Browsing by Subject "Hormone"
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Item A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes(The Endocrine Society, 2023) Hart, Phil A.; Kudva, Yogish C.; Yadav, Dhiraj; Andersen, Dana K.; Li, Yisheng; Toledo, Frederico G. S.; Wang, Fuchenchu; Bellin, Melena D.; Bradley, David; Brand, Randall E.; Cusi, Kenneth; Fisher, William; Mather, Kieren; Park, Walter G.; Saeed, Zeb; Considine, Robert V.; Graham, Sarah C.; Rinaudo, Jo Ann; Serrano, Jose; Goodarzi, Mark O.; Medicine, School of MedicinePurpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases.Item Diabetes mellitus due to the toxic misfolding of proinsulin variants(Elsevier, 2013) Weiss, Michael A.; Biochemistry and Molecular Biology, School of MedicineDominant mutations in the human insulin gene can lead to pancreatic β-cell dysfunction and diabetes mellitus due to toxic folding of a mutant proinsulin. Analogous to a classical mouse model (the Akita mouse), this monogenic syndrome highlights the susceptibility of human β-cells to endoreticular stress due to protein misfolding and aberrant aggregation. The clinical mutations directly or indirectly perturb native disulfide pairing. Whereas the majority of mutations introduce or remove a cysteine (leading in either case to an unpaired residue), non-cysteine-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the evolution of insulin has been constrained not only by its structure and function, but also by the susceptibility of its single-chain precursor to impaired foldability.Item Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes(Springer Nature, 2012-05-04) Houk, Christopher P.; Lee, Peter A.; Pediatrics, School of MedicineApproximately 10% of children born small for their gestational age (SGA) fail to show catch-up growth and may remain short-statured as adults. Despite treatment guidelines for children born SGA that recommend referral for growth hormone (GH) therapy evaluation and initiation by ages 2 to 4 years, the average age of GH treatment initiation is typically much later, at ages 7 to 9 years. Delayed referral for GH treatment is problematic as studies show younger age at GH treatment initiation in children born SGA is an independent predictor for responses such as optimal growth acceleration, normalization of prepubertal height, and most importantly, adult height (AH). This review discusses the importance and associated challenges of early diagnosis of children born SGA who fail to show catch-up growth, contrasts the recommended age of referral for these patients and the average age of GH treatment initiation, and discusses studies showing the significant positive effects of early referral and treatment with GH on AHs in short-statured children born SGA. To optimize the eventual height in short-statured SGA children who fail to manifest catch-up growth, a lowering of the average age of referral for GH therapy evaluation is needed to better align with consensus recommendations for SGA management. The importance of increasing parental and physician awareness that most children born SGA will do well developmentally and will optimally benefit from early initiation of GH treatment when short-statured is addressed, as is the need to shift the age of referral to better align with consensus recommendations.Item Introduction to the Special Issue “Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence” and a Summary of Patents Targeting other Neurotransmitter Systems(Bentham Science, 2012) Bell, Richard L.; Franklin, Kelle M.; Hauser, Sheketha R.; Zhou, Feng C.; Psychiatry, School of MedicineThis paper introduces the Special Section: Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence and provides a summary of patents targeting neurotransmitter systems not covered in the other four chapters. The World Health Organization notes that alcoholic-type drinking results in 2.5 million deaths per year, and these deaths occur to a disproportionately greater extent among adolescents and young adults. Developing a pharmacological treatment targeting alcohol abuse and dependence is complicated by (a) the heterogeneous nature of the disease(s), (b) alcohol affecting multiple neurotransmitter and neuromodulator systems, and (c) alcohol affecting multiple organ systems which in turn influence the function of the central nervous system. Presently, the USA Federal Drug Administration has approved three pharmacotherapies for alcoholism: disulfiram, naltrexone, and acamprosate. This chapter provides a summary of the following systems, which are not covered in the accompanying chapters; alcohol and acetaldehyde metabolism, opioid, glycinergic, GABA-A, neurosteroid, dopaminergic, serotonergic, and endocannabinoid, as well as patents targeting these systems for the treatment of alcoholism. Finally, an overview is presented on the use of pharmacogenetics and pharmacogenomics in tailoring treatments for certain subpopulations of alcoholics, which is expected to continue in the future.Item MsFLASH Analysis of Diurnal Salivary Cortisol and Palpitations in Peri and Postmenopausal Women(Wolters Kluwer, 2021-11-29) Carpenter, Janet S.; Tisdale, James E.; Larson, Joseph C.; Sheng, Ying; Chen, Chen X.; Von Ah, Diane; Kovacs, Richard; Reed, Susan D.; Thurston, Rebecca C.; Guthrie, Katherine A.; School of NursingObjective: To evaluate the relationship between diurnal salivary cortisol patterns and distress from heart palpitations in midlife women. Methods: We analyzed baseline data from 293 women who were eligible for a 3 × 2 factorial trial of exercise or yoga versus routine activity, and omega-3 fish oil versus placebo for vasomotor symptoms. Women self-collected salivary cortisol using swabs at four time points over 2 consecutive days and reported distress from heart racing or pounding during the past 2 weeks using a single item. Sample description and covariate data included demographics, clinical data, vasomotor symptom frequency from daily diaries, medication use, and validated questionnaires on depression, stress, and insomnia (Patient Health Questionnaire-8, Perceived Stress Scale, and Insomnia Severity index). Data were analyzed using descriptive statistics, chi-square and t tests, and repeated measure linear regression models. Results: Participants were on average 54.6 (SD = 3.6) years old, most were White (67%) postmenopausal (84%), and 26% reported distress related to palpitations. In adjusted models, the morning (wake plus 30-min) geometric mean daily salivary cortisol concentrations were significantly more blunted in those with distress from palpitations compared with those without distress (P ≤ 0.03). When all covariates were controlled, distress from palpitations was the sole significant predictor of wake plus 30-minute cortisol (-0.25 [-0.45 to -0.04], P = 0.02). Conclusions: Palpitations among midlife women may be associated with blunted morning cortisol, and this relationship is not explained by demographics, clinical variables, vasomotor symptoms, medications, depression, stress, or insomnia.Item “Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution(Elsevier, 2020-03-06) Rege, Nischay K.; Liu, Ming; Dhayalan, Balamurugan; Chen, Yen-Shan; Smith, Nicholas A.; Rahimi, Leili; Sun, Jinhong; Guo, Huan; Yang, Yanwu; Haataja, Leena; Phillips, Nelson F. B.; Whittaker, Jonathan; Smith, Brian J.; Arvan, Peter; Ismail-Beigi, Faramarz; Weiss, Michael A.; Biochemistry and Molecular Biology, School of MedicineGlobular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e. a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state. Here, we exploited the mutant proinsulin syndrome (a major cause of permanent neonatal-onset diabetes mellitus) to investigate whether toxic misfolding poses an evolutionary constraint. Our experiments focused on an invariant aromatic motif (PheB24-PheB25-TyrB26) with complementary roles in native self-assembly and receptor binding. A novel class of mutations provided evidence that insulin can bind to the insulin receptor (IR) in two different modes, distinguished by a "register shift" in this motif, as visualized by molecular dynamics (MD) simulations. Register-shift variants are active but defective in cellular foldability and exquisitely susceptible to fibrillation in vitro Indeed, expression of the corresponding proinsulin variant induced endoplasmic reticulum stress, a general feature of the mutant proinsulin syndrome. Although not present among vertebrate insulin and insulin-like sequences, a prototypical variant ([GlyB24]insulin) was as potent as WT insulin in a rat model of diabetes. Although in MD simulations the shifted register of receptor engagement is compatible with the structure and allosteric reorganization of the IR-signaling complex, our results suggest that this binding mode is associated with toxic misfolding and so is disallowed in evolution. The implicit threat of proteotoxicity limits sequence variation among vertebrate insulins and insulin-like growth factors.Item Sex Differences in Airway Remodeling and Inflammation: Clinical and Biological Factors(Frontiers Media, 2022-04-29) Ekpruke, Carolyn Damilola; Silveyra, Patricia; Medicine, School of MedicineAsthma is characterized by an increase in the contraction and inflammation of airway muscles, resulting in airflow obstruction. The prevalence of asthma is lower in females than in males until the start of puberty, and higher in adult women than men. This sex disparity and switch at the onset of puberty has been an object of debate among many researchers. Hence, in this review, we have summarized these observations to pinpoint areas needing more research work and to provide better sex-specific diagnosis and management of asthma. While some researchers have attributed it to the anatomical and physiological differences in the male and female respiratory systems, the influences of hormonal interplay after puberty have also been stressed. Other hormones such as leptin have been linked to the sex differences in asthma in both obese and non-obese patients. Recently, many scientists have also demonstrated the influence of the sex-specific genomic framework as a key player, and others have linked it to environmental, social lifestyle, and occupational exposures. The majority of studies concluded that adult men are less susceptible to developing asthma than women and that women display more severe forms of the disease. Therefore, the understanding of the roles played by sex- and gender-specific factors, and the biological mechanisms involved will help develop novel and more accurate diagnostic and therapeutic plans for sex-specific asthma management.Item Should Men and Women be Managed Differently in Glaucoma?(Springer, 2012) Abrams Tobe, Leslie; Harris, Alon; Trinidad, Jake; Chandrasekhar, Kaarthik; Cantor, Adam; Abrams, John; Amireskandari, Annahita; Siesky, Brent; Ophthalmology, School of MedicineIntroduction: To assess differences in associations of ocular perfusion pressure (OPP) as well as retinal and retrobulbar blood flow between men and women with primary open angle glaucoma (OAG). Methods: A total of 116 patients with OAG (age 66.9 ± 10.9 years, 70 females) participating in the Indianapolis Glaucoma Progression Study were assessed for OPP, retinal microcirculation, and retrobulbar blood flow. Confocal scanning laser Doppler flowmetry measured peripapillary retinal capillary blood flow. Color Doppler imaging measured peak systolic (PSV) and diastolic blood flow velocities and vascular resistance in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/T PCA). Bivariate Spearman correlation and multivariate linear regression analyses were performed. Results: In female patients with OAG, inferior retinal capillary flow was associated with OPP (r = 0.246, P = 0.044). In men, superior and inferior sector retinal blood flow was associated with OPP (r = -0.402, P = 0.006 and r = -0.357, P = 0.016, respectively). There was no statistically significant association between OPP and retrobulbar blood vessel flow velocities in male patients with OAG but there was an association between OA and TPCA PSV and OPP in female patients with OAG (r = 0.290, P = 0.015 and r = 0.357, P = 0.002, respectively). In female patients with OAG, multivariate regression showed no statistically significant effect of any variable on the superior retinal capillary blood flow, with CRA PSV as a sole predictor to the inferior retinal sector (partial rho = 0.302, P = 0.015) and in male patients with OAG, superior sector retinal capillary blood flow was independently associated with intraocular pressure (partial rho = -0.371, P = 0.016) and OPP (partial rho = -0.456, P = 0.002) with a trend of association with OPP in the inferior retina (partial rho = -0.301, P = 0.053). Conclusions: There was a positive linear association between retinal microcirculation and OPP in females and a negative association in males. Male and female patients with OAG may differ in their vascular autoregulation in response to changes in OPP.Item Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding(American Society for Biochemistry and Molecular Biology, 2018-01-05) Glidden, Michael D.; Yang, Yanwu; Smith, Nicholas A.; Phillips, Nelson B.; Carr, Kelley; Wickramasinghe, Nalinda P.; Ismail-Beigi, Faramarz; Lawrence, Michael C.; Smith, Brian J.; Weiss, Michael A.; Biochemistry and Molecular Biology, School of MedicineDomain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR α-subunit. This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world.Item Structural Lessons From the Mutant Proinsulin Syndrome(Frontiers Media, 2021-09-30) Dhayalan, Balamurugan; Chatterjee, Deepak; Chen, Yen-Shan; Weiss, Michael A.; Biochemistry and Molecular Biology, School of MedicineInsight into folding mechanisms of proinsulin has been provided by analysis of dominant diabetes-associated mutations in the human insulin gene (INS). Such mutations cause pancreatic β-cell dysfunction due to toxic misfolding of a mutant proinsulin and impairment in trans of wild-type insulin secretion. Anticipated by the “Akita” mouse (a classical model of monogenic diabetes mellitus; DM), this syndrome illustrates the paradigm endoreticulum (ER) stress leading to intracellular proteotoxicity. Diverse clinical mutations directly or indirectly perturb native disulfide pairing leading to protein misfolding and aberrant aggregation. Although most introduce or remove a cysteine (Cys; leading in either case to an unpaired thiol group), non-Cys-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the hormone’s evolution has been constrained not only by structure-function relationships, but also by the susceptibility of its single-chain precursor to impaired foldability. An intriguing hypothesis posits that INS overexpression in response to peripheral insulin resistance likewise leads to chronic ER stress and β-cell dysfunction in the natural history of non-syndromic Type 2 DM. Cryptic contributions of conserved residues to folding efficiency, as uncovered by rare genetic variants, define molecular links between biophysical principles and the emerging paradigm of Darwinian medicine: Biosynthesis of proinsulin at the edge of non-foldability provides a key determinant of “diabesity” as a pandemic disease of civilization.