Abstracts – Grad Students

The Role Of Intestinal L-cell Secretagogin In Circadian Glucagon-like Peptide-1 Secretion In A Murine Model Of Type 2 Diabetes

Andrew Biancolin [1], Christina Yuan [1], Patricia Brubaker [1,2]

  1. Department of Physiology, University of Toronto, Toronto, ON, Canada
  2. Department of Medicine, University of Toronto, Toronto, ON, Canada

 

Discussion

 

Human Spermatozoa Secrete Insulin In Response To Glucose Stimuli

David F. Carrageta [1], Pedro F. Oliveira [2], Alberto Barros [3,4,5], Mariana P. Monteiro [1], Marco G. Alves [1]

  1. QOPNA & LAQV, Department of Chemistry, University of Aveiro, Aveiro, Portugal
  2. Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
  3. i3S -Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
  4.  Centre for Reproductive Genetics Prof. Alberto Barros, Porto, Portugal
  5. Department of Anatomy, Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

 

Discussion

Can A Western Diet Drive The Development Of Diabetes In A Female Mouse Model With Pre-existing Beta Cell Endoplasmic Reticulum (er) Stress?

Lydia F. Daniels Gatward [1] Pratik Choudhary [1]Aileen JF. King [1]

  1. Department of Diabetes, School of Life Course Sciences, King’s College London, London, U.K.

 

Discussion

Adipocyte Yap Deletion Improves Glucose Homeostasis In Mice

Daniel Jong Jin Han [1,2], Ruhksana Aslam [2], Tanvi Ojha [2], Darren A. Yuen [1,2,3,4], Cynthia T. Luk1, [2,3,4]

  1. Institute of Medical Science, University of Toronto, Toronto, ON, Canada
  2. Keenan Centre for Biomedical Science, St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
  3. Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, ON, Canada
  4.  Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada

 

Discussion

Gut-liver B Cells Promote The Development Of Obesity-associated Insulin Resistance And Metabolic Disease

Saad Khan [1,2], Helen Luck [1,2], Fanta Barrow [3], Xavier S. Revelo [3]*, Daniel A. Winer [1,2]*

  1. Divison of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
  2. Department of Immunology, University of Toronto, Toronto, ON, Canada
  3. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, United States of America

*Senior authors jointly supervised this work

 

Discussion

Nutrient Sensing In The Dorsal Vagal Complex Regulates Hepatic Lipid And Glucose Metabolism In Rats

Rosa J.W. Li  [1,2], Battsetseg Batchuluun [2], Song-Yang Zhang [2], Mona A. Abraham [1,2], Beini Wang [1, 2], Yu-Mi Lim [2, 3], Jessica T.Y. Yue [4] & Tony K.T. Lam [1,2,5,6]

  1. Department of Physiology, University of Toronto, Toronto, Canada
  2. Toronto General Hospital Research Institute, UHN, Toronto, Canada
  3. Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
  4. Department of Physiology, University of Alberta, Edmonton, Canada
  5. Department of Medicine, University of Toronto, Toronto, Canada
  6. Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada

 

Discussion

Cell-specific Role Of Insulin In An In Vivo Model Of Restenosis

Zhiwei Liu [1], Marel Gonzalez Medina [1], Yusaku Mori [1,2], Adria Giacca [1, 3-5]

  1. Department of Physiology, University of Toronto, Toronto, ON, Canada
  2. Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
  3. Department of Medicine, University of Toronto, Toronto, ON, Canada
  4. Institute of Medical Science, University of Toronto, Toronto, ON, Canada
  5. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, S-214 28 Malmö, Sweden
  6. Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, Toronto, ON, Canada

Discussion

Ultra-fast Monomeric Insulin Formulation Enabled By Supramolecular Excipients

Caitlin L. Maikawa [1] , Joseph L. Mann [2], Eric A. Appel [1, 2]

  1. Department of Bioengineering, Stanford University, Stanford, CA, USA
  2. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

Discussion

Uncovering The Physiological Roles Of Gut Hormone Receptor Signalling In Dysregulated Triglyceride-rich Lipoprotein Secretion During Diet-induced Obesity

Nadya M. Morrow [1], My-Anh Nguyen [1], Natasha A. Trzaskalski [1], Antonio A. Hanson [1], Evgenia Fadzeyeva [1], Erin E. Mulvihill [1]

  1. Biochemistry, Microbiology, Immunology, University of Ottawa Heart Institute, Ottawa, ON, Canada

Discussion

Distinguishing Obese Healthy From Obese Unhealthy Prepubertal Children & The Importance Of Circulating Micrornas

Diana Santos [1], Patricia Porter-Gill [2], Sirish Bennuri [2], Grace Goode [2], Leanna Delhey [2], Anja Sorenson [3], Louise Torp Dalgaard [3], Shannon Rose [2], Elisabet Borhseim [2], Eugénia Carvalho [1,]

  1. Centro de Neurociências e Biologia Celular da Universidade de Coimbra (CNC), Coimbra, Portugal
  2. University of Arkansas for Medical Sciences; Arkansas Children’s Research Institute, Little Rock, Arkansas, United States
  3. Department of Science and Environment, Roskilde University, Roskilde, Denmark

 

Discussion

Bihormonal Islet Cells: A Transdifferentiating Effect Of Physical Exercise

Villaça CBP [1], Paula CC [1], Oliveira CC [1], Vilas-Boas, EA [3], Santos-Silva JC[2], Oliveira SF [1], Abdulkader F [3], Ferreira SM [4] and Ortis F [1]

  1. Department of Cell and Developmental Biology, Institute of Biomedical Sciences (ICB), University of Sao Paulo (USP), Sao Paulo, Brazil
  2. Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil
  3. Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
  4. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, Brazil

 

Discussion

Frequency Of Diabetes Team Contacts In Children And Adolescents Using Insulin Pumps

Funmbi Babalola [1], Michael Miller[2,3], Andrea Ens [2], Patrica Gallego [2], Robert Stein [2], Cheril Clarson [2,3]

  1. Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
  2. Children’s Hospital, London Health Sciences Centre, London, Ontario, Canada, Department of Paediatrics, University of Western Ontario, London, Ontario
  3.  Lawson Health Research Institute, London, Ontario

Discussion

Changes In Cardiovascular Biomarkers Associated With The Sodium Glucose Cotransporter-2 (sglt2) Inhibitor Ertugliflozin In Patients With Chronic Kidney Disease And Type 2 Diabetes

Patrick R. Lawler MD MPH [1,2,3]*, Hongyan Liu BMSc [4,5]*, Claudia Frankfurter MD [6], Leif Erik Lovblom MSc [7], Yuliya Lytvyn PhD [4,6], Dylan Burger PhD [8], Kevin D. Burns MD [8], Davor Brinc PhD [9,10], David Z. I. Cherney MD PhD [4,5,11]

 *These authors contributed equally.

  1. Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
  2.   2Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada
  3. Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada
  4.  Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
  5.  Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
  6.  Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  7.  Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
  8.  Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, Kidney Research Centre, University of Ottawa
  9.  Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada Canada
  10. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  11.  Department of Physiology and Institute of Medical Sciences, University of Toronto, Toronto, Ontario

Discussion

Interpolation Of Fgm Data For The Improved Identification Of Hypoglycaemic Episodes

C.L. Russon [1], N. Vaughan [1,3], R.C. Andrews [1,2]

  1. Exeter Centre of Excellence for Diabetes (ExCEeD)
  2.  Research and Development, Somerset NHS foundation Trust, Taunton, UK, 3Royal Academy of Engineering (RAEng), UK

 

Discussion

High-intensity Hospital Utilization Among Adults With Diabetic Foot Ulcers: Population-based Study

Muzammil H. Syed [1,2], Mohammed Al-Omran [2,3], Joel G. Ray [4], Muhammad Mamdani1, [5,6], Charles de Mestral [2,3,6]

  1. Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
  2.  Division of Vascular Surgery, Department of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
  3.   Diabetes Action Canada, Toronto, ON, Canada
  4. Divisions of General Internal Medicine and Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
  5.  Li Ka Shing Centre for Healthcare Analytics Research and Training (LKS-CHART), St. Michael’s Hospital 6Banting and Best Diabetes Centre (BBDC), University of Toronto, Toronto, ON, Canada

 

Discussion

Thymic B Cell Isotype Switching Contributes To Central T Cell Tolerance And Limits Autoimmune Diabetes

Félix Lombard-Vadnais [1,2], Geneviève Chabot-Roy [2], Javier Di Noia1, [3,4], Sylvie Lesage [2,3]

  1. McGill University, Montreal, Qc, Canada
  2. Centre de Recherche de l’Hôpital Maisonneuve-Rosemont, Montreal, Qc, Canada
  3. Université de Montréal, Montreal, Qc, Canada
  4. Institut de Recherches Clinique de Montréal, Montreal, Qc, Canada

Discussion

Upregulation Of Cytosolic Reducing Signaling Through Senp1 Is Required For Beta-cell Functional Compensation To Short-term High Fat Diet

Haopeng Lin1, [2, 8], Kunimasa Suzuki1, [2, 8], Nancy Smith [1, 2], Xi Li [3], Lisa Nalbach [4], Sonia Fuentes [3], Aliya F Spigelman [1, 2], Xiaoqing Dai [1, 2], Austin Bautista [1, 2], Mourad Ferdaoussi [6], Saloni Aggarwal [7], Andrew R Pepper [7], Emmanuel Ampofo [4], Leticia P Roma [5], Wen-hong Li [3], Patrick E MacDonald [1, 2] *

  1. Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada
  2. Alberta Diabetes Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada
  3. Departments of Cell Biology and Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9039, USA
  4. Institute for Clinical & Experimental Surgery, Saarland University, Homburg/Saar, Germany
  5. Biophysics Department, Center for Human and Molecular Biology, Saarland University, Homburg/Saar, Germany
  6. Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2E1, Canada
  7. Department of Surgery, University of Alberta, Edmonton, Canada

* These authors contributed to this study equally

 

Discussion

Role Of Nod1 Receptors In Fat-induced Insulin Resistance And ß-cell Dysfunction

S M Niazur Rahman [1] , Falak Shoaib [1], Alexandar Ivovic [1], Sydney Rivers [1], Justin Hou [1] Ming Yung [1], and Adria Giacca [1]

  1. Dept. of Physiology, University of Toronto, Toronto, ON, Canada

Discussion

Reducing The Need For Carbohydrate Counting In Type 1 Diabetes Using Closed-loop Automated Insulin Delivery (artificial Pancreas) And Empagliflozin: A Randomised Controlled Non-inferiority Crossover Pilot Trial

Ahmad Haidar [1,2,3], Jean-Francois Yale [2,3], Leif Erik Lovblom [4], Nancy Cardinez [4], Andrej Orszag [4], C. Marcelo Falappa [4], Nikita Gouchie-Provencher [2], Michael A. Tsoukas [2,3], Anas El Fathi [1], Jennifer Rene [1], Devrim Eldelekli [4], Sebastien O. Lanctôt [4], Daniel Scarr [4], Bruce A. Perkins [4,5]

  1. Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada 3775 University Street, Montréal, Québec, H3A 2B4
  2. The Research Institute of McGill University Health Centre 1001 Decarie Blvd, Montréal, Québec, H4A 3J1
  3. Division of Endocrinology, Department of Medicine, McGill University, Quebec, Canada. 1001 Decarie Blvd, Montréal, Québec, H4A 3J1
  4. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 600 University Ave, Toronto, Ontario, M5G 1X5
  5. Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Queen’s Park Crescent West, Third Floor, Toronto, ON, M5S 3H2

Discussion

Evaluating The Effects Of Olanzapine On Central Insulin Signaling And Cognitive Outcomes

Nicolette Stogios1 [2], Mahavir Agarwal [1 2 3 4], Adria Giacca [5], Ariel Graff-Guerrero [1 2 3], Daniel Mueller [1 2 3], Gary Remington [1 2 3], Aristotle Voineskos[1 2 3], Valerie Taylor [6], Satya Dash1 [4 7], Margaret Hahn [1 2 3 4]

  1. Institute of Medical Science, University of Toronto, Toronto, ON
  2. Centre for Addiction and Mental Health (CAMH), Toronto, ON
  3. Department of Psychiatry, University of Toronto, Toronto, ON
  4. Banting and Best Diabetes Centre (BBDC), University of Toronto, Toronto, ON
  5. Department of Physiology, University of Toronto, Toronto, ON
  6. Department of Psychiatry, University of Calgary, Calgary
  7. Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON

Discussion

Increased Apolipoprotein C3 And Inflammasome Activation In A Mouse Model Of Type 1 Diabetes-accelerated Atherosclerosis

Cheng-Chieh Hsu [1], Jenny E. Kanter [1], Yi He [1], Karin E. Bornfeldt [1,2]

  1. Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
  2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA

 

Discussion

Successful Islet Transplantation In The Subcutaneous Space For Type 1 Diabetes Using An Islet Viability Matrix

Divyansh Agarwal [1], Ming Yu [1], Chengyang Liu [1], Ali Naji [1]

  1. Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia PA 19104, U.S.A.

Discussion

Pkc-δ And P38 Mapk Mediate Free Fatty Acid-induced Hepatic Fat Accumulation And Triglyceride Secretion

Deborah Y. Joseph [1], Sydney Rivers [1] and Adria Giacca [1,2]

  1.  Department of Physiology, University of Toronto, Toronto, ON, Canada
  2. Banting and Best Diabetes Centre, University of Toronto

Discussion

Prediction Of Future Diabetic Neuropathy Using Corneal Confocal Microscopy: A Longitudinal Diagnostic Multinational Consortium Study

Bruce A. Perkins [1,2], Leif Erik Lovblom [1], Evan J.H. Lewis [1], Vera Bril [3], Maryam Ferdousi [7], Andrej Orszag [1], Katie Edwards [4], Nicola Pritchard [4], Anthony Russell [5], Cirous Dehghani [4], Danièle Pacaud [6], Kenneth Romanchuk [6], Jean K. Mah [6], Maria Jeziorska [7], Andrew Marshall [7], Roni M. Shtein [8], Rodica Pop-Busui [8], Stephen I. Lentz [8], Mitra Tavakoli [7,9], Andrew J.M. Boulton [7], Nathan Efron [4], Rayaz A. Malik [7, 10]

  1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada.
  2. Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto. Toronto, Ontario, Canada.
  3. The Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto. Toronto, Ontario, Canada.
  4. Queensland University of Technology. Brisbane, Queensland, Australia.
  5. University of Queensland. Woolloongabba, Queensland, Australia.
  6. Alberta Children’s Hospital, University of Calgary. Calgary, Alberta, Canada.
  7. University of Manchester. Manchester, UK.
  8. University of Michigan. Ann Arbor, MI, USA.
  9. University of Exeter Medical School. Exeter, UK.
  10. Weill Cornell Medicine-Qatar, Doha, Qatar.

Discussion

Is There Anything Left To Eat? Lived Experience Of Conflict And Disorder : T1d Vs Esrd Diet
Suzanne Schneider [1]

  1. MSc Faculty of Health and Human Sciences, Bournemouth University; Bournemouth, United Kingdom

 

Discussion

Experiencing Diabetes Distress Through The Prism Of A Patient And Their Close Ones

Judita Konecna [1],2, Karel D. Riegel [3]

  1. 3rd Department of Medicine – Department of Endocrinology and Metabolism, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic
  2. Department of Psychiatry, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic
  3. Department of Addictology, 1st Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic

Discussion

Ldt409 Promotes Weight Loss In Diet-induced Obese Mice By Decreasing Intestinal Lipid Absorption

Cigdem Sahin [1], Evan Pollock [2], Thais M.A. Ferreira [3], Minna Woo [2,4], Luiz A.S. Romeiro [3], Carolyn L. Cummins [1,4]

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada
  2. Toronto General Research Institute, University Health Network, Toronto, Ontario Canada
  3. Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil
  4. Banting and Best Diabetes Centre, Toronto, ON, Canada

Discussion

The L Cell Clock Is Required For Circadian Secretion Of The Incretin Hormone, Glucagon-like Peptide-1

Sarah E. Martchenko [1], Alexandre Martchenko [1], Andrew D. Biancolin [1], Patricia L. Brubaker [1,2]

  1. Department of Physiology, University of Toronto, Toronto, ON, Canada
  2. Department of Medicine, University of Toronto, Toronto, ON, Canada

Glucagon-like peptide-1 (GLP-1) is an incretin hormone released by the intestinal L-cell in response to nutrient intake (1).

Although recent studies identified a circadian rhythm in GLP-1 secretion (2-4), the extent to which the L-cell molecular clock regulates circadian GLP-1 secretion as well as diurnal metabolic homeostasis is unknown.

Upon oral glucose gavage at the known peak and trough timepoints of GLP-1 release, male and female Gcg-creERT2/+;Bmal1flox/flox KO mice lost the rhythmic GLP-1 secretory pattern in association with impaired secretion at the peak timepoint (vs. all genetic and chemical controls).

Unexpectedly, this did not translate to decreased insulin or hyperglycemia, likely due to concomitantly decreased glucagon levels. However, L-cell Bmal1 KO increased colonic weight, interleukin-6 and interferon-gamma expression, as well as the proportion of intraepithelial CD4+ T cells, consistent with a pro-inflammatory state.

Furthermore, KO animals had altered microbial composition and function evidenced by increased actinobacteria and decreased levels of cecal bile acids and short-chain fatty acids. Finally, siRNA-mediated knockdown of Bmal1 in the murine GLUTag L-cell line also resulted in impaired rhythmic GLP-1 secretion.

Together, these data establish the L-cell clock as an essential regulator of circadian GLP-1 secretion which is, then, critical to the prevention of intestinal inflammation.

Discussion

Ketogenesis And Ketone Excretion Before And After Short-term Empagliflozin Use In Type 1 Diabetes

Daniel Scarr [1], Erik Lovblom [1], Daniel Montemayor [2], Hongping Ye [2], Hongyan Liu [3], Yuliya Lytvyn [3], Kumar Sharma [2], David Z.I. Cherney [3], Bruce A. Perkins [1,4]

  1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital. Toronto, Ontario, Canada.
  2. Center for Renal Precision Medicine (CRPM), Division of Nephrology, Department of Medicine, University of Texas Health San Antonio. San Antonio, Texas, United States.
  3. Division of Nephrology, Department of Medicine, University Health Network, University of Toronto. Toronto, Ontario, Canada.
  4. Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto. Toronto, Ontario, Canada.

Adjunctive-to-insulin sodium glucose co-transporter 2 (SGLT2) inhibition has clinically meaningful benefits in T1D but represents a component cause of diabetic ketoacidosis (DKA) whose risk appears higher in females (1-2).

In post-hoc analysis, SGLT2-mediated changes in ketone concentrations were evaluated in 40 people with T1D enrolled in the ATIRMA trial (NCT01392560). Metabolomic analysis of plasma and urine beta-hydroxybutyrate (BHB) and acetoacetate (AA) were made at baseline and after 8 weeks of empagliflozin 25 mg QD during both clamped euglycemia (4-6 mmol/L) and hyperglycemia (9-11 mmol/L).

We found that even during mild hyperglycemia that BHB and AA levels in urine were substantially higher than in euglycemia, indicating greater production counterbalanced by additional fractional excretion.

However, after empagliflozin use plasma levels were higher but still within the normal range, and fractional excretion was attenuated, particularly in females. Female sex was associated with a greater SGLT2-mediated increase in plasma ketone levels (interaction p< 0.001). Increased ketogenesis even during mild hyperglycemia was compensated by greater ketone excretion, but this compensatory mechanism was attenuated after SGLT2 use.

Both of these phenomena (higher production and attenuated fractional excretion) appear to be more pronounced in females, indicating a physiological rather than behavioural sex-specific cause for higher DKA risk.

Discussion

Nod1-jnk1 Axis Plays A Causal Role In Palmitate-induced Beta-cell Dysfunction

Justin Hou Ming Yung [1], Aleksandar Ivovic [1], Fiona Li [1], Isabel Clark [1], Brian Lin [1], Yao Fang Tan [1], Adria Giacca [1]

  1. Department of Physiology, University of Toronto, Toronto, ON, Canada

Chronic elevation of free fatty acids (FFA) in obesity may cause ß-cell dysfunction leading to Type 2 Diabetes (T2D).

Recent studies have focused on innate immunity receptors due to evidence implicating inflammation in obesity-associated T2D. Previously, we showed that whole-body NOD1-null mice were protected from palmitate-induced ß-cell dysfunction in vivo. Also, islets of whole-body NOD1-null and JNK1-null mice were protected from ß-cell dysfunction induced by palmitate but not oleate in vitro, suggesting NOD1 activation is likely in ß-cells, is specific to saturated FFA and may cause ß-cell dysfunction via JNK1.

Thus, we hypothesized that ß-cell NOD1 mediates palmitate-induced ß-cell dysfunction in vivo, and that JNK1 is downstream of NOD1 activation. As expected, ethylpalmitate (EtPAL) infusion elevated plasma FFA. Control mice infused with EtPAL for 48 hours decreased disposition index (DI), the in vivo measure of ß-cell function measured by hyperglycemic clamp, while EtPAL-infused ß-cell specific NOD1-null mice had similar DI to ethanol vehicle-infused mice.

The NOD1 activator reduced insulin secretion in WT islets but not in JNK1-null islets. Together, these data implicate ß-cell NOD1-JNK1 axis in palmitate-induced ß-cell dysfunction and reveal a novel pathway that could be targeted for manipulation in order to preserve ß-cell function.

Discussion

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