Browsing by Author "Kirwan, John P."

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    Evidence of mononuclear cell preactivation in the fasting state in polycystic ovary syndrome
    (Elsevier, 2014-12) González, Frank; Kirwan, John P.; Rote, Neal S.; Minium, Judi; Department of Obstetrics and Gynecology, IU School of Medicine
    OBJECTIVE: We evaluated mononuclear cell (MNC) preactivation in women with polycystic ovary syndrome (PCOS) by examining the effect of in vitro lipopolysaccharide (LPS) exposure on cytokine release in the fasting state. STUDY DESIGN: Twenty women with PCOS (10 lean, 10 obese) and 20 weight-matched controls (10 lean, 10 obese) volunteered for study participation. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release was measured from mononuclear cells isolated from fasting blood samples and cultured in the presence and absence of LPS. Plasma IL-6 was measured from the same fasting blood samples. Insulin sensitivity was derived from an oral glucose tolerance test using the Matsuda index, and truncal fat was measured by dual-energy x-ray absorptiometry. RESULTS: The percent change from baseline in TNF-α and IL-6 release from MNC following LPS exposure was increased (P < .04) in lean and obese women with PCOS and obese controls compared with lean controls. Plasma IL-6 was increased (P < .02) in obese women with PCOS compared with lean women with PCOS, which in turn was increased (P < .02) compared with lean controls. The MNC-derived TNF-α and IL-6 responses from MNCs were negatively correlated with insulin sensitivity (P < .03) and positively correlated with testosterone (P < .03) and androstenedione (P < .006) for the combined groups. Plasma IL-6 was positively correlated with percentage truncal fat (P < .008). CONCLUSION: In PCOS, increased cytokine release from MNCs following LPS exposure in the fasting state reveals the presence of MNC preactivation. Importantly, this phenomenon is independent of obesity and may contribute to the development of insulin resistance and hyperandrogenism in PCOS. In contrast, the source of plasma IL-6 elevations in PCOS may be excess adiposity.
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    Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome
    (Elsevier, 2014-06) González, Frank; Kirwan, John P.; Rote, Neal S.; Minium, Judi; O’Leary, Valerie B.; Department of Obstetrics and Gynecology, IU School of Medicine
    Women with polycystic ovary syndrome (PCOS) have chronic low-grade inflammation, which can increase the risk of atherogenesis. We examined the effect of glucose ingestion and lipopolysaccharide (LPS) on markers of proatherogenic inflammation in the mononuclear cells (MNC) and plasma of women with PCOS. Sixteen women with PCOS (8 lean, 8 obese) and 15 weight-matched controls (8 lean, 7 obese) underwent a 3-h oral glucose tolerance test (OGTT). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) release from MNC cultured in the presence of LPS and plasma IL-6, C-reactive protein (CRP), and soluble vascular adhesion molecule-1 (sVCAM-1) were measured from blood samples drawn while fasting and 2 h after glucose ingestion. Truncal fat was measured by dual-energy absorptiometry (DEXA). Lean women with PCOS and obese controls failed to suppress LPS-stimulated IL-6 and IL-1β release from MNC after glucose ingestion. In contrast, obese women with PCOS suppressed these MNC-derived cytokines under the same conditions. In response to glucose ingestion, plasma IL-6 and sVCAM-1 increased and CRP suppression was attenuated in both PCOS groups and obese controls compared with lean controls. Fasting plasma IL-6 and CRP correlated positively with percentage of truncal fat. The absolute change in plasma IL-6 correlated positively with testosterone. We conclude that glucose ingestion promotes proatherogenic inflammation in PCOS with a systemic response that is independent of obesity. Based on the suppressed MNC-derived cytokine responses suggestive of LPS tolerance, chronic low-grade inflammation may be more profound in obese women with PCOS. Excess abdominal adiposity and hyperandrogenism may contribute to atherogenesis in PCOS.
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    Glucose-stimulated oxidative stress in mononuclear cells is related to pancreatic β-cell dysfunction in polycystic ovary syndrome
    (The Endocrine Society, 2014-01) Malin, Steven K.; Kirwan, John P.; Sia, Chang Ling; González, Frank; Department of Obstetrics and Gynecology, IU School of Medicine
    CONTEXT: Oxidative stress induced by reactive oxygen species (ROS) is involved in the development of pancreatic β-cell dysfunction. OBJECTIVE: We determined the relationship between mononuclear cell (MNC)-derived ROS generation and p47phox protein content in response to glucose ingestion and β-cell function in women with polycystic ovary syndrome (PCOS). DESIGN: This was a cross-sectional study. SETTING: This study was conducted at an academic medical center. PARTICIPANTS: Twenty-nine normoglycemic women with PCOS (13 lean, 16 obese) and 25 ovulatory controls (16 lean, 9 obese) underwent a 3-h 75-g oral glucose tolerance test (OGTT). MAIN OUTCOME VARIABLES: Pancreatic β-cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve0-30 min; GSIS)×Matsuda index-derived insulin sensitivity (ISOGTT). ROS generation was measured by chemiluminescence, and p47phox protein was quantified by Western blotting in MNC isolated from blood samples obtained at 0 and 2 hours of the OGTT. RESULTS: Compared with controls, women with PCOS exhibited a higher percent change from baseline in ROS generation and p47phox protein in conjunction with greater GSIS and a tendency toward lower β-cell function. Lean women with PCOS exhibited a greater percent change from baseline in ROS generation and p47phox protein yet had similar GSIS responses compared with lean controls despite having lower ISOGTT. For the combined groups, β-cell function was inversely related to ROS generation and p47phox protein. GSIS was directly related to body mass index, central obesity, and circulating androgens. CONCLUSION: In normoglycemic women, obesity plays a role in exaggerating GSIS. However, MNC-derived oxidative stress is independent of obesity and may contribute to the decline in β-cell function in women with PCOS.
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    Joint international consensus statement for ending stigma of obesity
    (Nature Research, 2020) Rubino, Francesco; Puhl, Rebecca M.; Cummings, David E.; Eckel, Robert H.; Ryan, Donna H.; Mechanick, Jeffrey I.; Nadglowski, Joe; Salas, Ximena Ramos; Schauer, Phillip R.; Twenefour, Douglas; Apovian, Caroline M.; Aronne, Louis J.; Batterham, Rachel L.; Berthoud, Hans-Rudolph; Boza, Camilo; Busetto, Luca; Dicker, Dror; de Groot, Mary; Eisenberg, Daniel; Flint, Stuart W.; Huang, Terry T.; Kaplan, Lee M.; Kirwan, John P.; Korner, Judith; Kyle, Ted K.; Laferrère, Blandine; le Roux, Carel W.; McIver, LaShawn; Mingrone, Geltrude; Nece, Patricia; Reid, Tirissa J.; Rogers, Ann M.; Rosenbaum, Michael; Seeley, Randy J.; Torres, Antonio J.; Dixon, John B.; Medicine, School of Medicine
    People with obesity commonly face a pervasive, resilient form of social stigma. They are often subject to discrimination in the workplace as well as in educational and healthcare settings. Research indicates that weight stigma can cause physical and psychological harm, and that affected individuals are less likely to receive adequate care. For these reasons, weight stigma damages health, undermines human and social rights, and is unacceptable in modern societies. To inform healthcare professionals, policymakers, and the public about this issue, a multidisciplinary group of international experts, including representatives of scientific organizations, reviewed available evidence on the causes and harms of weight stigma and, using a modified Delphi process, developed a joint consensus statement with recommendations to eliminate weight bias. Academic institutions, professional organizations, media, public-health authorities, and governments should encourage education about weight stigma to facilitate a new public narrative about obesity, coherent with modern scientific knowledge.
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    Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation
    (American Physiological Society, 2015-05) Malin, Steven K.; Kirwan, John P.; Sia, Chang Ling; Gonzalez, Frank; Department of Obstetrics and Gynecology, IU School of Medicine
    In polycystic ovary syndrome (PCOS), oxidative stress is implicated in the development of β-cell dysfunction. However, the role of mononuclear cell (MNC)-derived inflammation in this process is unclear. We determined the relationship between β-cell function and MNC-derived nuclear factor-κB (NF-κB) activation and tumor necrosis factor-α (TNF-α) secretion in response to a 2-h 75-g oral glucose tolerance test (OGTT) in normoglycemic women with PCOS (15 lean, 15 obese) and controls (16 lean, 14 obese). First- and second-phase β-cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve for 0-30 and 60-120 min, respectively) × insulin sensitivity (Matsuda Index derived from the OGTT). Glucose-stimulated NF-κB activation and TNF-α secretion from MNC, and fasting plasma thiobarbituric acid-reactive substances (TBARS) and high-sensitivity C-reactive protein (hs-CRP) were also assessed. In obese women with PCOS, first- and second-phase β-cell function was lower compared with lean and obese controls. Compared with lean controls, women with PCOS had greater change from baseline in NF-κB activation and TNF-α secretion, and higher plasma TBARS. β-Cell function was inversely related to NF-κB activation (1st and 2nd) and TNF-α secretion (1st), and plasma TBARS and hs-CRP (1st and 2nd). First- and second-phase β-cell function also remained independently linked to NF-κB activation after adjustment for body fat percentage and TBARS. In conclusion, β-cell dysfunction in PCOS is linked to hyperglycemia-induced NF-κB activation from MNC and systemic inflammation. These data suggest that in PCOS, inflammation may play a role in impairing insulin secretion before the development of overt hyperglycemia.
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    The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of Network organization, procedures and interventions
    (Elsevier, 2022-02) Georas, Steve N.; Wright, Rosalind J.; Ivanova, Anastasia; Israel, Elliot; LaVange, Lisa M.; Akuthota, Praveen; Carr, Tara F.; Denlinger, Loren C.; Fajt, Merritt L.; Kumar, Rajesh; O’Neal, Wanda K.; Phipatanakul, Wanda; Szefler, Stanley J.; Aronica, Mark A.; Bacharier, Leonard B.; Burbank, Allison J.; Castro, Mario; Alexander, Laura Crotty; Bamdad, Julie; Cardet, Juan Carlos; Comhair, Suzy A. A.; Covar, Ronina A.; DiMango, Emily A.; Erwin, Kim; Erzurum, Serpil C.; Fahy, John V.; Gaffin, Jonathan M.; Gaston, Benjamin; Gerald, Lynn B.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; James, John; Jarjour, Nizar N.; Kenyon, Nicholas J.; Khatri, Sumita; Kirwan, John P.; Kraft, Monica; Krishnan, Jerry A.; Liu, Andrew H.; Liu, Mark C.; Marquis, M. Alison; Martinez, Fernando; Mey, Jacob; Moore, Wendy C.; Moy, James N.; Ortega, Victor E.; Peden, David B.; Pennington, Emily; Peters, Michael C.; Ross, Kristie; Sanchez, Maria; Smith, Lewis J.; Sorkness, Ronald L.; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zein, Joe; Zeki, Amir A.; Noel, Patricia; Pediatrics, School of Medicine
    Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma.
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    Safety and Tolerability of Whole Soybean Products: A Dose-Escalating Clinical Trial in Older Adults with Obesity
    (MDPI, 2023-04-16) Rebello, Candida J.; Boué, Stephen; Levy, Ronald J., Jr.; Puyau, Renée; Beyl, Robbie A.; Greenway, Frank L.; Heiman, Mark L.; Keller, Jeffrey N.; Reynolds, Charles F., III; Kirwan, John P.; Biology, School of Science
    Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70-85 years) with obesity. Whole green soybean pods grown under controlled conditions were processed to flour (WGS) at the United States Department of Agriculture using common cooking techniques such as slicing and heat treatment. WGS incorporated into food products was consumed at 10 g, 20 g, and 30 g/day for one week at each dose. The gastrointestinal outcomes, clinical biomarkers, and adverse events were evaluated. We explored the stimulation of phytoalexin (glyceollin) production in live viable soybean seeds (LSS-G). We compared the compositions of WGS and LSS-G with commercial soybean flour and its fermented and enzymatically hydrolyzed forms. We found that although 30 g WSG was well-tolerated, and it made participants feel full. Our processing produced glyceollins (267 µg/g) in LSS-G. Processing soybean flour decreased the iron content, but reduced the oligosaccharides, which could attenuate flatulence. Providing soybean flour at <30 g/day may be prudent for overall health and to prevent the exclusion of other food groups and nutrients in older adults with obesity.