Monosodium glutamate: feeding of large amounts in man and gerbils.

Oral administration of large amounts of glutamic acid to adult humans and animals in a formula diet appeared to cause no clinical pathological changes. The only biochemically demonstrable effect was a decrease in serum cholesterol and associated beta lipoproteins.

Aldosterone responsiveness in patients with diabetes mellitus.

Plasma aldosterone (PA) and plasma renin activity (PRA) were determined in 44 diabetics, of whom nine were normotensive but not nephropathic (group 1), 10 were hypertensive but not nephropathic (group 2), and 25 were hypertensive and nephropathic (group 3); they were kept in balance on a diet composed of 10 to 20 mEq. of sodium (Na) and 100 mEq. of potassium (K). Supine PA in group 1 was 38 +/- 7 ng. per deciliter, whereas in normals it was 24 +/- 2 ng. per deciliter (P less than 0.05); beyond that, neither supine nor upright PA or PRA differed significantly from normal in groups 1 and 2. By contrast, in group 3, supine PA was 13 +/- 1 ng. per deciliter and PRA 2.0 +/- 0.2 ng./ml. and upright PA was 39 +/- 7 ng. per deciliter and PRA 3.8 +/- 0.5 ng./ml., all significantly lower than those in the other groups (P less than 0.01). Nine patients, one in group 1 and eight in group 3, had low supine and upright PA and PRA; four had hyperkalemia. An additional nine patients in group 3 had low upright PA, with normal or low PRA; two had hyperkalemia. Of the 18 patients with low upright PA, K correlated with glucose (R = 0.46, P less than 0.05). These results suggest (1) the renin-aldosterone system generally responds normally in diabetics without nephropathy but responds subnormally when nephropathy is present, (2) hyporeninemic hypoaldosteronism is frequent in diabetics with nephropathy but may occur in the absence of clinical nephropathy, and (3) hyperkalemia in some diabetic patients may be secondary to hypoaldosteronemia and hyperglycemia.

Plasma renin activity and hypertension in diabetes mellitus.

Plasma renin activity (PRA) was determined in 48 patients with diabetes mellitus in sodium balance on a 10-20 mEq. Na diet. Nine were normotensive (group I), 11 11 were hypertensive without diabetic nephropathy (group III). Results were compared with those in 16 normal subjects and 49 nondiabetic patients with essential hypertension in similar Na balance. Mean supine PRA did not differ significantly among groups I and II, normal subjects, and patients with essential hypertension. Group III diabetics had a supine PRA of 2.4 +/- 0.4 ng./ml./hr. (x +/- S.E.M.), significantly lower than the other diabetic groups (P less than 0.005) and normal subjects (P less than 0.05). Upright PRA was 12.8 +/- 2.2 in group I diabetics, similar to that in normal subjects (13.3 +/- 2.3), and 8.1 +/- 1.4 in group II diabetics, similar to that in essential hypertensives (6.8 +/- 0.8). In group III diabetics, upright PRA was 4.0 +/- 0.5, significantly lower than that in any other group. These results suggest that (1) PRA is normal in normotensive diabetics, (2) upright PRA in diabetics with hypertension but no nephropathy is similar to that in essential hypertension, and (3) patients with diabetes, hypertension, and nephropathy have "low renin hypertension," explaining the virtual absence of malignant hypertension in this group. Although the major mechanism for this low PRA may be volume expansion, indicating the need for potent diuretics, other mechanisms include hyalinization of the afferent arteriole, decreased cathecholamine stimulation of renin release, and inadequate conversion of prorenin to renin.

Trapping of peripheral blood lymphocytes in the pancreas of patients with acute-onset insulin-dependent diabetes mellitus.

Involvement of humoral and cellular autoimmunity in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) is demonstrated by the presence of circulating autoantibodies and the early pancreatic lesion of insulitis. In an effort to detect the early pancreatic lesion in acute onset IDDM, we have labeled peripheral blood lymphocytes with indium oxine 111, reinjected these autologous cells intravenously into the patients, and followed their kinetics over 96 h using an emission computerized tomography (ECT) scanner. The reinjected cells are acutely distributed in the patients' lungs, liver, and spleen (2-12 h). At 24, 48, and 72 h, the labeled lymphocytes are no longer detectable in the lungs or the liver, but are clearly present in the spleen and in the pancreas. Lymphocytic pancreatic infiltration was observed in two of three acute-onset IDDM patients, but not in large number of patients undergoing similar scans for other diseases, suggesting ongoing mononuclear cell infiltration of the pancreas, a possible marker of the lesion of insulitis. Lymphocyte scanning may provide a powerful noninvasive tool for studying patients with IDDM and for selecting those who might benefit from immunosuppressive therapy.

Metoclopramide-induced neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS), an unusual idiosyncratic reaction to neuroleptic medications, may be fatal if unrecognized. Symptoms of NMS include rigidity, hyperpyrexia, altered consciousness, and autonomic instability. This syndrome is generally associated with neuroleptic medications used to treat psychotic and major depressive illnesses. We describe two diabetic patients at our institution who developed NMS in association with antiemetic metoclopramide hydrochloride.

Insulin resistance with pancreatic pseudocyst relieved by percutaneous drainage.

An insulin-requiring type 2 diabetic patient became insulin-resistant with development of a pancreatic pseudocyst following cholecystitis and cholecystectomy. Drainage of the cyst fluid was followed by rapid return to his prior insulin requirement. As there were no indications of insulin allergy, obesity, or hormonal imbalance, we postulate a subclinical state of pancreatitis that was relieved with drainage of the pseudocyst fluid.

Amyloid deposition in serosal membranes. Its occurrence with cardiac tamponade, bilateral ureteral obstruction, and gastrointestinal bleeding.

Widely dispersed amyloid deposition of the serosa occurring in a patient produced impairment of cardiac, renal, and gastrointestinal integrity by encasement. This patient survived the acute complications of both cardiac tamponade and bilateral ureteral obstruction due to amyloid. This case demonstrates the utility of resorting to aggressive life-support mechanisms despite an apparently systemic spread of amyloid disease in selected cases.

Fibrinogen and factor VII levels improve with glycemic control in patients with type 1 diabetes mellitus who have microvascular complications.

To determine whether the hypercoagulable state of patients with complications of diabetes can be reversed toward normal, a group of insulin-dependent individuals with proteinuria was treated with intensive insulin protocols. A statistically significant (P<.001) improvement in control of diabetes was achieved (mean +/- SEM glycosylated hemoglobin, 9.51% +/- 0.35% at baseline to 8.36% +/- 0. 39% at 12 months; and mean +/- SEM advanced glycosylated end products, 14.8 +/- 2.8 U/mL at baseline to 8.4 +/- 1.5 U/mL at 12 months). There were statistically significant decreases in 2 procoagulant factors: mean +/- SEM baseline elevated plasma factor VII, 128.69% +/- 5.63% at baseline to 106.24% +/- 3.43% at 12 months (P =.002); and mean +/- SEM plasma fibrinogen, 12.3 +/- 0.7 micromol/L (417.3 +/- 24.7 mg/dL) at baseline to 10.2 +/- 0.7 micromol/L (348.8 +/- 22.6 mg/dL) at 12 months (P =.04). Throughout the study, lipid fractions did not change significantly. Because plasma factor VII and fibrinogen concentrations were elevated while cholesterol and triglyceride concentrations were not, more attention should be paid to procoagulants as markers for thromboembolic complications in diabetic patients undergoing intensive insulin therapy.

Application of the ambulatory 24-hour electrocardiogram in the prediction of cardiac death in dialysis patients.

The value of a 24-hour ambulatory electrocardiogram (AmECG) in assessing the risk of cardiac death was studied in 122 stable-condition dialysis patients followed up from two to six years after monitoring. An abnormal AmECG was defined by second-degree or greater AV block or by Lown grade 3 or greater ventricular ectopy. The incidence of cardiac mortality or an abnormal AmECG was not influenced by hypokalemia or beta-blockers. Digitalis was associated with both an abnormal AmECG and a twofold increase in mortality whether or not the AmECG was normal. Cardiac mortality accounted for 26 of 33 deaths within the first year after the AmECG. In the absence of coronary artery disease, survival at six months was 100% in patients with normal AmECG vs 90% (abnormal AmECG). In the presence of coronary artery disease, survival at six months was 83% (normal AmECG) vs 54% (abnormal AmECG).

Decreased insulin requirement in acute renal failure in diabetic nephropathy.

Twelve of 13 diabetics with azotemic nephropathy experienced exacerbation of renal failure and decreased insulin requirement after coronary angiography utilizing radiographic contrast material. The single patient who did not develop acute renal failure had no evidence of decreased insulin requirement. Eleven of 12 patients had decreased insulin requirement: mean decrement in insulin dose, 40%; mean decrement in fasting blood glucose level, 33%; mean decrement in peak blood glucose level, 42%. The 12th patient underwent peritoneal dialysis against hypertonic glucose without need of an increased insulin dose. Eight of 11 patients experienced a total of 19 insulin reactions; one patient was hypoglycemic continuously, despite infusion of glucose and discontinuation of insulin. The decrement of insulin requirement was not proportional to the rise in either serum creatinine or potassium concentrations. We suggest that when acute renal failure occurs in diabetics, decreased insulin requirement should be anticipated and the insulin dose lowered.

Reversible acute pulmonary edema due to uncontrolled hyperglycemia in diabetic individuals with renal failure.

On eight separate occasions, four functionally anephric diabetic patients (on maintenance hemodialysis) experienced episodes of severe hyperglycemia with acute interstitial and alveolar pulmonary edema demonstrated clinically and by chest x-ray without electrocardiographic or enzymatic evidence of an acute myocardial lesion. Three patients had normal stress 201T1 scanning. The fourth patient, who experienced three such episodes, had normal coronary angiograms and only a mild elevation of the left-ventricular end-diastolic pressure. Clinical and chest x-ray improvement were immediate following insulin therapy and control of hyperglycemia, without phlebotomy or dialysis. Since these episodes were observed during a 1-yr period, this syndrome may be more common than suspected. It is concluded that in functionally anephric diabetic individuals: (1) pulmonary edema can be precipitated by uncontrolled diabetes; (2) endogenous fluid shifts may contribute to the cause of acute pulmonary edema; (3) clinical and radiologic improvement can be achieved with adequate insulin therapy; and (4) blood glucose levels should be monitored and controlled in diabetic patients with renal failure.

Ocular surgery in patients with diabetic nephropathy.

Patients with severe diabetic nephropathy often have diabetic retinopathy requiring eye surgery. During the course of their nephropathy, which was treated medically (group A, N = 34), with dialysis (group B, N = 18), or with renal transplantation (group C, N = 2), 54 diabetic patients have had eye surgery. The ophthalmologic procedures included cataract extraction, vitrectomy, scleral buckling, and cyclocryosurgery. The complications included postoperative hemorrhagic glaucoma and persistent retinal detachment. These were encountered in two patients of group A and in two of group B. All other cases showed uneventful intra- and postoperative courses. Major eye surgery can be performed safely during therapy for diabetic nephropathy, including hemodialysis with anticoagulation and transplantation with immunosuppression.

Improving survival after renal transplantation for diabetic patients with severe coronary artery disease.

After successful renal transplantation, seven diabetic renal failure patients with severe coronary artery disease returned to productive employment. Despite the requirement for additional peripheral vascular or ophthalmologic surgery in four patients, their renal function remained adequate. Following transplantation, diabetic complications included angina in three, myocardial infarction in three, and cerebrovascular accident in two patients. Two patients with adequate renal function died suddenly at 29 and 62 mo. Despite severe coronary artery disease, an increasing number of diabetic dialysis patients may be able to return to work after a successful kidney transplant.

Psychosocial crisis in diabetic renal failure.

Twenty-nine diabetic renal failure patients suffered a psychosocial crisis at the time when chronic dialysis or renal transplantation was required. These patients could be classified into groups as to the impact of the crisis in terms of participation in life-support therapy. Group 1 consisted of potentially lethal mechanism (9 patients): discontinued dialysis (5); refused to start dialysis (3); overt act to cause personal harm (1). Group 2 contained probably nonlethal mechanism (11 patients): threatened to discontinue dialysis or to never start dialysis if not given a chance for a transplant (5); threatened to discontinue dialysis or to never start dialysis (5); threatened to cause personal harm (1). Group 3 consisted of a combination of mechanisms (9 patients): with drug abuse (4); without drug abuse (5). Important similarities between the groups were easier to document than were subtle differences in the kinds of options in family and employment relationships; in the degree of objective and subjective handicap due to impaired vision; in the level of expectation and/or disappointment following renal transplantation; and in the capacity to cope with changing personal relationships produced by the complications of diabetes.

Nutritional status of diabetic and nondiabetic patients after renal transplantation.

To assess whether there was improvement in the nutritional status of Type I insulin-dependent diabetics treated with renal transplantation as compared with dialysis, 24 diabetics and 21 nondiabetics were studied 22.6 +/- 23.8 mo after transplantation. Nutritional assessment included weight, height, triceps skinfold thickness, midarm muscle circumference (MAMC), serum albumin, and transferrin. Mean age of the 28 males and 17 females was 37.1 +/- 9.4 yr. Weight of diabetics increased from 55.6 +/- 8.4 kg to 61.5 +/- 9.5 kg (p less than 0.05); weight for height, from 81 +/- 8% to 95 +/- 9% (p less than 0.001); and serum albumin, from 3.8 +/- 0.5 gm/dl to 4.3 +/- 0.4 gm/dl (p less than 0.001). Weight also increased significantly in nondiabetics from 64.5 +/- 10.5 kg to 72.1 +/- 13.5 kg (p = 0.05); weight for height, from 96 +/- 15% to 108 +/- 16% (p less than 0.05); but not albumin, 4.1 +/- 0.7 gm/dl to 4.4 +/- 0.6 gm/dl (p greater than 0.05). Serum transferrin was 210 +/- 62 mg/dl in diabetics and 226 +/- 52 mg/dl in nondiabetics. Forty-two percent of diabetics and 29% of nondiabetics had a MAMC less than 5th percentile, indicating protein-calorie malnutrition. Results suggest a significant improvement in nutritional status after transplantation in both diabetics and nondiabetics, but particularly in the diabetic group.

Preoperative evaluation for diabetic renal transplantation: impact of clinical, laboratory, and echocardiographic parameters on patient and allograft survival.

OBJECTIVE: To assess the impact on renal transplant patients and graft survival of clinical, laboratory, and echocardiographic parameters commonly measured prior to surgery. PATIENTS: Forty-seven consecutive diabetics with preoperative echocardiograms at the time of transplantation. METHODS: Clinical history, standard chest roentgenogram, electrocardiogram, blood tests, echocardiograms, and HLA testing at baseline; follow-up from 2 to 7 years with periodic reassessment of graft function. RESULTS: Patient survival did not appear to be influenced by age, sex, or type of allograft. A history of either myocardial infarction, congestive heart failure, or angina was present in 15 patients with 3-year survival of 50% (72% if not present, p less than 0.05). Histocompatibility testing did not impact on survival. Serum sodium, potassium, calcium, phosphate, and calcium-phosphate product did not discern different survival groups. A hematocrit greater than 30% was present in 15 patients with 3-year survival of 43% (73% if not present, p less than 0.05). Greater than 10% antibody sensitization of the recipient resulted in a 3-year survival of 38% in eight patients (68% if not present, p less than 0.05). Radiologic evidence of cardiomegaly or congestive heart failure and standard electrocardiographic evidence for left ventricular hypertrophy or strain did not impact on survival. Echocardiographic measurements of left ventricular end-diastolic diameter, posterior wall thickness, or ejection fraction were also not predictive. Increased end-systolic diameter (10 patients, 30% 3-year survival versus 69%, p less than 0.05) and decreased velocity of circumferential fiber shortening (11 patients, 45% 3-year survival versus 71%, p less than 0.05) both appeared to be related to survival. Increased accuracy of prediction could be obtained by adding risk factors so that a history of coronary artery disease and increased end-systolic diameter predicted 3-year survival of 42% versus 82% if neither was present. In terms of graft survival, no clinical, radiographic, or electrocardiographic result yielded predictive information. Among the laboratory tests, only highly antibody-sensitized patients (eight patients, 0% 3-year survival versus 66% 3-year survival, p less than 0.001) showed different survival patterns. Echocardiographic elevated end-systolic diameter predicted a significantly (p less than 0.001) decreased graft survival (3-year survival 33% versus 63%). CONCLUSION: Preoperative prediction of patient and graft survival in diabetic renal transplantation may be enhanced by echocardiographic assessment of systolic load and function. For patients with normal systolic function, whose hematocrit is below 30%, with preformed antibodies less than 10%, renal transplantation has an excellent prognosis; invasive cardiac procedures are not likely required. Since these risk factors are likely additive, a high-risk group may be identified. These latter patients should undergo coronary angiography.

Nephrotoxicity from angiographic contrast material. A prospective study.

Three hundred and seventy-eight hospitalized patients undergoing nonrenal angiography were evaluated for subsequent changes in renal function. Acute renal failure was defined as a rise in the serum creatinine level of 1.0 mg/dl or more. Several factors that appeared to play no significant role in causing acute renal failure included: the volume of contrast material injected, the anatomic site of injection and the presence of a prior history of cardiovascular disease or diabetes mellitus. The single risk factor identified was the presence of preexistent azotemia (blood urea nitrogen of 30 mg/dl and serum creatinine of 1.5 mg/dl). Whereas nonazotemic patients had a 2 percent incidence of definite acute renal failure, patients with chronic azotemia (mean blood urea nitrogen/creatinine = 47/2.3 mg/dl) had a 33 percent incidence. Three patients required short-term dialysis, and two required potassium-exchange resin therapy. No patient required permanent dialysis, and no patient died of acute renal failure. The persistence of a positive nephrogram 24 hours after angiography was a sensitive detector of a rise in the serum creatinine level although more expensive than the creatinine determination. While urine sediment analysis confirmed the diagnosis in many cases, it was relatively insensitive. Monitoring of urine volume proved to be of little value. We recommend a screening serum creatinine determination 24 to 48 hours after infusion of angiographic contrast material in azotemic patients.

Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus.

Heart rate variability (HRV) has been used to assess cardiac autonomic function noninvasively, understand the pathophysiologic mechanisms of heart disease, evaluate therapy, and assess long-term prognosis. We examined both the short- and long-term reproducibility of the time and frequency domain HRV parameters in 23 type I diabetics over a 12-month interval. Entry criteria included juvenile onset diabetes before age 35 years, >24-year duration of diabetes, diabetes difficult to control, and albuminuria. Standardized noninvasive autonomic testing and 24-hour ambulatory electrocardiographic recordings were obtained. Fifteen men and 8 women (mean age 36.7 years) were enrolled. Fifty-three percent of the men and 75% of the women were smokers, and women had higher cholesterol than men. All HRV parameters were markedly decreased when compared with normal persons. Using Pearson correlation, the time domain indicators of parasympathetic activity demonstrated very strong correlations at 3 and 6 months compared with baseline, with good correlations at 1 year. The average SD of all 5-minute RR intervals maintained a very strong correlation for the entire year (r >0.94). In the frequency domain, the measures of parasympathetic and sympathetic activity maintained a solid correlation for the entire study period. Reproducibility of HRV was also examined using repeated-measures analysis of variance. The time and frequency domain parameters demonstrated very little variation over the study period of 12 months. Thus, our investigation demonstrated that HRV in long-term diabetics using 24-hour ambulatory recordings is abnormal and reproducible over a 12-month interval; very little variation in all HRV parameters, especially in parameters of parasympathetic activity, occurred during the study period.

Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy.

Diabetes mellitus is associated with a marked increase in the risk of coronary events but with an altered circadian distribution that demonstrates an absent morning peak and higher infarction rate during the evening hours. To elucidate the mechanism of this phenomenon, the circadian pattern of heart rate variability was evaluated in 22 type I diabetic patients with diabetic autonomic neuropathy in conjunction with circadian changes of fibrinolytic and hemostatic factors. The circadian pattern (6 A.M. to 10 P.M. vs 10 P.M. to 6 A.M.) of 3 indexes of parasympathetic tone was evaluated using 24-hour heart rate variability analysis. The high-frequency power (3.0 +/- 0.2 vs 3.3 +/- 0.2 ms2, p = 0.08) and the percentage of RR intervals with >50 ms variation (0.47 +/- 0.18 vs 0.69 +/- 0.33 ms, p = 0.52) demonstrated no significant circadian variation. The square root of mean squared differences of successive RR intervals showed a small but significant increase during nighttime (8.5 +/- 0.7 vs 9.7 +/- 1.1 ms, p = 0.02). Fibrinolytic activity was significantly lower at 8 A.M. than at 4 P.M. (166.4 +/- 12.5 to 200.2 +/- 9.3 mm2, p = 0.0003), but with a low amplitude. Plasminogen activator inhibitor 1 showed no circadian variation. Factor VII and fibrinogen demonstrated a significant reduction from 8 A.M. to 4 P.M., but both peak and nadir values were elevated. The von Willebrand factor was markedly elevated with no circadian variation. Thus, diabetic autonomic neuropathy is associated with a loss of both the nocturnal predominance of parasympathetic activity and a prothrombotic state that persists throughout the day. These abnormalities may attenuate the relative protection from coronary events during the afternoon and nighttime.

Effect of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy.

Diabetic cardiac autonomic neuropathy (CAN) is associated with a high risk of cardiovascular events. Previous studies have shown that strict glycemic control slows the deterioration of CAN as assessed by standard autonomic function tests but fails to show reversibility. The aim of this study was to evaluate the effect of glycemic control on early and advanced CAN in type I diabetic patients using power spectral analysis of heart rate variability (HRV). Ten patients with early and 13 patients with advanced CAN were enrolled in a program of intensified insulin treatment. Standard autonomic function tests and 24-hour time and frequency domain HRV parameters were obtained at baseline, 3, 6, and 12 months. Hemoglobin A1C decreased from 9.5 +/- 0.4% to 8.4 +/- 0.5% (p = 0.02) in the early CAN group, and from 9.3 +/- 0.4% to 8.2 +/- 0.5% (p = 0.006) in the advanced CAN group. In general, both time and frequency domain HRV indexes tended to improve in patients with early CAN but continued to deteriorate in patients with advanced CAN. The low- and high-frequency power increased in patients with early CAN (229 +/- 95 to 626 +/- 563 ms2 and 62 +/- 30 to 183 +/- 168 ms2, respectively). The high-frequency power significantly improved at 12 months over baseline (p = 0.04), indicating increased parasympathetic tone. By contrast, these parameters continued to deteriorate in patients with advanced CAN (65 +/- 32 to 46 +/- 8 ms2 and 193 +/- 75 to 144 +/- 33 ms2, respectively). Autonomic function tests showed no significant change in both groups. These data show that a reversible metabolic component of CAN exists in patients with early CAN. Power spectral analysis of HRV allows early identification of potential reversibility as early as 1 year after the institution of strict glycemic control.