N-acetyl-beta-glucosaminidase isoenzymes in serum and urine of patients with diabetes mellitus

The isoenzyme pattern of N-acetyl-beta-glucosaminidase (NAG) in serum and urine was studied in two groups of patients with diabetes mellitus and in 30 control subjects. Total NAG activity was significantly (P less than 0.001) increased in the serum and urine of the 20 diabetics with vascular complications, but was insignificantly increased in the 20 diabetics without vascular complications. Ion-exchange chromatography demonstrated the presence of two major isoenzymes of NAG, A and B. The proportion of isoenzyme A activity always exceeded that of isoenzyme B. The proportion of isoenzyme B in serum of diabetics was lower than in controls; the reverse was true for urine of diabetics. The NAG isoenzymes pattern may provide additional diagnostic information regarding diabetic status and complications of diabetes.     

N-Acetyl-beta-D-glucosaminidase levels and diabetic microangiopathy.

N-Acetyl-beta-D-glucosaminidase (NAG) activity has been measured in the serum and urine of primary and secondary diabetics and in primary diabetics with microangiopathy. NAG activity has also been measured in the tears of diabetics with ocular complications and diabetics with no ocular changes. Results have shown significantly higher levels of urinary NAG in diabetics with proteinuria (p less than 0.001) and proteinuria and retinopathy (p less than 0.001). There was no correlation between urinary NAG activity and serum creatinine (r = 0.28) or urinary NAG and the degree of proteinuria (r = 0.24). Increased urinary NAG levels were also observed in secondary diabetes associated with haemochromatosis and acromegaly. Significantly higher serum NAG levels were found in newly diagnosed diabetics (p less than 0.01) and significantly lower levels in chemical diabetics (p less than 0.01). Compared to non-diabetic controls tear NAG levels were significantly higher in the diabetic controls (p less than 0.01), in diabetics with retinopathy (p less than 0.01), and in diabetics with cataract formation (p less than 0.05). An assessment of this enzyme is made in relation to the development of diabetic microangiopathy.     

Serum and urine N-acetyl-beta-D-glucosaminidase in diabetics on diagnosis and subsequent treatment, and stable insulin dependent diabetics.

N-Acetyl-beta-D-glucosaminidase (NAG) activity has been measured in the serum and urine of diabetics. Results have shown significantly higher levels of serum NAG in newly diagnosed diabetics (945 +/- 372 units/ml) compared to non-diabetic controll (668 +/- 225, p less than 0.005) and the levels were reduced by treatment (778 +/- 218, p less than 0.05). Changes occurred in the same direction when urinary NAG was measured falling from a mean of 572 +/- 298 units/mg urinary creatinine, on diagnosis to 291 +/- 176 after treatment (p less than 0.005), as compared with 177 +/- 86 in non-diabetic controls. Established insulin-treated diabetics had a urinary NAG activity of 461 +/- 440 and a serum NAG activity of 790 +/- 245. No correlation was found between urine NAG activity and urine glucose (r = 0.315), or serum NAG and serum glucose (r = 0.273). An assessment of this enzyme is made in relation to early microangiopathy.     

Serum N-acetyl-beta-D-glucosaminidase profiles in type 1 diabetes secondary complications: causes of changes and significance of determination

The connection between changes in the activity of serum N-acetyl-beta-D-glucosaminidase (NAG, E.C.3.2.1.30) and iso-enzymes and degree of secondary complications was analyzed in four groups of type 1 diabetic patients (n=69): without complications (n=22); with retinopathy (n=16); with retinopathy and polyneuropathy (n=13), and with retinopathy, neuropathy, and nephropathy (n=18). In all groups statistically significant higher (P<0.001) percent fraction of A form (83.84+/-6.09, 84.37+/-5.74, 81.76+/-6.02, 76.37+/-7.38%, resp.) and lower (P<0.001, P<0.01) fraction of B form (15.87+/-5.65, 15.66+/-5.74, 18.33+/-5.98, 23.63+/-7.38, resp.) in total NAG compared with the control (A=69.38+/-4.79%, B=30.61+/-4.78%) were found. The differences in A as well as B forms between diabetic groups were not statistically significant. Significant strong positive correlations between total NAG and glycemia (0.494-0.623), total NAG and A form (0.934-0.966), and A form and glycemia (0.512-0.638) were found in all groups. No correlation was found between the fractions of B and A forms, except in the fourth group. The A form of diabetic patients in the fourth group was more acidic compared with the control and other diabetic groups. It was concluded that the changes in serum NAG and iso-enzymic profiles in diabetes are the consequence of its increased exocytose, especially of the A form, in hyperglycemia and posttranslational modifications of iso-enzymes. The total activity of serum NAG and iso-enzymic profiles cannot be used for monitoring the development and distinction of type 1 diabetes secondary complications.     

Quantitative evaluation of the dermal vasculature of diabetics

The dermal microvasculature has been compared in 51 diabetics and 51 matched non-diabetic controls using tissue measurement techniques and functional assessments of blood vessel reactivity. Blood vessel walls were thicker in different groups of diabetics than the controls (p less than 0.01) but the degree of thickness did not differ between patients with insulin-dependent diabetes mellitus and those with non-insulin-dependent diabetes mellitus or between diabetics with and without vascular complications. Vascular lumina were narrower in diabetics than in controls (p less than 0.01) and diabetics with vascular complications had a greater reduction in luminal area than those without such complications (p less than 0.001) but the luminal area did not differ between the insulin-dependent and the non-insulin-dependent groups. The luminal perimeter was also reduced in the diabetic group compared to controls. The weal and flare response to intracutaneous histamine acid phosphate (50 micrograms) was markedly decreased (p less than 0.001) in diabetic subjects compared with controls, as was the response to a topically applied vasodilator (Transvasin). The degree of reduction did not differ between patients with insulin-dependent diabetes mellitus and those with the non-insulin-dependent disease but diabetics with vascular complications show impaired responses as compared to those without. The maximum increase in skin temperature on the volar surface of the right middle finger during a period of reactive hyperaemia following 3 min of cuff-induced ischaemia was also markedly decreased in diabetics compared with control subjects. It did not differ between those with insulin-dependent diabetes mellitus and those with the non-insulin-dependent disease but did between diabetics with vascular complications as compared with those without. This study confirms that the cutaneous vasculature of diabetics differs markedly from that of matched control subjects. The results also indicate that there are significant differences between diabetics with vascular complications and those without. The quantitative approaches adopted may have predictive value.     

Dopaminergic and cholinergic control of argininevasopressin secretion in type I diabetic men

Abstract. Enhanced cholinergic and dopaminergic controls of anterior pituitary function have been described in insulin-dependent diabetes mellitus (IDDM). In order to verify whether similar neurotransmitter alterations also affect the regulation of posterior pituitary hormone secretion, the argininevasopressin (AVP) responses to the dopaminergic agonist apomorphine and in a different occasion to physostigmine, an acetylcholinesterase inhibitor, were evaluated in normal ( n =10) and type I diabetics ( n = 16). In addition, a control test with normal saline was performed in all subjects. None of the diabetic patients were affected by neuropathy or other diabetic complications. They were divided into two groups according to the duration of their disease (less than 10 years: group 1, n = 8; more than 10 years: group 2, n = 8). Physostigmine (12.5 μg kg^-1) was infused intravenously over 10 min; apomorphine (60 μg kg^-1) was injected subcutaneously. Basal AVP concentrations were similar in all groups and remained constant during the control test. In contrast, both drugs induced significant increments in plasma AVP levels in the normal controls and diabetic subjects. However, physostigmine- and apomorphine-induced AVP increments were twofold higher in diabetics than in control subjects. No significant differences were observed between diabetics of groups 1 and 2. No significant correlations between duration of diabetes and peak AVP responses to physostigmine or apomorphine were found within each group or when all diabetic subjects were considered together. These data indicate enhancement of both dopaminergic and cholinergic stimulatory regulations of AVP secretion in patients with uncomplicated IDDM, regardless of the duration of diabetes.     

Glycation of lipoproteins and accelerated atherosclerosis in non-insulin-dependent diabetes mellitus

Summary We used a new and remarkably simple method to examine the extent of in vivo lipoprotein glycation in type II diabetic patients with atherosclerosis and diabetic patients with no complications. Serum glycated lipoprotein levels were determined by agarose gel film electrophoresis in 48 non-diabetic control subjects and 39 diabetic patients, of whom 26 had no complications and 13 had atherosclerotic heart disease. Fasting serum glucose, glycohemoglobin and serum fructosamine concentrations (indicators of glycemia) and total cholesterol, triglyceride, low-density lipoprotein-, very low-density lipoprotein-and high-density lipoprotein-cholesterol concentrations and the low-density lipoprotein/high-density lipoprotein ratio (serum lipid profile) were also detewrmined in the control and diabetic subjects. Glycated low-density lipoprotein and very low-density lipoprotein concentrations were significantly increased in diabetic patients compared with controls; but only glycated very low-density lipoprotein was significantly increased in atherosclerotic patients compared with diabetics without complications. The lipid profile parameters were not significantly increased in patients compared with controls. In diabetics, especially those with poorly controlled hyperglycemia and atherosclerosis, glycation of lipoprotein fractions might be more important than serum lipid and lipoprotein abnormalities. The significant correlation between atherosclerosis and glycated very low-density lipoprotein, suggests that very low-density lipoprotein glycation could be responsible for the development of atherosclerosis in diabetes.     

A role for alpha-adrenergic receptors in abnormal insulin secretion in diabetes mellitus.

To determine whether endogenous alpha-adrenergic activity contributes to abnormal insulin secretion in nonketotic, hyperglycemic, diabetic patients, alpha-adrenergic blockade was produced in normal and diabetic subjects. The diabetics had a significantly (P less than 0.01) greater increase in circulating insulin 1 h after an intravenous phentolamine infusion than did the normal subjects. During the phentolamine infusion, there was also a significant augmentation of acute insulin responses to intravenous glucose (20 g) pulses in normal subjects (P less than 0.05) and diabetics (P less than 0.02); this augmentation was fivefold greater in the diabetics. Simultaneous treatment with the beta-adrenergic blocking agent, propranolol, did not alter these findings. Thus a role for exaggerated endogenous alpha-adrenergic activity in abnormal insulin secretion of the diabetic subjects is suggested. To determine whether this alpha-adrenergic activity might be related to elevated circulating catecholamines, total plasma-catecholamine levels were compared in normal and nonketotic diabetic subjects given intravenous glucose pulses. These levels were significantly greater (P less than 0.02) in the diabetic compared to the normal group before the glucose pulse, and increased significantly in both groups (P less than 0.02 and less than 0.001, respectively) after the pulse. These data suggest that excessive catecholamine secretion may lead to an abnormal degree of endogenous alpha-adrenergic activity, which contributes to defective insulin secretion in diabetic subjects.     

Urinary excretion of glycated protein determined with a specific radioimmunoassay

We developed a simple and highly sensitive RIA for glycated protein (GP), and used it to measure GP in serum and urine from 15 normal controls and 30 diabetics (14 with urinary excretion rate of albumin, Ualb less than 15 micrograms/min, group A; nine with 15 less than or equal to Ualb less than or equal to 150 micrograms/min, group B; and seven with Ualb greater than 150 micrograms/min, group C). The mean serum concentration of GP was above normal in all groups of diabetics, and the mean glycation ratios of serum protein (SGP) were higher in groups B and C than in normal subjects. Urinary concentrations of GP also were increased in groups B and C, although the glycation ratio of urinary protein (UGP) was decreased in group C. Consequently, the selectivity of urinary excretion of GP (UGP/SGP) was significantly decreased in group C. Moreover, there was a significant difference in the mean values of selectivity between groups of patients with various degrees of retinopathy. We suggest that measurements of serum and urinary GP are useful to evaluate the progression of diabetic complications.     

Urinary N-acetyl-beta-D-glucosaminidase activity does not predict development of diabetic nephropathy

Urinary activity of N-acetyl-beta-D-glucosaminidase (NAG) has been suggested as a marker for diabetic nephropathy. In this study, urinary activity of NAG was measured with an interval of 5 yr in 36 insulin-dependent diabetic subjects to evaluate its predictive value for development of diabetic nephropathy. During the observation period, 9 patients developed detectable signs of diabetic nephropathy. In these patients, urinary albumin concentration had increased to 503 +/- 185 mg/L, compared to 16 +/- 1 mg/L in patients without nephropathy (P less than .01; means +/- SE), and the fractional albumin excretion rate was 0.21 +/- 0.07 X 10(-3), compared to 0.01 +/- 0.00 X 10(-3) (P less than .01). However, the activity of urinary NAG was not different in these patients compared with the patients without nephropathy (0.69 +/- 0.15 and 0.61 +/- 0.09 U/mmol creatinine, respectively). Furthermore, no increase in the activity of urinary NAG was seen during the observation period in either group. We concluded that the urinary activity of NAG is not related to the development of microalbuminuria and therefore cannot be used as a predictor for the development of diabetic nephropathy.     

Modifications induced by diabetes on the physicochemical and functional properties of erythrocyte plasma membrane

Increasing evidence suggests that in experimental diabetes an impairment in Na+,K+-ATPase activity plays a central role in the pathophysiology of diabetic complications, while only a few data are available with regard to human subjects. We studied the erythrocyte membrane Na+,K+-ATPase activity and membrane fluidity in insulin-dependent and non-insulin-dependent diabetic subjects. A significant decrease in the enzyme activity and in fluorescence polarization values was found in both groups compared with normal subjects. Neither Na+,K+-ATPase activity nor membrane fluidity was found to be related to metabolic control, assessed by means of fasting blood glucose levels and HbA1c. On the contrary, a significant correlation was observed between Na+,K+-ATPase activity and membrane fluidity in both insulin-dependent and non-insulin-dependent diabetic subjects. The present work provides evidence that a reduction in the Na+,K+-ATPase activity is present in the plasma membranes of insulin-dependent and non-insulin-dependent diabetics. Furthermore, it suggests that the change in enzyme activity might be related to modifications in membrane fluidity.     

Elevated cholesteryl ester transfer protein activity in IDDM men who smoke. Possible factor for unfavorable lipoprotein profile

OBJECTIVES: To determine the effect of cigarette smoking on the activity of cholesteryl ester transfer protein (CETP) and high-density (HDL), low-density (LDL), and very-low-density (VLDL) lipoproteins in insulin-dependent diabetic (IDDM) men with microvascular complications. RESEARCH DESIGN AND METHODS: We performed a case-control study in a referral-based diabetes clinic on a sequential sample of 9 cigarette-smoking and 12 nonsmoking IDDM men with microvascular complications and 12 nonsmoking control men. CETP activity was determined in each serum with an isotope assay with exogenous cholesteryl ester-labeled LDL and HDL. The method is independent of the endogenous lipoprotein present in serum. RESULTS: The HDL-cholesterol (VLDL and LDL) ratio was lower in the smoking diabetic men than in the other groups (P less than 0.05 vs. the nonsmoking diabetic men and P less than 0.01 vs. the control subjects). CETP activity was 70% higher in the smoking diabetic men than in the control subjects (P less than 0.01) and 30% higher than in the nonsmoking diabetic men (P less than 0.05). The HDL-cholesterol (VLDL and LDL) ratio and the apolipoprotein A-I-B ratio were inversely correlated to CETP activity in the diabetic patients (r = -0.52, P less than 0.02 and r = -0.45, P less than 0.05, respectively). CONCLUSIONS: CETP activity is increased in cigarette-smoking IDDM men with microvascular complications. High CETP activity may contribute to the unfavorable lipoprotein profile in these patients.     

Serum angiogenin concentrations in young patients with diabetes mellitus

BACKGROUND: Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long-term glycemic control and microvascular complications. MATERIALS AND METHODS: Four groups of patients were compared to 223 age- and sex- matched healthy controls: 196 type 1 diabetic patients (age range 3-24 years, onset of diabetes before the age of 12 years; duration of disease longer than 2 years), without microvascular complications were divided into three groups on the basis of age (group 1, n = 37, age < 6 years; group 2, n = 71, age 6-12 years; group 3, n = 88, age > 12 years); 53 adolescents and young adults (age 16.1-29.7 years) with diabetic microvascular complications (background, preproliferative or proliferative retinopathy, albumin excretion rate 20-200 microg min-1) (group 4). RESULTS: Angiogenin serum levels were significantly increased in diabetic pre-school and pre-pubertal children, and particularly elevated in pubertal subjects compared with age- and sex-matched controls. Adolescents and young adults with microvascular complications had very high angiogenin concentrations. One-year mean HbA1c values were correlated with angiogenin levels (r = 0.389; p < 0.01). In poorly controlled diabetics (HbA1c > 10%), long-term (2 years) improvement of glycemic control determined a significant reduction of angiogenin concentrations in both pre-school and pre-pubertal children as well as in pubertal youngsters. CONCLUSIONS: Angiogenin serum concentrations are increased in diabetic children even before puberty. Severity of microvascular complications is associated with markedly increased angiogenin serum levels. Long-term tight glycemic control determines a consistent reduction of angiogenin concentrations.     

血清脂联素与2型糖尿病及其大血管病变的相关性研究

目的 测定正常人群与2型糖尿病及其大血管病变患者的血清脂联素水平,探讨脂联素与2型糖尿病及其大血管病变的相关性.方法 正常对照组102例,2型糖尿病组116例、2型糖尿病并大血管病变组123例,比较各组的血清脂联素水平,分析其影响因素.结果 ①型糖尿病组及其大血管病变组的血清脂联素水平[分别为(8.62±2.97)、(6.17±2.55)mg/L]较正常对照组[(10.03±4.41)mg/L]降低,大血管病变组的血清脂联素水平较2型糖尿病组更低,差异均有统计学意义(P均<0.05);②相关分析显示,脂联素水平与体重指数、腰臀比、胰岛素抵抗指数、空腹胰岛素、糖化血红蛋白、甘油三酯负相关(r值分别为-0.492、-0.581、-0.813、-0.754、-0.619、-0.387,P均<0.05);③多元逐步回归分析显示脂联素与胰岛素抵抗指数、空腹胰岛素、糖化血红蛋白呈负相关(r值分别为-0.828、-0.769、-0.631,P均<0.01).结论 2型糖尿病及其大血管病变患者的血清脂联素水平降低,低脂联素血症可能与2型糖尿病及其大血管病变相关,在糖尿病动脉粥样硬化的发生、发展过程中有重要作用.     

Determination of urinary enzymes as a marker of early renal damage in diabetic patients

Diagnosis of diabetic nephropathy in the early stages is very important since there are no clinical signs or symptoms. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion has been recommended as a tubular dysfunction marker that elevates before other markers, such as microalbuminuria and a decrease in creatinine clearance. In this study, we compared excretion of urinary enzymes with other markers that are used routinely in diabetic nephropathy assessment. Urinary NAG, lactate dehydrogenase (LDH), alkaline phosphatase (AP) activities, urea, creatinine, and albumin, with levels of serum glucose and creatinine and whole blood glycosylated hemoglobin (HbA1c) were measured in 32 diabetes mellitus patients and 25 healthy subjects (controls). Notably, urinary NAG, AP, LDH excretion, and microalbuminuria in the diabetic patients group were significantly increased compared to those in the control groups (P<0.001, P<0.05, P<0.01, and P<0.01, respectively). Meanwhile, our results showed that the urinary NAG excretion had the highest sensitivity and specificity (100% and 87.5%, respectively) compared to other markers. We showed that measuring urinary NAG excretion could be useful for the assessment of renal failure in diabetes mellitus patients and confirmed the use of NAG as a routine screening test.     

The activity of N-acetyl-beta-D-glucosaminidase and tumor necrosis factor-alpha at early stage of diabetic retinopathy development in type 1 diabetes mellitus children

OBJECTIVE: The assessment of the clinical significance of TNF-alpha, IL-10 and NAG with its A and B isoforms concentrations in children with DM type 1 for the detection of early stages of both diabetic retinopathy and nephropathy. PATIENTS AND METHODS: One hundred and two children with DM type 1 and 35 healthy controls were analyzed. Levels of TNF-alpha, IL10 and total NAG enzyme activity with its A and B isoforms were measured in serum and urine of all participants. RESULTS: Children with diabetic retinopathy had a significantly higher levels of TNFalpha in serum (P=0.01) in comparison to those without retinopathy. The activity of NAG (P=0.002) and its isoform A (P=0.006) and isoform B (P=0.001) were significantly higher in children with diabetic retinopathy in comparison to those without this complication. Conversely, within the group with retinopathy, more children had detectable concentrations of IL10 in serum as compared to those without retinopathy (P=0.01). CONCLUSIONS: These results suggest that NAG activity and TNF-alpha concentration in diabetic retinopathy patients might show a relationship with a degree of renal glomeruli epithelial cells and renal proximal tubules damage.     

3项指标联合检测对糖尿病肾病的早期诊断价值

目的探讨联合检测尿转铁蛋白(TRF)、N-乙烯-β-D-氨基葡萄糖苷酶(NAG)及血半胱氨酸蛋白酶抑制剂C(Cys C)对糖尿病肾病的早期诊断价值。方法用免疫比浊法检测尿TRF和血Cys C,终点法检测尿NAG,并比较其在各组中的差异。结果 TRF、NAG及血Cys C在糖尿病无蛋白尿组(A组)中的浓度分别为(3.12±0.45)mg/L(、2.26±0.97)U/mmoL和(1.83±0.37)mg/L,糖尿病蛋白尿组(B组)中的浓度分别为(10.66±3.50)mg/L(、4.30±1.74)U/mmoL和(3.14±0.96)mg/L,A组中各指标的浓度均显著高于健康对照组中相应的浓度,B组中各指标的浓度均显著高于A组中相应的浓度(P<0.05)。单纯检测一项或两项指标阳性率较低,而联合检测则能提高阳性率。结论联合检测尿TRF、NAG及血Cys C能反映糖尿病肾病的早期损害,对糖尿病的早诊断、早治疗有重要的临床价值。     

Serum 8-hydroxy-guanine levels are increased in diabetic patients

OBJECTIVE: The production of reactive oxygen species is increased in diabetic patients, especially in those will poor glycemic control. We have investigated oxidative damage in type 2 diabetic patients using serum 8-hydroxyguanine (8-OHG) as a biomarker. RESEARCH DESIGN AND METHODS: We studied 41 type 2 diabetic patients and compared them with 3 nondiabetic control subjects. Serum 8-OHG concentration was assayed using high-pressure liquid chromatography. RESULTS: The type 2 diabetic patients had significantly higher concentrations of 8-OHG in their serum than the control subjects (5.03 +/- 0.69 vs. 0.96 +/- 0.15 pmol/ml P < 0.01). There was no association between the levels of 8-OHG and HbA1c. We also could not and any correlation between serum 8-OHG levels and age, duration of diabetes, serum lipids, or creatinine or albumin exeretion rate. Creatinine clearance showed marginal correlation with serum 8-OHG levels (P = 0.06). Among the diabetic patients, those with proliferative retinopathy had significantly higher 8-OHG levels than those with nonproliferative retinopathy or without retinopathy. Likewise, the serum 8-OHG levels in patients who had advanced nephropathy (azotemia) were higher than in patients with normoalbuminuria, microalbuminuria, or overt proteinuria. CONCLUSIONS: Our findings show that measuring serum 8-OHG is a novel convenient method for evaluating oxidative DNA damage. Diabetic patients, especially those with advanced microvascular complications, had significantly higher serum 8-OHG levels; this suggests that such changes may contribute to the development of microvascular complications of diabetes.     

Serum UDP-galactose: glycoprotein galactosyltransferase in diabetics with microangiopathy.

1. Levels of serum UDP-galactose:glycoprotein galactosyltransferase in 117 unselected diabetics were compared with those in 60 non-diabetic healthy controls. 2. Enzyme activity (mean +/- 2 S.D.) of control sera was found to be 90.2 +/- 21.5 etamoles/ml/hr at 37 degrees. In 30 of the 117 diabetic sera (26%) enzyme activity was elevated (greater than mean + 2 S.D. of the controls). Sixteen of 19 (84%) patients with retinopathy, 16 of 26 (62%) patients with peripheral vasculopathy and 13 of 26 (50%) patients with neuropathy had higher levels of serum enzyme. When serum enzyme levels of groups of diabetics with retinopathy, peripheral vasculopathy and neuropathy were compared with the enzyme level in all diabetics, there was a significant difference with p values of 0.001, 0.05 and 0.05 respectively.     

Hemodynamics in diabetic orthostatic hypotension.

Hemodynamic variables (blood pressure, cardiac output, heart rate, plasma volume, splanchnic blood flow, and peripheral subcutaneous blood flow) and plasma concentrations of norepinephrine, epinephrine, and renin were measured in the supine position and after 30 min of quiet standing. This was done in normal subjects (n = 7) and in juvenile-onset diabetic patients without neuropathy (n = 8), with slight neuropathy (decreased beat-to-beat variation in heart rate during hyperventilation) (n = 8), and with severe neuropathy including orthostatic hypotension (n = 7). Blood pressure decreased precipitously in the standing position in the diabetics with orthostatic hypotension, whereas moderate decreases were found in the other three groups. Upon standing, heart rate rose and cardiac output and plasma volume decreased similarly in the four groups. The increases in total peripheral resistance, splanchnic vascular resistance and subcutaneous vascular resistance were all significantly lower (P less than 0.025) in the patients with orthostatic hypotension compared with the other three groups. The increase in plasma norepinephrine concentrations in the patients with orthostatic hypotension was significantly lower (P less than 0.025) than in the patients without neuropathy, whereas plasma renin responses to standing were similar in the four groups. We conclude that in diabetic hypoadrenergic orthostatic hypotension the basic pathophysiological defect is lack of ability to increase vascular resistance, probably due to impaired sympathetic activity in the autonomic nerves innervating resistance vessels; cardiac output and plasma volume responses to standing are similar to those found in normal subjects and in diabetics without neuropathy.