Biomedical subjects

D Porte

Publications and source records attributed to D Porte.

At least 109 records · Page 6Linked to original sources

PubMed1986

The insulin sensitivity index in nondiabetic man. Correlation between clamp-derived and IVGTT-derived values.

Although the minimal-model-based insulin sensitivity index (S1) can be estimated from the results of a simple 180-min intravenous glucose tolerance test (IVGTT), its relationship to widely accepted but technically more difficult clamp-based techniques has not been resolved in humans. Therefore we measured S1 by standard IVGTT, modified IVGTT, and clamp methods in 10 nondiabetic men with %IBW of 109 +/- 12 (mean +/- SD). In the euglycemic clamp studies, insulin was infused to bring insulin levels (IRI) from basal, 8 +/- 4 microU/ml, to plateaus of 21 +/- 5 and 35 +/- 6 microU/ml. S1[clamp], measured as the increase in glucose (G) clearance per increase in IRI [delta INF/(delta IRI X G)], averaged 0.29 +/- 0.09 ml/kg X min per microU/ml. In the IVGTT studies, 300 mg/kg G was given as an i.v. bolus, and G and IRI were measured for 180 min; in the modified (mod) IVGTT, tolbutamide (300-500 mg) was given i.v. 20 min after the G to observe the effect of an IRI peak on G removal after G level was free of initial "mixing" effects. The S1 estimated by computer did not differ significantly between standard [(6.9 +/- 3.4) X 10(-4) min-1 per microU/ml] and modified [(6.7 +/- 3.5) X 10(-4) min-1 per microU/ml] tests, indicating no bias due to the differing insulin patterns and levels. There was a strong positive correlation between S1 (mod IVGTT) and S1(clamp): r = 0.84; N = 10; P less than 0.002. The correlation between S1(standard IVGTT) and S1(clamp) was 0.54, suggesting the modified test is less "noisy." Nonetheless, in eight euglycemic women with a wider range of adiposity, S1(standard IVGTT) has been significantly correlated with %IBW (r = -0.72) and basal IRI (r = -0.84). The correlation between S1 measures by clamp and IVGTT methods provides one step toward validation of the minimal model for studies of insulin action in man.

Adult↗

PubMed1986

A sensitive radioimmunoassay for human proinsulin, with sequential use of antisera to C-peptide and insulin.

In this assay for immunoreactive human proinsulin (IRPI), it first is separated from plasma by use of an antiserum to human C-peptide. An immunoprecipitate is then formed by using a precipitating antiserum and polyethylene glycol, after which IRPI is dissociated from the antiserum by incubation in warm HCl, pH 2.0. The resulting mixture is assayed for insulin immunoreactivity by a double-antibody tracer-competition method involving incubation for four days with a high-affinity anti-insulin antiserum. Human proinsulin of recombinant-DNA origin is used as the standard. Added C-peptide at supraphysiological concentrations did not interfere with or react in the assay. Human insulin cross reacted by 1.5%. The detection limit for IRPI (2 SD from zero-dose binding) is 3 pmol/L. Proinsulin conversion intermediates are measured nearly as well as intact proinsulin. IRPI concentrations in 10 nondiabetic human subjects averaged 12.0 (SEM 1.6) pmol/L. The ratio of proinsulin to immunoreactive insulin averaged 14.3 (SEM 2.2)%. After intravenous arginine, the increase in proinsulin was less than that of insulin, and it declined more slowly.

Arginine↗

PubMed1985

Glucose regulation in non-insulin-dependent diabetes mellitus. Interaction between pancreatic islets and the liver.

The degree of fasting hyperglycemia in patients with non-insulin-dependent diabetes mellitus is dependent on the rate of hepatic glucose production. The basal rate of hepatic glucose production is increased in patients with non-insulin-dependent diabetes mellitus, and there is a positive correlation between hepatic glucose production and fasting glucose levels. Diminished secretion of insulin, impaired hepatic sensitivity to insulin's effects, or a combination of these factors could contribute to the elevated hepatic glucose production in patients with non-insulin-dependent diabetes mellitus. The relationship between insulin secretion and hepatic glucose production is regulated by a closed feedback loop operating between glucose levels and pancreatic beta cells. Although fasting insulin levels are usually comparable between patients with non-insulin-dependent diabetes mellitus and normal subjects, insulin secretion is markedly impaired in non-insulin-dependent diabetes mellitus in relation to the degree of hyperglycemia present. In fact, the degree of fasting hyperglycemia in a given patient with non-insulin-dependent diabetes mellitus is closely related to the degree of impaired pancreatic beta-cell responsiveness to glucose. Such findings suggest that impaired insulin secretion leads to increased hepatic glucose production, which raises the plasma glucose level. The resulting hyperglycemia helps to maintain relatively normal basal insulin output. Chronic sulfonylurea drug therapy of patients with non-insulin-dependent diabetes mellitus enhances pancreatic islet sensitivity to glucose, leading to increased insulin secretion, suppression of hepatic glucose production, and a decline in the steady-state fasting glucose level.

Arginine↗

PubMed1985

Genetically obese Zucker rats have abnormally low brain insulin content.

The concentration of immunoreactive insulin (IRI) extracted from the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, amygdala, midbrain, and hindbrain was significantly lower in obese (fa/fa) and heterozygous (Fa/fa) Zucker rats in comparison to lean (Fa/Fa) Zucker rats. This deficit in brain IRI content was most severe in the hypothalamus and olfactory bulb and was independent of severe obesity since the marked reduction of brain IRI content was also found in heterozygous rats which possessed only one copy of the fa allele. These results demonstrate that in the 2-3 month-old female Zucker rat, the fa allele is associated with defective regulation of insulin in the brain.

Animals↗

PubMed1985

Pathophysiology of insulin secretion in diabetes mellitus.

In normal man, glucose serves to regulate basal insulin secretion by its participation with insulin in a feedback loop. In addition, glucose stimulates insulin secretion directly and potentiates insulin responses to nonglucose stimuli such as amino acids, beta-adrenergic stimuli, and gut hormones. Maximal glycemic potentiation of the acute insulin response to IV arginine occurs at a glucose level of approx. 450 mg/dl. In patients with noninsulin dependent diabetes mellitus (NIDDM), basal insulin levels have usually been reported as normal, but if plasma glucose is lowered to normal levels, a deficiency of basal insulin becomes apparent. In addition, the first phase (0-10 min) insulin response to IV glucose is absent in virtually all patients with overt NIDDM. In contrast, the second-phase (greater than 10 min) response is often preserved in NIDDM due to its maintenance by ambient hyperglycemia. Similarly, insulin responses to nonglucose stimuli such as arginine often appear normal in NIDDM because of potentiation by hyperglycemia. However, insulin responses to arginine are lower than those of nondiabetic controls when compared at multiple matched glucose levels. Indeed, maximal potentiation by glucose of the insulin response to arginine is markedly subnormal in NIDDM, suggesting a loss of functional B cell secretory capacity. In patients with long-standing insulin-dependent diabetes mellitus (IDDM), basal insulin secretion and insulin responses to all stimuli are virtually absent. However, in a remission phase, or in IDDM of short duration, basal insulin secretion and insulin responses to nonglucose stimuli may be relatively preserved. Therefore, islet dysfunction in IDDM and NIDDM, while etiologically different, share some common pathophysiological features.

Arginine↗

PubMed1985

Insulin: its relationship to the central nervous system and to the control of food intake and body weight.

This article describes the close relationship among the hormone insulin, the central nervous system, and the regulation of food intake and body adiposity. The initial section documents the control of insulin output from the pancreas by the central nervous system, and a later section describes the relationship of insulin levels in the blood to the degree of adiposity. Another section documents the ability of insulin to gain access to the brain and to elicit responses there. Finally, the behavioral effects of insulin added to the brain, and especially its ability to reduce food intake and body weight, is discussed. The implications to obesity are stressed throughout.

Adipose Tissue↗

PubMed1985

Pentobarbital effects on plasma catecholamines: temperature, heart rate, and blood pressure.

The effects of intravenous pentobarbital were studied in dogs. Plasma pentobarbital concentrations were inversely related to epinephrine and norepinephrine concentrations. Plasma catecholamines appeared fully suppressed at pentobarbital levels greater than 25-30 micrograms/ml. Furthermore, pentobarbital levels were negatively related to rectal temperature, heart rate, and mean blood pressure. The methods of pentobarbital administration influenced plasma pentobarbital as well as epinephrine and norepinephrine levels, temperature, heart rate, and blood pressure. These observations suggest the possibility that pentobarbital inhibits the sympathetic nervous system, which in turn may affect temperature, heart rate, and blood pressure. Because pentobarbital anesthesia affects plasma catecholamine concentrations, the regimen used in animal models requires consideration when interpreting data potentially influenced by the sympathetic nervous system.

Animals↗

PubMed1985

Acute and chronic gastrin-releasing peptide decreases food intake in baboons.

Gastrin-releasing peptide (GRP) is a peptide structurally related to bombesin that appears to be localized to the mammalian gastrointestinal tract. This study examined the ability of GRP, when administered on either an acute or chronic basis, to suppress food intake in baboons. When administered at 8 micrograms/kg iv before a morning meal, GRP significantly suppressed both food intake and the postprandial rise of plasma glucose and insulin. GRP at doses of 1, 2, 4, and 8 micrograms/kg stimulated basal insulin secretion. Chronic administration of GRP (q.o.d. for 11 days) at a low dose before the A.M. meal resulted in suppression of the A.M. meal and an initial suppression of total food intake, which recovered before the end of the treatment period. In conclusion, GRP appears to be effective in acute suppression of food intake and stimulation of basal insulin secretion in the nonhuman primate.

Animals↗

PubMed1985

Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene.

Insulin binding was measured in membrane particles prepared from the liver and several brain regions of 4-month-old female Zucker fa/fa (obese), Fa/fa (heterozygous), and Fa/Fa (lean) rats. High affinity insulin binding was decreased in the olfactory bulb of fatty (0.23 pmol bound/mg protein) and heterozygous (0.16 pmol/mg) rats compared with that in the lean controls (0.64 pmol/mg). Total binding was not changed in the cerebral cortex or hypothalamus. High affinity insulin binding was also decreased in the liver of both fatty (0.44 +/- 0.22 pmol/mg; P less than 0.01) and heterozygous (0.75 +/- 0.35 pmol/mg) animals compared with that in the lean rats (2.10 +/- 1.55 pmol/mg). This decreased binding is probably not due to down-regulation of receptors in the heterozygous rats, as they do not exhibit the hyperinsulinemia observed in the fatty rats. Rather, our findings suggest that there is a gene-related alteration in insulin binding in the Zucker rat, as low binding was observed in rats carrying either one (Fa/fa) or two (fa/fa) doses of the gene. We postulate that this central defect in insulin binding may contribute to inadequate perception of a central insulin feedback signal and to the hyperphagia observed in the obese rats.

Animals↗

PubMed1985

Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function.

To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18-36 yr old) and 10 older (57-82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values. Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: SI, the insulin sensitivity index; phi 1 and phi 2, indices of first and second phase beta-cell responsiveness to glucose; n, fractional insulin clearance, and SG, a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated beta-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate, 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P less than 0.01). This intolerance was the result of both a beta-cell defect and insulin resistance. The potentiation slope (r = -0.67; P less than 0.02) and phi 2 (r = -0.47; P less than 0.05) both decreased with age. In addition, SI in the older group was diminished 63% (2.4 vs. 6.5; 10(-4) min-1/microU/ml; P less than 0.001) and was unrelated to differences in body fat. No differences were found in either n or SG. These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both beta-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance.

Adipose Tissue↗

PubMed1985

Abnormalities of islet B-cell function, insulin action, and fat distribution in women with histories of gestational diabetes: relationship to obesity.

Although obese women with histories of gestational diabetes mellitus (former GDM) are highly predisposed to develop noninsulin-dependent diabetes mellitus (NIDDM), lean former GDM women are less predisposed. To explore reasons for this difference, we performed measures of islet B-cell function and insulin action in eight lean former GDM women [ideal body weight (IBW), 107 +/- 2% (mean +/- SEM)], 11 obese former GDM (IBW, 161 +/- 11%), and 19 normal women subjects who were individually pair-matched to former GDM for % IBW and age. The first phase (0-10 min) insulin secretory response to iv glucose was significantly lower in both lean and obese former GDM compared to that in normal women (3,480 +/- 548% vs. 8,234 +/- 1,337% basal . min and 3,444 +/- 682 vs. 10,251 +/- 2,465). The second phase (10-60 min) insulin response to glucose was also significantly lower in lean former GDM women and tended to be lower in obese former GDM women compared to that in their respective controls. Insulin action was assessed by the insulin sensitivity index (SI) using Bergman's minimal modeling technique. SI values in lean former GDM women were similar to those in their controls (4.42 +/- 1.3 X 10(-4) ml min-1 microU-1 vs. 5.19 +/- 1.2 X 10(-4). In contrast, SI values in obese former GDM women were significantly lower than those in their controls (0.77 +/- 0.28 X 10(-4) vs. 2.04 +/- 0.43 X 10(-4). To assess whether differences in fat distribution and fat cell size were associated with these differences in insulin sensitivity, the waist to thigh circumference ratio, the waist to hip ratio, and abdominal fat cell diameter were measured. All three were significantly greater in the obese former GDM women than in controls. Thus, an abnormal central distribution of adiposity appears to be associated with the insulin action defect in obese former GDM women. We conclude that both lean and obese former GDM women have insulin secretion defects. Although a modest insulin action defect in lean former GDM women may have been missed by this technique, only in the obese former GDM women, who have a higher risk for future NIDDM, was an insulin action defect demonstrable. Thus, impairments of both insulin secretion and insulin action may be necessary to cause a marked predisposition toward NIDDM.

Adipose Tissue↗

PubMed1985

Islet beta-cell function and polymorphism in the 5'-flanking region of the human insulin gene.

The present study investigates the possible relationship between human beta-cell secretory capacity and polymorphism in the 5'-flanking region of the human insulin gene. The glucose potentiation slope was measured in normal and non-insulin-dependent diabetic subjects (NIDDM). This slope, as reported previously (Ward, W. K., et al., Am. J. Physiol. 1984; 246:E405-11), is an index of the ability of hyperglycemia to potentiate the insulin response to arginine and as such is a measure of beta-cell responsiveness to glucose. Restriction enzyme analysis using a human insulin gene probe was performed on leukocyte DNA isolated from the same individuals. We conclude that a 1.6 kb polymorphism in the 5'-flanking region of the human insulin gene in both normal and NIDDM subjects has no association with insulin secretory responses as defined here by the glucose potentiation slope.

Adult↗

PubMed1985

Insulin resistance and impaired insulin secretion in subjects with histories of gestational diabetes mellitus.

NIDDM is characterized by decreased insulin secretory responses to glucose and to nonglucose stimuli, hyperglucagonemia, and decreased tissue sensitivity to insulin. However, it has been unclear which of these abnormalities, if any, precedes the others. Since women with histories of gestational diabetes mellitus (GDM) are at high risk for eventual development of NIDDM, we measured B- and A-cell function and tissue sensitivity to insulin in eight normoglycemic, postpartum women with recent histories of GDM and in eight control subjects pair-matched for age and percent of ideal body weight. Fasting plasma glucose levels in subjects with former GDM tended to be slightly higher than in matched controls (98 +/- 3 versus 92 +/- 2 mg/dl, P = 0.07). Basal plasma insulin in subjects with former GDM was significantly higher than in controls (22 +/- 4 versus 14 +/- 2 microU/ml, P = 0.05). During an intravenous glucose tolerance test (IVGTT), relative first- and second-phase insulin responses to glucose were decreased in subjects with former GDM (2316 +/- 560 versus 7798 +/- 1036% of basal X min, P = 0.004; and 8340 +/- 946 versus 14,509 +/- 2556, P = 0.04). An index of sensitivity to insulin, SI, calculated from the IVGTT, was also lower in former GDM (1.23 +/- 0.69 X 10(-4) versus 3.58 +/- 0.78 X 10(-4) min-1/microU/ml, P = 0.001). Acute insulin responses to 5 g i.v. arginine were measured at plasma glucose levels of approximately 95, 215, and 600 mg/dl. The response at 600 mg/dl is termed the AIRmax and is used as an index of glucose-regulated insulin secretory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Adaptation of B and A cell function during prolonged glucose infusion in human subjects.

States of insulin resistance are characterized by hyperinsulinemia that often appears to be out of proportion to the minimal degree of hyperglycemia. One possible explanation for these findings is that mild hyperglycemia per se can cause an adaptive increase in islet sensitivity to glucose, leading to increased insulin output at a given glucose level. To test this hypothesis, we compared acute insulin responses (AIR) and acute glucagon responses (AGR) to 5-g arginine injections before and after 20-h glucose infusions (200 mg X m-2 X min-1) in 11 healthy men of varying age and degree of adiposity. The 20-h glucose infusion caused an increase in fasting plasma glucose (PG) in all subjects (95 +/- 2 vs. 130 +/- 3 mg/dl). PG was clamped at three levels (approximately 95, 165, and 235 mg/dl) before and after the 20-h glucose infusion. Despite matching of PG levels, consistent increases of AIR were observed after the 20-h glucose infusion: 86 +/- 10 vs. 57 +/- 8 at PG = 95 (P = 0.002); 241 +/- 20 vs. 192 +/- 22 at PG = 165 (P = 0.02); and 508 +/- 59 vs. 380 +/- 50 microU/ml at PG = 235 mg/dl (P = 0.009). In addition, the slope of the relationship between AIR and PG level (potentiation slope), a measure of B cell sensitivity to glucose, increased consistently from 2.28 +/- 0.35 (control) to 3.07 +/- 0.45 (P = 0.004) after the 20-h infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Islet function and stress hyperglycemia: plasma glucose and epinephrine interaction.

Catecholamines and a number of other hormones released during stress states contribute to the development of hyperglycemia by directly stimulating glucose production and interfering with tissue disposal of glucose. However, hyperglycemia stimulates the secretion of insulin and inhibits the secretion of glucagon, effects that will diminish the degree of hyperglycemia resulting from direct actions of stress hormones on glucose production and disposal. The key additional role of catecholamines in the development of stress hyperglycemia is interference with the normal feedback control of insulin and glucagon secretion by circulating glucose levels. Although pancreatic islet responses to hyperglycemia may be modulated by catecholamines, any increase of insulin secretion or suppression of glucagon secretion that does occur may be important for limiting the degree of elevation of circulating glucose that results. Thus, plasma insulin and glucagon levels during stress states will reflect the interaction between the opposing effects of hyperglycemia and catecholamines. Diabetic patients who have impaired islet responses to glucose will be particularly prone to the development of marked hyperglycemia during stress states because they may be unable to respond to the influence of hyperglycemia in counteracting adrenergic inhibition of insulin secretion and stimulation of glucagon secretion.

Animals↗

PubMed1984

Dexamethasone-induced insulin resistance enhances B cell responsiveness to glucose level in normal men.

To determine whether islet adaptation during insulin resistance involves increased responsiveness to the level of plasma glucose, insulin resistance was induced in nine normal men by giving dexamethasone (Dex) (3 mg twice daily for 2 days). Plasma insulin and acute insulin responses (AIR) to isoproterenol were measured at three different glucose levels under control and Dex conditions. During Dex there were elevations above control levels of basal glucose (104 +/- 2 vs. 94 +/- 3 mg/dl) and insulin (21 +/- 3 vs. 13 +/- 2 microU/ml, both P less than 0.03). When glucose levels were raised stepwise by matching amounts using glucose clamps, AIR to isoproterenol rose as a linear function of glucose level under both conditions but rose more steeply during Dex. That is, the potentiating effect of glucose (delta AIR/delta glucose) was greater during Dex: 1.3 +/- 0.2 vs. 0.8 +/- 0.2 (P less than 0.01). Similarly, matched increments in glucose level produced greater increments in prestimulus insulin level during Dex (P less than 0.03). We conclude that 48 h of Dex raises the "gain" of the potentiating effect of glucose. Because the direct effect of glucocorticoids on B cell function has been reported to be inhibitory, the observed stimulation is likely to be a result of the insulin resistance caused by Dex.

Adaptation, Physiological↗

PubMed1984

Suppression of food intake by intravenous nutrients and insulin in the baboon.

Intravenous nutrients were infused at 25 and 50% of total base-line daily caloric intake to determine the role of circulating factors on spontaneous food ingestion in young adult male baboons (Papio cynocephalus). Glucose infusion suppressed food intake (15.1%) when 25% of total calories was infused (P less than 0.05) and 41.8% when 50% of total calories was infused (P less than 0.05) for 14-21 days. Both infusions produced basal hyperglycemia (82-172 mg/dl during 25% glucose and 120-239 mg/dl during 50% glucose). Both infusions also caused an increase in circulating insulin (48.1-63.1 microU/ml during 25% glucose and 68.5-77.2 microU/ml during 50% glucose). The simultaneous infusion of exogenous insulin (0.33 mU X kg-1 X min-1) prevented hyperglycemia (85.8-87.9 mg/dl during 25% glucose) but maintained raised basal peripheral insulin levels (52.4-84.4 microU/ml). The 13% suppression of food intake (P less than 0.05) was similar to glucose infusion alone. Comparable infusions of Intralipid as 25 and 50% of total daily calories also suppressed spontaneous food intake but did not produce hyperglycemia or elevated insulin levels. The magnitude of suppression was similar to that of glucose: 16% when 25% of basal calories was infused (P less than 0.05) and 31.3% when 50% of basal calories was infused (P less than 0.05). However, the pattern was different with a more rapid effect, which tended to diminish in time, rather than the slow effect found with glucose, which was maintained for 14 days. We conclude that circulating nutrients can regulate food intake independent of gastrointestinal absorption in primates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Pentobarbital anesthesia suppresses basal and 2-deoxy-D-glucose-stimulated plasma catecholamines.

Since pentobarbital anesthesia is known to attenuate certain autonomic reflexes, we tested whether pentobarbital would suppress both basal and stimulated levels of plasma catecholamines and whether a large stimulus might counterbalance this suspected suppression. In untrained dogs, sampled by venipuncture, pentobarbital (30 mg/kg iv) decreased the plasma concentration of epinephrine (E) from 146 +/- 9 to 38 +/- 8 (SE) pg/ml (n = 46) and norepinephrine (NE) from 276 +/- 13 to 91 +/- 10 pg/ml (both P less than 0.0005), suggesting that barbiturate anesthesia suppresses sympathetic outflow in these mildly stressed animals. Pentobarbital also had a marked suppressive effect on the lower baseline catecholamines (E, 84 +/- 14 pg/ml; NE, 118 +/- 10 pg/ml; n = 6) of trained, chronically catheterized dogs, suggesting that it was capable of suppressing resting sympathetic outflow as well. To determine whether pentobarbital anesthesia also suppressed reflex activation of the sympathetic nervous system, the plasma catecholamine response to the neuroglucopenic agent, 2-deoxy-D-glucose (2-DG), was measured in conscious and in pentobarbital-anesthetized dogs. In conscious dogs, the administration of 2-DG (100 mg/kg iv) doubled the base-line plasma concentration of E and NE 30 min after the 2-DG injection. In contrast, the administration of 2-DG (100 mg/kg iv) to pentobarbital-anesthetized dogs produced no significant increase of either plasma catecholamine, suggesting marked suppression of this sympathetic reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, General↗