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294 results on '"DiMarchi, Richard D"'

1. GLP-1-directed NMDA receptor antagonism for obesity treatment

Author

Petersen, Jonas, Ludwig, Mette Q., Juozaityte, Vaida, Ranea-Robles, Pablo, Svendsen, Charlotte, Hwang, Eunsang, Kristensen, Amalie W., Fadahunsi, Nicole, Lund, Jens, Breum, Alberte W., Mathiesen, Cecilie V., Sachs, Luisa, Moreno-Justicia, Roger, Rohlfs, Rebecca, Ford, James C., Douros, Jonathan D., Finan, Brian, Portillo, Bryan, Grose, Kyle, Petersen, Jacob E., Trauelsen, Mette, Feuchtinger, Annette, DiMarchi, Richard D., Schwartz, Thue W., Deshmukh, Atul S., Thomsen, Morten B., Kohlmeier, Kristi A., Williams, Kevin W., Pers, Tune H., Frølund, Bente, Strømgaard, Kristian, Klein, Anders B., and Clemmensen, Christoffer

Published
2024
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2. Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy

Author

Sánchez-Garrido, Miguel A., Serrano-López, Víctor, Ruiz-Pino, Francisco, Vázquez, María Jesús, Rodríguez-Martín, Andrea, Torres, Encarnación, Velasco, Inmaculada, Rodríguez, Ana Belén, Chicano-Gálvez, Eduardo, Mora-Ortiz, Marina, Ohlsson, Claes, Poutanen, Matti, Pinilla, Leonor, Gaytán, Francisco, Douros, Jonathan D., Yang, Bin, Müller, Timo D., DiMarchi, Richard D., Tschöp, Matthias H., Finan, Brian, and Tena-Sempere, Manuel

Published
2024
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3. Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice

Author

Liskiewicz, Arkadiusz, Khalil, Ahmed, Liskiewicz, Daniela, Novikoff, Aaron, Grandl, Gerald, Maity-Kumar, Gandhari, Gutgesell, Robert M., Bakhti, Mostafa, Bastidas-Ponce, Aimée, Czarnecki, Oliver, Makris, Konstantinos, Lickert, Heiko, Feuchtinger, Annette, Tost, Monica, Coupland, Callum, Ständer, Lisa, Akindehin, Seun, Prakash, Sneha, Abrar, Faiyaz, Castelino, Russell L., He, Yantao, Knerr, Patrick J., Yang, Bin, Hogendorf, Wouter F. J., Zhang, Shiqi, Hofmann, Susanna M., Finan, Brian, DiMarchi, Richard D., Tschöp, Matthias H., Douros, Jonathan D., and Müller, Timo D.

Published
2023
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7. GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Author

Quarta, Carmelo, Stemmer, Kerstin, Novikoff, Aaron, Yang, Bin, Klingelhuber, Felix, Harger, Alex, Bakhti, Mostafa, Bastidas-Ponce, Aimee, Baugé, Eric, Campbell, Jonathan E., Capozzi, Megan, Clemmensen, Christoffer, Collden, Gustav, Cota, Perla, Douros, Jon, Drucker, Daniel J., DuBois, Barent, Feuchtinger, Annette, Garcia-Caceres, Cristina, Grandl, Gerald, Hennuyer, Nathalie, Herzig, Stephan, Hofmann, Susanna M., Knerr, Patrick J., Kulaj, Konxhe, Lalloyer, Fanny, Lickert, Heiko, Liskiewicz, Arek, Liskiewicz, Daniela, Maity, Gandhari, Perez-Tilve, Diego, Prakash, Sneha, Sanchez-Garrido, Miguel A., Zhang, Qian, Staels, Bart, Krahmer, Natalie, DiMarchi, Richard D., Tschöp, Matthias H., Finan, Brian, and Müller, Timo D.

Published
2022
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8. Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome

Author

Maity-Kumar, Gandhari, Ständer, Lisa, DeAngelis, Meri, Lee, Sooyeon, Molenaar, Anna, Becker, Lore, Garrett, Lillian, Amerie, Oana V., Hoelter, Sabine M., Wurst, Wolfgang, Fuchs, Helmut, Feuchtinger, Annette, Gailus-Durner, Valerie, Garcia-Caceres, Cristina, Othman, Ahmed E., Brockmann, Caroline, Schöffling, Vanessa I., Beiser, Katja, Krude, Heiko, Mroz, Piotr A., Hofmann, Susanna, Tuckermann, Jan, DiMarchi, Richard D., Hrabe de Angelis, Martin, Tschöp, Matthias H., Pfluger, Paul T., and Müller, Timo D.

Published
2022
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13. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling

Author

Zhang, Qian, Delessa, Challa Tenagne, Augustin, Robert, Bakhti, Mostafa, Colldén, Gustav, Drucker, Daniel J., Feuchtinger, Annette, Caceres, Cristina Garcia, Grandl, Gerald, Harger, Alexandra, Herzig, Stephan, Hofmann, Susanna, Holleman, Cassie Lynn, Jastroch, Martin, Keipert, Susanne, Kleinert, Maximilian, Knerr, Patrick J., Kulaj, Konxhe, Legutko, Beata, Lickert, Heiko, Liu, Xue, Luippold, Gerd, Lutter, Dominik, Malogajski, Emilija, Medina, Marta Tarquis, Mowery, Stephanie A., Blutke, Andreas, Perez-Tilve, Diego, Salinno, Ciro, Sehrer, Laura, DiMarchi, Richard D., Tschöp, Matthias H., Stemmer, Kerstin, Finan, Brian, Wolfrum, Christian, and Müller, Timo D.

Published
2021
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14. Targeted pharmacological therapy restores β-cell function for diabetes remission

Author

Sachs, Stephan, Bastidas-Ponce, Aimée, Tritschler, Sophie, Bakhti, Mostafa, Böttcher, Anika, Sánchez-Garrido, Miguel A., Tarquis-Medina, Marta, Kleinert, Maximilian, Fischer, Katrin, Jall, Sigrid, Harger, Alexandra, Bader, Erik, Roscioni, Sara, Ussar, Siegfried, Feuchtinger, Annette, Yesildag, Burcak, Neelakandhan, Aparna, Jensen, Christine B., Cornu, Marion, Yang, Bin, Finan, Brian, DiMarchi, Richard D., Tschöp, Matthias H., Theis, Fabian J., Hofmann, Susanna M., Müller, Timo D., and Lickert, Heiko

Published
2020
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18. CNS-targeting pharmacological interventions for the metabolic syndrome

Author

Stemmer, Kerstin, Muller, Timo D., DiMarchi, Richard D., Pfluger, Paul T., Tschop, Matthias H., and Scherer, Philipp E.

Subjects
Obesity -- Development and progression, Hypertension -- Development and progression, Phendimetrazine, Zonisamide, Bariatric surgery, Type 2 diabetes -- Development and progression, Body weight, Sibutramine, Lorcaserin, Weight loss -- Development and progression, Etiology (Medicine), Surgery, Adipose tissue, Heart attack, Disabilities, Pharmacology, Hyperglycemia, Alzheimer's disease, Comorbidity, Health care industry
Abstract

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae., Introduction The metabolic syndrome (MetS) encompasses a cluster of pernicious metabolic diseases that include visceral obesity, dyslipidemia, hyperglycemia, and hypertension (1). It is considered to be a silent killer owing [...]

Published
2019
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20. Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

Author

Quarta, Carmelo, Clemmensen, Christoffer, Zhu, Zhimeng, Yang, Bin, Joseph, Sini S., Lutter, Dominik, Yi, Chun-Xia, Graf, Elisabeth, García-Cáceres, Cristina, Legutko, Beata, Fischer, Katrin, Brommage, Robert, Zizzari, Philippe, Franklin, Bernardo S., Krueger, Martin, Koch, Marco, Vettorazzi, Sabine, Li, Pengyun, Hofmann, Susanna M., Bakhti, Mostafa, Bastidas-Ponce, Aimée, Lickert, Heiko, Strom, Tim M., Gailus-Durner, Valerie, Bechmann, Ingo, Perez-Tilve, Diego, Tuckermann, Jan, Hrabě de Angelis, Martin, Sandoval, Darleen, Cota, Daniela, Latz, Eicke, Seeley, Randy J., Müller, Timo D., DiMarchi, Richard D., Finan, Brian, and Tschöp, Matthias H.

Published
2017
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29. Correction: GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease.

Author

Sachs, Stephan, Götz, Anna, Finan, Brian, Feuchtinger, Annette, DiMarchi, Richard D., Döring, Yvonne, Weber, Christian, Tschöp, Matthias H., Müller, Timo D., and Hofmann, Susanna M.

Subjects
THORACIC aorta, AORTIC valve, WEIGHT loss, ATHEROSCLEROTIC plaque, SUBCUTANEOUS injections
Abstract

This document is a correction notice for an article published in the journal Cardiovascular Diabetology. The authors have identified errors in Figure 2 and the Results section of the original article. The corrected figure shows the effects of acyl-GIP treatment on dyslipidemia and atherosclerotic plaque formation in male LDLR-/- mice. The authors clarify that acyl-GIP treatment was accompanied by reduced plaque formation within the aortic valve and a trend towards decreased fat streaks along the descending aorta. The correction notice is provided by the authors Stephan Sachs, Anna Götz, and others. [Extracted from the article]

Published
2024
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30. Author Correction: Targeted pharmacological therapy restores β-cell function for diabetes remission

Author

Sachs, Stephan, Bastidas-Ponce, Aimée, Tritschler, Sophie, Bakhti, Mostafa, Böttcher, Anika, Sánchez-Garrido, Miguel A., Tarquis-Medina, Marta, Kleinert, Maximilian, Fischer, Katrin, Jall, Sigrid, Harger, Alexandra, Bader, Erik, Roscioni, Sara, Ussar, Siegfried, Feuchtinger, Annette, Yesildag, Burcak, Neelakandhan, Aparna, Jensen, Christine B., Cornu, Marion, Yang, Bin, Finan, Brian, DiMarchi, Richard D., Tschöp, Matthias H., Theis, Fabian J., Hofmann, Susanna M., Müller, Timo D., and Lickert, Heiko

Published
2020
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36. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Author

Finan, Brian, Yang, Bin, Ottaway, Nickki, Smiley, David L., Ma, Tao, Clemmensen, Christoffer, Chabenne, Joe, Zhang, Lianshan, Habegger, Kirk M., Fischer, Katrin, Campbell, Jonathan E., Sandoval, Darleen, Seeley, Randy J., Bleicher, Konrad, Uhles, Sabine, Riboulet, William, Funk, Jurgen, Hertel, Cornelia, Belli, Sara, Sebokova, Elena, Conde-Knape, Karin, Konkar, Anish, Drucker, Daniel J., Gelfanov, Vasily, Pfluger, Paul T., Muller, Timo D., Perez-Tilve, Diego, DiMarchi, Richard D., and Tschop, Matthias H.

Subjects
Obesity -- Complications and side effects -- Care and treatment -- Research, Diabetes -- Risk factors -- Prevention -- Research, Peptides -- Physiological aspects -- Research, Biological sciences, Health
Abstract

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders., Obesity and its comorbidities, including type 2 diabetes, represent a global health threat and a rapidly increasing burden to economic prosperity (1). Therapeutic intervention is urgently required because lifestyle modification [...]

Published
2015
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39. Optimized clinical performance of growth hormone with an expanded genetic code

Author

Cho, Ho, Daniel, Tom, Buechler, Ying Ji, Litzinger, David C., Maio, Zhenwei, Putnam, Anna-Maria Hays, Kraynov, Vadim S., Sim, Bee-Cheng, Bussell, Stuart, Javahishvili, Tsotne, Kaphle, Sami, Viramontes, Guillermo, Ong, Mike, Chu, Stephanie, GC, Becky, Lieu, Ricky, Knudsen, Nick, Castiglioni, Paola, Norman, Thea C., Axelrod, Douglas W., Hoffman, Andrew R., Schultz, Peter G., DiMarchi, Richard D., and Kimmel, Bruce E.

Published
2011

41. Targeted estrogen delivery reverses the metabolic syndrome

Author

Finan, Brian, Yang, Bin, Ottaway, Nickki, Stemmer, Kerstin, Muller, Timo D., Yi, Chun-Xia, Habegger, Kirk, Schrieverla, Sonja C., Garcia-Caceres, Cristina, Kabra, Dhiraj G., Hembree, Jazzminn, Holland, Jenna, Raver, Christine, Seeley, Randy J., Hans, Wolfgang, Irmler, Martin, Beckers, Johannes, Angelis, Martin Hrabe de, Tiano, Joseph P., Mauvais-Jarvis, Franck, Perez-Tilve, Diego, Pfluger, Paul, Zhang, Lianshan, Gelfanov, Vasily, DiMarchi, Richard D., and Tschop, Matthias H.

Subjects
Peptide hormones -- Physiological aspects -- Research, Metabolic syndrome X -- Care and treatment -- Patient outcomes -- Research, Estrogen -- Analysis -- Health aspects -- Physiological aspects -- Research, Biological sciences, Health
Abstract

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1--targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1--estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases., Pharmaceutical intervention in chronic diseases often requires a polypharmaceutical approach in which multiple agents individually address specific disease mechanisms. For instance, type 2 diabetes therapy often includes separate drugs targeting [...]

Published
2012
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42. GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats

Author

Habegger, Kirk M., Heppner, Kristy M., Amburgy, Sarah E., Ottaway, Nickki, Holland, Jenna, Raver, Christine, Bartley, Erin, Muller, Timo D., Pfluger, Paul T., Berger, Jose, Toure, Mouhamadoul, Benoit, Stephen C., DiMarchi, Richard D., Perez- Tilve, Diego, D'Alessio, David A., Seeley, Randy J., and Tschop, Matthias H.

Subjects
Diabetes -- Care and treatment, Gastric bypass -- Patient outcomes, Gastrointestinal hormones -- Identification and classification, Health
Abstract

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1-based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet-induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP1-induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome. Diabetes 2014;63:505-513 | DOI: 10.2337/db13-0511, Both developed and developing countries have seen increased rates of obesity over the last 30 years that has been paralleled by an unprecedented increase in the incidence of metabolic disturbances [...]

Published
2014
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43. Combinatorial libraries of synthetic peptides as a model for shotgun proteomics

Author

Bohrer, Brian C., Li, Yong Fuga, Reilly, James P., Clemmer, David E., DiMarchi, Richard D., Radivojac, Predrag, Tang, Haixu, and Arnold, Randy J.

Subjects
Peptides -- Chemical properties, Peptides -- Models, Proteomics -- Research, Liquid chromatography -- Methods, Mass spectrometry -- Methods, Chemistry
Abstract

A synthetic approach to model the analytical complexity of biological proteolytic digests has been developed. Combinatorial peptide libraries ranging in length between 9 and 12 amino acids that represent typical tryptic digests were designed, synthesized, and analyzed. Individual libraries and mixtures thereof were studied by replicate liquid chromatography-ion trap mass spectrometry and compared to a tryptic digest of Deinococcus radiodurans. Similar to complex proteome analysis, replicate study of individual libraries identified additional unique peptides. Fewer novel sequences were revealed with each additional analysis in a manner similar to that observed for biological data. Our results demonstrate a bimodal distribution of peptides sorting to either very low or very high levels of detection. Upon mixing of libraries at equal abundance, a length-dependent bias in favor of longer sequence identification was observed. Peptide identification as a function of site-specific amino acid content was characterized with certain amino acids proving to be of considerable importance. This report demonstrates that peptide libraries of defined character can serve as a reference for instrument characterization. Furthermore, they are uniquely suited to delineate the physical properties that influence identification of peptides, which provides a foundation for optimizing the study of samples with less defined heterogeneity. 10.1021/ac100910a

Published
2010

45. GLP-1R Agonism Enhances Adjustable Gastric Banding in Diet-Induced Obese Rats

Author

Habegger, Kirk M., Kirchner, Henriette, Yi, Chun-Xia, Heppner, Kristy M., Sweeney, Dan, Ottaway, Nickki, Holland, Jenna, Amburgy, Sarah, Raver, Christine, Krishna, Radhakrishna, Müller, Timo D., Perez-Tilve, Diego, Pfluger, Paul T., Obici, Silvana, DiMarchi, Richard D., D’Alessio, David A., Seeley, Randy J., and Tschöp, Matthias H.

Published
2013
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46. Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

Author

Habegger, Kirk M., Stemmer, Kerstin, Cheng, Christine, Müller, Timo D., Heppner, Kristy M., Ottaway, Nickki, Holland, Jenna, Hembree, Jazzminn L., Smiley, David, Gelfanov, Vasily, Krishna, Radha, Arafat, Ayman M., Konkar, Anish, Belli, Sara, Kapps, Martin, Woods, Stephen C., Hofmann, Susanna M., D’Alessio, David, Pfluger, Paul T., Perez-Tilve, Diego, Seeley, Randy J., Konishi, Morichika, Itoh, Nobuyujki, Kharitonenkov, Alexei, Spranger, Joachim, DiMarchi, Richard D., and Tschöp, Matthias H.

Published
2013
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47. Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes.

Author

Tan, Qiming, Akindehin, Seun E., Orsso, Camila E., Waldner, Richelle C., DiMarchi, Richard D., Müller, Timo D., and Haqq, Andrea M.

Subjects
TYPE 2 diabetes, REGULATION of body weight, OBESITY, DRUGS, DIABETES
Abstract

The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2–3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation.

Author

Dhayalan, Balamurugan, Glidden, Michael D., Zaykov, Alexander N., Chen, Yen-Shan, Yang, Yanwu, Phillips, Nelson B., Ismail-Beigi, Faramarz, Jarosinski, Mark A., DiMarchi, Richard D., and Weiss, Michael A.

Subjects
PEPTIDES, PROINSULIN, INSULIN derivatives, NUCLEAR magnetic resonance spectroscopy, ETIOLOGY of diabetes, TYPE 2 diabetes
Abstract

The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin's biosynthetic precursor. Also designated mutant INS-gene induced diabetes of the young (MIDY), this syndrome defines molecular determinants of foldability in the endoplasmic reticulum (ER) of β-cells. Here, we describe a peptide model of a key proinsulin folding intermediate and variants containing representative clinical mutations; the latter perturb invariant core sites in native proinsulin (LeuB15→Pro, LeuA16→Pro, and PheB24→Ser). The studies exploited a 49-residue single-chain synthetic precursor (designated DesDi), previously shown to optimize in vitro efficiency of disulfide pairing. Parent and variant peptides contain a single disulfide bridge (cystine B19-A20) to provide a model of proinsulin's first oxidative folding intermediate. The peptides were characterized by circular dichroism and redox stability in relation to effects of the mutations on (a) in vitro foldability of the corresponding insulin analogs and (b) ER stress induced in cell culture on expression of the corresponding variant proinsulins. Striking correlations were observed between peptide biophysical properties, degree of ER stress and age of diabetes onset (neonatal or adolescent). Our findings suggest that age of onset reflects the extent to which nascent structure is destabilized in proinsulin's putative folding nucleus. We envisage that such peptide models will enable high-resolution structural studies of key folding determinants and in turn permit molecular dissection of phenotype-genotype relationships in this monogenic diabetes syndrome. Our companion study (next article in this issue) employs two-dimensional heteronuclear NMR spectroscopy to define site-specific perturbations in the variant peptides. [ABSTRACT FROM AUTHOR]

Published
2022
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49. Peptide Model of the Mutant Proinsulin Syndrome. II. Nascent Structure and Biological Implications.

Author

Yang, Yanwu, Glidden, Michael D., Dhayalan, Balamurugan, Zaykov, Alexander N., Chen, Yen-Shan, Wickramasinghe, Nalinda P., DiMarchi, Richard D., and Weiss, Michael A.

Subjects
PEPTIDES, MORPHOLOGY, PROINSULIN, OVERHAUSER effect (Nuclear physics), INSULIN derivatives
Abstract

Toxic misfolding of proinsulin variants in β-cells defines a monogenic diabetes syndrome, designated mutant INS-gene induced diabetes of the young (MIDY). In our first study (previous article in this issue), we described a one-disulfide peptide model of a proinsulin folding intermediate and its use to study such variants. The mutations (LeuB15→Pro, LeuA16→Pro, and PheB24→Ser) probe residues conserved among vertebrate insulins. In this companion study, we describe 1H and 1H-13C NMR studies of the peptides; key NMR resonance assignments were verified by synthetic 13C-labeling. Parent spectra retain nativelike features in the neighborhood of the single disulfide bridge (cystine B19-A20), including secondary NMR chemical shifts and nonlocal nuclear Overhauser effects. This partial fold engages wild-type side chains LeuB15, LeuA16 and PheB24 at the nexus of nativelike α-helices α1 and α3 (as defined in native proinsulin) and flanking β-strand (residues B24-B26). The variant peptides exhibit successive structural perturbations in order: parent (most organized) > SerB24 >> ProA16 > ProB15 (least organized). The same order pertains to (a) overall α-helix content as probed by circular dichroism, (b) synthetic yields of corresponding three-disulfide insulin analogs, and (c) ER stress induced in cell culture by corresponding mutant proinsulins. These findings suggest that this and related peptide models will provide a general platform for classification of MIDY mutations based on molecular mechanisms by which nascent disulfide pairing is impaired. We propose that the syndrome's variable phenotypic spectrum—onsets ranging from the neonatal period to later in childhood or adolescence—reflects structural features of respective folding intermediates. [ABSTRACT FROM AUTHOR]

Published
2022
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