Abstracts – Post Doc

Glycerol-3-phosphate Phosphatase / Pgp : A Novel Calorie Restriction Enzyme Mimetic In C. Elegans

Elite Possik [1,2], Clémence Schmitt [1,2], Anfal Al-Mass [1,2], Johanne Morin [1,2], Heidi Erb [1,2], Wahab Kahloan [1,2], J Alex Parker [3], S.R. Murthy Madiraju [1,2], and Marc Prentki [1,2]

  1. Department of Nutrition, Université de Montréal, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada
  2. Department of Biochemistry and Molecular Medicine, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada
  3. Department of Neurosciences, CRCHUM, Montréal, Canada

 

Discussion

 

Il-1β Represses Identity Factors In Islet Endocrine Cells
Jennifer S. Stancill [1], Moujtaba Y. Kasmani [2,3], Achia Khatun [2,3], Weiguo Cui [2,3], and John A. Corbett [1]

  1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
  2. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin
  3. Versiti Blood Center of Wisconsin, Milwaukee, Wisconsin

 

Discussion

Fxr In The Dorsal Vagal Complex Is Sufficient And Necessary For Upper Small Intestinal Microbiome-mediated Changes Of Tcdca To Alter Insulin Action In Rats

Song-Yang Zhang [1], Rosa J.W. Li [1,2], Yu-Mi Lim [1,3], Battsetseg Batchuluun [1], Huiying Liu [4], T.M. Zaved Waise [1], Tony K.T. Lam [1,2,5,6]

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

 

Discussion

The Simplicit1 Study: Hepatoselective Glucokinase Activation Via Ttp399 For The Treatment Of Type 1 Diabetes Mellitus

Klara R. Klein [1], Jennifer L. R. Freeman [2], Imogene Dunn [2], Chris Dvergsten [2], M. Sue Kirkman [1], John B. Buse [1], and Carmen Valcarce [2]

  1. Division of Endocrinology and Metabolism, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  2. vTv Therapeutics LLC, High Point, NC, USA

 

Discussion

Sex And Age-based Differences In Fasting Homa-ir Among Patients With Mild To Moderate Myalgic Encephalomyelitis/ chronic Fatigue Syndrome: A Novel Approach To Glucose/insulin Anomalies

Rahaf Al Assil [1], Selena Tianyi Shao [2]

  1. Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada
  2. Department of Public Health Sciences, Queen’s University, Kingston, ON, Canada

 

Discussion

Rgs9 Is Required For Glucose-induced Beta-cell Proliferation In Ex Vivo Pancreatic Islets

Scott Campbell [1], Anais Szpigel [1], Caroline Tremblay [1], Julien Ghislain[1], Vincent Poitout [1]

  1. Centre de Recherche du CHUM, Montreal, Quebec, Canada

 

Discussion

Deficiency Of Gsa In Pancreatic A Cells Leads To Enlarged Islets

Akiko Taira-Sunahara [1], Hui Sun [1], Satoshi Sunahara [1], Min Chen [1] and Lee Weinstein [1]

  1. Metabolic Diseases Branch and
  2. Mouse Metabolism Core Laboratory, NIDDK, NIH, Bethesda, MD 20892 USA

 

Discussion

 

Ppm1k Regulates Pancreatic βeta-cell Physiology Via Mtor Independent Regulation Of Ribosomal Protein S6 Phosphorylation

Yann Deleye [1], Jacob Herring [2], Kavan H. Hess [2], Brennan Leininger [2], Robert W. McGarrah [1], Jeffery S. Tessem [2] and Phillip J. White [1]

  1. Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA; Departments
  2. Nutrition, Dietetics and Food Science Department, Brigham Young University, Provo, UT 84602, USA

 

Discussion

3d Fib-sem Reconstruction Of Microtubule-organelle Interaction In Whole Primary Mouse Beta Cells

Andreas Müller [1,2,3], Deborah Schmidt [4,5], C. Shan Xu [6], Song Pang [6], Joyson Verner D’Costa [1,2,3], Susanne Kretschmar [7], Carla Münster [1,2,3], Thomas Kurth [7], Florian Jug [4,5,8], Martin Weigert [9], Harald F. Hess [6], Michele Solimena [1,2,3,5]

  1. Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
  2. Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the TU Dresden, Dresden, Germany
  3. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
  4. Center for Systems Biology Dresden (CSBD), Dresden, Germany
  5. Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
  6. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
  7. Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, TU Dresden, Dresden, Germany
  8. Fondazione Human Technopole, Milano, Italy
  9. Institute of Bioengineering, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland

 

Discussion

Microvessels Support Engraftment And Functionality Of Hesc-derived Pancreatic Progenitors And Human Islets In Diabetes Models

Yasaman Aghazadeh [1,2], Frankie Poon [3], Farida Sarangi [1], Xuetao Sun [2], Rupal Hatkar [2], Sara Nunes Vasconcelos [2,4], Maria Cristina Nostro [1,3]

  1. McEwen Stem Cell Institute, University Health Network, Toronto
  2. Toronto General Hospital Research Institute, University Health Network, Toronto
  3. Department of Physiology, University of Toronto, Toronto
  4. Institute of Biomedical Bioengineering, University of Toronto, Toronto

 

Discussion

 

Loss Of The Diabetes Risk Gene Zmiz1 Impairs Insulin Secretion And Beta-cell Function

Tamadher A. Alghamdi [1], Nicole A. J. Krentz [2], Nancy Smith [1], Aliya F. Spigelman [1], Zijie Sun [3], Anna L. Gloyn [2,4], Patrick E. MacDonald [1]

  1. Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
  2.  Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
  3. Beckman Research Institute, City of Hope, Duarte, CA, USA
  4. Stanford Diabetes Research Centre, Stanford University, Stanford, CA, USA

 

Discussion

Deletion Of 14-3-3ζ In Pancreatic β-cells Potentiates Glucose-stimulated Insulin Secretion

Yves Mugabo [1,2,4], Maria Galipeau [3], Ju Jing Tan [1,2], Evgenia Fadzeyeva [5], Erin E. Mulvihill [5], Ryszard Grygorczyk [1,2], and Gareth E. Lim [1,2,4]

  1. CRCHUM, Montréal, QC H2X 0A9, Canada
  2. Department of Medicine, Université de Montréal, QC H3T 1J4, Canada
  3. Department of Biochemistry, Université de Montréal, QC H3T 1J4, Canada
  4. Montreal Diabetes Research Center, Montreal, QC H2X 0A9, Canada
  5. University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada

Rationale: Pancreatic β-cells continuously sense levels of blood sugar and secrete insulin to maintain normoglycermia1,2,3. In β-cells, ATP couples glucose sensing to insulin granule exocytosis, whereby it triggers closure of ATP-sensitive potassium channels to promote an increase in intracellular calcium, and ultimately insulin secretion1,2. 14-3-3 proteins, and in particular 14-3-3ζ, have been found to regulate ATP-synthase and mitochondrial respiration4,5, suggesting that they may regulate glucose-stimulated insulin secretion (GSIS). Thus, we hypothesized that 14-3-3 proteins may regulate mitochondrial function in β-cells and GSIS.

Findings: Pan-inhibition of 14-3-3 proteins in mouse and human islets potentiated ex- vivo GSIS, which correlated with glucose-dependent respiration and ATP production. To understand the role of 14-3-3ζ in β-cells, we generated β-cell specific knockout mice(β-KO). β-KO mice significantly enhanced insulin secretion following i.p. glucose (2 g/kg). In addition to increase Ins2, Mafa and Pdx1 mRNA levels, an increase in ATP production was detected in islets of β-KO mice, as well as in human islets treated with 14-3-3 inhibitors. Conclusions: These results suggest that 14-3-3 proteins, in particular 14-3-3ζ, have important roles in GSIS, through effects on ATP production.

Additionally, these data suggest that 14-3-3ζ inhibition may represent a promising target to enhance β-cell function and treat diabetes.

Discussion

Diminished Sphingolipid Metabolism, A Hallmark Of Future Type 2 Diabetes Pathogenesis, Is Linked To Pancreatic β-Cell Dysfunction

Saifur R. Khan [1, 2], Yousef Manialawy [1, 2], Andreea Obersterescu [1], Brian J. Cox [1, 3], Erica P. Gunderson[4], Michael B. Wheeler [1, 2]

  1. Department of Physiology, University of Toronto, ON, Canada
  2. Advanced Diagnostics, Metabolism, Toronto General Research Institute, ON, Canada
  3. Department of Obstetrics and Gynaecology, University of Toronto, ON, Canada
  4. Kaiser Permanente Northern California, Division of Research, Oakland, CA, USA

 Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women.

Methods: To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history.

Women who were non-diabetic 6–9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics and lipidomics were performed on baseline plasma to identify metabolic pathways, their genetic predispositions, and a predictive signature associated with T2D risk.

Results: Diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic β cell function.

Conclusion: These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to β cell dysfunction and T2D risk.

Discussion

 

Sex And Insulin Resistance Define A Human Cell Autonomous Supernetwork Of Protein Phosphorylation

Nida Haider [1], Jasmin Lebastchi [1,2], Ashok Kumar Jayavelu [3], Thiago M. Batista [1], Hui Pan [4], Jonathan M. Dreyfuss [4], Ivan Carcamo-Orive [5], Joshua W. Knowles [5], Matthias Mann [3], C. Ronald Kahn [1,6]

  1. Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA. 02215, USA
  2. Division of Endocrinology, Brown, Alpert Medical School, Providence, RI. 02903, USA
  3. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
  4. Bioinformatics and Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA. 02215, USA
  5. Division of Cardiovascular Medicine, Cardiovascular Institute and Diabetes Research Center, Stanford University School of Medicine, Stanford, CA. 94305, USA
  6. Lead contact

Insulin resistance in muscle precedes and predicts type 2 diabetes in offspring of diabetic parents and is also observed in ~25% of the general population.

However, whether these changes represent cell autonomous defects or are secondary to changes in circulating factors is unclear. The aim of this study was to uncover the cell autonomous determinants of insulin resistance on cellular signaling using human induced pluripotent stem cell-derived myoblasts (iMyos).

We have utilized iMyos from 10 insulin sensitive and 10 insulin resistant non-diabetic individuals as assessed using the steady-state plasma glucose approach. Here, we show that iMyos from insulin resistant non-diabetic individuals show impaired insulin signaling, defective insulin-stimulated glucose uptake and glycogen synthase activity compared to insulin sensitive individuals.

Global phosphoproteomics uncovered a large network of altered protein phosphorylations in insulin resistance, most outside the canonical insulin-signaling cascade.

Surprisingly, we also observed striking differences in the phosphoproteomic signature in male versus female subjects in DNA/RNA processing, GTPase signaling, and SUMOylation/ubiquitination associated with functional differences in their downstream actions.

These findings reveal cell autonomous mechanisms underlying insulin resistance and demonstrate a previously unrecognized supernetwork of signaling differences in males and females, which can contribute to sex-based differences in normal physiology and disease.  

 

Discussion

Physical Activity And Nerve Structure And Function In Patients With Longstanding Type 1 Diabetes

Evan J. H. Lewis [1], Leif E. Lovblom [1], Sebastien Lanctot [1], Marina Cardinez [2], Daniel Scarr [1], Genevieve Boulet [2], Alanna Weisman [1,2], Julie A. Lovshin [2,3], Yuliya Lytvyn [3], Hillary A. Keenan [4], Michael H. Brent [5], Narinder Paul [6], Vera Bril [7], David Z.I. Cherney [3], Bruce A. Perkins [1,2]

  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. Division of Nephrology, Department of Medicine, University of Toronto. Toronto, Ontario, Canada.
  4. Research Division, Joslin Diabetes Center. Boston, Massachusetts, USA.
  5. Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto. Toronto, Ontario, Canada.
  6. Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network. Toronto, Ontario, Canada.
  7. 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.

While physical activity (PA) can improve glycemic control, the effect on nerve structure and function is unclear.

We aimed to determine the relationship between PA and peripheral nerve structure and function in longstanding T1D.

Data from 75 participants was collected as part of the Canadian Study of Longevity in T1D. Extensive phenotyping for complications was performed and patient-reported variables were included along with self-reported PA from the preceding 12-months. The weekly mean PA time was 156 ± 132 min and 35(47%) reported ≧150 minutes/week. PA time was associated with a greater cooling detection threshold (r=0.24; p=0.043), higher peroneal and sural amplitude (r=0.36; p=0.0017, rs=0.26; p=0.024) and conduction velocity (rs=0.28; p=0.015, r=0.23; p=0.050). Vibration perception threshold at the toe was inversely associated with PA (r=-0.31; p=0.025), whereas there was no association at the finger.

Linear regression for NCS, adjusting for age and A1c, showed that for each 30 min of PA there was an 0.09 mv higher peroneal amplitude (p=0.032) and 0.048 ms lower peroneal F-wave latency (p=0.022). In individuals with longstanding T1D, PA is associated with substantially better large nerve fiber function in the lower limbs and some better measures of small nerve fiber function.  

 

Discussion

Beta-cell Gs Is Essential For Insulin Secretion And Euglycemia

Megan E. Capozzi [1], Sarah M. Gray [1], Jepchumba Koech [1], David A. D’Alessio [1,2], Jonathan E. Campbell [1,2,3]

  1. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
  2. Department of Medicine, Duke University, Durham, NC, USA
  3. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

The GLP-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are critical to generate the full extent of insulin secretion by beta-cells. The canonical signaling pathway used by these incretin receptors to stimulate insulin secretion is through Gs activation of cAMP levels (1).

However, there are reports of additional pathways independent of Gs (Gq, beta-arrestins) by which incretin receptors can induce insulin secretion (2-4). To directly test the importance of Gs in beta-cells, we generated beta-cell specific, temporally controlled Gs knockout mice (Gnasbcell-/-).

We compared these mice to an additional model with beta-cell specific deletion of GLP-1R, GIPR, and the glucagon receptor (GCGR) (Glp1r;Gipr;Gcgrbcell-/- mice), the predominant GPCRs that signal via Gs/cAMP in beta-cells.

We observed that Gnasbcell-/- mice were severely hyperglycemic and unable to increase insulin secretion or lower glycemia in response to any incretin peptides in vivo or in isolated islets ex vivo.

Interestingly, Glp1r;Gipr;Gcgrbcell-/- mice displayed normal glucose tolerance in vivo despite a lack of insulin secretion to incretin peptides, suggesting a compensatory response that maintains b-cell function. Together, these findings demonstrate the essential nature of Gs for incretin receptor signaling, b-cell function, and the maintenance of euglycemia in mice.

 

Discussion

 

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