with microalbuminuria), none of whom had symptomatic neuropathy, and 10 control subjects were studied. Vasoconstrictor responses were measured in dorsal hand veins using noradrenaline and phenylephrine. Conduction in median, peroneal and sural nerves was assessed using electrophysiology, and autonomic function using standard cardiovascular reflex tests. The noradrenaline dose causing 50% vasoconstriction was significantly lower in the microalbuminuric diabetic subjects compared with normoalbuminuric (3.6(1.7) mean (SEM) ng/min vs 20.1(6.0) ng/min, p = 0.0002) and non-diabetic subjects (35.1(5.0) ng/min; p < 0.0001). However, reactivity to phenylephrine did not differ between the groups. Median nerve motor conduction velocity was significantly slower in microalbuminuric (48.4(1.4) m/s) than in normoalbuminuric (52.7(1.2) m/s, p = 0.04) and non-diabetic subjects (56.7(0.9) m/s, p = 0.0001). In the diabetic group overall, there was a strongly positive linear correlation between vascular response to noradrenaline and conduction velocity in both the median nerve (r = 0.62, p = 0.0009) and peroneal nerve (r = 0.53, p = 0.006). There was no correlation between phenylephrine-induced responses and motor conduction velocity in either nerve, nor were indices of autonomic function correlated with vascular reactivity to either agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Smoking attenuates the vasoconstrictor response to noradrenaline in type I diabetic patients and normal subjects: possible relevance to diabetic nephropathy.

Exaggerated vascular reactivity has been implicated in the pathogenesis of diabetic nephropathy, and several studies suggest that smoking accelerates its progression. We therefore assessed the vasoactive effects of smoking by comparing noradrenaline-induced vasoconstriction in dorsal hand-veins between smoking and non-smoking groups of Type I diabetic patients with and without microalbuminuria and in non-diabetic subjects. Smokers had a significantly higher dose causing 50% vasoconstriction (reduced sensitivity to noradrenaline) in all three groups: microalbuminuric diabetic smokers vs. nonsmokers, 20.2(4.6) (SEM) vs. 6.6(2.3) ng min-1 (P = 0.02); normoalbuminuric, 76.9(29.4) vs. 22.8(9.1) ng min-1 (P = 0.03); non-diabetic subjects, 97.8(30.0) vs. 38.0(12.8) ng min-1 (P = 0.01). Both microalbuminuric diabetic groups showed significantly greater sensitivity to noradrenaline-induced vasoconstriction than the other smoking and non-smoking groups, respectively (P < 0.01). Vasoconstrictors responses to noradrenaline are attenuated in smokers, possibly due to alpha-adrenoceptor down-regulation. Smoking could increase urinary albumin losses and accelerate renal damage through catecholamine surges which raise systemic and, perhaps, intraglomerular blood pressure. This hypothesis deserves further consideration.

Hypercalcaemia due to parathyroid hormone-related protein: long-term circulating levels may not reflect tumour activity.

Parathyroid hormone-related protein is responsible for the hypercalcaemia caused by many tumours. Measurement of parathyroid hormone-related protein is becoming more accessible with the introduction of commercial assays. We report a case of hypercalcaemia of malignancy secondary to parathyroid hormone-related protein in a woman with renal carcinoma. The parathyroid hormone-related protein was assayed using a new immunoradiometric assay. We demonstrated an initial fall in parathyroid hormone-related protein and calcium levels after surgery and a rise in both before clinical relapse. However, the clinical relapse was itself associated with a fall in serum parathyroid hormone-related protein, nephrogenous cAMP and calcium, suggesting that the tumour had stopped producing parathyroid hormone-related protein or perhaps that post-translational processing had occurred as the tumour advanced. The tumour was investigated for parathyroid hormone-related protein mRNA content using reverse transcriptase polymerase chain reaction, both at diagnosis in surgically removed material, and using post-mortem specimens. The level of parathyroid hormone-related protein mRNA, while present, was much reduced in the recurrent tumour suggesting that active parathyroid hormone-related protein production fell substantially as the tumour advanced. This case suggests that, although demonstration of parathyroid hormone-related protein in hypercalcaemia is useful for diagnosis, tumoral secretion of this product may alter.

Parathyroid carcinoma presenting with a brown tumour of the mandible in a young man.

A 27-year-old man presented to his dentist with a swelling in his lower jaw. Histology revealed this to be a brown tumour associated with primary hyperparathyroidism and severe but asymptomatic hypercalcaemia. A large parathyroid adenoma was removed and the serum calcium fell to normal. Hypercalcaemia recurred and re-exploration of the neck revealed parathyroid metastases in cervical lymph nodes. A modified radical neck dissection was performed and he has remained normocalcaemic on Vitamin D analogues for 2 years. Bone disease of the mandible is a very rare presentation of primary hyperparathyroidism. The diagnosis of parathyroid malignancy is often difficult histologically, and the optimum treatment is uncertain.

Exaggerated sensitivity to NE-induced vasoconstriction in IDDM patients with microalbuminuria. Possible etiology and diagnostic implications.

Increased urinary albumin excretion rate (AER) in the microalbuminuric phase of diabetic nephropathy has been attributed to intraglomerular hypertension. This could be caused by constriction of efferent glomerular arterioles, which carry alpha-adrenoceptors. We tested the hypothesis that insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria are hypersensitive to vasoconstriction induced by norepinephrine (NE). We studied 15 IDDM patients with microalbuminuria (AER 32-295 mg/24 h), 13 IDDM patients with normal AER (5-24 mg/24 h), and 9 nondiabetic subjects (AER 8-22 mg/24 h). All were normotensive. NE-induced vasoconstriction was measured in dorsal hand veins, which carry alpha-receptors similar to those of glomerular efferent arterioles. Vein diameter was measured with a linear displacement probe during a stepped NE infusion (1-32 ng/min) into the vein, and venoconstriction was expressed as a percentage of the maximum passively distended venous diameter. Microalbuminuric IDDM patients exhibited significantly greater vasoconstriction (P less than 0.005) at all NE infusion rates than both other groups. The NE infusion rate producing 50% of maximal venoconstriction (ED50) in the microalbuminuric IDDM group (median 1.1 ng/min, range 0.2-25.2 ng/min) was significantly less than in both the normoalbuminuric IDDM group (median 12.5 ng/min, range 4.9-40.5 ng/min, P = 0.00007) and the nondiabetic group (median 17.7 ng/min, range 5.9-42.2 ng/min, P = 0.0003). Dose-response curves and ED50 did not differ significantly between normalbuminuric IDDM and nondiabetic groups. IDDM patients with microalbuminuria are hypersensitive to NE-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Human insulin and awareness of acute hypoglycaemic symptoms in insulin-dependent diabetes.

Some insulin-dependent diabetic patients who have clear symptoms of hypoglycaemia during animal insulin treatment have reported loss of these symptoms when human insulin preparations are introduced. A survey of Mersey Region, UK, identified eleven patients whose awareness of hypoglycaemia was lost after introduction of human insulin but returned with animal insulin treatment; seven took part in the study. Acute hypoglycaemia was induced in these patients on two occasions by intravenous infusion of porcine or human soluble insulin (2.5 mU.kg-1, min-1) in random order. There was no significant difference between porcine and soluble insulin in the plasma glucose profile; mean (SEM) plasma glucose fell from 7.1 (0.4) mmol/l to a nadir of 1.5 (0.1) mmol/l with porcine insulin and from 7.1 (0.5) mmol/l to 1.6 (0.2) mmol/l with human insulin. An acute autonomic reaction occurred in all seven patients, at a similar plasma glucose concentration (1.9 [0.1] mmol/l with porcine insulin; 2.0 [0.2] mmol/l with human insulin). There were no significant differences in the frequency of symptoms or signs of hypoglycaemia between the two insulin species, nor any consistent differences in plasma glucagon, cortisol, growth hormone, adrenaline, or noradrenaline responses to hypoglycaemia. Symptomatic and hormonal responses to acute hypoglycaemia induced by porcine and human soluble insulins therefore seem to be almost indistinguishable, even in patients carefully selected for their apparent loss of hypoglycaemia awareness with human insulin.

How accurate is the smoking history in newly diagnosed diabetic patients?

A smoking history was obtained from 94 consecutive newly diagnosed diabetic patients referred to an adult diabetic clinic. The smoking load was measured using urinary cotinine/creatinine ratios (COT/Cr). Fifty-six patients (60%) claimed to be non-smokers, but COT/Cr suggested active smoking in five of these. The patients who admitted to smoking were given standardised anti-smoking advice. At 3 months, 32 smoking patients were reviewed and 21 (66%) claimed to have reduced or stopped smoking. However, the median COT/Cr in the 32 patients showed no significant reduction (11.15 vs. 9.30 micrograms/mg). Urinary COT/Cr indicated that 6 patients had stopped smoking (median COT/Cr 6.98 fell to 0.97 micrograms/mg), but several patients had a marked rise in COT/Cr, demonstrating that their smoking habit had increased considerably. Therefore the smoking history obtained from new diabetic patients can be very misleading. An objective measure of smoking habits in the initial assessment and follow-up of diabetes may be worthwhile. Anti-smoking counselling at diagnosis of diabetes may persuade some smokers to stop.