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Biomedical subjects

J D Tobin

Publications and source records attributed to J D Tobin.

At least 73 records · Page 4Linked to original sources
PubMed1982

Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity.

We investigated the possible existence of a negative short-loop feedback of circulating insulin on the parent beta cell in 10 lean Caucasians, 10 obese Caucasians, and 10 obese Pima Indians. Plasma insulin levels were raised acutely by 100 microunits per milliliter for 90 minutes, and plasma glucose was maintained by the "clamp" technique. C-peptide levels were suppressed in all groups to approximately 50 per cent of basal values. However, the obese groups had absolute C-peptide levels much higher than those of the lean group. During the hour after infusion, the rate and magnitude of C-peptide recovery in the obese groups were higher than in the lean group. Thus, negative short-loop insulin-beta-cell feedback was operative in both the lean and obese states. Despite this suppression, the insulin-secretion rate in obese subjects was still greater than that in non-obese subjects. Inadequate feedback suppression may account in part for the prevailing hyperinsulinemia of the obese.

Adult↗
PubMed1982

Association of varicella, myocarditis, and congestive cardiomyopathy.

A retrospective study of children dying with active varicella revealed 11 of 17 cases who had unsuspected interstitial myocarditis at the time of their death. In addition, a prospective study of 6 children, consecutively admitted to the hospital with active varicella, were evaluated for evidence of cardiac dysfunction by echocardiography, ECG, and serum enzyme levels. All 6 children had Reye's syndrome in association with active varicella. Evidence of myocardial involvement, consistent with acute congestive cardiomyopathy, was documented in 4 of the 6 children. This study suggests that the heart is commonly involved in varicella infections and that cardiac involvement should be considered in children with this disease.

Adolescent↗
PubMed1982

Longitudinal changes in serum cholesterol in man: an epidemiologic search for an etiology.

Serum cholesterol levels were determined in 1011 male participants of the Baltimore Longitudinal Study of Aging. This study presents the longitudinal changes in serum cholesterol from 1 July 1963 to 30 June 1977. Serum cholesterol values dropped 6% between 1970 and 1972. The span of this study was divided into two eras, one preceding and one following the drop. The effects of obesity, selected dietary constituents and physical activity were examined in an attempt to explain the secular change in serum cholesterol. Serum cholesterol levels were not significantly correlated to levels of weight or body mass index. Changes in weight were significantly positively correlated with changes in serum cholesterol. Overall, however, the study population did not experience a significant drop in weight and therefore, this relationship could not explain the observed drop in serum cholesterol. There were virtually no significant correlations between the absolute value of any of the dietary variables examined and the absolute level of serum cholesterol. There were significant but small changes in most dietary constituents; however, only changes in caloric intake were significantly positively correlated with changes in serum cholesterol. Because the overall change in caloric intake was small, it could explain less than 1 mg/dl of the 11 mg/dl drop. There was no overall change in physical activity. No significant correlations were found between either the level or change in physical activity and the level or change in serum cholesterol. It is concluded that neither weight nor physical activity could account for the observed changes in serum cholesterol. Changes in dietary constituents were significant and in a direction which would predict a lower serum cholesterol. However, for the group, dietary changes could not fully explain the drop in serum cholesterol. For individuals, the changes in diet poorly predicted changes in serum cholesterol. It is suggested that the observed secular drop in serum cholesterol may be due to factor(s) other than those studied.

Adolescent↗
PubMed1982

Effect of age and obesity on fasting levels of glucose, insulin, glucagon, and growth hormone in man.

The influence of age and obesity on glucose homeostasis may be mediated via changes in basal levels of the main glucoregulatory hormones, insulin, glucagon, and growth hormone. Fasting plasma levels of these hormones and of glucose were measured in 186 normal male volunteers, 23 to 93 years old. Obesity was assessed as obesity index and by a more accurate anthropometric method as percentage of fat. Age and obesity index had a significant but low linear correlation (r = -.16, p less than .05). Age was not significantly correlated to any other metabolic variable. Percentage of fat was, however, significantly related to the fasting plasma levels of glucose (r = .27, p less than .001), insulin (r = .26, p less than .01), and glucagon (r = .16 less than .05). Fasting glucose was significantly correlated to insulin (r = .30 , p less than .001). These significant correlations persisted when age was held constant. In the basal state the main glucoregulatory hormones are not influenced by age, but plasma glucose, insulin, and glucagon levels are influenced by obesity.

Adult↗
PubMed1982

Effect of aging on the cardiothoracic ratio of men.

The potential usefulness of chest radiographs in the assessment of physical dimensions was examined in 243 men (age range 20-95 years) who had been followed up for an average of 12.3 years. From 1,124 of these films, measurements of cardiac diameter (CD) and thoracic diameter (TD) were made, and the cardiothoracic ratio (CTR) was calculated. Cross-sectional age differences were associated with a tendency toward increases in the CD and CTR throughout the lifespans of the 243 men, regardless of the presence or absence of heart disease. The thoracic diameter (TD) was greater in middle-aged than in young subjects, but less in the oldest than in the middle-aged subjects. Cumulative percentage curves for the CTR showed a shift to higher fiftieth to ninetieth percentile values with age. However, among the subjects free of heart disease, only one (age 95) had a CTR exceeding 50 per cent. Longitudinal analysis data agreed with the cross-sectional data. Forty-nine deceased subjects were matched with living subjects of the same heart disease classifications. Increases in the CD and CTR were predictive of death in the group with heart disease but not in the group without identifiable heart disease. An increase in CD was not correlated with an increase in systolic blood pressure. The decline in TD appeared to reflect a decline in rib-cage mobility with aging.

Adult↗
PubMed1982

Interaction of arginine and gastric inhibitory polypeptide on insulin release in man.

The interrelations of the insulin secretagogues, glucose, arginine (Arg), and gastric inhibitory polypeptide (GIP) were quantified in six normal young men in five sets of experiments with the hyperglycemic clamp technique (125 mg/dl above basal glucose levels for 2 h). After 60 min of intravenous glucose alone, one of the following was added: A) oral glucose (OG) (40 g/m2); B) 15 g.m-2.h-1 Arg infusion; C) 15 g.m-2.h-2 Arg infusion and OG; D) 7.5 g.m-2.h-1 Arg; E) 7.5 g.m-2.h-1 Arg and OG. The clearance rate of Arg was similar for B, C, D, and E. In all experiments, plasma GIP levels were unchanged from the basal level during the 1st h. The increases in plasma GIP levels in experiments C and E were similar to the increase when OG alone was ingested (A). When the stimulatory effect of the secretagogue(s) alone on insulin (IRI) is computed, the increase due to OG (A) and to 7.5 g.m-2.h-1 Arg (D) were similar and additive (A + D approximately equal to E). However, the stimulatory effect of 15 g.m-2.h-1 Arg + OG (C) on IRI was not significantly greater than 15 g.m-2.h-1 alone (B). The 15 and 7.5 g.m-2.h-1 Arg infusion produced different patterns of insulin and glucagon secretions. At the lower dose, the response of both hormones to Arg decreased with time. Arg and GIP act through a similar and possibly common mechanism on the beta-cell. However, only Arg was found to be alpha-cytotropic. GIP does not appear to influence the metabolic clearance of Arg. The dose-response relationships to Arg of the beta- and alpha-cell appear similar.

Adult↗
PubMed1981

Discrepant performance on oral and intravenous glucose tolerance tests: the role of gastric inhibitory polypeptide.

Analysis of a large study population revealed a group of eight healthy men whose tolerance to oral glucose was markedly greater than their tolerance to iv glucose (disparate group). The physiological basis of the anomalous performance was investigated using a variation of the hyperglycemic glucose clamp technique. This technique allows separation of the effects of hyperglycemia and intestinal insulinotropic factors on B-cell response. The eight subjects with disparate tolerance tests were compared to eight healthy control subjects whose tolerances on the two tests were very similar. The disparate performers showed 1) higher basal circulating gastric inhibitory polypeptide (GIP) levels, 2) lower immunoreactive insulin (IRI) responses to hyperglycemia (iv glucose alone), 3) enhanced GIP response to oral glucose, and 4) enhanced IRI response to oral glucose. These results may be interpreted as indicating a role for GIP in the improved tolerance for oral glucose, although other unknown gastrointestinal hormones could theoretically also be involved. Enhanced release of GIP after oral glucose may compensate for the reduced IRI release in response to hyperglycemia. The mechanism underlying the enhanced GIP response in these studies remains to be explored. It will be of interest to follow these subjects to see whether their anomalous gut beta-cell balance has any long term pathogenetic implications.

Administration, Oral↗
PubMed1979

Glucose clamp technique: a method for quantifying insulin secretion and resistance.

Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

Glucose↗
PubMed1979

Kinetics of native insulin in diabetic, obese, and aged men.

The kinetics of unlabeled porcine insulin were studied in 69 nondiabetic male subjects aged 18-83 yr with obesity indexes of 0.93 - 1.51 and in 12 maturity-onset diabetics age 46-78 yr with obesity indexes of 0.95-1.56 by using the euglycemic clamp technique. Analysis of the insulin kinetic data by using a mathematical model permitted the determination, for each individual, of steady state distribution masses and degradation rate constants. The individuals were grouped to allow comparison of the results on the basis of age, obesity index, or diabetes. The responses over a period of 120 min to an infusion and wash out of insulin show some transient as well as steady state differences with age, obesity, or diabetes. Analysis of these data by use of compartmental models leads to the conclusion that in the steady state the ratio of insulin in extravascular spaces to that in plasma (T/P) is decreased in the moderately obese group (26%) and in the diabetic group (17%) but increased in the older group (13%) when each is compared with the appropriate control. Since extravascular insulin includes both insulin bound to receptors and insulin in the interstitial fluid, the observed changes in the extravascular to plasma mass ratio most likely reflect changes in in vivo binding to receptors, although the magnitude of the change would be modified somewhat by changes in the size of the interstitial spaces relative to plasma. In addition, the rate of entry of new insulin into plasma (BSDR) was increased in the diabetic population (45%; P less than 0.02) as well as in the moderately obese group (27%) but was decreased somewhat in the older group (11%). The following general conclusions can be drawn from the results: The pattern of parameter changes seen with obesity is similar to that seen with maturity-onset diabetes. The decrease in T/P seen with obesity and with maturity-onset diabetes cannot be accounted for solely by changes in fasting plasma insulin levels in these populations. The pattern of changes seen in the older subjects is opposite that seen in the maturity-onset diabetics, which suggests that diabetes is a perturbation distinct from the normal aging process. Finally, the changes in the metabolism of insulin are not large, making it unlikely that they are the sole cause of the major alterations in glucose tolerance seen with aging, obesity, or diabetes.

Adolescent↗
PubMed1978

The response of arginine vasopressin to intravenous ethanol and hypertonic saline in man: the impact of aging.

The effect of age on the hypothalamic-hypophyseal-renal axis in normal man was determined by assaying plasma arginine vasopressin (AVP) responses to inhibitory and to secretory stimuli. Nine young (21-49 years) and 13 old (54-92 years) subjects received IV ethanol (375 mg/m2 per min). AVP levels fell progressively during the infusion in the young group, but fell for only 30 min in the old group and then rose paradoxically despite the continuing increase in blood ethanol. Eight young (22-48 years) and 8 old (52-66 years) men were provided identical osmolal loads by a 2-hour IV infusion of 3% NaCl at 0.1 ml/kg per min. Serum AVP rose 2.5 times the baseline in the young and 4.5 times the baseline in the old men despite identical free water clearances. Osmoreceptor sensitivity (the slope of AVP on osmolality) was greater in the old subjects. The heightened sensitivity to hyperosomolality helps examine the paradoxical response to ethanol, since osmolality increased during that time. This increased AVP response may severe to compensate for the reduced renal ability to conserve salt and water in aging man.

Adult↗
PubMed1978

Oral glucose augmentation of insulin secretion. Interactions of gastric inhibitory polypeptide with ambient glucose and insulin levels.

Gastric inhibitory polypeptide, or GIP, has been postulated as the major enteric hormonal mediator of insulin release. The release of immuno-reactive GIP (IR-GIP) after oral glucose and its role in insulin release was studied in normal men by the glucose clamp technique. In 24 subjects studied with the hyperglycemic clamp, blood glucose was maintained at 125 mg/dl above basal for 2 h via a primed-continuous IV glucose infusion coupled to a servo-controlled negative feedback system. 40 g glucose per m(2) surface area was ingested at 60 min, and the blood glucose was maintained at the steady-state hyperglycemic level. Plasma IR-GIP and insulin (IRI) levels were measured throughout the 2-h period. IR-GIP levels changed little when IV glucose alone was given; the mean basal value was 305+/-34 (SEM) pg/ml. After oral glucose, IR-GIP levels began to rise within 10 min and reached a peak within 40 min of 752+/-105 pg/ml. Plasma IRI responded initially to the square wave of hyperglycemia in the typical biphasic pattern. After oral glucose, plasma IRI levels rose strikingly above the elevated levels produced by hyperglycemia alone, reaching a peak of 170+/-15 muU/ml within 45 min. The time course of the rise in IR-GIP and IRI was nearly identical. To assess whether the maintenance of euglycemia would affect this process, the euglycemic clamp was employed in 11 subjects to maintain basal blood glucose levels during a similar 2-h study. A primed-continuous insulin infusion, with a constant rate of 120 mU/m(2) per min was given together with a servo-controlled glucose infusion. This resulted in hyper-insulinemia of approximately 300 muU/ml. Glucose was ingested by six subjects at 60 min. Plasma IR-GIP responded to oral glucose similarly to the effect seen in the hyperglycemic studies. No increase in endogenous insulin release was seen despite the increase in IR-GIP when euglycemia was maintained. However, in five of seven subjects given insulin whose blood glucose concentration rose by 20 mg/dl or more after oral glucose, there was an increase in plasma insulin concentration associated with the elevation in IR-GIP. Thus, the effect of glucose-released IR-GIP on insulin secretion is dependent upon the presence of some degree of hyper-glycemia and is not inhibited in the presence of marked hyperinsulinemia.

Adolescent↗
PubMed1978

Glucose intolerance in uremia. Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin.

The relative contributions of impaired insulin secretion and of tissue insensitivity to insulin to the carbohydrate intolerance of uremia were investigated in 10 chronically uremic subjects. Two types of glucose-clamp experiments were performed in each patient before and after 10 wk of thrice weekly hemodialysis. In both types the blood glucose concentration was maintained at a constant level by the periodic adjustment of a variable glucose infusion with a negative feedback formula.Hyperglycemic clamp. The blood glucose concentration was acutely raised and maintained 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate is an index of glucose metabolism (M). After dialysis M increased in all patients from an average of 4.23 to 6.30 mg/kg body wt per min (P < 0.001). The plasma insulin responses (I) both pre- and postdialysis were biphasic with an early burst within the first 2-5 min, followed by a phase of gradually increasing insulin concentration. After dialysis the plasma insulin response diminished slightly. Consequently, the M/I ratio, an index of tissue sensitivity to endogenous insulin, increased postdialysis in all subjects by an average of 92% (P < 0.01). Euglycemic clamp. The plasma insulin concentration was acutely raised and maintained by a primecontinuous insulin infusion. The blood glucose concentration was held constant at the basal level by a variable glucose infusion as above. M/I again is a measure of tissue sensitivity to insulin (exogenous) and increased in all patients postdialysis by an average of 57% (P < 0.01). In two patients hepatic glucose production was measured with tritiated glucose during the euglycemic clamp and declined by 84% predialysis. A similar decrease (82%) was observed postdialysis. Thus, both the hyperglycemic and euglycemic clamp techniques demonstrated tissue insensitivity to insulin to be the dominant carbohydrate defect in uremia. The surprising apparent lack of consistency in the change in beta cell response postdialysis is explained by the strong inverse correlation between beta cell sensitivity to glucose and tissue sensitivity to insulin (r = -0.920; P < 0.001). Those individuals who showed the most striking improvement in tissue sensitivity to insulin actually decreased their serum insulin response to hyperglycemia; those whose improvement in tissue sensitivity was more modest showed increases in beta cell responses.

Administration, Oral↗
PubMed1978

Loss of insulin response to ingested amino acids after jejunoileal bypass surgery for morbid obesity.

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.

Amino Acids↗
PubMed1977

Aging and ethanol metabolism.

The effect of aging on the distribution and elimination of ethanol was studied in a group of 50 healthy subjects ranging in age from 21 to 81 yr (mean, 53.3). Ethanol was administered in a continuous 1-hr infusion at a mean rate of 375 mg/m2 body surface area/min (equivalent to a mean dose of 0.57 gm/kg body weight). Serial blood samples for the determination of ethanol concentration was obtained at 15- to 30-min intervals for up to 4 hr post infusion. Ethanol elimination and distribution were evaluated with the aid of a two-compartment model. Rates of ethanol elimination were not affected by age. Peak ethanol concentration in blood water at the end of the infusion period was correlated with age (r= 0.55, p less than 0.001). Lean body mass and total volume of distirbution fo the ethanol were negatively correlated with age. The smaller volume of distirbution, in association with the decreased lean body mass, most likely explains the higher peak ethanol concentration found in the blood after administration of an ethanol does on the basis of surface area in the old as compared with the young subjects. This study demonstrates that age-related changes in body composition are important factors in the study of ethanol metabolism and its pharmacologic effects.

Adult↗
PubMed1977

A test of the hypothesis that the rate of fall in glucose concentration triggers counterregulatory hormonal responses in man.

The hypothesis that the rate of fall in glucose concentration triggers counterregulatory hormonal responses was tested in five subjects following one hour of sustained hyperglycemia. Despite a rapidly falling blood glucose concentration, no increase in plasma growth hormone, cortisol, glucagon, or catecholamines occurred as long as the blood glucose concentration remained above fasting levels. Plasma growth hormone, cortisol, and catecholamines were not released until the mean blood glucose reached 28 mg./100 ml., 39 mg./100 ml., and 39 mg./100 ml., respectively, below the fasting level. Plasma glucagon was suppressed during the period of hyperglycemia. As the blood glucose concentration fell below basal levels, a progressive increase in glucagon occurred. Plasma glucagon returned to fasting values when the nadir in blood glucose was attained. During the period of rapidly falling blood glucose, only plasma insulin showed any change; its response lagged behind the decline in blood glucose. By the time the fasting glucose level was attained, the plasma insulin was still almost three times the basal level. We concluded that under our experimental conditions the rate of fall in blood glucose and the degree of hypoglycemia achieved is primarily determined by the plasma insulin concentration.

Blood Glucose↗