Type-2 Diabetes Mellitus (T2DM) is a complex disease that afflicts more than 400 million people worldwide.  Available data indicate that genetic, epigenetic, developmental, and lifestyle factors collectively contribute to T2DM involving a myriad of the metabolic pathologies including pancreatic cell dysfunction, hyperglucagonemia, renal glucose reabsorption, fatty liver disease, and inflammation.  This virtual issue comprises a representative selection of outstanding peer-reviewed original research and topical reviews on T2DM and related topics that have recently published in Pharmacology Research & Perspectives (PR&P) as well as the other ASPET journals including Pharmacological Reviews, Drug Metabolism and Disposition, Journal of Pharmacology and Experimental Therapeutics, and Molecular Pharmacology. The articles in this virtual issue offer a diverse array of important scientific insights into cell-surface receptors, biochemical signaling mechanisms, and animal models that collectively contribute an increased understanding of insulin deficiency and resistance as well as potential strategies for improved glucose control.   The articles contained in this joint virtual issue should be of considerable interest to all investigators working to better understand T2DM and develop new therapeutic interventions. We encourage potential authors to review these excellent papers as they consider venues for communicating their pharmacology research on diabetes mechanisms and treatments.

Andrew J. Lawrence
Editor-in-Chief

Michael F. Jarvis
Deputy Editor

Table of Contents

Pharmacological Reviews | Drug Metabolism and Disposition | Journal of Pharmacology and Experimental Therapeutics | Molecular Pharmacology | Pharmacology Research & Perspectives

All of these articles are freely accessible; some are open access.

Glucagon-Like Peptite-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes
Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M. Sexton, Laurence J. Miller, Jung-Mo Ahn, Jiayu Liao, Madeleine M. Fletcher, Dehua Yang, Alastair J. H. Brown, Caihong Zhou, Jiejie Deng and Ming-Wei Wang
Pharmacological Reviews 2016 68 (4) 954-1013 DOI: https://doi.org/10.1124/pr.115.011395

G Protein-Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus
Darren Riddy, Philippe Delerive, Roger J Summers, Patrick M. Sexton, and Christopher J. Langmead
Pharmacological Reviews 2017, 70 (1) 39-67 DOI: https://doi.org/10.1124/pr.117.014373

Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression      
Ajay C Donepudi, Qiuqiong Cheng, Zhenqiang James Lu, Nathan J. Cherrington, Angela L. Slitt
Drug Metabolism and Disposition 2016, 44 (4) 518-526 DOI: https://doi.org/10.1124/dmd.115.066779     

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats
Xin Zhou, Luc R.A. Rougée, David W. Bedwell, Jeff W. Cramer, Michael A. Mohutsky, Nathan A. Calvert, Richard D. Moulton, Kenneth C. Cassidy, Nathan P. Yumibe, Lisa A. Adams, and Kenneth J. Ruterbories
Drug Metabolism and Disposition 2016, 44 (8) 1184-1192 DOI: https://doi.org/10.1124/dmd.116.070623

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics Of Vildagliptin In Vivo
Mitsutoshi Asakura, Tatsuki Fukami, Miki Nakajima, Hideaki Fujii, Koichiro Atsuda, Tomoo Itoh, and Ryoichi Fujiwara
Drug Metabolism and Disposition 2017, 45 (2) 237-245 DOI: https://doi.org/10.1124/dmd.116.073866     

Transporter-Mediated Disposition, Clinical Pharmacokinetics and Cholestatic Potential of Glyburide and Its Primary Active Metabolites
Rui Li, Yi-an Bi, Anna Vildhede, Renato J. Scialis, Sumathy Mathialagan, Xin Yang, Lisa D. Marroquin, Jian Lin, Manthena V.S. Varma
Drug Metabolism and Disposition 2017, 45 (7) 737-747 DOI: https://doi.org/10.1124/dmd.116.074815     

 Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria
Flora Scott, Sandra G. Gonzalez Malagon, Brett A. O'Brien, Diede Fennema, Sunil Veeravalli, Clarissa R. Coveney, Ian R. Phillips, and Elizabeth A. Shephard
Drug Metabolism and Disposition 2017, 45 (9) 982-989 DOI: https://doi.org/10.1124/dmd.117.076612

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin
Gnanapragasam Arunachalam, Arun Prasath Lakshmanan, Samson Mathews Samuel, Chris R. Triggle, and Hong Ding    
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (2) 314-323 DOI: https://doi.org/10.1124/jpet.115.226894

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma
Hilary Nicholson, Christophe Mesangeau, Christopher R. McCurdy, and Wayne D. Bowen
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (2) 232-243 DOI: https://doi.org/10.1124/jpet.115.228387

Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle
Liang Zhou, Yongquan Pan, Ritsu Chonan, Robert Batey, Xianglu Rong, Johji Yamahara, Jianwei Wang, and Yuhao Li
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (1) 74-84 DOI: https://doi.org/10.1124/jpet.115.229005

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice
Eryun Zhang, Bo Gao, Li Yang, Xiaojun Wu, and Zhengtao Wang
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (2) 324-332 DOI: https://doi.org/10.1124/jpet.115.229369

A Novel Allosteric Insulin Receptor–Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys
Padma Bezwada, Jingsong Zhao, Ken Der, Bob Shimizu, Liching Cao, Ago Ahene, Paul Rubin, and Kirk Johnson
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (2) 466-473 DOI: https://doi.org/10.1124/jpet.115.229690

Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide
Toshihiro Sakurai, Akiko Sakurai, Boris L. Vaisman, Marcelo J. Amar, Chengyu Liu, Scott M. Gordon, Steven K. Drake, Milton Pryor, Maureen L. Sampson, Ling Yang, Lita A. Freeman, and Alan T. Remaley
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (2) 341-353 DOI: https://doi.org/10.1124/jpet.115.229740

A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat
Carine M. Boustany-Kari, Paul C. Harrison, Hongxing Chen, Kathleen A. Lincoln, Hu Sheng Qian, Holly Clifford, Hong Wang, Xiaomei Zhang, Kristina Gueneva-Boucheva, Todd Bosanac, Diane Wong, Ryan M. Fryer, Jeremy G. Richman, Chris Sarko, and Steven S. Pullen
Journal of Pharmacology and Experimental Therapeutics 2016, 356 (3) 712-719 DOI: https://doi.org/10.1124/jpet.115.230706

Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas
Ryo Ito, Yoshiyuki Tsujihata, Masami Suzuki, Kazumasa Miyawaki, Kae Matsuda, and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics 2016, 357 (1) 217-227 DOI: https://doi.org/10.1124/jpet.115.230730

In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog
Rebecca A. Owens, Ryan J. Hansen, Steven D. Kahl, Chen Zhang, Xiaoping Ruan, Anja Koester, Shun Li, Hui-Rong Qian, Mark W. Farmen, M. Dodson Michael, Julie S. Moyers, Gordon B. Cutler, Andrew Vick, and John M. Beals
Journal of Pharmacology and Experimental Therapeutics 2016, 357 (3) 459-465 DOI: https://doi.org/10.1124/jpet.115.231035

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic β-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet
Amna Abderrazak, Khadija El Hadri, Elodie Bosc, Bertrand Blondeau, Mohamed-Naceur Slimane, Berthold Büchele, Thomas Simmet, Dominique Couchie, and Mustapha Rouis
Journal of Pharmacology and Experimental Therapeutics 2016, 357 (3) 487-494 DOI: https://doi.org/10.1124/jpet.116.232934

Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy
Christopher T. Salatto, Russell A. Miller, Kimberly O. Cameron, Emily Cokorinos, Allan Reyes, Jessica Ward, Matthew F. Calabrese, Ravi G. Kurumbail, Francis Rajamohan, Amit S. Kalgutkar, David A. Tess, Andre Shavnya, Nathan E. Genung, David J. Edmonds, Aditi Jatkar, Benjamin S Maciejewski, Marina Amaro, Harmeet Gandhok, Mara Monetti, Katherine Cialdea, Eliza Bollinger, John M. Kreeger, Timothy M. Coskran, Alan C. Opsahl, Germaine G. Boucher, Morris J. Birnbaum, Paul DaSilva-Jardine, and Tim Rolph
Journal of Pharmacology and Experimental Therapeutics 2017, 361 (2) 303-311 DOI: https://doi.org/10.1124/jpet.116.237925

PDE5 Inhibitor Tadalafil and Hydroxychloroquine Cotreatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice
Rui Wang, Lei Xi, and Rakesh C. Kukreja
Journal of Pharmacology and Experimental Therapeutics 2017, 361 (1) 29-38 DOI: https://doi.org/10.1124/jpet.116.239087

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice
David R. Powell, Melinda G. Smith, Deon D. Doree, Angela L. Harris, Jennifer Greer, Christopher M. DaCosta, Andrea Thompson, Sabrina Jeter-Jones, Wendy Xiong, Kenneth G. Carson, Nicole C. Goodwin, Bryce A. Harrison, David B. Rawlins, Eric D. Strobel, Suma Gopinathan, Alan Wilson, Faika Mseeh, Brian Zambrowicz, and Zhi-Ming Ding    
Journal of Pharmacology and Experimental Therapeutics 2017, 362 (1) 85-97 DOI: https://doi.org/10.1124/jpet.117.240820

The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Works as Adjunct to Metformin on Fasting Hyperglycemia and HbA1c in a Rat Model of Type 2 Diabetes
Sara T. Hjuler, Sofie Gydesen, Kim V. Andreassen, Morten A. Karsdal, and Kim Henriksen
Journal of Pharmacology and Experimental Therapeutics 2017, 362 (1) 24-30 DOI: https://doi.org/10.1124/jpet.117.241281

Melatonin Receptor Agonist Piromelatine Ameliorates Impaired Glucose Metabolism in Chronically Stressed Rats Fed a High-Fat Diet
Jun Zhou, Deng Wang, XiaoHong Luo, Xu Jia, MaoXing Li, Moshe Laudon, RuXue Zhang, and ZhengPing Jia
Journal of Pharmacology and Experimental Therapeutics 2018, 364 (1) 55-69 DOI: https://doi.org/10.1124/jpet.117.243998

Etiopathogenesis and Pharmacological Prevention of a Type-2 Diabetes Model in Male Mice
Alberto Loizzo, Santi M. Spampinato, Gabriele Campana, and Stefano Loizzo
Journal of Pharmacology and Experimental Therapeutics 2018, 364 (2) 347-358 DOI: https://doi.org/10.1124/jpet.117.244707

Phosphorylation of RS1 (RSC1A1) Steers Inhibition of Different Exocytotic Pathways for Glucose Transporter SGLT1 and Nucleoside Transporter CNT1, and a RS1-Derived Peptide Inhibits Glucose Absorption       
Maike Veyhl-Wichmann, Alexandra Friedrich, Alexandra Vernaleken, Smriti Singh, Helmut Kipp, Valentin Gorboulev, Thorsten Keller, Chakravarthi Chintalapati, Rüdiger Pipkorn, Marçal Pastor-Anglada, Jürgen Groll, and Hermann Koepsell
Molecular Pharmacology 2016, 89 (1) 118-132 DOI: https://doi.org/10.1124/mol.115.101162

Biochemical Pharmacology of the Sigma-1 Receptor
Uyen Chu and Arnold E. Ruoho
Molecular Pharmacology 2016, 89 (1) 142-153 DOI: https://doi.org/10.1124/mol.115.101170

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures
Denise Wootten, Christopher A. Reynolds, Cassandra Koole, Kevin J. Smith, Juan C. Mobarec, John Simms, Tezz Quon, Thomas Coudrat, Sebastian G. B. Furness, Laurence J. Miller, Arthur Christopoulos, and Patrick M. Sexton
Molecular Pharmacology 2016, 89 (3) 335-347 DOI: https://doi.org/10.1124/mol.115.101246

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells     
Myrian Velasco, Carlos Manlio Díaz-García, Carlos Larqué, and Marcia Hiriart
Molecular Pharmacology 2017, 90 (3) 341-357 DOI: https://doi.org/10.1124/mol.116.103861

A Fibroblast Growth Factor 21–Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4  in Nonalcoholic Fatty Liver Disease
Sarah J. Woolsey, Melanie D. Beaton, Sara E. Mansell, Matilde Leon-Ponte, Janice Yu, Christopher L. Pin, Paul C. Adams, Richard B. Kim, and Rommel G. Tirona      
Molecular Pharmacology 2017 90 (4) 437-446 DOI: https://doi.org/10.1124/mol.116.104687

Molecular Basis for Inhibition of the Na+/Citrate Transporter NaCT (SLC13A5) by Dicarboxylate Inhibitors          
Ana M. Pajor, Cesar A. de Oliveira, Kun Song, Kim Huard, Veerabahu Shanmugasundaram, and Derek M. Erion
Molecular Pharmacology 2017, 90 (6) 755-765 DOI: https://doi.org/10.1124/mol.116.105049

For Better or Worse: FFAR1 and FFAR4 Signaling in Cancer and Diabetes
JM Houthuijzen
Molecular Pharmacology 2017, 90 (6) 738-743 DOI: https://doi.org/10.1124/mol.116.105932

State-Dependent Allosteric Inhibition of the Human SLC13A5 Citrate Transporter by Hydroxysuccinic Acids, PF-06649298 and PF-06761281 
Marie-Laure Rives, Morena Shaw, Bin Zhu, Simon A. Hinke, and Alan D. Wickenden
Molecular Pharmacology 2017, 90 (6) 766-774 DOI: https://doi.org/10.1124/mol.116.106575

Activation of the Orphan G Protein–Coupled Receptor GPR27 by Surrogate Ligands Promotes β-Arrestin 2 Recruitment
Nadine Dupuis, Céline Laschet, Delphine Franssen, Martyna Szpakowska, Julie Gilissen, Pierre Geubelle, Arvind Soni, Anne-Simone Parent, Bernard Pirotte, Andy Chevigné, Jean-Claude Twizere, and Julien Hanson  
Molecular Pharmacology 2018, 91 (6) 595-608 DOI: https://doi.org/10.1124/mol.116.107714

Probe-Dependent Negative Allosteric Modulators Of The Long-Chain Free Fatty Acid Receptor FFA4
Kenneth R. Watterson, Steffen V. F. Hansen, Brian D. Hudson, Elisa Alvarez-Curto, Sheikh Zahir Raihan, Carlos M. G. Azevedo, Gabriel Martin, Julia Dunlop, Stephen J. Yarwood, Trond Ulven, and Graeme Milligan
Molecular Pharmacology 2017, 91 (6) 630-641 DOI: https://doi.org/10.1124/mol.116.107821

Structure and Dynamics of the Liver Receptor Homolog 1–PGC1α Complex
Suzanne G. Mays, C. Denise Okafor, Micheal L. Tuntland, Richard J. Whitby, Venkatasubramanian Dharmarajan, Józef Stec, Patrick R. Griffin, and Eric A. Ortlund
Molecular Pharmacology 2017, 92 (1) 1-11 DOI: https://doi.org/10.1124/mol.117.108514

Altenusin, a Nonsteroidal Microbial Metabolite, Attenuates Nonalcoholic Fatty Liver Disease by Activating the Farnesoid X Receptor
Zhihui Zheng, Zanmei Zhao, Shuqiang Li, Xinhua Lu, Mengxi Jiang, Jie Lin, Yunqi An, Yang Xie, Meishu Xu, Wenbin Shen, Grace L. Guo, Yixian Huang, Song Li, Xuexia Zhang, and Wen Xie 
Molecular Pharmacology 2017, 92 (4) 425-436 DOI: https://doi.org/10.1124/mol.117.108829

Pharmacogenomics of Chemically Distinct Classes of Keap1-Nrf2 Activators Identify Common and Unique Gene, Protein, and Pathway Responses In Vivo      
Ryan S. Wible, Quynh T. Tran, Samreen Fathima, Carrie H. Sutter, Thomas W. Kensler, and Thomas R. Sutter
Molecular Pharmacology 2018, 93 (4) 297-308 DOI: https://doi.org/10.1124/mol.117.110262

Fasiglifam (TAK-875) has dual potentiating mechanisms via G alpha q-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion
Kensuke Sakuma, Chiori Yabuki, Minoru Maruyama, Akiko Abiru, Hidetoshi Komatsu, Nobuyuki Negoro, Yoshiyuki Tsujihata, Koji Takeuchi, Yugo Habata, and Masaaki Mori              
Pharmacology Research & Perspectives 2016, 4 (3) DOI: https://doi.org/10.1002/prp2.237

Chronic treatment of (R)-α-lipoic acid reduces blood glucose and lipid levels in high-fat diet and low-dose streptozotocin-induced metabolic syndrome and type 2 diabetes in Sprague-Dawley rats
Hardik Ghelani, Valentina Razmovski‐Naumovski, and Srinivas Nammi                
Pharmacology Research & Perspectives 2017, 5 (3) DOI: https://doi.org/10.1002/prp2.306

 Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated with unexpected renal effects
Leonie van Meer, Marloes van Dongen, Matthijs Moerland, Marieke de Kam, Adam Cohen, and Jacobus Burggraaf                       
Pharmacology Research & Perspectives 2017, 5 (1) DOI: https://doi.org/10.1002/prp2.292

 A selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes
Yanyun Chen, Min Song, Jonathan P. Riley, Charlie C. Hu, Xianbu Peng, Donalyn Scheuner, Krister Bokvist, Pranab Maiti, Steven D. Kahl, Chahrzad Montrose‐Rafizadeh, Chafiq Hamdouchi, and Anne Reifel Miller                      
Pharmacology Research & Perspectives 2016, 4 (6) DOI: https://doi.org/10.1002/prp2.278                       

 A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose-dependent insulin secretion and improves glucose homeostasis in rats
Naoto Tsuda, Atsuko Kawaji, Toshihiro Sato, Mitsuhiro Takagi, Chika Higashi, Yutaka Kato, Kumiko Ogawa, Hiroyasu Naba, Munetaka Ohkouchi, Masaki Nakamura, Yoshitaka Hosaka, and Junichi Sakaki            
Pharmacology Research & Perspectives 2017, 5 (4) DOI: https://doi.org/10.1002/prp2.340                       

 Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome
Ayako Uchinaka, Mamoru Yoneda, Yuichiro Yamada, Toyoaki Murohara, and Kohzo Nagata     
Pharmacology Research & Perspectives 2017, 5 (4) DOI: https://doi.org/10.1002/prp2.331                       

 Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria
Peter U. Bassi, Adeline I. Osakwe, Comfort K. Ogar, Cassandra Elagbaje, Biyaya B. Nwankwo,  Sulayman T. Balogun, Godwin N. Ntadom, and Ambrose O. Isah            
Pharmacology Research & Perspectives 2017, 5 (2) DOI: https://doi.org/10.1002/prp2.302                       

 Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice
Takashi Hatanaka, Daisuke Ogawa, Hiromi Tachibana, Jun Eguchi, Tatsuyuki Inoue, Hiroshi Yamada, Kohji Takei, Hirofumi Makino, and Jun Wada                   
Pharmacology Research & Perspectives 2016, 4 (4) DOI: https://doi.org/10.1002/prp2.239                       

 Functional imaging of pharmacological action of SGLT2 inhibitor ipragliflozin via PET imaging using C-11-MDG
Keisuke Mitsuoka, Yuka Hayashizaki, Yoshihiro Murakami, Toshiyuki Takasu, Masanori Yokono, Nobuhiro Umeda, Shoji Takakura, Akihiro Noda, and Sosuke Miyoshi
Pharmacology Research & Perspectives 2016, 4 (4) DOI: https://doi.org/10.1002/prp2.244