We want to build up a complete picture of all the key steps, from sensing of glucose and other signals to secretion of insulin by pancreatic beta cells. We want to understand how the individual steps are coordinated and finally relate impairments in those processes to the pathogenesis of diabetes.
We primarily focus on the basic biophysical mechanisms underlying insulin secretion from pancreatic beta-cells. This is of basic physiological interest and important for understanding the causes and treatment of type 2 diabetes, which generally arises from a combination of defects in insulin secretion and insulin action. The scope or our research ranges from the individual beta cell to the electrical and chemical coupling of beta cells within the islets of Langerhans (micro-organs within the pancreas consisting of hundreds to thousands of beta cells as well as other endocrine cells) and to the coordination of the islets in the pancreas (hundreds in rodents to hundreds of thousands in humans) that produce pulsatile insulin secretion observed in the plasma. In addition to the wide range of spatial scales, we are interested in temporal behavior which consists of oscillations on time scales ranging from milliseconds (action potentials), to tens of seconds (bursts of electrical activity), to minutes (corresponding to the plasma insulin pulses). Finally, this core rhythm-generating system is modulated by a number of signaling pathways involving insulin itself, cyclic adenosine monophosphate, and protein kinase C.
The primary focus of our research is supported by mathematical modeling of electrical activity and calcium handling in neurons and endocrine cells in the pituitary and hypothalamus. This work aids in the search for general principles and mechanisms as well as for the specificities that distinguish one cell type from another.
The main tool we use in both beta cell and general neuroendocrine work is mathematical modeling, most typically based on ordinary differential equations similar to those pioneered by Hodgkin and Huxley (Nobel Prize winners in 1952) to explain action potentials in neurons. A major addition to their models is the primary role of calcium, which is both a mediator of membrane depolarization and a second messenger that triggers secretion and modulates a variety of signaling proteins. Among the latter, we are particularly interested in models of calcium-triggered exocytosis downstream of the calcium entry resulting from electrical activity in both nerve terminals and in beta cells. In all of our work, close collaboration with experimentalists is critical, with multiple iterations of modeling, prediction, and testing of model-generated hypotheses leading to progressive refinement of knowledge and understanding.
This work has led to an appreciation of the relationship between calcium entry and calcium storage in internal organelles, particularly the endoplasmic reticulum, and how the two membrane systems communicate with each other. Two examples of the latter are cytosolic calcium levels themselves and interactions mediated by the store content, such as putative store operated channels.
In addition to impaired secretion of insulin, impaired action of insulin on target tissues is a key contributor to type 2 diabetes. Dysfunction in fat storage has been implicated in the pathogenesis of insulin resistance. Although both insulin resistance and type 2 diabetes are generally associated with obesity, most overweight and obese individuals do not develop diabetes, and some lean individuals are insulin resistant. Our aim is therefore to distinguish between the acquired characteristic of obesity and a possible underlying genetic defect at the level of the fat-storing adipocyte, and their respective contributions to diabetes.
Additionally, although insulin action to promote glucose uptake quantitatively is most important in muscle, it is known that disturbances of adipocyte function can lead to insulin resistance in the muscle tissue. Thus, adipocytes seem to have a central role in the disease process, but the nature of their involvement needs further clarification.
Applying our Research
The basic theoretical work we do helps guide experiments, making them more efficient by providing a roadmap. Advances in understanding insulin secretion in health and disease will contribute to making more intelligent interventions to prevent and treat disease. It will also be a landmark success in integrating knowledge on many levels to understand a complex system of biomedical importance.
Need for Further Study
How does beta cell dysfunction lead to diabetes? How do cells regulate their properties to stay within the functional range in the face of changing conditions?