Position title: Beta cell biology and diabetes
VA Hospital, C-wing, Room C4134A
2500 Overlook Terrace
Madison, WI 53705
Cellular & Molecular Metabolism; Physiology
Research in the Merrins laboratory centers on the control of insulin release from the endocrine pancreatic islets of Langerhans, and how this is disrupted in diabetes. Our main interests lie in two features of nutrient metabolism in islet beta cells, (1) the ability to trigger pulses of insulin release, and (2) the ability to trigger cell proliferation, when the demand for insulin increases (e.g. during aging and obesity). These adaptive responses to environmental stress ultimately fail in diabetes.
To understand how this occurs, we utilize rodent models of obesity and aging in combination with biochemistry, patch clamp electrophysiology, and quantitative imaging. A central focus of the lab is the use of fluorescence microscopy (FRET, optogenetics, super-resolution and FLIM/2-photon) to monitor biochemical reactions as they occur in living cells. Our recent work is focused on the design and utilization of biosensors useful for real-time measurements of glycolysis, as well as the development of NAD(P)H FLIM as a non-invasive optical approach to study the TCA cycle and electron transport chain. Using these tools, we have been able to monitor metabolite production and second messenger signaling in a variety of pathways.
Regulation of insulin and glucagon secretion by pyruvate kinase
There are three isoforms of PK expressed in the pancreatic islets cells – constitutively active PKM1, and the dynamically regulated isoforms PKM2 and PKLR. We are working to understand how these crucial glycolytic enzymes control metabolic and electrical activity in alpha and beta cells.
Impacts of age and obesity on islet function
Currently we are studying the effects of two cyclin-dependent kinases, CDK1 and CDK2, on beta cell mitochondrial metabolism and electrical activity. These kinases are responsive to age and obesity, two major risk factors for diabetes.
Nutrient regulation of islet cell-cell communication: 3D lightsheet imaging and optogenetics
To understand precisely how nutrients control hormone secretion, the goals of this project are: 1) measure the activity of every islet cell, 2) manipulate the activity of every cell, and 3) computationally analyze/model these circuits and their failure in diabetes. We’ve constructed a 3D lightsheet microscope capable of recording biosensors in intact islets at speeds up to 10 Hz, while stimulating or repressing islet cell activity using optogenetics.