ABSTRACT
AIM: To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. MATERIALS AND METHODS: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). RESULTS: Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). CONCLUSION: Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.
Subject(s)
Insulin Resistance , Prediabetic State , Humans , Incretins/therapeutic use , Liraglutide/therapeutic use , Plasminogen Activator Inhibitor 1 , Prediabetic State/complications , Prediabetic State/drug therapy , Fibrinolysis , Diet, Reducing , Obesity/complications , Obesity/drug therapy , Hypoglycemic Agents/therapeutic use , Sitagliptin Phosphate/therapeutic use , Weight Loss , Inflammation/drug therapy , Glucagon-Like Peptide-1 Receptor/agonistsABSTRACT
Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS: Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Insulin Resistance , Prediabetic State , Humans , Liraglutide/pharmacology , Liraglutide/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Dipeptidyl Peptidase 4/metabolism , Glucagon/metabolism , Prediabetic State/drug therapy , Diet, Reducing , Cross-Over Studies , Obesity/drug therapy , Blood Glucose/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Sitagliptin Phosphate/pharmacology , Sitagliptin Phosphate/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide 1/metabolism , Weight LossABSTRACT
Nonfunctioning pituitary adenomas (NFPA) are typically benign neoplasms that can cause significant morbidity through local mass effects. MIB-1/Ki-67 and p53 immuno-reactivity are used to predict aggressive behavior but have known limitations. No marker to date is widely used to reliably predict tumor progression. Phospho-histone H3 (pHH3) is a protein phosphorylated during chromatin condensation in mitosis, and thus anti-pHH3 immunocytochemistry is able to assess mitotic activity. Study objectives were to determine the relationship among pHH3, MIB-1/Ki-67, and p53 in NFPA, and to evaluate the relationship between these indices and time to progression (TTP). Seventy-six patients with NFPA operated on by a single neurosurgeon at University of Texas M. D. Anderson Cancer Center from 1992 to 2006 were identified from a database and met all criteria for inclusion in this clinicopathology study. PHH3, MIB-1/Ki-67, and p53 immuno-reactivity was evaluated in each case. Retrospective review was used to determine TTP. With 282 person-years of follow-up, 19 progression events were observed. A correlation was found between MIB-1/Ki-67 and p53 immuno-reactivity (r = 0.25, p = 0.031). PHH3 did not correlate with either. When markers were dichotomized at the median, only MIB-1/Ki-67 correlated with TPP (log rank p = 0.018). Rank correlation analysis confirmed a significant inverse correlation between both MIB-1/Ki-67 (Dxy = -0.33, p = 0.036) and p53 (Dxy = -0.40, 0.016) immuno-reactivity and TTP. Our results support previous data suggesting that MIB-1/Ki-67 and p53 have clinical utility as prognostic markers for tumor progression. PHH3 did not prove to be associated with TTP in this retrospective study limited by few progression events.
Subject(s)
Histones/metabolism , Pituitary Neoplasms/metabolism , Adult , Aged , Female , Humans , Ki-67 Antigen/metabolism , Male , Middle Aged , Phosphorylation , Tumor Suppressor Protein p53/metabolism , Young AdultABSTRACT
CONTEXT: Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. OBJECTIVE: We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. METHODS: Eighteen women with PCOS participated in a double-blind, crossover study. They received sitagliptin either 100 mg or placebo daily for 1 month, with crossover treatments separated by an 8-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT) and assessments of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. RESULTS: During OGTT, sitagliptin increased glucagon-like peptide-1 (P < 0.001), early insulin secretion (from mean [± SD] insulinogenic index 1.9 ± 1.2 to 3.2 ± 3.1; P = 0.02), and decreased peak glucose (mean -17.2 mg/dL [95% CI, -27.7 to -6.6]; P < 0.01). At 1 month, sitagliptin decreased VAT (from 1141.9 ± 700.7 to 1055.1 ± 710.1 g; P = 0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9 ± 3.6 to 17.0 ± 6.8 min, N = 16; P = 0.04) and interpulse interval (from 53.2 ± 20.0 to 77.3 ± 38.2 min, N = 16; P < 0.05) but did not increase mean overnight GH (P = 0.92 vs placebo). CONCLUSIONS: Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. CLINICAL TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov as NCT02122380 prior to enrollment of the first participant.
Subject(s)
Blood Glucose/metabolism , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Intra-Abdominal Fat/drug effects , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Sitagliptin Phosphate/therapeutic use , Adolescent , Adult , Biomarkers/analysis , Blood Glucose/analysis , Blood Glucose/drug effects , Cross-Over Studies , Double-Blind Method , Female , Follow-Up Studies , Glucose Tolerance Test , Human Growth Hormone/metabolism , Humans , Middle Aged , Polycystic Ovary Syndrome/pathology , Prognosis , Young AdultABSTRACT
The evaluation and management of patients with residual Cushing's disease is one of the more complex issues facing neurosurgeons and neuroendocrinologists in clinical practice. There is considerable controversy over several relevant issues such as the timing of the assessment of whether a patient is in remission, what biochemical parameters define remission, the most appropriate course of action to take after residual disease has been defined, etc. As a consequence of the controversies, treating physicians develop notions and fall into certain practice patterns based on evidence of varying levels, their anecdotal experiences, and information gleaned from scientific meetings. This practice pattern, we believe, constitutes the "art of medicine." We conducted a PubMed literature search to identify manuscripts containing data relevant to Cushing's disease, outcomes of various therapeutic modalities, and recurrences. Reference lists were used to identify additional relevant manuscripts. We focused our review on manuscripts that included reasonably large series of patients, those reflecting the experience of pituitary centers and physicians recognized as experts in the field, and those papers felt to represent seminal contributions to the literature. Furthermore, trends in the evaluation and management of relevant patients have been incorporated by the senior author who has seen and evaluated over 750 patients with documented Cushing's syndrome over the past 18 years in clinical practice. An analysis of current evidence indicated that, despite advances in neurosurgical techniques and recent developments in adjuvant therapies, patients with residual Cushing's disease present significant management challenges to treating physicians. In this era, however, it is indeed possible to gain control of the hypercortisolism in most patients. Despite the wide variability in research methodology designed to collect relevant data, a step-wise approach to the management of these patients can be achieved. A logical step-wise approach to the evaluation of postoperative patients with Cushing's disease is essential. Patients with residual disease require the development of an individualized plan of management that takes into account numerous factors pertaining to status of disease, the experience of treating physicians, and available therapeutic modalities.
Subject(s)
Pituitary ACTH Hypersecretion/diagnosis , Pituitary ACTH Hypersecretion/therapy , Pituitary Gland/surgery , Adrenalectomy/methods , Humans , Hydrocortisone/metabolism , Neurosurgical Procedures/methods , Pituitary ACTH Hypersecretion/pathology , PubMed/statistics & numerical data , RadiotherapyABSTRACT
Aging is a major risk factor for the development of cardiovascular disease. Aging is also associated with a decline in the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis. This axis impacts endothelial and vascular smooth muscle cell biology, as well as cardiac function. The number of endothelial progenitor cells (EPCs) also decreases with age and is emerging as a surrogate measurement of vascular senescence. Studies suggest that EPCs impact vascular health by modulating vascular repair and function. Current evidence demonstrates that EPC number and function is restored with a GH-mediated increase in serum IGF-1. Modulation of the GH and IGF-1 system may therefore provide a useful therapy in the prevention of age-associated changes in the cardiovascular system and in future regenerative cell-based therapies.
Subject(s)
Aging/physiology , Cardiovascular Physiological Phenomena/drug effects , Growth Hormone/therapeutic use , Human Growth Hormone/physiology , Human Growth Hormone/therapeutic use , Insulin-Like Growth Factor I/physiology , Stem Cells/physiology , Aged , Animals , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/physiopathology , Clinical Trials as Topic , Hormone Replacement Therapy , Human Growth Hormone/deficiency , Humans , Indoles/therapeutic use , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/physiology , Risk , Spiro Compounds/therapeutic use , Stem Cell TransplantationABSTRACT
OBJECTIVE: Endothelial progenitor cells (EPCs) mobilize from the bone marrow secondary to a stimulus and home to sites of injury, where they differentiate into endothelial cells and contribute to the repair of damaged vasculature. We hypothesized that growth hormone (GH) administration would increase the number of circulating EPCs in adults and thereby represent a mechanism to enhance vascular health. DESIGN: A prospective trial of low-dose GH (0.03mg/kg/week for 4 weeks followed by 0.06mg/kg/week for a maximum of four additional weeks) in 10 healthy adults (6 males and 4 females; mean age 37 years, range 26-65). Primary outcomes measured included the number of circulating EPCs as assessed by colony-forming unit (CFU) assay and flow cytometry. Secondary outcomes included plasma measurements of known mediators of EPC mobilization and indices of nitric oxide (NO). Outcomes were measured at baseline and at study completion. RESULTS: GH administration increased serum IGF-1 (143ng/mL [IQR 121-164] to 222 [IQR 194-244]; P=0.005). The increase in early-outgrowth EPCs (13 CFU per high-power field [IQR 6-24] to 19 [IQR 13-40]; P=0.005) correlated with the peak IGF-1 after adjustment for the baseline number of early-outgrowth EPCs (r=0.719 [95% CI 0.06, 0.93]; P=0.027). The number of late-outgrowth EPCs as well as CD34+, VEGFR2(KDR)+, and AC133+ cells did not significantly change. Other mediators of EPC mobilization were stable while plasma nitrite trended upwards (1.3micromol/L [IQR 0-2.5] to 3.7 [IQR 2.2-8.9]; P=0.052). CONCLUSIONS: GH administration selectively augments the early-outgrowth EPC population in healthy individuals. These findings both support GH replacement in the setting of GH deficiency to maintain vascular integrity and have implications for the use of GH in future regenerative cell-based therapies. Furthermore, the decrease in EPCs observed with aging may in part be explained by the declining somatotropic axis, and thereby contribute to cardiovascular senescence.
Subject(s)
Cell Movement/drug effects , Endothelial Cells/drug effects , Health , Human Growth Hormone/administration & dosage , Human Growth Hormone/pharmacology , Stem Cells/drug effects , Adult , Aged , Cells, Cultured , Drug-Related Side Effects and Adverse Reactions , Female , Human Growth Hormone/adverse effects , Humans , Male , Middle Aged , Nitric Oxide/metabolism , Prospective StudiesABSTRACT
BACKGROUND: Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity. METHODS AND RESULTS: Healthy adults participated in a 2-part double-blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (rs=-0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA. CONCLUSIONS: Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Human Growth Hormone/blood , Sitagliptin Phosphate/administration & dosage , Vasodilation/drug effects , Administration, Oral , Adult , Cross-Over Studies , Double-Blind Method , Female , Fibrinolysis/drug effects , Humans , Insulin-Like Growth Factor I/metabolism , Male , Secretory Pathway , Sex Factors , Time Factors , Tissue Plasminogen Activator/blood , Up-Regulation , Young AdultABSTRACT
CONTEXT: Adults with GH deficiency (GHD) have multiple cardiovascular risk factors, including an unfavorable lipid profile and body composition as well as impairments in endothelial function and cardiac performance. We hypothesized that GHD is associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of plasminogen activation in the circulation. OBJECTIVE: The objective of the study was to determine the fibrinolytic profile of adults with GHD in comparison with controls. STUDY DESIGN AND PARTICIPANTS: This was a prospective, observational study including 12 adults with GHD. Twelve gender-, age-, and body mass index-matched adults served as controls. MAIN OUTCOME MEASURES: The primary outcome measures were circadian plasma PAI-1 antigen with corresponding tissue-plasminogen activator (tPA) activity values. Endothelial function was assessed by flow-mediated vasodilation and fibrinolytic potential by venous occlusion test. RESULTS: Adults with GHD exhibited an unfavorable 24-h fibrinolytic profile characterized by a mean 62% elevation in PAI-1 antigen (2.77 ng/ml after adjustment for baseline PAI-1; P = 0.049) in the setting of a mean 24% reduction in tPA activity (-0.17 IU/ml after adjustment for baseline tPA; P = 0.003). Fibrinolytic response was defective in GHD, as demonstrated by a sustained elevation in PAI-1 activity greater than 4 IU/ml after venous occlusion [7.2 IU/ml (interquartile range 0.8-17.4); P = 0.018]. Endothelial function was impaired in GHD, as quantified by percent flow-mediated vasodilation over 120 sec [area under the curve 3.8 (interquartile range -2.4 to 7.9) vs. 12.8 (interquartile range 2.1-19.4); P = 0.043]. CONCLUSIONS: Adults with GHD demonstrate alterations in plasma fibrinolytic balance, including elevated levels of PAI-1 antigen with decreased tPA activity. These changes may contribute to the increased cardiovascular morbidity within this population.
Subject(s)
Cardiovascular Diseases/etiology , Fibrinolysis/physiology , Growth Disorders/complications , Growth Disorders/physiopathology , Growth Hormone/deficiency , Adult , Case-Control Studies , Circadian Rhythm , Endothelium, Vascular/physiology , Female , Fibrin/metabolism , Growth Disorders/blood , Growth Disorders/metabolism , Homeostasis/physiology , Humans , Male , Plasminogen Activator Inhibitor 1/blood , Plasminogen Activator Inhibitor 1/metabolism , Risk Factors , Tissue Plasminogen Activator/blood , Tissue Plasminogen Activator/metabolismABSTRACT
CONTEXT: Patients with diabetes often have comorbidities such as hypertension. It is not known how individual characteristics influence response to dipeptidyl peptidase-4 (DPP4) inhibitors. OBJECTIVE: We tested the hypothesis that individual characteristics, sitagliptin dose, and genetic variability in DPP4 influence DPP4 activity during sitagliptin. DESIGN AND SETTING: Post hoc analysis of clinical and laboratory data from individuals randomized to sitagliptin versus placebo in crossover studies. PATIENTS AND INTERVENTIONS: Sixty-five subjects [27 with type 2 diabetes mellitus (T2DM) and hypertension, 38 healthy controls] were randomized to 100 mg/d sitagliptin or 200 mg sitagliptin and matching placebo in double-blind, crossover fashion. Fasting blood was obtained at baseline and 60 to 180 minutes after sitagliptin or placebo. MAIN OUTCOME MEASURES: DPP4 activity and antigen during placebo and sitagliptin and DPP4 inhibition during sitagliptin. RESULTS: Sitagliptin 100 mg/d was less effective at inhibiting DPP4 activity in individuals with T2DM and hypertension than in healthy controls (P = 0.001, percent inhibition). In healthy controls, 100 mg/d sitagliptin was not as effective as single-dose 200 mg sitagliptin (P = 0.001, percent inhibition). DPP4 genotypes rs2909451 TT (P = 0.02) and rs759717 CC (P = 0.02) were associated with DPP4 activity during sitagliptin. In multivariable analyses, T2DM with hypertension, sitagliptin dose, age, systolic blood pressure, DPP4 activity during placebo, and rs2909451 genotype were significantly associated with DPP4 activity during sitagliptin. CONCLUSIONS: Sitagliptin is less effective in inhibiting DPP4 in individuals with T2DM and hypertension than in healthy controls. Higher doses of DPP4 inhibitors may be required in patients with the metabolic syndrome.
ABSTRACT
OBJECTIVE: Body weight blunts the growth hormone (GH) response to provocative stimuli. The appropriate GH cut-off to confirm GH deficiency in obese and overweight patients undergoing the glucagon stimulation test (GST) has recently been questioned. We hypothesized that the peak GH would be inversely related to the nadir blood glucose (BG) after glucagon and that this may be a mechanism influencing peak GH in overweight patients. This retrospective study examined effects of gender, body weight, and BG dynamics on GH response to GST in patients evaluated in our Pituitary Center. DESIGN: Adult patients who underwent GST from September 2009-2014 were included. Continuous variable comparisons were analyzed using the Mann-Whitney U-test and categorical data by Fisher's Exact Test. Spearman correlation was used to determine associations between continuous variables. RESULTS: 42 patients (N=28, 66.7% female) had sufficient data for analysis. Obese patients (N=26) had a reduced GH response, summarized as GH area under the curve (AUC) (p=0.03 vs. non-obese patients) and higher BG during GST, summarized as AUC (p<0.01 vs. non-obese patients). Obese women (N=19), in particular, stimulated lower (p=0.03 vs. non-obese women) and had a higher nadir BG (p=0.03 vs. non-obese women). While weight correlated with extent (rs=0.35; p=0.02) and timing (rs=0.31; p=0.05) of nadir BG reached, there was no significant correlation between BG dynamics and the GH response in the total population (N=42). Ten patients (7 with pan anterior hypopituitarism, defined as 3 anterior pituitary deficiencies) had a peak GH≤0.1ng/mL during GST. When these subjects with a negligible peak GH response were excluded from the analysis, weight was associated with GH AUC (rs=-0.45; p=0.01), peak GH response (rs=-0.42; p=0.02) and nadir BG (rs=0.48; p<0.01). Furthermore, the nadir BG achieved during GST was inversely related to GH AUC (rs=-0.38; p=0.03) and peak GH (rs=-0.37; p=0.04) such that patients (N=32) with higher nadir BG had lower peak GH in response to glucagon. CONCLUSIONS: Obese patients, particularly women, do not respond as robustly to glucagon stimulation. These data suggest that there exists an altered BG profile during GST in obese individuals, and that a less robust hypoglycemic stimulus may contribute to an impaired GH response. We suggest measuring BG levels during glucagon stimulation testing to assist with clinical interpretation of GH dynamics. The diagnostic accuracy of the GST in patients with known disorders in glucose metabolism and those taking anti-diabetic medications deserves further study.
Subject(s)
Blood Glucose/metabolism , Body Weight/physiology , Glucagon/pharmacology , Human Growth Hormone/metabolism , Pituitary Diseases , Adolescent , Adult , Aged , Diagnostic Techniques, Endocrine , Female , Humans , Male , Middle Aged , Pituitary Diseases/diagnosis , Pituitary Diseases/epidemiology , Pituitary Diseases/metabolism , Retrospective Studies , Sex Factors , Young AdultABSTRACT
A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti-thrombotic prostacyclin. This study tested the hypothesis that extended-release aspirin (NHP-554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate-release aspirin (ASA). Thirty-six healthy subjects were randomized to NHP-554C or ASA groups. Within each group, subjects were randomized to 5-day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2-week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11-dehydro-thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3-dinor-6-keto-PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP-554C 81 mg/d and 162.5 mg/d reduced 11-dehydro-thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3-dinor-6-keto-PGF1α 13.4% and 18.5%, respectively. NHP-554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP-554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3-dinor-6-keto-PGF1α. Nevertheless, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-PGF1α responses to bradykinin were statistically similar during ASA and NHP-554C. In conclusion, at doses of 81 and 162.5 mg/d immediate- and extended-release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin-stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP-554C.
ABSTRACT
Pituitary adenomas are common in the general population. They can be complicated by intratumoral hemorrhage, otherwise known as apoplexy, which frequently presents with neurologic deficits that may necessitate urgent surgical decompression. Many risk factors for pituitary apoplexy have been suggested in the literature. We present a case of symptomatic apoplexy in a woman following the intravitreal administration of the vascular endothelial growth factor (VEGF) inhibitor ranibizumab. Ophthalmoplegia resolved and visual acuity significantly improved following gross total resection of the tumor via an endoscopic endonasal surgical approach. The association between intravitreal injection of a VEGF inhibitor and pituitary apoplexy has not been previously described, but physicians performing these procedures should be aware of this potential complication.
Subject(s)
Acute-Phase Reaction/etiology , Fasciitis, Necrotizing/physiopathology , Acute-Phase Reaction/diagnosis , Acute-Phase Reaction/therapy , Combined Modality Therapy , Fasciitis, Necrotizing/diagnosis , Fasciitis, Necrotizing/therapy , Humans , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/therapyABSTRACT
UNLABELLED: Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. CLINICAL TRIAL REGISTRATION: - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Dipeptidyl Peptidase 4/drug effects , Enzyme Inhibitors/pharmacology , Neurotransmitter Agents/pharmacology , Peptidyl-Dipeptidase A/drug effects , Substance P/pharmacology , Sympathetic Nervous System/drug effects , Adult , Blood Pressure/drug effects , Bradykinin/pharmacology , Cross-Over Studies , Double-Blind Method , Enalaprilat/pharmacology , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Norepinephrine/metabolism , Pyrazines/pharmacology , Sitagliptin Phosphate , Triazoles/pharmacology , Vascular Resistance/drug effectsABSTRACT
BACKGROUND: Dipeptidyl-peptidase 4 (DPP4) inhibitors improve glycemic control in patients with diabetes mellitus by preventing the degradation of glucagon-like peptide-1 (GLP-1). GLP-1 causes vasodilation in animal models but also increases sympathetic activity; the effect of GLP-1 in the human vasculature and how it is altered by DPP4 inhibition is not known. DPP4 also degrades the vasodilator brain natriuretic peptide (BNP) to a less potent metabolite. This study tested the hypothesis that DPP4 inhibition potentiates the vasodilator responses to GLP-1 and BNP in the human forearm. METHOD AND RESULTS: Seventeen healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received DPP4 inhibitor (sitagliptin 200 mg by mouth) or placebo. Sitagliptin increased forearm blood flow and decreased forearm vascular resistance without affecting mean arterial pressure and pulse. GLP-1 and BNP were infused in incremental doses via brachial artery. Venous GLP-1 concentrations were significantly higher during sitagliptin use, yet there was no effect of GLP-1 on forearm blood flow in the presence or absence of sitagliptin. BNP caused dose-dependent vasodilation; however, sitagliptin did not affect this response. GLP-1 and BNP had no effect on net norepinephrine release. CONCLUSIONS: These data suggest that GLP-1 does not act as a direct vasodilator in humans and does not contribute to sympathetic activation. Sitagliptin does not regulate vascular function in healthy humans by affecting the degradation of GLP-1 and BNP. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov/ Unique identifier: NCT01413542.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Forearm/blood supply , Glucagon-Like Peptide 1/drug effects , Natriuretic Peptide, Brain/drug effects , Pyrazines/pharmacology , Regional Blood Flow/drug effects , Triazoles/pharmacology , Vasodilation/drug effects , Adult , Cross-Over Studies , Double-Blind Method , Female , Glucagon-Like Peptide 1/blood , Healthy Volunteers , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Sitagliptin PhosphateABSTRACT
Pituitary tumors are a unique class of intracranial neoplasms with the potential to disrupt hormone function and water metabolism. Preoperative and postoperative endocrine assessment is mandatory to recognize and promptly treat new deficiencies and identify those that have resolved. Close collaboration among neurosurgical, endocrine, and anesthetic teams is equally vital during the perioperative period. Appropriate patient education at the time of discharge regarding the symptoms of diabetes insipidus, hyponatremia, and adrenal insufficiency is increasingly important.
Subject(s)
Diabetes Insipidus, Neurogenic/therapy , Hypopituitarism/therapy , Pituitary Neoplasms/therapy , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/therapy , Diabetes Insipidus, Neurogenic/complications , Humans , Hyponatremia/diagnosis , Hyponatremia/therapy , Hypopituitarism/diagnosis , Hypopituitarism/etiology , Pituitary Neoplasms/complications , Pituitary Neoplasms/diagnosis , Preoperative CareSubject(s)
Brain Injuries/complications , Hypopituitarism/diagnosis , Hypopituitarism/etiology , Magnetic Resonance Imaging , Pituitary Hormones/metabolism , Accidents, Traffic , Adult , Blood Chemical Analysis , Brain Injuries/diagnosis , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Injury Severity Score , Pituitary Hormones/analysis , Pituitary-Adrenal Function Tests , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
OBJECTIVE: To determine whether a random postoperative day-3 cortisol value of 10 µg/dL or greater is predictive of adrenal sufficiency 3 to 10 weeks after transsphenoidal surgery (TSS) and during long-term clinical follow-up. METHODS: We retrospectively reviewed the case records of patients who underwent TSS at our institution between 1991 and 2008. Inclusion criteria were as follows: random cortisol measured on the morning of postoperative day 3, adrenal dynamic testing performed 3 to 10 weeks after TSS, and clinical assessment of the hypothalamic-pituitary-adrenal (HPA) axis at least 6 months after TSS. RESULTS: A total of 466 patients underwent TSS at our institution during the study period. Eighty-three patients met study inclusion criteria. Sensitivity of a random postoperative day-3 serum cortisol value of 10 µg/dL or greater for the prediction of adrenal sufficiency at a median follow-up of 42 days was 64.81% (95% confidence interval, 50.6%-77.32%), with an odds ratio of 3.1 (95% confidence interval, 1.08-8.58). Specificity was 62.1% (95% confidence interval, 42.3%-79.3%). At a median follow-up of 500 days, only 2 patients with a postoperative day-3 cortisol value of 10 µg/dL or greater required hydrocortisone replacement, both of whom had multiple anterior pituitary hormone deficiencies and evidence of pituitary dysfunction during the perioperative period. CONCLUSIONS: In the appropriate clinical context, a postoperative day-3 cortisol value of 10 µg/dL or greater accurately predicts the integrity of the HPA axis. The final decision regarding corticosteroid replacement should be personalized, considering the postoperative day-3 cortisol level, the clinical context in which the measurement was obtained, and any evidence of concomitant pituitary dysfunction in the perioperative period.