Biomedical subjects

D Elahi

Publications and source records attributed to D Elahi.

At least 55 records · Page 3Linked to original sources

PubMed1995

Hypotensive response to atrial natriuretic peptide administration is enhanced with age.

BACKGROUND: Plasma levels of atrial natriuretic peptide (ANP) increase with age. To test the hypothesis that the cardiovascular response to ANP is age dependent and to examine the role of the increased levels of ANP in the hypotensive response to orthostatic challenge, we compared the hemodynamic response of young and elderly subjects to ANP infusion and orthostatic challenge. METHODS: Blood pressure, heart rate, forearm cutaneous resistance, plasma ANP, and plasma norepinephrine were measured in the supine position and following upright tilt before and after a 60-minute infusion of atrial natriuretic peptide (0.05 microgram/kg/min) in 7 young (27 +/- 4 years) and 5 elderly (74 +/- 4 years) normotensive, healthy subjects. RESULTS: Prior to ANP infusion, the response to upright tilt was similar in both groups. Infusion of ANP produced similar steady state plasma levels of ANP in both groups (young: 435 +/- 49 pg/ml; elderly: 429 +/- 32 pg/ml). Supine systolic blood pressure decreased by 4 +/- 2 mmHg in the young subjects and by 18 +/- 8 mmHg in the elderly subjects after infusion (p < .08). In contrast, changes in supine heart rate, forearm cutaneous resistance, and plasma norepinephrine were similar in both groups (delta heart rate: young +5 +/- 3 beats/min, elderly +4 +/- 2 beats/min; delta forearm cutaneous resistance: young -38 +/- 9%, elderly -40 +/- 6%; delta norepinephrine: young +55 +/- 11%, elderly: +43 +/- 13%). ANP infusion abolished the vasoconstrictor response normally associated with orthostatic challenge in both groups, despite a significant release of catecholemines and an enhanced heart rate response. This resulted in significant systolic blood pressure reduction in both young (-7 +/- 2 mmHg, p < .05) and elderly subjects (-16 +/- 4 mmHg, p < .05). The drop in systolic blood pressure in response to upright tilt and ANP infusion was four times larger in the elderly subjects (change from pre-ANP level: young -8 +/- 3 mmHg, elderly -32 +/- 5 mmHg, p < .005).

Adult↗

PubMed1995

Resistive training increases fat-free mass and maintains RMR despite weight loss in postmenopausal women.

Percent body fat increases with age and is often accompanied by a loss in muscle mass, strength, and energy expenditure. The effects of 16 wk of resistive training (RT) alone or with weight loss (RTWL) on strength (isokinetic dynamometer), body composition (dual-energy X-ray absorptiometry), resting metabolic rate (RMR) (indirect calorimetry), and sympathetic nervous system activity (catecholamines) were examined in 15 postmenopausal women (50-69 yr). RT resulted in significant improvements in upper and lower body strength in both groups (P < 0.01). The nonobese women in the RT group (n = 8) did not change their body weight or fat mass with training. In the obese RTWL group (n = 7), body weight, fat mass, and percent body fat were significantly decreased (P < 0.001). Fat-free mass and RMR significantly increased with training in both groups combined (P < 0.05). There were no significant changes in resting arterialized plasma norepinephrine or epinephrine levels in either group with training. RT increases strength with and without weight loss. Furthermore, RT and RTWL increase fat-free mass and RMR and decrease percent fat in postmenopausal women. Thus, RT may be a valuable component of an integrated weight management program in postmenopausal women.

Aged↗

PubMed1994

The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects.

Despite similar glycemic profiles, higher insulin levels are achieved following oral versus intravenous administration of glucose. This discrepancy is due to the incretin effect and is believed to be mediated via stimulation of beta-cells by hormone(s) released from the gut. The leading gut hormone candidates are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1). To determine the relative insulinotropic activity of these peptides, we infused GLP-1(7-37) and GIP into normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In normal subjects during euglycemia, GLP-1(7-37) stimulated insulin release, whereas GIP did not. Using the Andres clamp technique, we established stable hyperglycemia for 2 h (5.4 mmol/l above the basal level). During the second hour, either GIP, GLP-1(7-37), or both were infused in normal healthy volunteers and in patients with NIDDM. In normal subjects, at a glucose level of 10.4 mmol/l, the 90-120 min insulin response was 279 pmol/l. GIP at a dose of 1, 2 or 4 pmol/kg/min augmented the 90-120 min insulin response by 69, 841 and 920 pmol/l, while GLP-1(7-37), at a dose of 1.5 pmol/kg/min augmented the insulin response by 2106 pmol/l. When both hormones were administered simultaneously, the augmentation was additive--2813 pmol/l. In the diabetic subjects, GIP had no effect, while GLP-1(7-37) augmented the insulin response by 929 pmol/l. We conclude that in normal healthy subjects, GLP-1(7-37), on a molar basis, is several times more potent than GIP at equivalent glycemic conditions. The additive insulinotropic effect suggests that more than one incretin may be responsible for the greater insulin levels observed following oral administration of glucose compared to the intravenous route. In NIDDM, GIP had no insulinotropic effect, while GLP-1(7-37) had a marked effect. This suggests that GLP-1(7-37) may have therapeutic potential as a hypoglycemic agent in NIDDM patients.

Administration, Oral↗

PubMed1994

Splanchnic neural regulation of somatostatin secretion in the isolated perfused human pancreas.

OBJECTIVE: The somatostatin-secreting delta cells in the islets of Langerhans appear to be regulated by neural mechanisms that have not been defined clearly. In this study, the celiac neural bundle of the human pancreas was electrically stimulated in the presence and absence of selective neural antagonists. SUMMARY BACKGROUND DATA: The authors previously reported on studies of the splanchnic neural regulation of insulin, glucagon, and pancreatic polypeptide secretion. In these studies, alpha-adrenergic fibers appeared to have a predominant effect, strongly inhibiting the secretion of insulin, glucagon, and pancreatic polypeptide secretion. Cholinergic fibers appeared to stimulate strongly, although beta-adrenergic fibers weakly stimulated, the secretion of these hormones. Investigations of neural regulatory mechanisms governing human somatostatin release in vitro have not been previously reported. METHODS: Pancreata were obtained from eight cadaveric organ donors. The isolated perfused human pancreas technique was used to assess the regulation of somatostatin secretion by the various neural fibers contained within the celiac plexus. The secretory response of somatostatin was examined in the presence of 16.7 mmol/L glucose, with and without neural stimulation, and specific neural antagonists. RESULTS: The basal somatostatin secretion was 88 +/- 26 fmol/g/min and increased 131 +/- 23% (n = 8, p < 0.01) in response to 16.7 mmol/L glucose. The augmentation seen with glucose was inhibited 66 +/- 22% (n = 8, p < 0.05) during celiac neural bundle stimulation. Alpha-adrenergic blockade resulted in a 90 +/- 30% (n = 6, p < 0.01) augmentation of somatostatin release. Beta-adrenergic blockade caused a 13 +/- 2% (n = 6, p < 0.05) suppression of somatostatin release. Complete adrenergic blockade resulted in a 25 +/- 23% (n = 5, p = not significant) inhibition of somatostatin release. Cholinergic blockade resulted in a 40 +/- 10% (n = 6, p < 0.02) suppression of somatostatin release. CONCLUSIONS: The predominant effect of celiac neural bundle stimulation was inhibition of somatostatin secretion through an alpha-adrenergic effect. Beta-adrenergic fibers stimulate somatostatin secretion; cholinergic fibers have a negligible effect on somatostatin secretion. These data suggest that the splanchnic innervation of the pancreas has a potent regulatory role in somatostatin release in this in vitro human model.

Adolescent↗

PubMed1993

Effect of glucose, insulin, and hypertonicity on atrial natriuretic peptide levels in man.

To determine the effects of hyperglycemia and hyperinsulinemia on atrial natriuretic peptide (ANP) levels in man, we studied normotensive nondiabetic volunteers (aged 25 to 63 years) during infusion of insulin and/or 20% dextrose (glucose clamp technique) to achieve three different states of "glycemia/hyperinsulinemia," as follows: (1) euglycemia for 2 hours during infusion of insulin (80 mU.m-2.min-1), resulting in plasma insulin levels of approximately 1,200 pmol/L (n = 9); (2) moderate stable hyperglycemia at a level of 11 mmol/L (198 mg/dL) for 2 hours, with infusion of glucagon-like peptide-1 (7-37) amide (GLP-1) during the second hour, which increased endogenous insulin responses to approximately 2,100 pmol/L (n = 9); and (3) marked stable hyperglycemia at a level of 18.5 mmol/L (330 mg/dL) for 2 hours, with endogenous insulin responses of approximately 720 pmol/L (n = 9). In addition, six patients with non-insulin-dependent diabetes mellitus were studied with the GLP-1 protocol at a hyperglycemic level of 14.5 mmol/L (261 mg/dL). In normal subjects, plasma ANP levels increased significantly from 3.0 +/- 0.4 to 4.6 +/- 0.8 pmol/L during marked hyperglycemia, but did not change during euglycemia or moderate hyperglycemia despite higher insulin levels (P < .01, ANOVA). Sodium excretion rates were also highest during the marked hyperglycemic study (125 +/- 14 v 91 +/- 7 v 74 +/- 10 mumol/min, P < .05, marked v moderate hyperglycemia v euglycemia). In diabetic subjects, ANP levels increased significantly from 12.5 +/- 4.1 to 21.1 +/- 5.0 pmol/L during hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans.

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

Adult↗

PubMed1993

The pituitary-adrenal glucocorticoid response is altered by gender and disease.

BACKGROUND: This study examined the role of age, gender, and disease in the regulation of the pituitary-adrenal axis. METHODS: Serum cortisol and immunoreactive corticotropin (ACTH) were measured for five hours after a bolus administration of ovine corticotropin releasing hormone (oCRH, 1 microgram/kg) during three separate investigations: 1) age: comparison was made between young men (26 +/- 3 years [means +/- SE]) vs old men (73 +/- 2 years); 2) gender: comparison between old men (73 +/- 2 years) vs old women (68 +/- 3 years); and 3) disease: comparison was made between healthy subjects (no disease, 44 +/- 6 years) vs subjects with a chronic stable disease (diabetes mellitus [DM] or hypertension [HBP], 48 +/- 5 years). RESULTS: Basal concentrations of cortisol were significantly higher in younger men (127 +/- 17 vs 74 +/- 11 nmol/L, p < .03), as were peak cortisol levels (499 +/- 30 vs 397 +/- 36 nmol/L, p < .05, ANOVA). However, the 5-hour nadir of cortisol, area under the curve, delta area under the curve, time to peak, and variability of the responses during three separate admissions were similar in young and old. When the responses to oCRH in old men and old women were compared, old women had significantly higher basal values of cortisol (163 +/- 30 vs 75 +/- 11 nmol/L, p < .02), peak levels of cortisol (p < .0001) and the 5-hour nadir of cortisol was 124% higher in older women (657 +/- 61 vs 298 +/- 50 nmol/L, p < .0006). When the response to oCRH was examined in healthy subjects and subjects with disease (DM and HBP), men with disease had a peak cortisol response 40% higher (p < .003) than healthy men and the level remained 85% higher (p < .0005) at 5 hours. The responses of ACTH to oCRH were not different in the groups being compared for any study. The variation of cortisol response could be explained by the peak cortisol levels (R2 = .718, p < .0001), with a small significant contribution from disease (R2 = .013, p < .002). In summary, the adrenal response to oCRH remained elevated throughout the period of study in elderly women. In addition, subjects with a chronic disease (DM and HBP) had a greater response of cortisol to oCRH compared with healthy subjects. CONCLUSION: This study demonstrated that the pituitary-adrenal response to oCRH in the elderly is gender specific and chronic stable disease (DM and HBP) is associated with altered regulation of the adrenal glucocorticoid response.

Adrenocorticotropic Hormone↗

PubMed1993

Hyperinsulinemia after pancreatic transplantation. Prediction by a novel computer model and in vivo verification.

OBJECTIVE: The authors evaluated systemic venous insulin release as a cause of the hyperinsulinemia (HNS) associated with pancreatic transplantation (PTX) with respect to the mechanism and metabolic consequences. SUMMARY BACKGROUND DATA: Many investigators believe the postoperative anatomy associated with common PTX techniques to be the sole cause of the two- to threefold posttransplantation HINS. However, this concept remains to be conclusively proved and characterized quantitatively. METHODS: The authors used three approaches to achieve their objectives. First, a computer model was generated based on established data concerning blood flow and tissue insulin extraction to determine whether it was mathematically possible for HINS to be caused by systemic insulin release. Second, HINS clamps were applied to normal dogs using the Andres clamp technique to quantify the in vivo differences in peripheral insulin levels and the metabolic consequences of systemic versus portal insulin infusion. Third, prolonged insulin half-life was evaluated as a possible mechanism of HINS from systemic insulin release by determination of biexponential rates of plasma disappearance from an endogenous pulse of insulin in surgically induced dog models of systemic and portal insulin release. RESULTS: First, the computer model calculated a 1.4- to 2.9-fold increase in peripheral venous insulin levels with systemic versus portal insulin release, verifying mathematically the concept of HINS resulting from systemic insulin release. Second, the actual systemic insulin infusion produced a 1.3- to 1.4-fold increase in peripheral venous insulin levels compared with portal infusion (p < 0.05). No significant differences in hepatic glucose output, total glucose disposal, or glucose infusion requirements were seen. Third, although the basal insulin level was twofold higher in the surgically induced animal models with systemic insulin release (p < 0.003), there were no differences in biexponential insulin clearance parameters. CONCLUSIONS: The HINS produced by systemic insulin release did not significantly alter glucose metabolism and was not the result of altered peripheral insulin clearance parameters. In vivo systemic venous insulin infusion studies produce HINS, but not to the degree calculated by mathematic modeling or that occurs after clinical PTX, making it likely that other factors also play a role in the HINS after PTX.

Animals↗

PubMed1993

Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance.

A decline in insulin sensitivity is associated with aging, inactivity, and obesity. The effects of exercise training on glucose homeostasis independent of weight loss in older glucose-intolerant individuals are not well established. We examined the effects of exercise training on oral glucose tolerance, insulin action, and concentration of the GLUT-4 glucose transporters in skeletal muscle. Exercise training at 50 and 75% of heart rate reserve was performed for 12 wk in 18 individuals (age = 64 +/- 2, body fat = 37.0 +/- 1.5%). Peripheral insulin action was determined 96 h after the last exercise bout using a two-step hyperinsulinemic-euglycemic glucose clamp (insulin = 192 and 708 pmol/l). Percent body fat and fat-free mass (FFM) were unchanged with training. Diet composition, assessed by diet record, did not change over the 12 wk. Improved oral glucose tolerance was observed, as exhibited by lower plasma glucose concentrations after training (P < 0.05), whereas plasma insulin response remained unchanged. The rate of glucose disposal was unchanged during the low insulin concentration but increased 11.0% at the high insulin concentration (P < 0.05) after training (54.4 +/- 4.4 vs. 60.4 +/- 5.5 mumol.kg FFM-1.min-1). Skeletal muscle glycogen and GLUT-4 concentration increased 24 and 60%, respectively, with training. There was no direct relationship between the change in GLUT-4 protein and the change in glucose disposal rate. These findings demonstrate that chronic exercise training without changes in body composition improves peripheral insulin action in subjects with impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1993

Effects of recombinant human IGF-I on glucose and leucine kinetics in men.

To examine the effects of recombinant human (rh) insulin-like growth factor I (IGF-I), insulin, and saline on metabolic parameters, we studied 20 young nonobese healthy men. Euglycemic clamps with 240-min IGF-I infusions at two doses (49 and 33 pmol.kg-1 x min-1, n = 8 and 12 subjects) were performed and compared with hyperinsulinemic-euglycemic clamps (2.25 pmol.kg-1 x min-1, n = 9). Leucine and glucose kinetics were examined with L-[1-13C]leucine and [3-3H]glucose. Glucose rate of appearance (Ra) declined equivalently in the 49 pmol.kg-1.min-1 IGF-I and insulin clamps but remained at basal levels during the 33 pmol.kg-1 x min-1 IGF-I infusions. In contrast, Rd of glucose was increased by 176% in the 49 pmol.kg-1 x min-1 IGF-I and 78% in the 33 pmol.kg-1 x min-1 IGF-I infusions. Furthermore, to prevent hypoglycemia after the termination of both rhIGF-I infusions, it was necessary to infuse glucose for an additional 2-20 h. Ra of leucine was suppressed significantly by both IGF-I and insulin, whereas leucine oxidation was not affected by either hormone. Therefore, the rate of disappearance of leucine expressed as the difference between Ra and oxidation rates was significantly reduced in all clamps. In addition, IGF-I significantly suppressed beta-cell secretion without affecting the other glucoregulatory hormones. In contrast to insulin, IGF-I had no apparent effect on lipolysis, as measured by changes in nonesterified fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

An epidemiological test of the hyperinsulinemia-hypertension hypothesis.

The association between hyperinsulinemia and hypertension was tested in a population of 421 men and 228 women from the Baltimore Longitudinal Study of Aging. Subjects are white, middle-class, generally healthy, community-dwelling volunteers who ranged in age from 17-95 yr. Those with disease or medications known to influence any of the studied variables were excluded from the analysis. Twenty-five percent of the subjects were borderline or hypertensive [systolic blood pressure (BP) > or = 140 or diastolic BP > or = 90 mm Hg]. Standard oral glucose tolerance tests were performed; the logarithms of the fasting insulin level and insulin area were used in the analyses. In addition, body mass index and percent body fat (from age and skinfold thickness equations) and waist hip ratio were computed. In simple correlations, systolic BP and diastolic BP were statistically significantly related to insulin levels (only 1-4% of the variance was explained). Since age, body fat, fat distribution, insulin levels, and BP were highly intercorrelated, insulin and blood pressure correlations were examined after controlling for the confounding variables. Correlations of BP and insulin levels adjusted for age, body fat, and fat distribution were entirely nonsignificant. In this large noninterventive population study, the hyperinsulinemia-hypertension hypothesis is not confirmed.

Adolescent↗

PubMed1993

Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance.

We have performed clinical, physiological, in vitro biochemical and genetic studies of a patient with severe insulin resistance associated with the phenotype of "pseudoacromegaly," defined as the presence of acromegaloid features in the absence of elevated levels of GH or insulin-like growth factor-I (IGF-I). Despite marked hyperinsulinemia, insulin and IGF-I binding to circulating blood cells and cultured skin fibroblasts was normal. Insulin and IGF-I-stimulated autophosphorylation of their respective receptors in cultured skin fibroblasts was also normal. However, neither insulin nor IGF-I were able to stimulate 2-deoxy D-glucose uptake by cultured skin fibroblasts. In contrast, the ability of insulin and IGF-I (or IGF-II) to stimulate amino acid uptake and thymidine incorporation into DNA was not impaired. This unique discordant signaling defect through both insulin and IGF-I receptors appeared not to be the consequence of altered expression or primary structure of the insulin receptor or the GLUT-4 glucose transporter, as assessed by several genetic and biochemical techniques. GLUT-4 expression in muscle was normal on Western blots, and SSCP screening of all 11 exons of the gene for nucleotide variation revealed no variations from normal. DNA sequencing and SSCP screening of exons 2-22 of the insulin receptor gene revealed only one variation predicted to alter the amino acid sequence (Val985-->Met). No functional differences between Met985 and wild-type human insulin receptors were evident in studies performed with Chinese hamster ovary cell transfectants that overexpress either receptor. This data combined with our previously published epidemiological data concerning the frequency of the Met985 allele, indicate that this variant insulin receptor is not responsible for the insulin resistant glucose uptake or the clinical syndrome of pseudoacromegaly. We conclude that: 1) The molecular lesion responsible for the selective biochemical defect in this individual appears to involve a signaling intermediate required for insulin and IGF-I regulation of glucose transport, and/or an effector mechanism operative in this process. 2) Cells derived from this patient may be a valuable tool in the search for such molecular mechanisms. 3) The Met985 allele is a relatively common variant which has no demonstrable adverse consequences for insulin receptor function. 4) Pseudoacromegaly can be viewed as the expected result of hyperinsulinemia driving the unopposed mitogenic and anabolic actions of insulin.

Acromegaly↗

PubMed1993

The effect of glyburide on beta-cell sensitivity to glucose-dependent insulinotropic polypeptide.

OBJECTIVE: To assess whether treatment with glyburide alters beta-cell sensitivity to GIP in NIDDM patients. RESEARCH DESIGN AND METHODS: We studied 5 untreated NIDDM patients in a meal study (Ensure, 240 ml/M2) and a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above fasting). From 60 to 120 min of the clamp, GIP was infused in a primed continuous manner at a rate of 2 pmol.kg-1 x min-1. Subjects then were treated with glyburide. After they had been on a stable dose of medication for 1 mo, the meal study and glucose clamp studies were repeated. RESULTS: In response to treatment, a decrease in fasting glucose and an increase in weight was observed (12.8 +/- 1.8 vs. 8.5 +/- 0.8 mM and 74.3 +/- 6.3 vs. 76.1 +/- 6.3 kg, respectively, P < 0.05). In response to the meal study, the AUC for glucose was less, for insulin was increased, and for GIP was unchanged after treatment (16.9 +/- 2.1 vs. 12.6 +/- 6.9 mM, P < 0.05; 161 +/- 47 vs. 242 +/- 60 pM, P < 0.05; and 199 +/- 22 vs. 219 +/- 18 pM, respectively). During the hyperglycemic clamp, steady-state glucose and 90- to 120-min GIP values were equivalent before and after treatment (18.0 +/- 1.3 vs. 18.3 +/- 1.3 mM and 302 +/- 59 vs. 298 +/- 37 pM, respectively). The 90-120 min insulin responses to the hyperglycemic clamp were greater after therapy (123 +/- 37 vs. 283 +/- 80 pM, P < 0.05) reflecting increased beta-cell responses to GIP. CONCLUSIONS: We conclude that glyburide enhances beta-cell sensitivity to GIP.

Adult↗

PubMed1992

Atrial natriuretic peptide levels in the prediction of congestive heart failure risk in frail elderly.

OBJECTIVE: To develop a noninvasive clinical predictive model for acute congestive heart failure (CHF) in a frail elderly cohort using bedside clinical assessment (medical history and physical examination) and venous atrial natriuretic peptide (ANP) levels. DESIGN: One-year prospective blinded cohort study. SETTING: Life care facility. PARTICIPANTS: Three hundred thirty-one frail, elderly volunteers free of acute illness at study entry (mean +/- SD age, 88 +/- 7 years; 23% male, 77% female). MAIN OUTCOME MEASURE: Clinical episodes of CHF with confirmation of acute pulmonary edema by chest roentgenogram. RESULTS: Fifteen percent of the elderly cohort developed at least one episode of CHF during the 1-year follow-up period. Those developing CHF had significantly higher mean +/- SE ANP values at study entry: 493 +/- 55 vs 207 +/- 15 pmol/L. The risk for development of CHF rose progressively with increasing ANP levels at study entry. In multivariate analysis, only two independent variables significantly predicted CHF: ANP value greater than 200 pmol/L (adjusted odds ratio [OR], 7.9; 95% confidence interval [CI], 3.2 to 19.2) and history of CHF in the previous year (adjusted OR, 7.0; 95% CI, 2.9 to 17). Stratifying the cohort by these two variables results in three CHF risk groups: 55% of the population at 3% annual risk of CHF, 37% of the population at 20% to 24% annual risk of CHF, and 8% of the population at 66% annual risk of CHF. CONCLUSIONS: This simple clinical prediction model identifies elderly subjects at risk for CHF and allows appropriate focusing of medical resources for prevention, early detection, and treatment of this highly morbid clinical syndrome.

Acute Disease↗

PubMed1992

The effect of pancreatic polypeptide on glucose disposal after surgical alterations of the pancreas.

Surgical alterations of the pancreas result in anatomic changes that can affect postoperative glucose metabolism. Pancreas transplantation results in reduction of beta-cell mass, systemic release of insulin, and denervation. The authors hypothesized that such alterations affect peripheral glucose disposal to induce an "insensitivity" to endogenously (systemically) released insulin. Additionally, they hypothesized that surgically induced deficiency of the postprandial hormone, pancreatic polypeptide, might contribute to altered glucose disposal. The authors studied two surgical models in dogs known to be devoid of pancreatic polypeptide--70% proximal pancreatectomy (PPx) and PPx plus distal pancreas autotransplantation (PAT/B). Oral glucose challenge and euglycemic hyperinsulinemic clamp studies were performed before and after a 16-day "pulsed" infusion of pancreatic polypeptide. Both surgical procedures resulted in elevations in the integrated glucose response after oral glucose, which was not affected by pancreatic polypeptide infusion. Euglycemic clamp studies showed decreased hepatic glucose output (Ra) and overall glucose disposal (Rd) in the fasted state for both surgical groups. The transplant animals demonstrated significant decreases in Rd during the hyperinsulinemic challenge (3.2 +/- 0.01 versus 5.7 +/- 0.01 mg/kg/minute at 60 to 120 minutes for PAT/B versus control). After 16 days of pancreatic polypeptide infusion, however, basal Ra, as well as basal and 60- to 120-minute Rd values, were returned to control values in the transplant group. The authors conclude that pancreas transplantation results in altered glucose disposal, possibly due to an altered effectiveness of systemically released insulin. They conclude that pancreatic polypeptide is an important modulator of peripheral insulin action. Therefore, the role of pancreatic polypeptide must be taken into account when evaluating postoperative glucose metabolism in canine models of pancreas transplantation.

Animals↗

PubMed1991

Protein discharge from immature secretory granules displays both regulated and constitutive characteristics.

At physiological glucose concentrations, isolated pancreatic islets release a minor portion of their newly synthesized insulin and precursors in a phase of secretion which is largely complete by 4 h of chase. Discharge during this period can be amplified by secretagogues, yet is not abolished by conditions which fully suppress regulated release from dense core secretory granules. The ability to stimulate the secretion and the biochemical profile of released proinsulin-related peptides indicate that secretion during this period originates from immature granules. The stoichiometry of release of labeled C-peptide:insulin during this phase is 1:1 at high glucose concentrations. However, at physiologic or low concentrations, C-peptide is released in molar excess of insulin as if the exocytotic vesicles carrying this secretion were budding from a post-Golgi compartment in which the lumen was composed of condensing insulin and soluble C-peptide. These findings can be explained by a model for regulated secretory protein traffic in which direct exocytosis of young granules is stimulated by higher glucose concentrations and vesicle budding from immature granules occurs at lower concentrations. Thus, insulin targeting from immature granules exhibits both regulated and constitutive-like characteristics.

Animals↗

PubMed1991

Influence of age and dose on the end-organ responses to atrial natriuretic peptide in humans.

To test the hypothesis that age differentially affects the natriuretic, hemodynamic, and humoral response to exogenous ANP, we studied seven young (Y, 20 to 39 years) and five old (O, 65 to 83 years) healthy, normotensive, nonobese men during infusion of synthetic human ANP1,28 at two different rates: 1) 0.05 microgram/kg/min (high dose) for 1 h and 2) 0.005 microgram/kg/min (low dose) for 1 h. Compared to young, the old had higher basal ANP levels (O = 142 +/- 41 v Y = 29 +/- 4 pmol/L, P less than .025), achieved higher plasma levels with low-dose infusion (O = 327 +/- 24 v Y = 155 +/- 37 pmol/L, P less than .001) and had a longer ANP half-life (O = 7.8 +/- 0.6 v Y = 4.3 +/- 0.6 min, P less than .001), suggesting decreased catabolism in the old compared to the young. Despite these age-related differences in ANP levels, there was no difference in urinary sodium or cyclic GMP excretion. After termination of the low-dose infusion, plasma ANP and urinary cGMP promptly returned to baseline levels. Despite this, a sustained natriuresis (2-fold above control) was observed for 3 h in both groups. Low-dose infusion was associated with sustained suppression of aldosterone with minimal hemodynamic changes. During high-dose infusions there was no difference in natriuresis or peak ANP levels between the two groups (O = 1299 +/- 93 v Y = 1140 +/- 54 pmol/L). In contrast to the low-dose infusion, the high-dose infusion produced a transient natriuresis lasting only for the duration of the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation.

To investigate the influence of aging on dopaminergic modulation of pulsatile thyrotropin (TSH) secretion, we examined changes in circulating TSH levels during the day and night, with and without a dopamine antagonist metoclopramide, in healthy young (20-35 yr old) and old (69-83 yr old) subjects, with the use of cluster analysis. Baseline thyroid function tests including serum thyroxine, 3,5,3'-triiodothyronine (T3), T3 resin uptake, and TSH and the response of TSH to thyrotropin-releasing hormone were within normal limits in young and old subjects, and antimicrosomal and anti-thyroglobulin antibodies were absent in all participants. Pulsatile TSH secretion was identified in all subjects, and as a group there were significant increases in nocturnal peak height (P less than 0.01), amplitude (P less than 0.01), and mean TSH (P less than 0.001). TSH pulse amplitude increased 160% (P less than 0.05) at night compared with day in the young but was unchanged at night in the old. After the administration of metoclopramide there was a significant increase in peak height (P less than 0.01), amplitude (P less than 0.01), and mean TSH (P less than 0.01). However, the effect of metoclopramide was different in young and old subjects. In the young, daytime administration of metoclopramide increased TSH pulse height (P less than 0.02) and mean TSH (P less than 0.05); pulse parameters remained unchanged at night. In comparison, in old subjects after metoclopramide, pulse parameters were unchanged during the day but pulse amplitude significantly (P less than 0.01) increased at night. TSH pulse frequency remained stable with age and was unaltered after metoclopramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗