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Biomedical subjects

D C Robbins

Publications and source records attributed to D C Robbins.

71 records · Page 4Linked to original sources
PubMed1984

Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.

Familial hyperproinsulinemia, a hereditary syndrome in which individuals secrete high amounts of 9,000-mol wt proinsulin-like material, has been identified in two unrelated cohorts. Separate analysis of the material from each of the two cohorts had suggested that the proinsulin-like peptide was a conversion intermediate in which the C-peptide remained attached to the insulin B-chain in one case, whereas it was a conversion intermediate in which the C-peptide remained attached to the insulin A-chain in the other. To reinvestigate this apparent discrepancy, we have now used chemical, biochemical, immunochemical, and physical techniques to compare in parallel the structures of the immunoaffinity chromatography-purified, proinsulin-like peptides isolated from the serum of members of both families. Our results show that affected individuals in both cohorts secrete two-chained intermediates of proinsulin conversion in which the COOH-terminus of the C-peptide is extended by the insulin A-chain and from which the insulin B-chain is released by oxidative sulfitolysis. Analysis of the conversion intermediates by reverse-phase high-performance liquid chromatography using two different buffer systems showed that the proinsulin-related peptides from both families elute at a single position very near that of the normal intermediate des-Arg31, Arg32-proinsulin. Further, treatment of these peptides with acetic anhydride prevented trypsin-catalyzed cleavage of the C-peptide from the insulin A-chain, a result demonstrating the presence of Lys64 and the absence of Arg65 in both abnormal forms. We conclude that individuals from both cohorts with familial hyperproinsulinemia secret very similar or identical intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A chain and in which Arg65 has been replaced by another amino acid residue.

Acetic Anhydrides↗
PubMed1984

Effects of chronic beta-receptor stimulation on sympathetic nervous system activity, energy expenditure, and thyroid hormones.

The effects of hyper- and hypothyroidism on sympathetic nervous system activity and energy expenditure are well recognized. The impact of altered sympathetic nervous system activity on energy expenditure and thyroid hormone metabolism has not been well studied. We investigated the effects of orally administered terbutaline sulfate, a beta 2-receptor agonist (5 mg, three times per day for 2 weeks), on the activity of the sympathetic nervous system, energy expenditure, and thyroid hormone metabolism in six normal men, aged 21-36 yr. The cardiovascular, metabolic, and thermogenic responses to an infusion of the beta-adrenergic agonist isoproterenol were clearly blunted after 2 weeks of treatment with terbutaline sulfate, indicating down-regulation of beta-receptors and/or development of reduced sensitivity. There were no significant changes in the cardiovascular, metabolic, or thermogenic responses to an infusion of the alpha-adrenergic agonist phenylephrine. Basal metabolic rate was significantly increased by the chronic administration of terbutaline sulfate [5.040 +/- 0.167 (+/- SE) vs. 5.421 +/- 0.234 kJ/min; P less than 0.05]. There was a highly significant change in the serum T3 to T4 ratio (19.4 +/- 1.0 vs. 24.4 +/- 1.0; P less than 0.001). This was a result of increased serum T3 concentrations (136 +/- 9 vs. 160 +/- 14 ng/dl; P less than 0.05) and decreased serum T4 concentrations (7.2 +/- 0.8 vs. 6.7 +/- 0.8 micrograms/dl; P = NS). Chronic beta-receptor stimulation with terbutaline sulfate increases the basal metabolic rate and T3 concentrations. These changes occurred despite down-regulation of beta-receptors and/or decreased sensitivity in response to chronic terbutaline administration.

Adrenergic alpha-Agonists↗
PubMed1984

Effects of chronic beta receptor stimulation on glucose metabolism.

The acute administration of a beta receptor-stimulating agent profoundly affects insulin-mediated glucose metabolism; however, little is known about the impact of chronic beta receptor stimulation on glucose metabolism and insulin sensitivity. We therefore investigated the effect of the chronic administration of a beta-2-agonist, terbutaline sulfate (TS), on glucose metabolism in 7 healthy, normal-weight, male volunteers between the ages of 21 and 30 yr. Studies were performed using the euglycemic, hyperinsulinemic (1.0 mU/min X kg) clamp technique before and after the oral administration of 5 mg of TS three times a day for 1 and 2 wk. Basal endogenous glucose production (EGP) (2.54 +/- 0.11 versus 2.64 +/- 0.14 mg/min X kg) and basal glucose oxidation (1.87 +/- 0.16 versus 2.0 +/- 0.2 mg/min X kg) were unchanged by the chronic administration of TS. However, insulin-stimulated total glucose metabolism increased by 29% (7.0 +/- 0.47 versus 9.05 +/- 0.67 mg/min X kg; P less than 0.02). Insulin-stimulated, nonoxidative glucose disposal increased by 45% (3.62 +/- 0.42 versus 5.26 +/- 0.48 mg/min X kg; P less than 0.01), while insulin-stimulated glucose oxidation did not change significantly (3.38 +/- 0.15 versus 3.79 +/- 0.22 mg/min X kg). EGP was completely suppressed under both conditions. Mean basal plasma insulin concentration (41 +/- 9 versus 49 +/- 15 pmol/L) and insulin clearance during the clamp procedure was unchanged (477 +/- 45 versus 474 +/- 37 ml/min X m2). We conclude that chronic beta receptor stimulation with TS improves insulin-stimulated glucose disposal in man, mostly by improving nonoxidative glucose disposal, i.e., "glucose storage."(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Effects of physical training and diet therapy on carbohydrate metabolism in patients with glucose intolerance and non-insulin-dependent diabetes mellitus.

The effects of 12 wk of physical training in addition to hypocaloric diet (DPT group, N = 10) on body composition, carbohydrate (CHO) tolerance, and insulin secretion and action were compared with the effects of diet therapy alone (D group, N = 8) in CHO-intolerant and non-insulin-dependent diabetic subjects. Fat mass, fat-free mass (FFM), mean fasting plasma glucose, serum C-peptide, and insulin concentrations decreased similarly in both groups. The mean plasma glucose response to a mixed meal decreased approximately 20% in both treatment groups, and, after i.v. glucose, decreased 12% in the D group (P less than 0.05), but did not change in the DPT group (NS between groups). The acute serum insulin response (0-6 min) after IG increased significantly in the DPT group only (NS between groups). The mean basal endogenous glucose production (BEGP) decreased 17% (P less than 0.025) in the DPT group and by 31% (P less than 0.01) in the D group (NS between groups). Hepatic sensitivity to insulin, estimated by BEGP suppression during the euglycemic clamp, increased significantly by 25% in both groups. Total glucose disposal during the euglycemic clamp increased from 3.51 +/- 0.04 milligrams of glucose per kilogram of fat-free mass per minute (mg/kg-FFM/min) to 4.45 +/- 0.54 mg/kg-FFM/min (P less than 0.05) in the DPT group, but no change occurred in the D group (NS between groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Comparative effects of aspirin and enteric-coated aspirin on loss of chromium 51-labeled erythrocytes from the gastrointestinal tract.

Sodium chromate Cr 51 was used to label red blood cells of 19 healthy male volunteers, whose stools were collected for four days before and four days during oral administration of either uncoated (N = 9) or enteric-coated (N = 10) aspirin. Each subject received 2.925 gm/day of aspirin, in three equal doses separated by eight-hour intervals, for a total of seven days. During drug use, stools were collected on days 4 through 7. Fecal blood content, estimated by measuring radioactivity in the stools, was significantly higher (P less than 0.001) during use of either type of aspirin than at baseline, but losses measured during use of the coated aspirin (mean, 1.54 ml/day) were significantly lower (P less than 0.001) than those measured during use of the uncoated aspirin (mean, 4.33 ml/day). The two types of aspirin produced equivalent serum concentrations of salicylates. We conclude that enteric-coated aspirin reduces gastrointestinal blood loss.

Adolescent↗
PubMed1983

Thermic effect of infused glucose and insulin in man. Decreased response with increased insulin resistance in obesity and noninsulin-dependent diabetes mellitus.

The thermic effect of infused glucose and insulin was measured by combining the hyperinsulinemic euglycemic clamp technique with indirect calorimetry, in 10 normal weight volunteers (group I), 7 obese subjects with normal glucose tolerance (group II), and 13 obese subjects with abnormal glucose tolerance or noninsulin-dependent diabetes mellitus before (group IIIa) and after weight loss of 10.8 +/- 0.4 kg (group IIIb). During hyperinsulinemia (760-1,100 pmol/liter), total glucose disposal from combined endogenous production and glucose infusion was 545 +/- 49, 441 +/- 70, 233 +/- 35, 231 +/- 31 mg/min and energy expenditure changed by + 0.476 +/- 0.080, +0.293 +/- 0.095, -0.114 +/- 0.063, and +0.135 +/- 0.082 kJ/min in group I, II, IIIa, and IIIb, respectively. The increased energy expenditure correlated with glucose storage (measured cost of processing the glucose: 1.33 kJ/g). In group IIIa there was no increase in energy expenditure in response to glucose and insulin infusions. After therapy (group IIIb) there was a significant recovery (P less than 0.05) of the thermic effect of infused glucose although total glucose disposal was unchanged. It is proposed that the recovered thermic effect of infused insulin/glucose is due to the different contributions of gluconeogenesis in the fasting state and during the glucose clamp before and after weight loss. In addition we hypothesize that some of the lower thermic effect of food reported in obese noninsulin-dependent diabetics may be explained by decreased energy expenditure due to a greater suppression of hepatic gluconeogenesis as well as by lower storage rate.

Blood Glucose↗
PubMed1982

Absence of exercise-induced hypoglycaemia in type i (insulin-dependent) diabetic patients during maintenance of normoglycaemia by short-term, open-loop insulin infusion.

To assess the risk and possible mechanisms of hypoglycaemia during moderate exercise in Type I (insulin-dependent) diabetic patients receiving constant insulin infusion, five insulin-dependent male diabetic patients were exercised 18 h after their last meal and 30 h after their last injection of intermediate acting insulin. Intravenous insulin was initially delivered via a closed-loop infusion system programmed to lower mean blood glucose from 11.3 +/- 1.8 to 4.8 +/- 0.4 mmol/l over approximately 3.5 h. Blood glucose was then maintained at this level for 4 h. At this time, the closed-loop infusion was discontinued and replaced by an open-loop system. The average amount of insulin infused per min during the 4 h normoglycaemic closed-loop period was calculated and this amount was infused at a constant rate during both a 30 min period of exercise on a bicycle ergometer (approximately 65% maximum oxygen uptake) and a 30 min rest period which followed. Five nondiabetic males served as control subjects. Despite significantly higher free insulin concentrations (p less than 0.05) and identical pre-exercise blood glucose concentrations, blood glucose rose during exercise only in the diabetic group (0.5 +/- 0.2 mmol/l; p less than 0.01). Changes in the serum concentrations of lactate, glycerol, glucagon, cortisol, non-esterified fatty acids and growth hormone were similar in the two groups and did not account for the increment of blood glucose in the diabetic patients. Beta-hydroxybutyrate concentrations were, however, higher in the diabetic patients at the onset of exercise (p less than 0.01) and decreased significantly more than the control subjects during exercise. We conclude that exercise under these conditions in diabetic patients is not attended by hypoglycaemia.

3-Hydroxybutyric Acid↗
PubMed1982

The interaction of free fatty acids in radioimmunoassays for reverse triiodothyronine.

We have investigated the effect of FFA on the RIA of rT3 because of our previous findings of a correlation between serum rT3 values and increased FFA concentrations during prolonged exercise and reports of interference by FFA in other thyroid hormone assays. Apparent rT3 values increased by 19% and 34% in in vivo studies of acute lipolysis in subjects 5 min post exercise or 10 min post heparin, respectively, while T3 and T4 concentrations were unchanged. Varying concentrations of palmitic acid were added in vitro to four normal sera, and the increase in FFA concentration correlated significantly with the increase in apparent rT3 values. The mean +/- SE of the regression slope was 9.3 +/- 1.8 ng/dl rT3/mM FFA (r = 0.96 +/- 0.02). The addition of linoleic acid produced a similar effect. T3 and T4 concentrations were unchanged. The interaction of FFA in the rT3 RIA was unrelated to the procedure used to separate the assay, to the concentration of 8-anilino-1-napthalene-sulfonic acid in the assay buffer, to FFA binding directly to the antisera or to use of a particular antisera. The magnitude of the effect was similar in charcoal-treated sera, and the addition of 2 mM palmitic acid to the assay standard curve decreased the y intercept but did not alter the slope, suggesting an interaction of rT3 with FFA, rather than change in affinity of the antisera.

Energy Intake↗
PubMed1982

Insulin resistance and insulin receptors in hepatic cirrhosis.

To explore the influence of extrahepatic factors in the pathogenesis of insulin resistance in hepatic cirrhosis, we studied 125I-insulin binding to erythrocytes and monocytes of 14 clinically stable cirrhotic individuals and compared the results with a normal control group. All patients had fasting normoglycemia at the time of the study but abnormal glucose tolerance was detected in 7 of 9 cirrhotic patients after an oral glucose load. Seven patients (group N) had normal fasting serum insulin levels, and 7 patients (group H) manifested fasting hyperinsulinemia. However, all patients had elevated insulin levels after oral glucose. Insulin binding to erythrocytes was significantly decreased in both cirrhotic subgroups; monocyte studies in 5 hyperinsulinemic patients revealed a similar decrease in binding. Scatchard analysis in monocytes suggests that this decreased binding is secondary to a decrease in the receptor number per cell. No correlation between insulin binding and fasting plasma insulin, glucagon, or growth hormone levels was seen. Sera from 4 patients were examined for the presence of a non-specific inhibitor of insulin binding, but no evidence for such a factor was found. We conclude that the decrease in insulin binding is mediated in the monocyte by a reduction of receptor concentration; in the erythrocyte the mechanism for decreased binding could not be clearly delineated. The insulin resistance seen in cirrhosis may result in part from decreased binding of insulin to target tissues; an additional postreceptor defect cannot be excluded in hyperinsulinemic individuals.

Adult↗
PubMed1979

Changes in serum concentrations of 3,3',5'-triiodothyronine and 3,5,3'-triiodothyronine during prolonged moderate exercise.

The effect of moderate bicycle exercise (3.5 h) on peripheral thyroid hormone metabolism was studied under two conditions (with and without glucose infusion) in four normal males. Serum T3, rT3, total protein, plasma glucose, and FFA were determined. Exercise induced an increase in rT3 from 29 to 40 ng/dl (P less than 0.01), a decrease in T3 from 154 to 147 ng/dl (P less than 0.01), and an increase in T4 from 7.1 to 7.5 micrograms/dl (P less than 0.05). When glucose was infused during exercise, the changes in rT3 were blunted (P less than 0.01) and the changes in T3 and T4 were diminished. During exercise, rT3 correlated with FFA (r = 0.95) and plasma glucose (r = -0.87). When glucose was infused during exercise, these correlations decreased (r = 0.81 and -0.56, respectively). Since moderate, prolonged exercise induces a state of early or acute starvation it is concluded that the changes in peripheral thyroid hormone metabolism reported here are similar to those found in starvation. The temporal changes of rT3, FFA, and plasma glucose during exercise suggest a relationship between thyroid hormone metabolism and the uptake and utilization of FFA and glucose or the mixture of these body fuels.

Adult↗
PubMedDate not supplied

Biphasic patterns of peripheral insulin and glucose levels after lunch in normal subjects.

The dynamic relationship of glucose concentrations and insulin secretion during the postabsorptive state is complex and has been associated with a variety of cyclic rhythms. To study the pattern of insulin and glucose response immediately after a mixed meal, we collected blood every 15 min from 0730 to 1645 h from eight normal resting men (age 24.9 +/- 2.1 yr). They took identically constituted mixed meals at 0800 and 1145 h. Concentrations of glucose and insulin were measured in samples taken throughout the study, whereas levels of C-peptide, glucagon, and alpha-NH2 were determined in samples taken after 1130 h only. Computer-assisted analysis was used to identify significant increments and declines in concentrations and to quantify the coincidence of peaks of glucose, C-peptide, glucagon, and alpha-NH2 with peaks of insulin. Coefficients of correlation between data points were calculated for each individual. The patterns of blood insulin and glucose after breakfast and lunch were different. After breakfast, a single simultaneous peak in insulin and glucose occurred approximately 60 min after starting the meal. In contrast, the pattern after lunch in seven of the eight subjects was clearly biphasic. There were secondary, significant coincident peaks in serum insulin, glucose, and C-peptide occurring 1.75-2.25 h after the meal was served. The secondary peak appeared unrelated to the late absorption of protein because it was not associated with consistent changes in serum alpha-NH2 concentration. Erratic variations characterized the postlunch pattern of glucagon levels, excluding a role for this counterregulatory hormone in the control of the biphasic insulin and glucose response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Postprandial oscillatory patterns of blood glucose and insulin in NIDDM. Abnormal diurnal insulin secretion patterns and glucose homeostasis independent of obesity.

Compared with control subjects, non-insulin-dependent diabetes mellitus (NIDDM) subjects had both quantitative and qualitative abnormalities in blood insulin and glucose concentrations. The purpose of this study was to determine whether and to what extent normally observed multiphasic patterns of insulin and glucose responses to mixed meals are deranged in NIDDM. A total of 24 volunteers were studied while eating three meals of identical composition at 0745, 1145, and 1645. Twelve had NIDDM, and the remainder were healthy nondiabetic age- and weight-matched control subjects. Blood was withdrawn every 10 min from 0630 to 1930 for measurement of C-peptide, insulin, and glucose concentrations. Peaks were analyzed by computer-based algorithms. Diabetic volunteers displayed several differences from control subjects. First, although the number of insulin peaks was similar, there was a consistent delay of 20-30 min in the appearance of the first postprandial peak. Second, insulin concentrations after lunch were higher than after breakfast, whereas the reverse pattern occurred in control subjects. Third, integrated glycemia was greater after breakfast than after lunch. Fourth, glucose concentrations decreased during the first 30 min after lunch, suggesting accelerated glucose disposal and/or enhanced suppression of endogenous glucose production at this time of day. These data demonstrate that insulin secretion and action and glucose homeostasis in NIDDM are more complex than commonly appreciated. This dynamic state is undetected unless there is frequent blood sampling for measurement of insulin and glucose. The quantitative and qualitative abnormalities that we observed in these parameters are independent of obesity and suggest the need to expand the pathophysiological definition of NIDDM.

Adult↗
PubMedDate not supplied

Recurrent ketoacidosis in acquired, total lipodystrophy (lipoatrophic diabetes).

The absence of ketoacidosis is thought to be characteristic of generalized lipoatrophic diabetes. It is widely believed that lipoatrophic diabetic patients are able to tolerate starvation and therapeutic insulin withdrawal, due to absence of subcutaneous body fat, the substrate essential for ketogenesis. In this article, we document nine episodes of acidosis and accelerated ketone body formation in a 24-yr-old woman whose deterioration followed episodes of dietary excesses without evidence of intercurrent infection or other identifiable forms of metabolic stress. Serum C-peptide measurements demonstrated that an absolute insulin deficiency did not exist. During short-term, experimental, dietary manipulations, excess dietary calories worsened the hyperglycemia and hyperlipidemia but did not reproduce the ketoacidotic state. Excess fat added to the diet was the most poorly tolerated of the food groups, causing ketonuria, hypertriglyceridemia, and abdominal pain. Our experience with this patient suggests that increased food consumption, insufficient insulin relative to an insulin-resistant state, and increased amounts of insulin counterregulatory hormones (stress), acted in concert to cause acidosis and increased ketone body formation.

Adult↗