Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis.

The Joint British Diabetes Societies guidelines for the management of diabetic ketoacidosis (these do not cover Hyperosmolar Hyperglycaemic Syndrome) are available in full at: (i) http://www.diabetes.org.uk/About_us/Our_Views/Care_recommendations/The-Management-of-Diabetic-Ketoacidosis-in-Adults; (ii) http://www.diabetes.nhs.uk/publications_and_resources/reports_and_guidance; (iii) http://www.diabetologists-abcd.org.uk/JBDS_DKA_Management.pdf. This article summarizes the main changes from previous guidelines and discusses the rationale for the new recommendations. The key points are: Monitoring of the response to treatment (i) The method of choice for monitoring the response to treatment is bedside measurement of capillary blood ketones using a ketone meter. (ii) If blood ketone measurement is not available, venous pH and bicarbonate should be used in conjunction with bedside blood glucose monitoring to assess treatment response. (iii) Venous blood should be used rather than arterial (unless respiratory problems dictate otherwise) in blood gas analysers. (iv) Intermittent laboratory confirmation of pH, bicarbonate and electrolytes only. Insulin administration (i) Insulin should be infused intravenously at a weight-based fixed rate until the ketosis has resolved. (ii) When the blood glucose falls below 14 mmol/l, 10% glucose should be added to allow the fixed-rate insulin to be continued. (iii) If already taking, long-acting insulin analogues such as insulin glargine (Lantus(®), Sanofi Aventis, Guildford, Surry, UK) or insulin detemir (Levemir(®), Novo Nordisk, Crawley, West Sussex, UK.) should be continued in usual doses. Delivery of care (i) The diabetes specialist team should be involved as soon as possible. (ii) Patients should be nursed in areas where staff are experienced in the management of ketoacidosis.

Stabilizing effect of exenatide in a patient with C-peptide-negative diabetes mellitus.

BACKGROUND: Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon-like peptide 1 (GLP-1), it helps restore underlying pathophysiological abnormalities. CASE REPORT: We report the successful use of exenatide, combined with insulin, in a 66-year-old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose-lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C-peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA(1c)) 10.2%, body mass index (BMI) 31.5 kg/m(2)] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA(1c) had fallen by 2% with an 8-kg weight loss and 10-unit reduction in daily insulin dose. Quality of life dramatically improved. C-peptide remains undetectable. CONCLUSIONS: This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.

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.

Lack of relationship between sympathetic nervous system activity, measured by two circulating markers, and blood pressure in diabetic and nondiabetic subjects.

Two putative sympathetic nervous system (SNS) markers, noradrenaline and neuropeptide Y (NPY) were related to 24-h ambulatory blood pressure (BP) in 59 normotensive subjects, 34 non-insulin-dependent diabetics, and 25 controls. Plasma NPY levels were not significantly different between the two groups [non-insulin-dependent (NIDDM) diabetes mellitus 4.33 (3.25-5.78), controls 5.68 (3.39-6.97) p=0.26] as were those of noradrenaline (1.51+/-0.69 versus 1.78+/-0.55; p=0.053). There were correlations, controlled for age and obesity, of plasma NPY with clinic and night time diastolic BP in the control group only (r=0.49 [p=0.013] and r=0.48 [p=0.023] respectively). No similar correlation was found in the NIDDM group, or between plasma noradrenaline and blood pressure in either group. No correlation was found between plasma insulin and NPY or noradrenaline levels. There is a weak independent relationship between NPY and blood pressure in normotensive nondiabetics but not in NIDDM subjects. We found no evidence for the hypothesis that insulin modulates blood pressure through activity of the SNS.

Diabetic renal disease: microalbuminuria, implications and intervention.

Diabetic nephropathy is the leading cause of end-stage renal failure in the developed world. Proteinuria ("macroalbuminuria" > 200 micrograms/min; or 300 mg/24 h) heralds a phase of established renal pathology with inexorable decline to end-stage renal disease, although its progression can be delayed by antihypertensive medication, in particular the angiotensin-converting enzyme inhibitors (ACEI). Control of blood pressure is vital; even if in the normal range, it is usually raised compared with that in nondiabetic control groups. Reducing blood pressure can lower the rate of decline of the glomerular filtration rate by 90%. Before established proteinuria there is a "microalbuminuric" (20-20 micrograms/min, or 30-300 mg/24 h) phase, and during this time preventive intervention may be effective. In so-called "normotensive" microalbuminuric subjects antihypertensive medications, in particular the ACEI, significantly reduce the progression to macroalbuminuria. Control of glycemia is important; recent evidence has shown that it is particularly important before the development of microalbuminuria; thereafter the role of glycemic control is not clear. Some researchers have suggested that protein restriction may be helpful, but more data are required. For the moment, improved glycemic control in the normoalbuminuric diabetic subjects and treatment with ACEI after the onset of microalbuminuria would seem appropriate in light of knowledge today. Furthermore, any level of hypertension is totally unacceptable and should be treated aggressively; the ACEI seem to be becoming the "agents of choice."

Evaluation of management of Graves' disease in District General Hospital: achievement of consensus guidelines.

The management of Graves' disease in a District General Hospital was audited. A local care pathway was designed, which was inclusive of diagnosis, treatment and follow-up. This was then compared with consensus guidelines proposed by the Royal College of Physicians. Forty-six patients with Graves' disease attended the endocrine clinic. The diagnosis was based on clinical and biochemical features of autoimmune thyrotoxicosis, a raised thyroid-stimulating hormone receptor antibody (TRAB) and a diffusely increased uptake in thyroid technetium scan. They were treated for 18 months with antithyroid medications, which was subsequently discontinued provided satisfactory euthyroid state was achieved. Patients were followed up to assess remission and relapse status. The audit suggested that care pathway was in keeping with the guidelines. A few excess TRAB tests were requested. The relapse rate was 42% in our series and one-third of them (33%) chose to continue medical therapy.

The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy.

We report two cases in which osteomalacia developed in patients on tenofovir-containing highly active antiretroviral therapy (HAART) in the context of Fanconi syndrome with hypophosphataemia. Bone pain was the presenting feature and myopathy followed in one case. Disability was reversed with withdrawal of the drug and with mineral supplementation. The cases highlight the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir. A possible association with incipient acute renal failure, particularly during nonsteroidal anti-inflammatory drug (NSAID) use, needs further investigation.

Suppression of post-glucose hyperinsulinaemia does not affect blood pressure in either normotensive or hypertensive subjects.

1. Hyperinsulinaemia and insulin resistance are thought to be intimately involved in the development of hypertension, but controversy remains as to whether hyperinsulinaemia is a consequence or a cause of hypertension per se, and whether it plays a role in the short-term regulation of blood pressure. 2. We studied six hypertensive patients [blood pressure 161(9)/101(2) mmHg] and seven normotensive control subjects [blood pressure 122(6)/76(4) mmHg], (P < 0.005) using two oral glucose tolerance tests of 3 h duration. In one of these tests the endogenous insulin response was inhibited with subcutaneous octreotide. 3. After placebo, hypertensive patients had slightly but significantly higher blood glucose levels than controls (P < 0.0001), but comparable insulin concentrations (P > 0.5). Plasma noradrenaline levels were consistently lower in the hypertensive group (P < 0.001). Blood pressure did not change in either group during the 3 h after glucose ingestion. 4. Octreotide completely abolished the immediate insulin response to glucose in all subjects (both P < 0.0001) and caused a delayed and significantly increased glycaemic response in both groups (P < 0.0001). There were no significant differences in plasma glucose responses between groups: however, after octreotide, the hypertensive subjects had a greater insulin suppression than the controls (P < 0.02). Octreotide suppressed noradrenaline levels in the normotensive group (P < 0.001); they were also suppressed in the hypertensive group, but just failed to reach significance (P = 0.056). Throughout the study the hypertensive group's noradrenaline levels remained generally lower than those in the control group (P < 0.0001). 5. In this study there were no differences between hypertensive and normotensive subjects in fasting or post-glucose insulin levels, nor any significant change in blood pressure in either group when post-glucose hyperinsulinaemia was suppressed. This argues against insulin playing a direct role in the short-term regulation of blood pressure.

Therapeutic options in diabetic renal disease and hypertension.

Diabetic renal disease must now be regarded as a condition that can be prevented in a proportion of cases. Improved glycaemic control in the early stages of type I disease, and blood pressure control at all stages is essential in all patients with diabetes.

The diabetic patient with hypertension.

Hypertension and diabetes co-exist more commonly than would be expected from their individual prevalences. Elevated blood pressure is most commonly due to coexisting essential hypertension, or diabetic renal disease. Early stages of diabetic renal disease can be identified by detecting microalbuminuria. Standard measures of blood pressure are not necessarily raised, but 24-hour ambulatory measures frequently identify a loss of nocturnal drop in blood pressure. Treating hypertension aggressively is important in slowing the inexorable decline in glomerular filtration rate. In diabetes there appears to be no 'J'-shaped relationship between blood pressure and cardiovascular events, thus removing any concern about attaining low blood pressures as long as the patient is asymptomatic. Morbidity and mortality in these patients is usually associated with cardiovascular events, and it is important to assess the effect of drugs on left ventricular hypertrophy and metabolic parameters. Many drugs are effective at lowering blood pressure, but angiotensin-converting enzyme inhibitors may have an additional renoprotective action. alpha-Adrenergic antagonists may improve lipid profiles and calcium antagonists are probably lipid neutral, making these drugs useful alternatives. Dihydropyridine calcium antagonists (eg, nifedipine) may augment protein-uria, and hence non-dihydropyridine calcium antagonists (eg, verapamil, diltiazem) would be preferred. beta-Blockers and thiazide diuretics have the disadvantage of causing a deterioration in glycaemic and lipid profiles, but can be useful on occasions.

Acute intermittent porphyria treated by testosterone implant.

The hereditary disorder acute intermittent porphyria is potentially fatal. Many more females present with active disease than males and some have attacks related to their menstrual cycle and pregnancy. We present a female patient who was diagnosed while pregnant at 19 years. She subsequently developed life-threatening attacks pre-menstrually at 24 years; these were associated with weight loss. Initial treatment was with high calorie feeding via a naso-gastric tube, followed by a gastrostomy. Subsequent gonadotrophin suppression with intranasal luteinizing hormone-releasing hormone analogue (buserelin) thrice daily met with limited success. We implanted 100 mg of testosterone subcutaneously in November 1989. The buserelin was discontinued in January 1990 and menses returned 3 months later. There have been no serious attacks since then. Repeat implantation was performed at 6 monthly intervals until her present pregnancy. Baseline biochemical parameters have remained high and unaltered despite treatment although the testosterone has clearly had a marked clinical benefit, without side effects.

Endocrine emergencies.

Diabetic and endocrine emergencies are traditionally treated by the acute medical admitting team or accident and emergency department staff. Most will see diabetic emergencies on a regular basis, as they are common and both type 1 and type 2 disease are increasing in prevalence. Diabetic emergencies are usually easily treated and the patients discharged. However, it is vital not to become complacent as these disorders can lead to death. It is particularly important to follow local guidance and to involve the diabetes team both during and after each episode. Recently it has become clear that about 30% of patients admitted with acute coronary syndrome (including infarction) have either diabetes or "stress hyperglycaemia"; evidence suggests that these patients should be treated not only as a cardiac emergency but also as a diabetic one. Thus, every patient with acute coronary syndrome or acute myocardial infarction needs diabetes to be excluded. The other endocrine emergencies are less common, but in some ways more important simply because of their rarity. A high level of suspicion is often required to make a diagnosis, although some, such as myxoedema coma, are usually obvious. Treatment must be started before the diagnosis can be confirmed. Guidance on making the diagnosis and initiating treatment should be made available on the local NHS intranet for non-endocrinologists to access; and where possible expert advice made available by telephone. The basic management steps in the common diabetic and endocrine emergencies are outlined; this is not a complete list, but rather an insight for those involved in non-selected emergency admissions.

Insulin-induced attenuation of noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent.

1. We studied the mechanism of insulin-mediated attenuation of noradrenaline-induced vasoconstriction in mesenteric resistance arteries (approximately 210 microns diameter) from 10-week-old male Wistar rats (n = 10; weight 321 +/- 11 g). Exposure to physiological concentrations of insulin (50 m-units/l) significantly blunted the contractile response to noradrenaline over the concentration range 3 x 10(-6) to 3 x 10(-5) mol/l (16 vessels; 13.1 +/- 4.3% reduction in maximum tension at 3 x 10(-5) mol/l noradrenaline; P < 0.01 versus no insulin). 2. This effect of insulin was prevented by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10(-4) mol/l; 16 vessels; 3.3 +/- 9.1% reduction in maximum tension; P = 0.8 versus no insulin). There was no evidence of fatigue in four noradrenaline dose-response curves for 16 control vessels in the absence of insulin and NG-nitro-L-arginine methyl ester (P = 0.8; first versus second dose-response curve). With L-arginine present in the incubation medium, insulin again attenuated the noradrenaline-induced vasoconstriction (10.7 +/- 3.2% reduction in tension; P = 0.02 versus L-arginine and no insulin; P = not significant versus insulin and no L-arginine). 3. Endothelium-dependent relaxation was initially confirmed in all vessels by demonstrating normal acetylcholine- (5.4 x 10(-7) to 1.1 x 10(-4) mol/l) induced vasodilatation in vessels preconstricted with noradrenaline (6 x 10(-6) mol/l) in the absence of NG-nitro-L-arginine methyl ester, L-arginine and insulin (P = not significant between the different groups of vessels). 4. We conclude that insulin attenuates noradrenaline-induced vasoconstriction in resistance arteries by stimulation of nitric oxide release. Abnormal insulin-stimulated nitric oxide release could be of relevance in the pathogenesis of hypertension and diabetic microvascular disease.

Impaired insulin-induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistant obese Zucker rats.

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (approximately 220 microns diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 +/- 3%, P < 0.05; 500 m-units/l: 13 +/- 3%, P < 0.02; 5000 m-units/l: 13 +/- 2%, P < 0.02). 3. Vessels from obese rats failed to show any such response to insulin (2 +/- 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of L-arginine (3 mmol/l). 4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 x 10(-8)-10(-4) mol/l) (obese: 64.1 +/- 3.7% relaxation; lean: 77.3 +/- 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 +/- 10.6% relaxation; lean: 79.1 +/- 9.7% relaxation; not significant). 5. Systolic blood pressure was not significantly different in lean (126 +/- 8 mmHg) and obese (127 +/- 7 mmHg) rats at the time of study (not significant). 6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.

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)

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.

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.

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.