促红细胞生成素对大鼠脑缺血后神经元凋亡及热休克蛋白27和血管内皮生长因子表达的影响

目的探讨促红细胞生成素对大鼠脑缺血的保护作用。方法采用线栓法阻断大鼠一侧大脑中动脉制作大鼠局灶性缺血再灌注模型。促红细胞预处理组于缺血开始前2h予腹腔注射促红细胞生成素3000u/kg;缺血再灌注组和假手术组在手术前2h予腹腔注射等量生理盐水。再灌注24h后进行细胞凋亡检测及热休克蛋白27和血管内皮生长因子免疫组织化学染色。结果再灌注24h后,缺血再灌注组可见较多的POD阳性细胞(67.48±11.17个/高倍视野),促红细胞生成素预处理组缺血区阳性细胞数目减少(45.25±4.72个/高倍视野,P<0.01),假手术组偶见个别阳性细胞,正常组未见凋亡细胞;与缺血再灌注组(25.60±4.42个/高倍视野)相比,促红细胞生成素预处理组热休克蛋白27表达增加(67.56±13.84个/高倍视野,P<0.01);促红细胞生成素预处理组血管内皮生长因子表达较缺血再灌注组亦增加(74.90±11.64个/高倍视野比40.14±7.50个/高倍视野,P<0.01))。结论促红细胞生成素预处理后可抑制缺血损伤后缺血侧皮层细胞凋亡,其机制可能是通过上调热休克蛋白27和血管内皮生长因子基因表达而实现的。     

A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy

Aims/hypothesis. Experimental studies have shown that abnormalities of nerve microcirculation are important factors in the pathogenesis of diabetic neuropathy but there have been few clinical studies. We have applied microlightguide spectrophotometry to measure intravascular oxygen saturation (HbO₂%) and blood flow in human sural nerve. Methods. We studied ten patients with mild-moderate sensory motor diabetic neuropathy, nine patients without neuropathy and nine control subjects. We took 300 measurements of oxygen saturation under direct visual control through a 1.9 mm rigid endoscope over three regions of the nerve. Spectrophotometric measurements of nerve fluorescence were taken after an intravenous injection of sodium fluorescein and the rate of increase in nerve fluorescence (rise time) was used as an indicator of nerve blood flow. Results. Nerve oxygen saturation was reduced in patients with neuropathy compared with control subjects (67.1 ± 2.2 % vs 76.7 ± 2.1 %, p = 0.006). Fluorescein rise time was prolonged in patients with neuropathy compared with the control group (48.5 ± 7.0 s vs 14.0 ± 3.1 s, p = 0.001) suggesting impaired nerve blood flow. There was a correlation between rise time, nerve oxygen saturation, glycaemic control and sural nerve sensory conduction velocity (p < 0.01). Conclusion/interpretation. The combination of microlight-guide spectrophotometry and micro-endoscopy provides a valuable minimally invasive technique for clinical investigation of nerve microcirculation. We have shown reduced nerve oxygenation and impaired blood flow in diabetic neuropathy and these findings strongly support a central role of microvascular disease in the pathogenesis of diabetic neuropathy. [Diabetologia (1999) 42: 737–742] Received: 8 October 1998 and in revised form: 7 January 1999     

Exaggerated vasopressin secretion and attenuated osmoregulated thirst in human survivors of hyperosmolar coma

Aims/hypothesis. To test the hypothesis that subnormal thirst sensation could contribute to the development of the hypernatraemia characteristic of hyperosmolar coma, we studied osmoregulation in survivors of hyperosmolar coma. Methods. Eight survivors of hyperosmolar coma, eight control subjects with Type II (non-insulin-dependent) diabetes mellitus and eight healthy control subjects underwent water deprivation during which measurements of thirst, plasma osmolality and vasopressin were taken. Results. Water deprivation caused greater peak plasma osmolality in the hyperosmolar coma group (301.7 ± 2.7 mmol/kg) than in Type II diabetic (294.3 ± 3.2 mmol/kg, p < 0.01) or control group (296.9 ± 3.0 mmol/kg, p < 0.01) and a greater increase in plasma vasopressin concentration (hyperosmolar coma, 5.8 ± 1.3 pmol/l, Type II diabetes, 1.8 ± 1.3 pmol/l, p < 0.001, control subjects, 2.2 ± 1.8 pmol/l, p < 0.001). Thirst ratings were lower following water deprivation in the hyperosmolar coma group (3.5 ± 0.8 cm) than in Type II diabetes (7.7 ± 1.6 cm, p < 0.001) or control subjects (7.4 ± 1.3 cm, p < 0.001), and the hyperosmolar group patients drank less in 30 min following water deprivation (401 ± 105 ml) than Type II diabetic (856 ± 218 ml, p < 0.001) or control subjects (789 ± 213 ml, p < 0.001). Conclusion/interpretation. Survivors of hyperosmolar coma have subnormal osmoregulated thirst and fluid intake, which might contribute to the hypernatraemic dehydration typical of the condition. [Diabetologia (1999) 42: 534–538] Received: 22 October 1998 and in final revised form: 10 December 1998     

Factors Related to the Electric Taste Threshold in Type 1 Diabetic Patients

To specify the factors related to taste function in Type 1 diabetes mellitus, 50 diabetic out-patients and 50 control subjects paired for age and sex were screened for taste disorders. None of them consumed significant amounts of alcohol, smoked, or had disease or took drugs capable of altering taste. Taste was studied with electrogustometry, retinopathy was detected by fluorescein angiography, nephropathy by measurement of albuminuria and microalbuminuria, peripheral neuropathy by electroneurography and electromyography, and autonomic neuropathy by cardiovascular function tests. The electrogustometric threshold was, on average, significantly higher in the diabetic group (133 ± 30 μA) than in the control group (29 ± 9 μA; p < 0.001). Electric hypogeusia (electrogustometric threshold > 100 μA) was found among 54% of the diabetic patients vs 2% of the control subjects (p < 0.001). In the diabetic group, the electrogustometric threshold was associated with complications of diabetes, especially with peripheral neuropathy (210 ± 24 vs 90 ± 22 μA; p < 0.001) and microalbuminuria (185 ± 25 vs 86 ± 21 μA; p < 0.01). It was correlated with age (r = 0.37; p < 0.01) and duration of diabetes (r = 0.52; p < 0.001) but not with HbA_1c (r = ?0.04). Using multivariate analysis, duration of diabetes and peripheral neuropathy had the strongest association with taste impairment. These results support previous findings, suggesting that taste impairment is a degenerative complication of diabetes mellitus.     

The platelet functions in patients with ankylosing spondylitis: Anti-TNF-α therapy decreases the mean platelet volume and platelet mass

The present study was designed to investigate the interaction between platelet indices (mean platelet volume (MPV), platelet count (PLC) and platelet mass (PLM)), inflammatory markers and disease activity in ankylosing spondylitis (AS) subjects. The effects of anti-TNF-α therapy and conventional treatment on platelet indices were also compared. We studied 68 patients with AS (group I, 46 men, age: 36.4 ± 6.9 years) and as control group 34 age and sex-matched healty subjects. All patients received conventional therapy (CT) at the beginning (Group I). The patients were reevaluated after 3 months according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Group II consisted of 35 subjects who responded to the CT and continued to take the same therapy for 3 months additionally. Group III consisted of 33 subjects who had a high disease activity score (BASDAI > 4) after 3 months and were accepted refractory to the CT therapy. In Group III the treatment was switched to infliximab and continued for 3 months at the standard intravenous dose. Significantly higher baseline MPV, PLC and PLM was reported as compared to controls decreased by therapy (9.12 ± 1.20 vs. 8.35 ± 0.94 fl, p < 0.001, 340 ± 69 vs. 251 ± 56 (×10³/ µL) p < 0.0001, 3096 ± 736 vs. 2110 ± 384; p < 0.0001, respectively). In the same way, they were substantially lowered by both treatments in group II and group III. PLC and PLM were positively correlated with WBC and ESR (r : 0.44; p < 0.0001, r : 0.41; p = 0.001, r : 0.52; p < 0.0001, r : 0.41; p = 0.001), respectively) in AS patients. Additionally, MPV and PLM were positively correlated with BASDAI score (r : 0.41; p < 0.001, r = 0.29; p < 0.001 respectively). We have found that increased platelet activity reduced by therapy in AS patients. Additionally, it was correlated with inflammatory markers and disease activity. According to these results, it can be suggested that both anti-TNF-α and conventional therapy might contribute to a decrease in the risk of cardiovascular morbidity and mortality in AS patients.     

Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial

To test the efficacy of surgical treatment of non-infected neuropathic foot ulcers compared to conventional non-surgical management, a group of diabetic outpatients attending our diabetic foot clinic were studied. All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were randomized into two groups. Group A received conservative treatment, consisting of relief of weight-bearing, regular dressings; group B underwent surgical excision, eventual debridement or removal of bone segments underlying the lesion and surgical closure. Healing rate, healing time, prevalence of infection, relapse during a 6-month period following intervention and subjective discomfort were assessed. Twenty-four ulcers in 21 patients were treated in group A (17 Type 2 DM/3 Type 1 DM, age 63.24 ± 13.46 yr, duration of diabetes 18.2 ± 8.41 yr, HbA_1c 9.5 ± 3.8%) and 22 ulcers in 21 patients in group B (19 Type 2 DM/2 Type 1 DM, age 65.53 ± 9.87 yr, duration of diabetes 16.84 ± 10.61 yr; HbA_1c 8.9 ± 2.2%). Healing rate was lower (79.2% = 19/24 ulcers) in group A than in group B (95.5% = 21/22 ulcers; p < 0.05), and healing time was longer (128.9 ± 86.60 days vs 46.73 ± 38.94 days; p < 0.001). Infective complications occurred significantly more often in group A patients (3/24, 12.5% vs 1/22, 4.5%; p < 0.05), as did relapses of ulcerations (8 vs 3; p < 0.01). There were only two minor perioperative complications in group B patients. Patients reported a higher degree of satisfaction in group B (p < 0.01) as well as lower discomfort (p < 0.05) and restrictions (p < 0.05). Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time, complications, and relapses, and can be safely performed in an outpatient setting. © 1998 John Wiley & Sons, Ltd.     

Evidence for Impaired Pancreatic Beta Cell Function in South African Indians with Impaired Glucose Tolerance

In a prospective study of South African Indians with impaired glucose tolerance (IGT), the serum insulin response during a 75 g oral glucose tolerance test (OGTT) was examined in 128 subjects who were classified as IGT 1 year previously (year 0) and in 60 matched control subjects. Based on the results at year 1, study subjects were divided into three groups, using World Health Organization criteria for glucose tolerance: IGT (n = 47), diabetes (n = 41), and transient IGT (normal glucose tolerance) (n = 40). When compared with the control group, despite higher plasma glucose concentrations, the IGT group showed similar fasting insulin, but lower 30-min insulin response (57.4 ± 1.9 mUI^?1 vs 86.5 ± 1.8, p<0.001) and lower 30-min insulin/glucose ratio (7.4 ± 5.2 vs 13.3 ± 8.7, p < 0.001). The insulinogenic index was lower in the IGT group than in the control group at 30, 60, 90, and 120 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively). The 2-h insulin response was higher in the IGT group (106.7 ± 1.9 mUI^?1 vs 59.2 ± 1.9, p < 0.01). The IGT group displayed a delayed pattern of insulin response with maximum levels only at 2-h. Insulin area was similar in the two groups. In the transient IGT group, despite similar plasma glucose levels, the insulin responses at 0, 15, 30, and 60 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively) were lower than in the control group; the 30-min insulin/glucose ratio (7.1 ± 5.1 vs 13.3 ± 8.7, p < 0.001) and 60-min insulinogenic index (46.9 ± 86.3 vs 123.4 ± 206.3, p < 0.001) were also lower in the transient IGT group. This study has shown that IGT in South African Indians is characterized by a diminished early phase insulin response and delayed (2-h) hyperinsulinaemia during OGTT. Such findings would suggest that in this population group impaired early beta cell function is an important pathophysiological abnormality underlying IGT.     

Electronegative low density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control

Summary We evaluated the effect of improving glycaemic control with intensive insulin therapy on LDL susceptibility to oxidation, electronegative LDL proportion, and LDL subfraction phenotype in a group of 25 patients with short-duration insulin-dependent diabetes mellitus (IDDM); 25 matched healthy control subjects were also studied. LDL susceptibility to oxidation was measured by continuous monitoring of conjugated diene formation. Electronegative LDL was isolated by anion exchange chromatography, and quantified as percentage of total LDL. Six LDL subfractions were isolated by density gradient ultracentrifugation and phenotype A or B classified as the quotient (LDL1-LDL3)/(LDL4-LDL6). Compared to the control group, IDDM subjects with poor glycaemic control showed higher electronegative LDL (19.03 ± 10.09 vs 9.59 ± 2.98 %, p < 0.001), similar LDL subfraction phenotype and lower susceptibility to oxidation (lag phase 45.6 ± 8.8 vs 41.2 ± 4.7 min, p < 0.05). After three months of intensive insulin therapy, HbA_{1 c} decreased from 10.88 ± 2.43 to 5.69 ± 1.54 % (p < 0.001), and electronegative LDL to 13.84 ± 5.15 % (p < 0.05). No changes in LDL susceptibility to oxidation or LDL subfraction phenotype were observed. Electronegative LDL appeared significantly correlated to HbA_{1 c} and fructosamine (p < 0.01 and p < 0.001) only in poorly controlled IDDM patients. These findings suggest that high electronegative LDL in IDDM subjects is related to the degree of glycaemic control, and could therefore be due to LDL glycation rather than to LDL oxidation or changes in LDL subfraction phenotype. [Diabetologia (1996) 39: 1469–1476] Received: 20 December 1995 and in final revised form: 19 June 1996     

Anxiety disorders are associated with increased plasma adrenomedullin level and left ventricular hypertrophy in patients with hypertension

Objective: To investigate the association between anxiety disorders and left ventricular hypertrophy in patients with essential hypertension.

Methods: Left ventricular structure and function were assessed with echocardiography in 56 patients with essential hypertension and anxiety disorder (study group) and in 56 patients with hypertension only (control group). Serum adrenomedullin levels were also measured in these patients.

Results: There was no statistically significant difference in the left ventricular ejection fraction between the study and the control group (54.21?±?88.81% versus 56.01?±?7.85%, p?>?0.05). The left ventricular mass index (LVMI) in study group was higher than in control group (137.05?±?9.42 versus 123.57?±?7.01?g/m², p?=?0.001). The plasma levels of adrenomedullin in study group was higher than in control group (25.97?±?5.48 versus 18.32?±?6.97?ng/L, p?=?0.001). Levels of plasma adrenomedullin were positively correlated with LVMI in the study (r?=?0.734, p?r?=?0.592, p?Conclusion: Anxiety disorders are associated with elevated plasma adrenomedullin levels and increased left ventricular hypertrophy in patients with essential hypertension. The clinical significance of these changes requires further investigation.     

Plasma levels of some blood coagulation parameters in Nigerian homozygous sickle cell patients (HbSS) in steady state

The plasma levels of some blood coagulation parameters; prothrombin time, (PT), partial thromboplastin time with kaolin (PTTK), thrombin clotting time, (TCT), fibrinogen and factor X assay were determined in 50 Nigerian homozygous (HbSS) patients and 50 HbAA healthy individuals for the purpose of assessing their baseline values and susceptibility of patients with sickle cell disease (SCD) to hyper coagulability. Standard procedures were used for all variables. The mean age of the study participants was 21.7 ± 5.0 years. The mean PT of 13.7 ± 1.4s in HbSS patients was found to be significantly longer than the mean PT value of 12.9 ± 1.0 in HbAA control subjects (p < 0.001). The mean PTTK values of 46.0 ± 9.6s in HbSS patients was also found to be significantly higher than the 41.0 ± 3.7s recorded among the control subjects (p < 0.001). The mean TCT of 6.4 ± 0.8s in HbSS patients was however found to be significantly lower than the mean value of 10.6 ± 0.8s obtained in the control group. Fibrinogen level (4.1 ± 2.1 g/l) in HbSS patients and 2.8 ± 0.9 g/l in HbAA controls was also found to be significantly different (p < 0.001). Factor X level in the sickle cell patients, (64.6 ± 14.9%) was equally found to be significantly lower than that of the apparently healthy HbAA control individuals (95.2 ± 7.2%) (p < 0.001).     

Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus

Aims/hypothesis. To determine causes of weight gain during insulin therapy with and without metformin in Type II (non-insulin-dependent) diabetes mellitus. Methods. Twenty-six patients with Type II diabetes (body mass index 28 ± 1 kg/m²) were treated with insulin alone (n = 13) or insulin and with metformin (n = 13). Components of energy balance (basal metabolic rate, energy intake, glucosuria) were measured at 0 and 12 months. Results. Glycaemic control improved similarly in patients using (HbA_{1 c} 10.5 ± 0.3 vs 7.6 ± 0.2 %, p < 0.001) and not using (10.2 ± 0.3 vs 7.8 ± 0.3 %, p < 0.001) metformin. The metformin group required 47 % less insulin than the group not using metformin (p < 0.001). Body weight increased by 3.8 ± 0.8 and 7.5 ± 1.6 kg (p < 0.05), respectively. Basal metabolic rate and glucosuria were similar at 0 and 12 months in both groups but the metformin group decreased energy intake by 1.12 ± 0.46 MJ/day, whereas it remained unchanged in the other group (0.15 ± 0.42 MJ/day). Changes in body weight and glycaemia were statistically significant independent determinants of basal metabolic rate. Their change in opposite directions explained why basal metabolic rate remained unchanged. Conclusion/interpretation. Improved glycaemia promotes weight gain by decreasing both basal metabolic rate and glucosuria. Use of metformin decreases weight gain by reducing energy intake and is therefore a useful adjunct to insulin therapy in patients with Type II diabetes. [Diabetologia (1999) 42: 406–412] Received: 3 September 1998 and in final revised form: 4 December 1998     

A Single Bolus of a Long-acting Erythropoietin Analogue Darbepoetin Alfa in Patients with Acute Myocardial Infarction: A Randomized Feasibility and Safety Study

Aims: Besides stimulating hematopoiesis, erythropoietin (EPO) protects against experimental ischemic injury in the heart. The present study evaluated the safety and tolerability of EPO treatment in non-anemic patients with acute myocardial infarction (MI). Methods and Results: In this single-center, investigator-initiated, prospective study, patients with a first acute MI were randomized to one bolus of 300 μg darbepoetin alfa or no additional medication before primary coronary intervention. Twenty-two patients (mean age 59 ± 2 years) were included. In the darbepoetin group, serum EPO-levels increased to 130–270 times that of controls, within the first 24 h. After darbepoetin administration, only small and non-significant changes in hematocrit levels were observed, while endothelial progenitor cells (EPCs, CD34+/CD45−) were increased at 72 h (2.8 vs. 1.0 cells/μl in control group, p < 0.01). No adverse events were recorded during the 30-day follow-up. After 4 months, left ventricular ejection fraction was similar in the two groups (52 ± 3% in darbepoetin vs. 48 ± 5% in control group, p = NS). Conclusions: Intravenous single high-dose darbepoetin alfa in acute MI is both safe and well tolerated. Darbepoetin treatment after MI stimulates EPCs mobilization. The results of this first pilot study support a larger scale clinical trial to establish efficacy of EPO administration in patients after acute MI.     

Chronic Erythropoietin Treatment Limits Infarct-size in the Myocardium in Vitro

Summary It has been well established that erythropoietin (EPO) can limit myocardial ischemia/reperfusion injury in a variety of acute settings. However, despite EPO being used chronically to treat anemia the infarct limiting effects of long term treatment (chronic) have never been fully investigated. In this study we examined the effects of a 3 week treatment of EPO (5,000 IU/Kg) in male Sprague Dawley rats in limiting myocardial infarction after 35 min ischemia and 2 h reperfusion in an in vitro isolated heart perfusion model. Treating the animals ‘once a week’ failed to limit infarct size significantly compared to a saline control (54.1% ± 3.5 v 52.3% ± 4.4), whereas a ‘3 times a week’ regime succeeded in significantly reducing infarct size (36.2% ± 3.2 v 52.3% ± 4.4, p < 0.05). To demonstrate that the effect was not due to improved oxygen supply caused by a raised hematocrit level, we also administered EPO 24 h prior to ischemia/reperfusion. This treatment again reduced infarct size compared to a saline control (39.9% ± 4.4 v 58.4% ± 5.0, p < 0.05). To examine the mechanism of protection we used the PI3K inhibitor wortmannin and the nitric oxide synthase inhibitor L-NAME to try to abrogate EPO mediated protection. Where wortmannin failed to block the effects of EPO (31.7% ± 6.0 v 36.2% ± 3.2), L-NAME did abrogate protection (51.6% ± 5.6 v 36.2% ± 3.2, p < 0.05). We demonstrate that chronic EPO treatment limits infarct size and that it does so in a nitric oxide dependent manner.     

Role of islet amyloid polypeptide secretion in insulin-resistant humans

Summary Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hypertensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034±0.004 min^–1 in control subjects, 0.058±0.008 in the obese and 0.050±0.008 in the hypertensive patients) was significantly different (p<0.01) in each group compared with that of insulin (0.14±0.03 min^–1) and similar to that of C-peptide (0.061±0.007 min^–1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4±0.4 min^–1/(μU/ml); p<0.0005) and the obese (2.7±0.5; p<0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1±1.3). Marked insulin hypersecretion was found in the hypertensive (57.6±5.2 nmol·l^–1 in 180 min; p<0.001) and obese (60.8±10.1; p<0.003) patients in comparison with control subjects (32.4±3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1±16.6 pmol/l in 180 min; p<0.02) and obese (78.6±13.1; p<0.005) patients than in control subjects (40.5±6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group. We conclude that, due to a significantly slower clearance of islet amyloid polypeptide in comparison to insulin, reliance on molar ratios between these two peptides might be misleading in the interpretation of islet amyloid polypeptide secretion especially under non-steady-state conditions. [Diabetologia (1994) 37: 188–194] Received: 10 June 1993 and in revised form: 20 August 1993     

The Splanchnic Circulation and Postural Hypotension in Diabetic Autonomic Neuropathy

Postural hypotension results from sympathetic failure to cause superior peripheral vasoconstriction. The importance of the splanchnic circulation was studied by measuring mesenteric artery blood flow with duplex Doppler scanning. Nine normal and 9 Type 1 diabetic controls were compared to 8 Type 1 patients with autonomic neuropathy whose pressure fell 40–113 mmHg (range) on tilting. Measurements were made supine and after vertical tilt, fasting without insulin and after a 550 kcal meal. Superior mesenteric artery diameter decreased on tilting in normal controls but not in diabetic control or neuropathy groups (supine vs tilted: controls. 6.3 ± 0.9 to 5 ± 0.9 mm, p = 0.004, diabetic controls: 6.0 ± 0.6 to 6.0 ± 1.0 mm, and neuropathy group: 6.4 ± 0.9 to 5.6 ± 0.9 mm), but proportional blood flow changes were similar in all subjects (controls: 407 ± 154 to 255 ± 67 ml min^?1 (-31%, p = 0.03), diabetic controls: 379 ± 140 to 306 ± 149 ml min^?1 (-8%, p = 0.28), neuropathy group: 639 ± 371 to 435 ± 142 ml min^?1 (-23%, p = 0.10). Postprandially supine superior mesenteric artery flow increased in all subjects but this did not affect the degree of systolic blood pressure drop on tilting (fasting vs postprandial blood flow: controls: 407 ± 154 to 775 ± 400 ml min^?1 (p = 0.04), diabetic controls: 379 ± 140 to 691 ± 262 ml min^?1 (p = 0.01), neuropathy group: 639 ± 371 to 943 ± 468 ml min^?1 (p < 0.06)). The similarity of superior mesenteric artery responses to tilting in the three groups, and the lack of exacerbation of postural hypotension in the presence of postprandial hyperaemia indicates that control of splanchnic blood flow is less important in the aetiology of diabetic autonomic postural hypotension than previously thought.     

Influence of Ambulatory Inhaled Treatment with Different Devices on the Duration of Acute Asthma Findings in Children

Background. Efficacy of bronchodilator treatment in children with asthma depends on the proper use of inhalation devices. The aim of this study was to compare the efficacy of inhaled bronchodilator treatment with a spacer and a nebulizer in children with acute asthma findings. Methods. Fifty-eight children with acute asthma findings who received ambulatory inhaled bronchodilator treatment with a nebulizer and 39 with a spacer were enrolled in the study. Duration of asthma, inhaled steroid treatment and the number of exacerbations during the previous year were recorded. Duration of current acute symptoms, exacerbation severity score and duration of respiratory findings after initiation of treatment were also recorded. Results. Children in both groups were similar in age (76.5 ± 30.3 months using a nebulizer vs 83.1 ± 25.1 in spacer group, p = 0.26). Duration after diagnosis of asthma, initiation of inhaled steroid treatment and exacerbation symptoms were similar between groups (p = 0.15, 0.76 and 0.93, respectively). Exacerbation severity score in the nebulizer group was not significantly different from the spacer group (2.6 ± 0.7 vs 2.8 ± 0.7 respectively, p = 0.19). Number of exacerbations in the previous year was not different (2.0 ± 1.2 in the nebulizer group vs 1.6 ± 0.9 in the spacer group, p = 0.08). Duration of acute asthma findings after initiation of inhaled bronchodilator treatment was similar between the two groups (6.5 ± 2.9 vs 7.2 ± 4.6 p = 0.34). Conclusion. Nebulizers and spacers have similar influence on the duration of acute asthma findings in children when used in ambulatory home bronchodilator treatment.     

Left Ventricular Hypertrophy in Non-insulin-dependent Diabetic Patients With and Without Diabetic Nephropathy

The aim of our cross-sectional case–control study was to evaluate putative mechanisms of the increased cardiac morbidity and mortality in NIDDM patients with or without diabetic nephropathy. Fifty-one NIDDM patients with diabetic nephropathy (38 males, age 61 ± 8 years, group 1), 53 NIDDM patients with normoalbuminuria (42 males, 61 ± 7 years, group 2), and 22 non-diabetic control subjects (15 males, 58 ± 8 years, group 3) were investigated. Previous antihypertensive treatment was withdrawn 2 weeks before the study. Left ventricular mass index (LVMI) and systolic function were determined by echocardiography. LVMI was elevated, mean ± SE, in group 1: 157 ± 6 g m⁻², and in group 2: 139 ± 7 g m⁻², as compared with group 3: 95 ± 5 g m⁻² (p < 0.001, for both), and in group 1 as compared with group 2 (p = 0.05). The prevalence of left ventricular hypertrophy (LVH) (LVMI > 131 g m⁻² in men and > 100 g m⁻² in women) was much higher in group 1: 75 % (95 % CI, 60–86), and group 2: 51 % (95 % CI, 37–65), as compared with group 3: 9 % (95 % CI, 1–29) (p < 0.001, for both), and in group 1 as compared with group 2 (p < 0.01). Shortening fraction of the left ventricle, % ± SE, was relatively reduced in group 1: 32.5 ± 1.1 %, and group 2: 33.4 ± 1.1 %, as compared with group 3: 41.2 ± 1.2 % (p < 0.01, for both). In a subgroup of 26 normoalbuminuric normotensive NIDDM patients, LVMI was higher than in 14 normotensive non-diabetic control subjects: 137 ± 10 g m⁻² vs 96 ± 7 g m⁻², respectively (p < 0.005). The prevalence of LVH was 42 % (95 % CI, 23–63) and 14 % (95 % CI, 2–43) (p = 0.07) in these two groups, respectively. In conclusion, normotensive and hypertensive NIDDM patients with and without diabetic nephropathy frequently suffer from LVH and relatively reduced systolic function which may constitute independent risk factors for fatal and non-fatal cardiac events. © 1997 John Wiley & Sons, Ltd.     

Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial

Aims/hypothesis: The management of charcot neuroarthropathy, a severe disabling condition in diabetic patients with peripheral neuropathy, is currently inadequate with no specific pharmacological treatment available. We undertook a double-blind randomised controlled trial to study the effect of pamidronate, a bisphosphonate, in the management of acute diabetic Charcot neuroarthropathy. Methods: Altogether 39 diabetic patients with active Charcot neuroarthropathy from four centres in England were randomised in a double-blind placebo-controlled trial. Patients received a single infusion of 90 mg of pamidronate or placebo (saline). Foot temperatures, symptoms and markers of bone turnover (bone specific alkaline phosphatase and deoxypyridinoline crosslinks) were measured over the 12 months, in 10 visits. All patients also had standard treatment of the Charcot foot. Results: Mean age of the study group (59 % Type II (non-insulin-dependent) diabetes mellitus) was 56.3 ± 10.2 years. The mean temperature difference between active and control groups was 3.6 ± 1.7 °C and 3.3 ± 1.4 °C, respectively. There was a fall in temperature of the affected foot in both groups after 2 weeks with a further reduction in temperature in the active group at 4 weeks (active and placebo vs baseline; p = 0.001; p = 0.01, respectively), but no difference was seen between groups. An improvement in symptoms was seen in the active group compared with the placebo group (p < 0.001). Reduction in bone turnover (means ± SEM) was greater in the active than in the control group. Urinary deoxypyridinoline in the pamidronate treated group fell to 4.4 ± 0.4 nmol/mmol creatinine at 4 weeks compared with 7.1 ± 1.0 in the placebo group (p = 0.01) and bone-specific alkaline phosphatase fell to 14.1 ± 1.2 u/l compared with 18.6 ± 1.6 u/l after 4 weeks, respectively (p = 0.03). Conclusion/interpretation: The bisphosphonate, pamidronate, given as a single dose leads to a reduction in bone turnover, symptoms and disease activity in diabetic patients with active Charcot neuroarthropathy. [Diabetologia (2001) 44: 2032–2037] Received: 20 April 2001 and in revised form: 26 June 2001     

Time–action Profile of Inhaled Insulin

We compared the pharmacodynamics of insulin after inhalation of 99 U microcrystalline solid insulin and subcutaneous injection of 10 U regular insulin and intravenous injection of 5 U regular insulin. The time–action profiles of the three insulin administrations were studied in 11 healthy volunteers using the euglycaemic glucose clamp technique. The insulins were administered to each volunteer on three separate occasions in random order. Onset of action, assessed as glucose infusion rate, after insulin inhalation was substantially more rapid than after subcutaneous injection and half-maximal action was reached earlier (31 ± 17 vs 54 ± 12 min; p < 0.001). Maximal metabolic response was reached earlier after insulin inhalation in comparison to subcutaneous injection (108 ± 49 vs 147 ± 53 min; p < 0.001). The maximal glucose infusion rate after inhalation of insulin was lower than after subcutaneous insulin injection (6.2 ± 2.4 vs 9.1 ± 2.5 mg kg⁻¹ min⁻¹; p < 0.001). The glucose infusion rates in the first 60 min after inhalation were significantly greater than after insulin injection (area under the glucose infusion rate curve: 0.23 ± 0.12 vs 0.13 ± 0.08 g kg⁻¹ 60 min⁻¹; p < 0.001). However, the total metabolic effect after inhalation was significantly lower than after insulin injection (1.44 ± 0.68 vs 1.90 ± 0.47 g kg⁻¹ 360 min⁻¹; p < 0.001). Relative effectiveness of inhaled insulin calculated with regard to the data from the intravenous insulin application was 9.5 ± 4.1 % and of the subcutaneous insulin application was 7.6 ± 2.9 %. With its rapid onset of action, inhaled insulin might have potential for clinical use. © 1997 by John Wiley & Sons, Ltd.     

Prevention of Type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland Study design and 1-year interim report on the feasibility of the lifestyle intervention programme

Aims/hypothesis. The aim of the Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying Type II (non-insulin-dependent) diabetes mellitus in subjects with impaired glucose tolerance, to evaluate the effects of the intervention programme on cardiovascular risk factors and to assess the determinants for the progression to diabetes in persons with impaired glucose tolerance. Methods. A total of 523 overweight subjects with impaired glucose tolerance ascertained by two oral glucose tolerance tests were randomised to either a control or intervention group. The control subjects received general information at the start of the trial about the lifestyle changes necessary to prevent diabetes and about annual follow-up visits. The intervention subjects had seven sessions with a nutritionist during the first year and a visit every 3 months thereafter aimed at reducing weight, the intake of saturated fat and increasing the intake of dietary fibre. Intervention subjects were also guided individually to increase their physical activity. Results. During the first year, weight loss in the first 212 study subjects was 4.7 ± 5.5 vs 0.9 ± 4.1 kg in the intervention and control group, respectively (p < 0.001). The plasma glucose concentrations (fasting: 5.9 ± 0.7 vs 6.4 ± 0.8 mmol/l, p < 0.001; and 2-h 7.8 ± 1.8 vs 8.5 ± 2.3 mmol/l, p < 0.05) were significantly lower in the intervention group after the first year of intervention. Favourable changes were also found in blood pressure, serum lipids and anthropometric indices in the intervention group. Conclusion/interpretation. The interim results show the efficacy and feasibility of the lifestyle intervention programme. [Diabetologia (1999) 42: 793–801] Received: 7 December 1998 and in revised form: 23 February 1999