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Matthew Merrins

Matthew J. Merrins

Ph.D. in Physiology, University of Michigan
Assistant Professor, Dept. of Medicine- Endocrinology, Diabetes & Metabolism; Depart. of Biomolecular Chemistry
merrins@wisc.edu
http://bmolchem.wisc.edu/merrins.htm


Pancreatic β Cell Metabolism in the Aged and Obese

My lab is focused on understanding oscillatory metabolic signaling in the pancreatic islet and its deficiency in type 2 diabetes. The incidence of type 2 diabetes is disproportionally high in the elderly, over 25%, by comparison to 10% in the adult population. Although insulin resistance and β cell mass have been heavily studied as contributors to impaired glucose tolerance and diabetes in the elderly, the underpinnings of β cell failure remain unclear. My lab is focused on understanding oscillatory metabolic signaling in the pancreatic islet and its deficiency in type 2 diabetes. The incidence of type 2 diabetes is disproportionally high in the elderly, over 25%, by comparison to 10% in the adult population. Although insulin resistance and β cell mass have been heavily studied as contributors to impaired glucose tolerance and diabetes in the elderly, the underpinnings of β cell failure remain unclear.

One potential strategy to discover the molecular drivers of aging relies on embracing the inherent heterogeneity of aging phenotypes - in this case the observation that genetically identical mice raised in homogenous environments can have different susceptibilities to age and diet. Humans, as well, can age and remain obese for years without becoming diabetic. By associating these organismal outcomes with cell level physiological readouts, phenotypic heterogeneity can be exploited to elucidate how β cells adapt to these challenges and why compensation succeeds or fails.

My lab specializes in single-cell approaches-- principally live-cell imaging and electrophysiology -- and since the lab's inception we have developed a number of exciting tools which have given us new insights into diabetes pathophysiology. One example is fluorescence lifetime imaging (FLIM) of NAD(P)H, which allows us to distinguish metabolic activity in each subcellular compartment of the pancreatic beta cell, including the mitochondria. Using NAD(P)H FLIM and FRET imaging, we hope to understand the bidirectional communication between mitochondrial metabolism and the cell cycle machinery, mediated by cyclin dependent kinases. We are also focused on characterizing a number of mitochondrial proteins initially identified by RNA-seq as type 2 diabetes-associated loci; in this case, we are using Phy-PIF optogenetics to elucidate the mechanisms by which these proteins alter mitochondrial dynamics, metabolic oscillations, and insulin secretion.



Representative Publications
Kim, S. Y., Lee, J. H., Merrins, M. J., Gavrilova, O., Bisteau, X., Kaldis, P., Satin, L. S., & Rane, S. G. (2017). Loss of cyclin dependent kinase 2 in the pancreas links primary beta-cell dysfunction to progressive depletion of beta cell mass and diabetes. Journal of Biological Chemistry. Advance online publication.
View publication via DOI: DOI:10.1074/jbc.M116.754077

Merrins, M. J., Poudel, C., McKenna, J. P., Ha, J., Sherman, A., Bertram, R., & Satin, L. S. (2016). Phase analysis of metabolic oscillations and membrane potential in pancreatic beta cells. Biophysical Journal, 110, 691-699.
View publication via DOI: DOI:10.1016/j.bpj.2015.12.029

McKenna, J., Ha, J., Merrins, M. J., Sherman, A., Satin, L. S., & Bertram, R. (2016). Ca2+ effects on ATP production and consumption have key regulatory roles on oscillatory islet activity. Biophysical Journal, 110, 733-742.
View publication via DOI: DOI:10.1016/j.bpj.2015.11.3526

Gregg, T., Poudel, C., Schmidt, B. A., Dhillon, R. S., Sdao, S. M., Truchan, N. A., Baar, E. L., Fernandez, L. A., Denu, J. M., Eliceiri, K. W., Rogers, J. D., Kimple, M. E., Lamming, D. W., & Merrins, M. J. (2016). Pancreatic beta-cells from mice offset age-associated mitochondrial deficiency with reduced KATP channel activity. Diabetes, 65(9), 2700-10.
View publication via DOI: DOI:10.2337/db16-0432

Fontana, L., Cummings, N. E., Arriola Apelo, S. I., Neuman, J. C., Kasza, I., Schmidt, B. A., ... Merrins, M. J., Alexander, C. M., Kimple, M. E., & Lamming, D. W. (2016). Decreased consumption of branched chain amino acids improves metabolic health. Cell Reports, 16(2), 520-30.
View publication via DOI: DOI:10.1016/j.celrep.2016.05.092

Watts, M., Fendler, B., Merrins, M. J., Satin, L. S., Bertram, R., & Sherman, A. (2014). Calcium and metabolic oscillations in pancreatic islets: Who's driving the bus? Society for Industrial and Applied Mathematics Journal on Applied Dynamical Systems, 13, 683-703.
View publication via DOI: DOI:10.1137/130920198

Alejandro, E. U., Gregg, B., Wallen, T., Kumusoglu, D., Meister, D., Chen, A., Merrins, M. J., Satin, L. S., Liu, M., Arvan, P., & Bernal-Mizrachi, E. (2014). Maternal diet-induced microRNAs and mTOR underlie β cell dysfunction in offspring. Journal of Clinical Investigation, 124, 4395-4410.
View publication via DOI: DOI:10.1172/JCI74237

Johnson, J. S., Kono, T., Tong, X., Yamamoto, W. R., Zarain-Herzberg, A., Merrins, M. J., Satin, L. S., Gilon, P., & Evans-Molina, C. (2014). Pancreatic and duodenal homeobox protein 1 (Pdx-1) maintains endoplasmic reticulum calcium levels through transcriptional regulation of sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) in the islet β cell. Journal of Biological Chemistry, 289, 32798-32810.
View publication via DOI: DOI:10.1074/jbc.M114.575191

Merrins, M. J., Van Dyke, A. R., Mapp, A. K., Rizzo, M. A., & Satin, L. S. (2013). Direct measurements of oscillatory glycolysis in pancreatic islet β-cells using novel fluorescence resonance energy transfer (FRET) biosensors for pyruvate kinase M2 activity. Journal of Biological Chemistry, 288, 33312-33322.
View publication via DOI: DOI:10.1074/jbc.M113.508127

Merrins, M. J., Bertram, R., Sherman, A., & Satin, L. S. (2012). Phosphofructo-2-kinase/fructose-2,6-bisphosphatase modulates oscillations of pancreatic islet metabolism. PLoS ONE. 7, e34036.
View publication via DOI: DOI:10.1371/journal.pone.0034036

Merrins, M. J., Fendler, B., Zhang, M., Sherman, A., Bertram, R., & Satin, L. S. (2010). Metabolic oscillations in pancreatic islets depend on the intracellular Ca2+ level but not Ca2+ oscillations. Biophysical Journal, 99, 76-84.
View publication via DOI: DOI: 10.1016/j.bpj.2010.04.012

Nunemaker, C. S., Dishinger, J. F., Dula, S. B., Wu, R., Merrins, M. J., Reid, K. R., Sherman, A., Kennedy, R. T., & Satin, L. S. (2009). Glucose metabolism, islet architecture, and genetic homogeneity in imprinting of [Ca2+](i) and insulin rhythms in mouse islets. PLoS ONE, 4, e8428.
View publication via DOI: DOI:10.1371/journal.pone.0008428

Merrins, M. J., & Stuenkel, E. L. (2008). Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic beta-cells. Journal of Physiolology, 586, 5367-5381.
View publication via DOI: DOI:10.1113/jphysiol.2008.15847

D'Andrea-Merrins, M., Chang, L., Lam, A. D., Ernst, S. A., & Stuenkel, E. L. (2007). Munc18c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. Journal of Biological Chemistry, 282, 16553-16566.
View publication via DOI: DOI:10.1074/jbc.M610818200

Gladycheva, S. E., Lam, A. D., Liu, J., D'Andrea-Merrins, M., Yizhar, O., Lentz, S. I., Ashery, U., Ernst, S. A., & Stuenkel, E. L. (2007). Receptor-mediated regulation of tomosyn-syntaxin 1A interactions in bovine adrenal chromaffin cells. Journal of Biological Chemistry, 282, 22887-22899.
View publication via DOI: DOI:10.1074/jbc.M701787200

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