Increased capillary permeability to albumin and diabetic neuropathy

An increase in the capillary permeability to albumin (CPA) has been reported in diabetic patients. We observed this frequently with a non-invasive isotopic test derived from the Landis method, using 99mTc-albumin and measuring residual radioactivity externally after removal of forearm venous compression. Evidence of the independent effects of hypertension and microangiopathy on CPA has already been found. The present work was designed to investigate CPA using the same test on diabetic patients without retinopathy and clinical proteinuria. Some of these patients had objective clinical distal and symmetrical polyneuropathy. Neuropathy was clearly present in 10 of the 11 patients with an abnormal test unexplained by causes other than diabetes and in only one of the 17 patients with a normal test. The most frequent abnormality affected the late radioactivity disappearance curve, which probably reflects an impaired lymphatic wash-out of interstitial albumin. These results strongly suggest a link between peripheral neuropathy and diabetic functional microangiopathy. An elevated blood flow secondary to sympathetic nerve failure may induce an increase in CPA and a saturation of lymphatic pumping which could also be deficient due to impaired lymphatic innervation.     

Relationship between esophageal dysfunction and neuropathy in diabetic patients

OBJECTIVE: Few studies have compared esophageal dysfunction with diabetic neuropathy, and their relationship is not yet clear. The aim of this study was to investigate the relationship between esophageal function and diabetic neuropathy. METHODS: A total of 59 patients with type 2 diabetes were studied. Long-term ambulatory esophageal pH and motility monitoring were performed. The motor nerve conduction velocity (MCV) and coefficient of variation of R-R intervals (CVRR) were also examined. RESULTS: The 59 patients were classified into four groups: group 1 consisted of patients with both diabetic autonomic neuropathy (DAN) and diabetic motor neuropathy (DMN), group 2 had DMN alone, group 3 had DAN alone, and group 4 had neither DAN nor DMN. In pH monitoring, differences were observed among the four groups in DeMeester score, total number of acid reflux episodes, and % time pH < 4 (p < 0.05). A correlation was observed between % time pH < 4 and MCV; however, no correlation with CVRR was observed. In motility monitoring, differences were observed among the four groups in amplitude of peristaltic waves (p < 0.001), rising velocity of peristaltic waves (p < 0.01), and percentage of effective peristalsis (p < 0.01). A correlation was observed between esophageal motility and MCV; however, no correlation with CVRR was observed. CONCLUSIONS: Esophageal motility disorder and abnormal acid reflux were related to DMN in diabetic patients. A significant correlation was found between esophageal dysfunction and MCV. However, no significant correlation was found between esophageal dysfunction and CVRR.     

牛磺酸对实验性糖尿病神经病变保护作用的机制探讨

目的研究牛磺酸对糖尿病大鼠神经病变的保护作用,并探讨其机制.方法对链脲菌素诱导的糖尿病大鼠模型,予以牛磺酸(0.5%饮水)治疗12周,观察其对血浆6-keto-PGF1.TXB3、坐骨神经糖化终产物、神经传导速度及神经结构的影响.结果牛磺酸可降低血浆TXB3及坐骨神经中糖化终产物,提高血浆6-keto-PGF1α含量,部分改善坐骨神经传导速度,减轻神经的病理改变.结论牛磺酸可通过降低血浆TXB2及坐骨神经糖基化终产物的含量,增加6-ketoPGF1α的生成,对糖尿病神经病变具有防治作用.     

Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy

Summary Clinical, electrophysiological and ultrastractural morphometric observations were made in 5 diabetic non-neuropathic patients, 5 diabetic patients with mild neuropathy and 11 diabetic patients with severe neuropathy. Capillary abnormalities were assessed in simultaneous nerve, muscle and skin biopsies and compared with results from 6 age-matched, non-diabetic control subjects.Nerve capillaries demonstrated markedly greater pathology than skin and muscle capillaries. Endoneurial capillary density was significantly reduced in severely neuropathic diabetic patients (p<0.01) when compared with control subjects. Capillary basement membrane (p<0.002), endothelial cell (p<0.003) and total diffusion barrier (endothelial cell, pericyte, basement membrane) (p<0.001) thickness were significantly increased, and oxygen diffusing capacity was significantly reduced (p<0.001) in the nerves of patients with severe diabetic neuropathy when compared to control subjects. Endothelial cell profile number and luminal perimeter were significantly increased in asymptomatic (p<0.01), (p<0.05) and severely neuropathic (p<0.001), (p<0.05) diabetic patients respectively. However, endothelial cell outer perimeter, a measure of capillary size, showed no significant increase in diabetic patients when compared with control subjects. An association was observed between neurophysiological and neuropathological measures of neuropathic severity. There was no significant correlation between the duration of diabetes and HbA₁ levels with capillary pathology or with neuropathic severity. Very few abnormalities of muscle and skin correlated with neuropathic severity. However, all measures of nerve capillary pathology correlated significantly with neurophysiological and neuropathological measures of neuropathic severity.     

Hepatic glucose extraction in normal and diabetic man

Fractional hepatic extraction of glucose was determined from the appearance in the systemic circulation of ingested 3-[3H]glucose. Using the glucose clamp technique, studies were done under steady-state conditions of basal glycemia and insulinemia, normoglycemia (0.8 mg/mL) and mild hyperinsulinemia (approximately 40 microU/mL), hyperglycemia (2 mg/mL-1) and hyperinsulinemia (approximately 100 microU/mL). Based on previous results in the dog, an oral glucose load of 2 g was used to label the portal vein glucose; this amount was chosen so as to minimize disturbance of the portal steady state but still avoid excessive loss during absorption. Additional subjects with hyperglycemia and hyperinsulinemia received an oral load of 50 g of glucose. Fractional extraction in normal subjects under near-basal conditions of glycemia and insulinemia was 19% in normal subjects and in patients with noninsulin-dependent diabetes mellitus (NIDDM) elevation of serum insulin, with or without hyperglycemia, which led to an average extraction rate of 32% of the ingested glucose. Absolute hepatic glucose uptake, calculated from the fractional extraction the plasma glucose concentration, and hepatic plasma flow accounted for 50% to 72% of total glucose use during the various steady states and following ingestion of 50 g of glucose. It is concluded that hepatic uptake or extraction, as opposed to net uptake, proceeds actively even when plasma glucose and insulin are within the normal basal range; it is increased in the presence of hyperinsulinemia, with or without hyperglycemia; and it is unaltered in NIDDM.     

赖诺普利对糖尿病大鼠周围神经病变的保护作用

目的 研究血管紧张素转换酶抑制剂(ACEI)赖诺普利对糖尿病大鼠早期周围神经病变的治疗作用,并初步探讨其作用机制.方法 赖诺普利给药8周,观察其对链脲佐菌素(STZ)诱导糖尿病大鼠周围神经功能及结构的影响;并测定神经组织超氧化物歧化酶(SOD)、丙二醛、Na+K+-ATP酶活性、血浆NO、一氧化氮合酶含量和坐骨神经内膜毛细血管密度.结果 赖诺普利可改善神经组织的功能和结构;改善神经组织的氧化应激状态、增加NO含量、提高Na+K+-ATP酶活性、增加神经内膜毛细血管密度.结论 ACEI是治疗糖尿病周围神经病变的有效措施,其机制可能与改善神经组织缺血及相关的代谢紊乱有关.     

Thermoregulatory sudomotor dysfunction and diabetic neuropathy develop in parallel in at-risk feet

Aims To establish the longitudinal relationship of foot complications to neuropathy based on a 4-year follow-up of diabetic patients stratified by sudomotor dysfunctions. Methods One hundred and nineteen Type 2 diabetic patients and 36 non-diabetic subjects were initially registered in the prospective cohort study. Plantar skin temperature and sympathetic skin response (SSR) were used to monitor sympathetic mediated thermoregulation and sudomotor function. Peripheral somatic and central autonomic functions were studied using clinical, nerve conduction and cardiovascular reflex tests. At enrolment, the diabetic patients were classified into one of three groups by the progressive stages of sudomotor dysfunction: SSR+ (SSR present; 49 patients), SSR− (SSR absent; 41 patients) and at-risk group (SSR absent but with cracked skin involving partial thickness of the dermis; 29 patients). Results The at-risk group had 13.4 times (95% confidence interval 1.4–125.7) higher plantar ulceration rates than the other two patient groups during the 4 years. Skin temperature elevation occurred in parallel with development of foot sweating problems. There were no significant differences between the three patient groups in the ratios of abnormal heart rate variation, orthostatic test and clinical neuropathy score at follow-up. After 4 years of follow-up, nerve conduction abnormalities were more frequent in the at-risk and SSR− groups than in the SSR+ group. Conclusions Early deterioration of small sympathetic fibres could not be quantified accurately by the clinical, somatic and autonomic tests. Assessing skin integrity and sudomotor function in at-risk individuals identifies early peripheral sympathetic neuropathy, even if the patients have no overt clinical symptoms.     

豆豉提取物对糖尿病模型小鼠血糖的影响

目的探讨豆豉提取物对糖尿病模型小鼠血糖水平的影响。方法腹腔注射四氧嘧啶建立糖尿病模型小鼠,给糖尿病小鼠灌胃豆豉提取物一个月,观察豆豉提取物对小鼠体重、空腹血糖、糖耐量的影响。结果豆豉提取物能降低糖尿病小鼠空腹血糖(P<0.05),改善其糖耐量(P<0.01),对正常小鼠体重、空腹血糖无明显影响。结论豆豉提取物能改善糖尿病模型小鼠的血糖水平。     

The role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man

In order to express in equivalent terms seemingly divergent results obtained with isotopic tracer studies as compared to hepatic venous catheter studies on the role of the liver in the metabolism of oral glucose, our previously published studies using the hepatic venous catheter technique in normals and diabetics given intravenous and/or oral glucose were analyzed with respect to the splanchnic fractional extraction of glucose, total splanchnic glucose influx, and the proportion of total glucose metabolism accounted for by net splanchnic glucose uptake. In normal subjects during extreme hyperinsulinemia (plasma insulin, 500–1,200 μU/ml) induced by i.v. insulin while maintaining the blood glucose concentration at basal levels (insulin clamp), total glucose metabolism rose to 10.5 ± 0.9 mg/min · kg, while splanchnic fractional extraction of glucose was 4.2 ± 1.1%, and net splanchnic glucose uptake accounted for only 5 ± 2% of total glucose turnover. During hyperglycemic (blood glucose, 200 mg/dl) hyperinsulinemia induced by i.v. glucose, net splanchnic glucose uptake was twice that observed with euglycemic hyperinsulinemia, and the proportion of total glucose metabolism occurring in the splanchnic bed rose to 14 ± 4%. These increments were due entirely to a rise in splanchnic glucose influx since the fractional extraction (3.4 ± 0.5%) remained unchanged from that observed with euglycemic hyperinsulinemia. After oral glucose (100 g), splanchnic glucose influx was comparable to hyperglycemic hyperinsulinemia induced with i.v. glucose, but splanchnic fractional extraction rose to 13.1 ± 1.9% (p < 0.001 versus i.v. glucose), a value comparable to that observed with isotopic studies of oral glucose metabolism. Total glucose turnover was, however, 30% lower than after i.v. insulin (p < 0.01), so that net splanchnic glucose uptake accounted for 54 ± 5% of total glucose metabolism. In maturity-onset diabetics, after 100 g oral glucose splanchnic glucose influx was 69% greater than in controls (p < 0.001), but net splanchnic glucose uptake was 44% below controls (2.3 ± 0.5 versus 4.1 ± 0.5 mg/min · kg, p < 0.02). This reduction in glucose uptake could be accounted for by a splanchnic fractional extraction ratio (4.7 ± 1.4%) that was 64% lower than in controls given oral glucose (p < 0.001). It is concluded that: (1) in normal subjects, the ability of the splanchnic area to extract circulating glucose (as reflected by the splanchnic fractional extraction) is 2–3-fold greater after oral glucose than after intravenous glucose; (2) the rise in splanchnic fractional extraction to levels of 13% in association with only moderate increases in total glucose turnover fully accounts for the predominance of the splanchnic area in the metabolism of oral as compared to intravenous glucose; and (3) in maturity-onset diabetics, oral glucose fails to induce a rise in splanchnic fractional extraction of glucose comparable to that observed in normal subjects.     

Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy

AIMS/HYPOTHESIS: A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary leakage. METHODS: Three matched groups were studied: 18 diabetic patients with documented peripheral neuropathy (DN), 18 diabetic patients without peripheral neuropathy (D), and 18 healthy control subjects (C). Sensory and motor nerve function of the distal extremities were assessed by standard neurography, and expressed in a sensory-motor nerve function score. Sympathetic vasomotion of the skin microcirculation was assessed by determining the power of blood flow variability in the low-frequency (0.02-0.14 Hz) band by spectral analysis of laser Doppler flowmetry at the median ankle. Skin capillary leakage was evaluated by sodium fluorescein videodensitometry at the same site of the foot. RESULTS: Sympathetically mediated vasomotion of the foot skin microcirculation was lower in diabetic patients with documented peripheral neuropathy compared with diabetic patients without peripheral neuropathy and control subjects (p<0.001). Capillary sodium fluorescein leakage was larger in 18 diabetic patients with documented peripheral neuropathy than in diabetic patients without peripheral neuropathy (p<0.02) and C (p<0.005). Multiple regression analysis disclosed that a reduced sympathetically mediated vasomotion, together with a lower sensory-motor nerve function score, independently contributed to the variance in sodium fluorescein leakage, for 30% (p<0.001) and 17% (p<0.01), respectively. CONCLUSIONS: A loss of sympathetic tone, apart from sensory-motor nerve dysfunction, seems to be a major determinant of an increased capillary permeability in diabetic patients with neuropathy.     

Relationship among esophageal dysfunction,diabetic gastroenteropathy,and peripheral neuropathy

Esophageal motor function was tested in 12 patients with a clinical diagnosis of diabetic gastroenteropathy by radionuclide transit (RT) studies. Other insulin-dependent diabetics with and without symptoms of peripheral neuropathy but with no symptoms of gastrointestinal disease were similarly studied. Eleven of the 12 patients with gastroenteropathy were found to have abnormal esophageal function, even though only five had esophageal symptoms. Half the diabetics with peripheral neuropathy symptoms, and a quarter of those with no symptoms had abnormal esophageal transit studies. No abnormalities were found in a group of asymptomatic volunteers studied in a similar manner. We conclude that esophageal dysfunction, often subclinical, is present in nearly all patients with suspected diabetic gastroenteropathy. Esophageal dysfunction correlates less well with peripheral neuropathy. This study implies that if a diabetic, presenting with diarrhea or nausea and vomiting, has normal esophageal transit, then a cause for these symptoms, other than diabetic gastroenteropathy, may exist.     

Influence of autonomic neuropathy upon left ventricular dysfunction in insulin-dependent diabetic patients

BACKGROUND: Diabetic cardiomyopathy is a well-defined complication of diabetes that occurs in the absence of ischemic, vascular, and hypertensive disease. HYPOTHESIS: The study was undertaken to test the relationship among autonomic neuropathy (AN), 24-h blood pressure (BP) profile, and left ventricular function. METHODS: Nineteen type-1 diabetic patients underwent autonomic tests and echocardiographic examination. Patients were divided according to the presence (AN+) or absence (AN-) of AN. RESULTS: In the AN+ group (n = 8), the E/A ratio at echo was lower than in the AN- group (n = 11) (1.1 +/- 0.3 vs. 1.6 +/- 0.3; p < 0.005). Systolic and diastolic BP reductions during sleep were smaller in the AN+ than in the AN- group (6.6 +/- 6.6 vs. 13.0 +/- 4.3%; p < 0.03 for systolic and 12.8 +/- 6.8 vs. 20.0 +/- 4.0% for diastolic BP reduction; p < 0.03, respectively). Considering all patients, the E/A ratio correlated inversely with awake diastolic BP (r - 0.63; p = 0.005); sleep systolic BP (r - 0.48; p = 0.04), and sleep diastolic BP (r - 0.67; p = 0.002). The AN correlated with diastolic interventricular septum thickness (r 0.57; p = 0.01), sleep systolic BP (r 0.45; p = 0.05), sleep diastolic BP (r 0.54; p = 0.02), and correlated inversely with systolic and diastolic sleep BP reduction (r - 0.49; p = 0.03 and r - 0.67; p = 0.002, respectively). Finally, E/A ratio and AN score correlated between themselves (r - 0.6; p = 0.005). CONCLUSION: Our results suggest that left ventricular diastolic dysfunction may be detected very early in type-1 diabetic patients with AN. Parasympathetic lesion and nocturnal elevations in BP could be the link between AN and diastolic ventricular dysfunction.     

醛糖还原酶抑制剂治疗糖尿病周围神经病变的临床研究

目的观察醛糖还原酶抑制剂治疗糖尿病周围神经病变（DPN）的疗效。方法DPN患者158例,随机分为治疗组（口服依帕司他）88例,对照组（仅控制血糖）70例,各组治疗前、后测FPG、2hPG、HbA1c、血浆内皮素（ET）并进行神经电生理检查。结果治疗前后治疗组与对照组的正中神经与腓神经的神经传导速度及ET水平的差异均有统计学意义。结论醛糖还原酶抑制剂可以提高DPN神经传导速度,具有显著疗效。     

Under-utilization of capillary glucose monitoring by type 2 diabetic patients

OBJECTIVES: Postprandial glycemic excursions contribute significantly to A1C level. Furthermore, postprandial plasma glucose (PPG) is an independent risk factor for cardiovascular disease. We have evaluated the frequency of monitoring and the level of PPG in type 2 diabetic patients followed by their family physician. PATIENTS AND METHODS: Canadian multicenter observational study, including 185 type 2 diabetic patients. Capillary blood glucose was measured with an Ultrasmart glucose meter (Life Scan) during a routine visit to their general practitioner. The patients also had to answer a questionnaire concerning the time since their last meal before the visit, and the frequency of postprandial monitorings defined as 10 mmol/L). A PPG >10 mmol/L was found in 18.8% (n=9), 43.5% (n=47) and 73.1% (n=19) of patients in Groups 1-3, respectively. Independent of treatment category, the mean (S.D.) PPG measured by capillary methods was above the recommended target: 10.6 mmol/L (3.7) <1-h postprandial; 10.0 mmol/L (4.2) between 1 and 2h postprandial meal; and 9.9 (3.9) 2 and 3h after meal. CONCLUSION: This observational study shows that a third of the patients measured their PPG and for those who did, only a third were within the recommended target. It suggests that the patients, and probably the treating physicians, are not aware of the importance of measuring PPG. Continued medical education strategies are required to implement the recommendations for measuring and treating PPG as part of the intensive treatment of diabetes.