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2. Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial

Author

Bardymova, Tatiana, Barrientos Perez, Margarita, Bethin, Kathleen, Bjornstad, Petter, Bondar, Irina, Chen, Mimi, Choi, Jin-Ho, Clements, Mark A, Colomar, Javier Ricardo, Daniels, Mark, Deerochanawong, Chaicharn, Desai, Vivek S, Desmangles, Jean-Claude G, Dillon, Robert G, Dixit, Naznin M, Du, Hongwei, Edelen, Rachel, Espinoza Peralta, Diego, Felipe Gacioppo, María Verónica, Ferraz, Tania Maria Bulcão Lousada, Galkina, Galina, Gallagher, Mary Patricia, George, Minu, Gonzalez, Edgar, Gottschalk, Michael Everett, Guido, Giancarlo, Hassan, Amir Ali, Hershkovitz, Eli, Huerta-Saenz, Lina P, Hwang, Jin Soon, Ibarra Gomez, Jaime Orlando, Irizarry Gonzalez, Lydia, Jain, Nina, Jelley, David H, Kim, Ho-Seong, Kovalenko, Tatiana, Laffel, Lori Michelle B, Leichter, Steven B, Liberatore Jr, Raphael Del Roio, Lynch, Jane, Mahmud, Farid Hussain, Malievskiy, Oleg Arturovich, Muir, Andrew, Nelson, Bryce A, Nevarez Ruiz, Luis Alejandro, Olson, Micah L, Pelayo Orozco, Emilia Susana, Peterkova, Valentina, Ramírez Mendoza, Fernando Ramón, Reddy, Konda Mohan, Rodriguez, Henry, Saenz, Javier Andres, Samoilova, Julia, Schwab, Karl-Otfried, Shah, Sejal H, Shehadeh, Naim, Shoemaker, Ashley H, Skorodok, Yulia, Sobolev, Aleksandr, Solís, Silvana Ernestina, Srinivasan, Shylaja, Tamborlane, William V, Tsalikian, Eva, Valeeva, Farida, Vance, Carl D, Velasquez-Mieyer, Pedro A, Violante Ortiz, Rafael Margarito, Votyakova, Olga, Wei, Haiyan, Weinstock, Ruth S, Wheeler, Mark D, Wicklow, Brandy Alexandra, Willi, Steven M, Wintergerst, Kupper A, Wolf, Risa M, Wood, Jamie Ruth, Yaliwal, Chandan, Yupanqui Lozno, Hernán, Laffel, Lori M, Danne, Thomas, Klingensmith, Georgeanna J, Willi, Steven, Zeitler, Philip, Neubacher, Dietmar, and Marquard, Jan

Published
2023
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4. Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial

Author

Laffel, Lori M, primary, Danne, Thomas, additional, Klingensmith, Georgeanna J, additional, Tamborlane, William V, additional, Willi, Steven, additional, Zeitler, Philip, additional, Neubacher, Dietmar, additional, Marquard, Jan, additional, Bardymova, Tatiana, additional, Barrientos Perez, Margarita, additional, Bethin, Kathleen, additional, Bjornstad, Petter, additional, Bondar, Irina, additional, Chen, Mimi, additional, Choi, Jin-Ho, additional, Clements, Mark A, additional, Colomar, Javier Ricardo, additional, Daniels, Mark, additional, Deerochanawong, Chaicharn, additional, Desai, Vivek S, additional, Desmangles, Jean-Claude G, additional, Dillon, Robert G, additional, Dixit, Naznin M, additional, Du, Hongwei, additional, Edelen, Rachel, additional, Espinoza Peralta, Diego, additional, Felipe Gacioppo, María Verónica, additional, Ferraz, Tania Maria Bulcão Lousada, additional, Galkina, Galina, additional, Gallagher, Mary Patricia, additional, George, Minu, additional, Gonzalez, Edgar, additional, Gottschalk, Michael Everett, additional, Guido, Giancarlo, additional, Hassan, Amir Ali, additional, Hershkovitz, Eli, additional, Huerta-Saenz, Lina P, additional, Hwang, Jin Soon, additional, Ibarra Gomez, Jaime Orlando, additional, Irizarry Gonzalez, Lydia, additional, Jain, Nina, additional, Jelley, David H, additional, Kim, Ho-Seong, additional, Kovalenko, Tatiana, additional, Laffel, Lori Michelle B, additional, Leichter, Steven B, additional, Liberatore Jr, Raphael Del Roio, additional, Lynch, Jane, additional, Mahmud, Farid Hussain, additional, Malievskiy, Oleg Arturovich, additional, Muir, Andrew, additional, Nelson, Bryce A, additional, Nevarez Ruiz, Luis Alejandro, additional, Olson, Micah L, additional, Pelayo Orozco, Emilia Susana, additional, Peterkova, Valentina, additional, Ramírez Mendoza, Fernando Ramón, additional, Reddy, Konda Mohan, additional, Rodriguez, Henry, additional, Saenz, Javier Andres, additional, Samoilova, Julia, additional, Schwab, Karl-Otfried, additional, Shah, Sejal H, additional, Shehadeh, Naim, additional, Shoemaker, Ashley H, additional, Skorodok, Yulia, additional, Sobolev, Aleksandr, additional, Solís, Silvana Ernestina, additional, Srinivasan, Shylaja, additional, Tsalikian, Eva, additional, Valeeva, Farida, additional, Vance, Carl D, additional, Velasquez-Mieyer, Pedro A, additional, Violante Ortiz, Rafael Margarito, additional, Votyakova, Olga, additional, Wei, Haiyan, additional, Weinstock, Ruth S, additional, Wheeler, Mark D, additional, Wicklow, Brandy Alexandra, additional, Willi, Steven M, additional, Wintergerst, Kupper A, additional, Wolf, Risa M, additional, Wood, Jamie Ruth, additional, Yaliwal, Chandan, additional, and Yupanqui Lozno, Hernán, additional

Published
2023
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5. 994-P: DINAMO—Diabetes Study of Linagliptin and Empagliflozin in Children and Adolescents with Type 2 Diabetes (T2D) : Innovative Study Design and Baseline Characteristics

Author

LAFFEL, LORI M., primary, DANNE, THOMAS, additional, TAMBORLANE, WILLIAM V., additional, KLINGENSMITH, GEORGEANNA J., additional, SCHROEDER, CHRISTY, additional, NEUBACHER, DIETMAR, additional, SOLEYMANLOU, NIMA, additional, MARQUARD, JAN, additional, ZEITLER, PHILIP, additional, and WILLI, STEVEN M., additional

Published
2022
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6. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

Author

Marquard, Jan, Otter, Silke, Welters, Alena, Stirban, Alin, Fischer, Annelie, Eglinger, Jan, Herebian, Diran, Kletke, Olaf, Klemen, Masa Skelin, Stozer, Andraz, Wnendt, Stephan, Piemonti, Lorenzo, Kohler, Martin, Ferrer, Jorge, Thorens, Bernard, Schliess, Freimut, Rupnik, Marjan Slak, Heise, Tim, Berggren, Per-Olof, Klocker, Nikolaj, Meissner, Thomas, Mayatepek, Ertan, Eberhard, Daniel, Kragl, Martin, and Lammert, Eckhard

Subjects
Medical research, Medicine, Experimental, Methyl aspartate -- Research, Diabetes therapy -- Research, Diabetes -- Drug therapy, Drug targeting -- Research, Type 2 diabetes -- Research, Biological sciences, Health
Abstract

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic [Ca.sup.2+] concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes., Type 2 diabetes mellitus (T2DM) is the most common metabolic disease worldwide, affecting more than 350 million people, and both its incidence and prevalence have been increasing globally (1). Peripheral [...]

Published
2015
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10. Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop

Author

Barrett, Jeffrey S., primary, Bucci‐Rechtweg, Christina, additional, Amy Cheung, S. Y., additional, Gamalo‐Siebers, Margaret, additional, Haertter, Sebastian, additional, Karres, Janina, additional, Marquard, Jan, additional, Mulugeta, Yeruk, additional, Ollivier, Cecile, additional, Strougo, Ashley, additional, Yanoff, Lisa, additional, Yao, Lynne, additional, and Zeitler, Philip, additional

Published
2020
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11. Low‐dose empagliflozin as adjunct‐to‐insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy

Author

Perkins, Bruce A., primary, Soleymanlou, Nima, additional, Rosenstock, Julio, additional, Skyler, Jay S., additional, Laffel, Lori M., additional, Liesenfeld, Karl‐Heinz, additional, Neubacher, Dietmar, additional, Riggs, Matthew M., additional, Johnston, Curtis K., additional, Eudy‐Byrne, Rena J., additional, Elmokadem, Ahmed, additional, George, Jyothis T., additional, Marquard, Jan, additional, and Nock, Valerie, additional

Published
2020
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12. NMDA receptor dependent anti-diabetic effects

Author

Marquard, Jan, Otter, Silke, Welters, Alena, Herebian, Diran, Demir, Fatih, Schroeter, Annett, Kletke, Olaf, Kragl, Martin, Eberhard, Daniel, Bartosinska, Barbara, Klemen, Masa Skelin, Stozer, Andraz, Köhler, Martin, Stirban, Alin, Schliess, Freimut, Heise, Tim, Wnendt, Stephan, Rupnik, Marjan Slak, Berggren, Per-Olof, Klöcker, Nikolaj, Meissner, Thomas, Mayatepek, Ertan, and Lammert, Eckhard

Published
2014
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13. Exploring Patient Preferences for Adjunct-to-Insulin Therapy in Type 1 Diabetes

Author

Perkins, Bruce A., primary, Rosenstock, Julio, additional, Skyler, Jay S., additional, Laffel, Lori M., additional, Cherney, David Z., additional, Mathieu, Chantal, additional, Pang, Christianne, additional, Wood, Richard, additional, Kinduryte, Ona, additional, George, Jyothis T., additional, Marquard, Jan, additional, and Soleymanlou, Nima, additional

Published
2019
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14. 1199-P: Analysis of Patient Preferences for Adjunct Therapy to Insulin in T1D

Author

PERKINS, BRUCE A., primary, ROSENSTOCK, JULIO, additional, SKYLER, JAY S., additional, LAFFEL, LORI M., additional, CHERNEY, DAVID, additional, MATHIEU, CHANTAL, additional, PANG, CHRISTIANNE, additional, WOOD, RICHARD, additional, KINDURYTE, ONA, additional, GEORGE, JYOTHIS, additional, MARQUARD, JAN, additional, and SOLEYMANLOU, NIMA, additional

Published
2019
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15. 1198-P: The M-EASE Studies: A Modeling and Simulation Approach to Further Characterize the Efficacy of Low-Dose Empagliflozin as Adjunctive to Insulin Therapy in Type 1 Diabetes (T1DM)

Author

PERKINS, BRUCE A., primary, SOLEYMANLOU, NIMA, additional, ROSENSTOCK, JULIO, additional, SKYLER, JAY S., additional, LAFFEL, LORI M., additional, LIESENFELD, KARL-HEINZ, additional, NEUBACHER, DIETMAR, additional, RIGGS, MATTHEW, additional, JOHNSTON, CURTIS K., additional, EUDY-BYRNE, RENA J., additional, ELMOKADEM, AHMED, additional, GEORGE, JYOTHIS, additional, MARQUARD, JAN, additional, and NOCK, VALERIE C., additional

Published
2019
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19. Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial

Author

Shimada, Akira, primary, Hanafusa, Toshiaki, additional, Yasui, Atsutaka, additional, Lee, Ganghyuck, additional, Taneda, Yusuke, additional, Sarashina, Akiko, additional, Shiki, Kosuke, additional, George, Jyothis, additional, Soleymanlou, Nima, additional, and Marquard, Jan, additional

Published
2018
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21. Randomized, double-blind, placebo-controlled dose-finding study of the dipeptidyl peptidase-4 inhibitor linagliptin in pediatric patients with type 2 diabetes

Author

Tamborlane, William V, primary, Laffel, Lori MB, additional, Weill, Jacques, additional, Gordat, Maud, additional, Neubacher, Dietmar, additional, Retlich, Silke, additional, Hettema, Willem, additional, Hoesl, Cornelia E, additional, Kaspers, Stefan, additional, and Marquard, Jan, additional

Published
2017
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23. Randomized, double‐blind, placebo‐controlled dose‐finding study of the dipeptidyl peptidase‐4 inhibitor linagliptin in pediatric patients with type 2 diabetes.

Author

Tamborlane, William V., Laffel, Lori M. B., Weill, Jacques, Gordat, Maud, Neubacher, Dietmar, Retlich, Silke, Hettema, Willem, Hoesl, Cornelia E., Kaspers, Stefan, and Marquard, Jan

Subjects
DRUG dosage, BLOOD sugar, TREATMENT of diabetes, DRUGS, DOSE-effect relationship in pharmacology, GLYCOSYLATED hemoglobin, TYPE 2 diabetes, RANDOMIZED controlled trials, TREATMENT effectiveness, BLIND experiment, PHARMACODYNAMICS, ADOLESCENCE, CHILDREN
Abstract

Objective: To identify the dose of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D). Methods: Double‐blind, randomized, controlled parallel group study comparing linagliptin 1 and 5 mg once daily, with placebo in 39 patients with T2D aged 10 to below 18 years. The primary efficacy endpoint was the change from baseline in glycated hemoglobin (HbA1c) after 12 weeks of treatment. The key pharmacodynamic endpoint was DPP‐4 inhibition during steady‐state. Results: Compared to placebo, there was a dose‐dependent reduction in mean HbA1c of 0.48% and 0.63% with linagliptin 1 and 5 mg, respectively, associated with corresponding declines in mean fasting plasma glucose (FPG) of 5.6 and 34.2 mg/dL. Median DPP‐4 inhibition was 38% with linagliptin 1 mg and 79% with linagliptin 5 mg. Geometric mean trough levels of linagliptin were 3.80 and 7.42 nmol/L in the 1 and 5 mg groups, respectively; levels that were slightly higher than in adult patients with T2D that were most likely caused by higher plasma DPP‐4 concentrations in the study population. There were no drug‐related adverse events during treatment with either dose of linagliptin. Conclusions: Linagliptin was well tolerated and induced dose‐dependent DPP‐4 inhibition that was accompanied by corresponding reductions in HbA1c and FPG levels in young people with T2D. The results are consistent with the clinical efficacy and safety profile that have been reported for linagliptin in adult patients with T2D, favoring linagliptin 5 mg over 1 mg. [ABSTRACT FROM AUTHOR]

Published
2018
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24. Population Pharmacokinetic– Pharmacodynamic Analysis to Characterize the Effect of Empagliflozin on Renal Glucose Threshold in Patients With Type 1 Diabetes Mellitus.

Author

Mondick, John, Riggs, Matthew, Kaspers, Stefan, Soleymanlou, Nima, Marquard, Jan, and Nock, Valerie

Subjects
BLOOD sugar, GLUCOSE, INSULIN, TYPE 1 diabetes, KIDNEYS, TYPE 2 diabetes, EMPAGLIFLOZIN, PHARMACODYNAMICS
Abstract

Abstract: Sodium glucose cotransporter 2 inhibitors increase urinary glucose excretion (UGE) by lowering the renal threshold for glucose (RTG). We aimed to quantify the effect of the sodium glucose cotransporter inhibitor empagliflozin on renal glucose reabsorption in patients with type 1 diabetes mellitus (T1DM) using a mechanistic population pharmacokinetic–pharmacodynamic (PK‐PD) model and to compare results with analyses in patients with type 2 diabetes mellitus (T2DM). The PK‐PD model was developed using data from a randomized phase 2 study in which patients with T1DM received oral once‐daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as an adjunct to insulin. The model assumed that UGE was dependent on plasma glucose and renal function and that empagliflozin lowered RTG. The final model was evaluated using visual predictive checks and found to be consistent with observed data. Calculated RTG with placebo was 181 mg/dL, and with empagliflozin (steady state) 1 mg and 2.5 mg was 53.4 mg/dL and 12.5 mg/dL, respectively. Empagliflozin 10 mg and 25 mg yielded negative RTG values, implying RTG was reduced to a negligible value. Although estimated PK‐PD parameters were generally comparable between patients with T1DM and patients with T2DM, slight differences were evident, leading to lower RTG and higher UGE in patients with T1DM compared with patients with T2DM. In conclusion, the model provided a reasonable description of UGE in response to administration of empagliflozin and placebo in patients with T1DM. [ABSTRACT FROM AUTHOR]

Published
2018
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25. Congenital Hyperinsulinism: Overview and Clinical Update

Author

MARQUARD, Jan, MAYATEPEK, Ertan, and MEISSNER, Thomas

Subjects
Congenital hyperinsulinism,hypoglycaemia,glucose
Abstract

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. This review gives an overview and update of pathogenesis, genetics, diagnosis and management of CHI. This diesease is a genetically heterogeneous disorder with both familial and sporadic variants and is biochemically characterized by an unregulated secretion of insulin from pancreatic beta cells in relation to the blood glucose concentration. To date, there are eight different genes described which lead to CHI. However, in 50% of patients the genetic mechanism is still unknown. The clinical presentation is heterogeneous with regard to age of onset, severity and manner of symptoms. This is explained by different pathogenetic mechanism resulting in inappropriate insulin secretion. An early and rapid diagnosis including initiation of an effective treatment is essential for preventing hypoglycaemic brain damage and neurological sequelae in affected children. Over the last years, substantial progress in diagnostic with 18F-L-dopa positron emission tomography for differentiating diffuse from focal disease and new laparoscopic surgery techniques has been made. In patients with diffuse form of CHI medical treatment with diazoxide, which is ineffective in patients with defects of the KATP channel, is the first line treatment. When medical treatment failed a near-total pancreatectomy has to be considered as a last resort. In patients with focal CHI a limited pancreatectomy can lead to complete cure of the disease. Patients should be managed by centres with a highly experienced team in diagnostic work-up and treatment of CHI.

Published
2011

35. A prospective clinical pilot-trial comparing the effect of an optimized mixed diet versus a flexible low-glycemic index diet on nutrient intake and HbA1c levels in children with type 1 diabetes.

Author

Marquard, Jan, Stahl, Anna, Lerch, Christian, Wolters, Mareen, Grotzke-Leweling, Maike, Mayatepek, Ertan, and Meissner, Thomas

Abstract

Background: Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD). Methods: This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record. Objectives: The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA1c levels. Results: In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA1c levels between the groups were observed. Conclusion: OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet. [ABSTRACT FROM AUTHOR]

Published
2011
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36. A prospective clinical pilot-trial comparing the effect of an optimized mixed diet versus a flexible low-glycemic index diet on nutrient intake and HbA1clevels in children with type 1 diabetes

Author

Marquard, Jan, Stahl, Anna, Lerch, Christian, Wolters, Mareen, Grotzke-Leweling, Maike, Mayatepek, Ertan, and Meissner, Thomas

Abstract

AbstractBackground:Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD).Methods:This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record.Objectives: The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA1clevels.Results:In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA1clevels between the groups were observed.Conclusion:OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet.

Published
2011
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37. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment

Author

Jan Eglinger, Maša Skelin Klemen, Olaf Kletke, Eckhard Lammert, Daniel Eberhard, Alena Welters, Silke Otter, Martin Köhler, Stephan Wnendt, Nikolaj Klöcker, Annelie Fischer, Jorge Ferrer, Tim Heise, Diran Herebian, Ertan Mayatepek, Thomas Meissner, Lorenzo Piemonti, Andraž Stožer, Freimut Schliess, Martin Kragl, Bernard Thorens, Per Olof Berggren, Marjan Slak Rupnik, Alin Stirban, Jan Marquard, Marquard, Jan, Otter, Silke, Welters, Alena, Stirban, Alin, Fischer, Annelie, Eglinger, Jan, Herebian, Diran, Kletke, Olaf, Klemen, MaÅ¡a Skelin, Stoå¾er, Andraå, Wnendt, Stephan, Piemonti, Lorenzo, Kã¶hler, Martin, Ferrer, Jorge, Thorens, Bernard, Schliess, Freimut, Rupnik, Marjan Slak, Heise, Tim, Berggren, Per Olof, Klã¶cker, Nikolaj, Meissner, Thoma, Mayatepek, Ertan, Eberhard, Daniel, Kragl, Martin, Lammert, Eckhard, and Pathology/molecular and cellular medicine

Subjects
Male, endocrine system diseases, medicine.medical_treatment, Dextromethorphan, Mice, Dextrorphan, Insulin-Secreting Cells, Pancrea, Insulin, Mice, Knockout, Glucose tolerance test, geography.geographical_feature_category, medicine.diagnostic_test, Research Support, Non-U.S. Gov't, Medicine (all), General Medicine, Middle Aged, Islet, 3. Good health, medicine.anatomical_structure, Peptide, Female, medicine.drug, Human, Adult, endocrine system, medicine.medical_specialty, Cell Survival, Nerve Tissue Proteins, Receptors, N-Methyl-D-Aspartate, General Biochemistry, Genetics and Molecular Biology, Cell Line, Islets of Langerhans, Research Support, N.I.H., Extramural, Internal medicine, Diabetes mellitus, Journal Article, medicine, Animals, Humans, Pancreas, geography, Biochemistry, Genetics and Molecular Biology (all), business.industry, Animal, Venoms, Pancreatic islets, Type 2 Diabetes Mellitus, Islets of Langerhan, Glucose Tolerance Test, medicine.disease, Venom, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Glucose, nervous system, Diabetes Mellitus, Type 2, Insulin-Secreting Cell, Drug Design, Nerve Tissue Protein, Exenatide, Calcium, business, Peptides
Abstract

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

Published
2014

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