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Research in the Merrins laboratory is focused on metabolic signaling in the pancreatic islets of Langerhans. As metabolic sensors for the organism, pancreatic islets regulate blood glucose by releasing the hormones insulin and glucagon. Our main interests lie in two characteristic features of islet cells, (1) their ability to use metabolism as a signaling pathway to elicit hormone secretion, and (2) their ability to fine-tune hormone secretion via G-protein coupled receptors (GPCRs) that respond to extracellular cues from incretin hormones and neighboring islet cells. To understand how these processes adapt to environmental stress, it is essential to study islet metabolism in real time. To do so, we utilize mouse models of obesity/diabetes in combination with biochemistry, electrophysiology, and quantitative imaging. A central focus of the lab is the use of fluorescence microscopy (3D light-sheet imaging, optogenetics, and 2-photon microscopy) to monitor biochemical reactions as they occur in living cells.
3D imaging of lactate
in islet beta cells.
Time-lapse imaging of islet calcium oscillations that trigger insulin secretion.
Visualizing pancreatic islet metabolism with
2-photon NAD(P)H fluorescence lifetime imaging
Regulation of insulin and glucagon secretion by localized glycolytic ATP signaling
My lab uncovered the pivotal roles of pyruvate kinase and the mitochondrial phosphoenolpyruvate (PEP) cycle in beta-cell nutrient sensing and hormone secretion. We discovered a novel paradigm in which the ATP-generating enzyme pyruvate kinase is part of a plasma membrane associated glycolytic metabolon that closes KATP channels to initiate insulin secretion. Based on these findings, we proposed a revised model of nutrient-stimulated insulin secretion, the MitoCat-MitoOx model, which challenges the canonical model that mitochondrial ATP initiates insulin secretion. To test this new model, we are working to understand whether the subcellular location of glycolysis is essential for controlling the metabolic and electrical activity in alpha and beta cells.
How do age and obesity impact beta cell GPCR signaling and drug responsivity?
In addition to sensing nutrients such as glucose and amino acids, beta cells respond to external cues arising from gut incretin hormones and neighboring alpha cells that act via beta cell GPCRs located on the plasma membrane. Some of these receptors, such as the GLP-1 and GIP receptors, are major targets of anti-diabetes medications that are making national headlines (semaglutide, tirzepatide, etc.). How do the signaling pathways downstream of these GPCRs work? And how do they respond to age and obesity, the major risk factors for diabetes?
How do alpha cells sense nutrients and signal to neighboring beta cells?
Glucagon secretion is important for maintaining blood glucose during hypoglycemia, and for boosting insulin secretion from neighboring beta cells in the fed state. Yet, nutrient regulation of pancreatic alpha cells is poorly understood. A challenge is that alpha cells exhibit significant heterogeneity in their nutrient response, especially to amino acids, which are the primary metabolic fuels for for glucagon secretion. To understand the molecular basis of alpha cell nutrient sensing, we are using mouse genetics in combination with lightsheet microscopy to image alpha cell heterogeneity and islet cell-to-cell communication within the intact islet in real-time.
Postdoctoral, Ph.D. students, and undergraduates interested in pursuing research in the Merrins laboratory should contact Dr. Merrins directly at firstname.lastname@example.org
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