Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers.
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Congenital Abnormalities↗
Biomedical subjects
R E Gleason
Publications and source records attributed to R E Gleason.
Clinical consequences of acquired transfusional iron overload in adults.
We assessed the clinical sequelae of transfusional iron overload in 15 nonthalassemic adults (40 to 71 years of age) with anemias requiring transfusions. Iron loading had been present for less than four years in 14 patients. The number of units of blood transfused ranged from 60 to 210 (mean, 120). Liver-biopsy specimens in 10 patients contained seven to 26 times the normal amount of iron and typically showed focal portal fibrosis. Left ventricular cardiac function was impaired in only the most heavily transfused patients or in those with coexisting coronary-artery disease, All patients had glucose intolerance associated with significantly reduced insulin output, compared with controls (P < 0.01). Pituitary reserve of ACTH was limited in 10 of 12 patients, and that of gonadotropin in five of 13. We conclude that widespread subclinical organ dysfunction can result from transfusional iron overload developing in adulthood. The pattern of organ involvement resembles that encountered in idiopathic hemochromatosis.
Adult↗
Reproducibility of the densitometric analysis of fluorescein angiograms.
Computer-aided operator-interactive densitometry was applied to assess the reproducibility or retinal-fluorescein angiograms. To achieve this, the fundus camera images of glass tubings of various diameter filled with fluorescein of varying concentrations were subjected to densitometric analysis. These studies were carried out repeatedly at 9-micrometer and 29-micrometer scanning resolutions by three observers and thus the inter- and intra-operator errors could be estimated. The scanned data were analyzed as both optical densities and intensities for some of the measurements. In both analyzing modes good linearity was obtained when the densitometric response was plotted against tubing diameter for various concentrations. To determine the reproducibility of transit time and retinal circulation time analyses, a randomly selected patient's angiogram was repeatedly analyzed by three observers and compared. From these data the inter- and intra-operator errors were also determined for successive frames and the reproducibility of the area under the dye dilution curves for both arteries and veins was computed. The overall densitometric reproducibility was found to be good; however, practical usefulness of the retinal circulation time remains to be established.
Angiography↗
Stability of hemoglobin AIc levels on repetitive determination in diabetic out-patients.
Hemoglobin (Hb) AIc levels were measured biweekly for 14 weeks in 49 diabetic out-patients and 20 nondiabetic subjects. As conventional indices of diabetes control, urine tests were performed four times per day, and plasma glucose concentrations were measured 2 h post breakfast. The diabetic group ranged in age from 15-73 yr and in duration of diabetes from 6 months to 45 yr. Eleven subjects were on diet therapy alone, three were on oral hypoglycemic agents, and 35 were on insulin therapy. The nondiabetic group ranged in age from 18-65 yr. On entry to the study, the mean (+/-SD) Hb AIc and plasma glucose levels of the diabetic group (8.60 +/- 2.11% and 142.5 +/- 99.9 mg/dl) were significantly higher than in the control group (4.68 +/- 0.60% and 102.4 +/- 21.7 mg/dl; P less than 0.001) and remained so throughout the study. The mean coefficient of variation for Hb AIc did not differ significantly between the control group and either the diet therapy or insulin therapy diabetic groups. Urine test values averaged over 2-week periods for each diabetic subject showed a high degree of stability. The mean Hb AIc levels for individual diabetic subjects correlated with the mean plasma glucose levels (r = 0.544; P less than 0.001), proportion of 2% urine tests (r = -0.798; P less than 0.001). These data provide further support for Hb AIc as a measure of diabetes control and, in addition, provide the first direct evidence that a single Hb AIc determination in a 3-month period is adequate for this purpose when the subjects are on a stable therapeutic regimen.
Adolescent↗
Measurement of hemoglobin A1 by liquid chromatography and by agar gel electrophoresis compared.
We compare measurement of total fast hemoglobin (HbA1) by "high-performance" liquid chromatography and by electrophoresis on agar gel. Blood samples were obtained from a diverse population (n = 222): offspring of two diabetic parents, diabetic patients with and without retinopathy, diabetic and non-diabetic pregnant women, patients in the coronary-care unit, and normal persons. Precision studies with a normal and an above-normal A1 sample resulted in overall CVs of 9.0% and 4.6% for the electrophoretic method and 4.4% and 2% for the chromatographic method. Linear regression analysis of values for total fast hemoglobin for the complete sample population and for each subgroup showed results of the electrophoretic method to be in excellent agreement with those by the chromatographic method. We conclude that the agar gel electrophoretic method offers a reproducible means for HbA1 determination that is comparable to the HPLC method in terms of accuracy and is highly suited for routine laboratory use.
Adolescent↗
Temporal relationship of glycosylated haemoglobin concentrations to glucose control in diabetics.
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Adult↗
Insulin secretory dynamics after two consecutive intravenous stimulations with glucose and/or tolbutamide.
Intravenous glucose and/or tolbutamide administered in two consecutive pulses 30 and 60 min apart to the same subjects using identical doses showed that insulin secretory responses was altered during a subsequent stimulation and that this was modulated by the time factor. Insulin response was more sustained after the second glucose pulses and the insulin peak response was delayed and diminished if the second glucose dose was given 30 min after the first, but not if given 60 min later. It is suggested that the beta-cell membrane might remain partially depolarized above a certain glucose level or that a postulated signal relay mechanism might become saturated. Responses to two tolbutamide pulses did not show these characteristics; however, the second insulin response was smaller than the first. When the first pulse was glucose and the second tolbutamide, or vice versa, the second responses were altogether different from those elicited by the double doses of either tolbutamide or glucose. To explain these characteristic patterns of insulin secretory dynamics, the existence of occult glucose receptors on the beta-cell that are opened up by tolbutamide was postulated. These studies do not support the two-pool theory, or at least restrict it to glucose-stimulated insulin response. The positive correlations between the first and the second insulin responses in all tests argue strongly against the existence of an insulin feedback mechanism in man.
Adult↗
Renal artery stenosis in hypertensive diabetics.
The incidence of atherosclerotic renal artery stenosis was compared in consecutive renal angiography of 28 hypertensive diabetics and 104 hypertensive non-diabetics. Mean age and sex distribution were comparable. Angiographic evidence of atherosclerotic renal artery stenosis was present in 10 diabetics (36 per cent) and 50 non-diabetics (48 per cent). Stenosis was considered hemodynamically significant if the renal vein renin ratio of the involved to uninvolved side was 1.4:1.0 or more. A renal vein renin ratio equal to or more than 1.4 was observed in 4 of 7 diabetics (57 per cent) and 31 of 47 non-diabetics (67 per cent). Fibromuscular hyperplasia was not seen in diabetics but was present in 12 per cent of the non-diabetics. Hypertension was treated surgically and improved in 2 of 3 diabetics (67 per cent) and in 17 of 19 non-diabetics (89 per cent) with angiographic and hemodynamic evidence of renal artery stenosis. In this series the incidence of atherosclerotic renal artery stenosis of physiologic consequence was not significantly different in hypertensive diabetics when compared to hypertensive non-diabetics.
Adult↗
Diabetes mellitus and genetic prediabetes. Decreased replicative capacity of cultured skin fibroblasts.
The idea that the gene(s) that cause diabetes mellitus can be expressed in extrapancreatic cells has been examined by tissue culture techniques. Skin biopsies were obtained from 25 normal subjects (N), 26 overt diabetics (D), 16 of juvenile onset (JOD) and 9 of maturity onset (MOD), and 21 subjects genetically predisposed to diabetes (P) on the basis of maturity-onset diabetes in both parents. Each biopsy was subdivided, multiple skin fragments were explanted in vitro, and several parameters of cellular outgrowth were monitored in primary and secondary cultures until cell division ceased because of senescence. In general, the rank order of growth vigor was N greater than P greater than D although differences were often marginal and statistically significant between N and JOD and(or) MOD. Outgrowth of epithelial cells was more vigorous in N explants in early stages, but later, JOD and MOD cells grew better than those of N. Outgrowth of fibroblast cells from N explants was more vigorous both at early and later stages and required less time to achieve maximum percent outgrowth. In secondary cultures, N cells grew faster than the other three groups so that fewer days elapsed between subcultures but significant differences were only seen between N and one or two of the other groups over some of the first seven subcultures. The onset of cellular senescence occurred earlier in P and JOD cultures both in mean population doublings and calendar time. N cultures had a higher percent surviving clones after picking than MOD, and a shorter recloning time than clones of JOD. The replicative life-spans of cultures (mean population doublings +/- SE) were N = 52.54 +/- 2.24, P = 47.84 +/- 2.43, JOD = 47.12 +/- 2.99, and MOD = 46.40 +/- 4.04, but differences did not reach significance for N vs the other three groups. The data demonstrate that cellular growth is impaired in both JOD and MOD types of cultures and to a generally lesser extent in P cultures. This is consistent with intrinsic genetic defects but the possibility that persistent deleterious effects of in vivo pathophysiology contribute alone or in combination cannot be ruled out. Therefore, the diabetic defect(s) can be expressed in extrapancreatic cells of mesenchymal origin. This system should prove useful in exploring the interplay between genetic and environmental factors in diabetes, the mechanisms(s) of hyperglycemia and other metabolic derangements, and the propensity that affected individuals have to develop degenerative diseases.
Adolescent↗
Metabolic effects of glucose, mannose, galactose, and fructose in man.
The effects of various hexoses upon immunoreactive insulin (IRI) secretion, glucose disposal, and gastric inhibitory polypeptide (GIP) release have been compared in 10 normal nonobese men. Rapid iv infusion (0.5 g/kg in 3 min) of D-mannose resulted in significant ITI release, the peak levels approaching those after D-glucose infusion. D-Galactose, however, was ineffective. The 60-min urine excretions of mannose, galactose, and glucose were 35 +/- 7%, 16 +/- 4%, and 5.5 +/- 0.7% (mean +/- SEM) of the administered dose, respectively. All subjects also received 50 g oral glucose, mannose, galactose, and fructose on different days, each followed by an iv glucose infusion 30 min later. The ingestion of glucose or galactose resulted in a similar increment of GIP (P less than 0.01), followed by a similar increment in the IRI response to iv glucose. Furthermore, the glucose disposal rate increased 2.5-fold compared to that after iv glucose alone (P less than 0.001). However, oral msnnose or oral fructose caused no significant GIP release, yet the IRI response to a subsequent iv glucose load was moderately augmented after oral mannose or oral fructose when compared to iv glucose alone. In addition, there was a similar enhancement of glucose disposal of the iv glucose load after both oral mannose and oral fructose (P less than 0.01). From these studies we conclude that 1) galactose does not elicit IRI secretion per se, yet, like glucose, potentiates GIP and IRI secretion; 2) mannose, despite weak transport across gut or kidney, evokes significant betacytotropic effects; and 3) mannose- and fructose-induced enhancement of glucose disposal might be mediated by a factor(s) other than GIP.
Adolescent↗
Reproducibility of hemoglobin AIc and sensitivity to various degrees of glucose intolerance.
To establish a normal range of hemoglobin (Hb) AIc, and ascertain the sensitivity and reproducibility of this test, three groups were studied: patients with suspected diabetes undergoing a standard oral glucose tolerance test, diabetic outpatients, and subjects with normal carbohydrate tolerance studies on two separate occasions. In Group 1, the mean Hb AIc (+/- SD) in 165 carbohydrate-tolerant subjects was 4.97 +/- 0.50% and the normal range was the mean +/- 2 standard deviations (4.0 to 6.0%). The mean Hb AIc (+/- SD) of the 63 carbohydrate-intolerant subjects was 6.45 +/- 1.14, significantly greater than the normal subjects. In both subgroups, Hb AIc correlated significantly with the fasting blood glucose but not with the glucose areas of the oral glucose-tolerance test. In Group 2, the Hb AIc values were normal in 39% of those diet treated, 10% of those on oral agents, and none of those on insulin therapy. In Group 3, the mean coefficient of variation of the two Hb AIc values for each subject was 6.86% but was 7.15% for the fasting blood glucose. These findings suggest that Hb AIc is highly reproducible and responsive to minor degrees of abnormality of glucose tolerance and may provide an alternative method for defining carbohydrate tolerance or the degree of blood sugar control.
Adolescent↗
Age affect and replicative life-span of fibroblasts of diabetic, prediabetic, and normal donors: another look at the data.
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Adolescent↗
Chronologic and physiologic age affect replicative life-span of fibroblasts from diabetic, prediabetic, and normal donors.
Cultured skin fibroblasts from subjects with clinically apparent diabetes mellitus and from subjects genetically predisposed to diabetes have a replicative lifespan that is inversely related to donor age. Fibroblasts from carefully defined normal subjects not predisposed to diabetes fail to show this correlation. The data support the idea that physiologic status of the tissue donor is a more precise determinant of fibroblast replicative lifespan than chronologic age.
Adolescent↗
Factors governing insulin and glucagon responses during normal meals.
An experimental model is described which can be used to study substrate and hormone responses to normal meals administered in very near normal circumstances. After 500, 300 and 125 calorie meals, the relative proportion of fat or protein content did not influence the plasma glucose except for minor differences between the high protein-high fat meals. The insulin response to such meals was correlated positively with the increment in glucose but reduction of protein content below 8 g caused a signficant reduction in the increment in plasma insulin per unit increase in plasma glucose. Alterations in protein content above 8 g made no difference. Fat content of the meal did not significantly alter the insulin response. No evidence was obtained for a major component of insulin release attributable to either bulk or preabsorption phenomena such as sight or smell. It is concluded that a significant accentuation of the insulin response to meals is dependent on a minimum amount of protein and that this is probably mediated by one of the gastro-intestinal hormones. Glucagon release is dependent on protein and carbohydrate content of the meal and is independent of the fat content. There may also be an early stimulation of glucagon release, regardless of content, which may also be hormonally mediated.
Adult↗
Asymptomatic coronary artery disease: angiographic assessment of diabetics evaluated for renal transplantation.
Twenty-one insulin-dependent diabetics with azotemic nephropathy were evaluated for renal transplantation by selective coronary angiography and cine left ventriculography. All had hypertension, retinopathy, neuropathy, and required salt restriction plus diuretics for volume overload. There was no clinical or electrocardiographic evidence of ischemic coronary artery disease in twenty. Ten patients (five males, five females, mean age 29.3 years; mean duration of diabetes 21.9 years; mean serum cholesterol 239 mg%) had significant coronary artery disease, seven demonstrating focal abnormalities in left ventricular wall motion. Two patients (one male, one female; mean age 36.5 years; mean duration of diabetes 28.5 years; mean serum cholesterol 250 mg%) had no significant coronary artery disease, but demonstrated diffusely abnormal left ventricular wall motion with diminished ejection fraction. Thirty-eight percent had significant coronary artery disease unpredictable by electrocardiographic or clinical data. The finding of no significant coronary artery disease in 52% of a group with severe renal-hypertensive complications of diabetes is surprising. Two patients may have a demonstrated cardiomyopathy.
Adult↗
A model of glucose-insulin homeostasis in man that incorporates the heterogeneous fast pool theory of pancreatic insulin release.
Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.
Computers↗
Reproducibility and comparative analysis of repeated intravenous and oral glucose tolerance tests.
We have developed a methodology for measuring the reproducibility of the oral glucose tolerance test (OGTT) and the intravenous glucose tolerance test (IVGTT) in normal subjects and in offspring of conjugal diabetic parents. Both groups of subjects revealed more striking correlations of several parameters of blood glucose and insulin secretion between two IVGTTs than between two OGTTs. Employing arbitrary criteria, we calculated a "reproducibility index" as a quantitative measure of blood glucose variability in each subject. No significant difference was found in the reproducibility of OGTT versus IVGTT, nor in normals versus the offspring. Only about 50 per cent of the tests in normals and in the offspring could be considered to be "reproducible." The offspring revealed greater correlations of several parameters, particularly insulin secretion, between the two IVGTTs and between the two OGTTs as compared with the normal group. However, the blood glucose variations tended to be considerably greater in the offspring from one to the other test.
Administration, Oral↗
Chronic renal failure in diabetes: survival with hemodialysis vs. transplantation.
Clinical observations for 49 diabetic patients who required chronic hemodialysis or renal transplantation during a four year period are presented. Twenty-seven dialysis patients had a two year cumulative survival of 74% compared to 54% for 22 transplantation patients. The cumulative survival of live-related donor recipients (77%) was similar to that of the dialysis group and significantly better than that of cadaveric allograft recipients (36%). While the incidences of cardiomegaly and of motor neuropathy were high among live-related donor recipients, dialysis patients more often demonstrated peripheral vascular disease. Causes of death in hemodialysis patients included cardipulmonary arrest and patient decision to discontinue therapy; in the transplantation group included cardiopulmonary arrest, sepsis, and stroke. Living-related transplantation remains the preferred mode of therapy because of the potential for rehabilitation. In terms of patient survival, the risks of cadaver transplantation must be weighted against the discomforts of chronic dialysis.
Adult↗