Research Profile

Rates of Type 2 diabetes mellitus (T2DM) have quadrupled over the past 40 years and affects more than 400 million people. Incretin mimetics, which act to potentiate glucose-stimulated insulin secretion (GSIS), are a widely used therapeutic strategy to manage T2D. The two incretins glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic peptide (GIP) are collectively responsible for as much as half the insulin response to a carbohydrate meal. Incretins generally do not stimulate insulin release in the absence of glucose co-stimulation, which adds to their excellent safety profile. However, therapeutics based on GIP lose their efficacy in T2D for reasons that are not well understood. Furthermore, incretin mimetics based on GLP-1R agonists (exendin-4, Exenatide?; liraglutide, Victoza?) fail to lower blood sugar in many patients, and cause nausea and discomfort in others, complicating adherence. We have discovered that the kinetics of cAMP signaling downstream of different beta cell incretin receptors is remarkably different, and differ between individual beta cells within the same islet. There are several reasons that potentially contribute to these differences, including potential differences in the involvement of downstream enzymes that control the rate of cAMP generation and differences in the kinetics of incretin receptor trafficking. Related to the possible differences in incretin receptor trafficking, we have linked the recycling of incretin receptors to a sorting protein known to control GPCR trafficking that has not previously been linked to incretin receptor trafficking in beta cells. We are investigating whether common natural human variants in this protein influence the recycling of human incretin receptors differently in different people. Understanding the differences between GIPR and GLP1R signaling is key to understand why current incretin therapies fail to provide benefit to a subset of T2D patients. If we understand why, this opens new opportunities to personalize incretin mimetic therapies to those patients currently do not benefit.

We widely prescribe incretin mimetics or drugs that delay the degradation of our own incretin hormones. While these drugs have become staples in the clinical management of T2D, and newer versions of these drugs such as Trizepatide have recently received FDA approval. Nevertheless, there are major gaps in our understanding of the mechanisms of their actions. For example, we know that both incretins GIP and GLP-1 are capable of stimulating insulin secretion when glucose exceeds the beta cell threshold. Nevertheless, therapies based on the actions of these incretins are not effective in managing glucose in all patients with T2D. Therapies based on GIP-mimetics in particular fail to provide clinically meaningful benefit in a subset of T2D patients, for reasons that are unclear. If we understand why incretin-based therapies work for some, but not all patients, we can modify existing incretin mimetics to tailor to individual patients. This is particularly true if we can learn to predict the genetic determinants that predispose patients to benefitting from certain incretin-based therapeutic strategies. This could open new opportunities to prescribe existing incretin mimetic therapies to those patients who likely benefit most, while we work to advance new incretin-based strategies tailored to patients who do not benefit from existing incretin drugs.

My start in the field of diabetes was a serendipitous one. I had focused my graduate work on the evolution of endocrine and immune systems, which earned me an invitation to join the group of the late Dr. Wylie Vale at the Salk Institute as a postdoctoral fellow. Long before I joined his lab, Dr. Vale together with Dr. Roger Guillemin rewrote the physiology textbooks by establishing in a series of heroic experiments that our hypothalamus releases a series of peptide hormones, including somatostatin, that control the activity of our pituitary gland, work for which Dr. Guillemin was a co-recipient of the Nobel Prize for Physiology and Medicine. Arguably the most famous of these hormones is Corticotropin Releasing Hormone (CRH), which kick-starts our endocrine stress response and was discovered by Wylie in 1981. When I joined his lab 25 years later, the focus of my studies became the role of CRH and urocortin3, a peptide hormone related to CRH that we had just discovered, but whose function was poorly understood. As one of the main sites of expression for urocortin3 were the beta cells in the pancreas, pancreatic islets became the source of my investigations. I had assumed at the time that our understanding of the pancreas would be nearly complete; after all hundreds of labs had studied this organ over decades. Instead, over the course of my independent career to date I have been able to add new insights into pancreas function, including the mechanism of feedback inhibition that prevents excess insulin release from beta cells via a novel feedback loop that involve Ucn3 and somatostatin. Both of these peptides, as well as related peptide hormones included glucagon, GLP-1 and GIP, mediate their effects on hormone secretion via the modulation of cAMP levels in pancreatic islet cells. It turns out that considerable heterogeneity exists between the kinetics of cAMP induced by each of these peptide hormones in the same beta cells and we do not know why. The receipt of this ADA Innovative Basic Science Award provides crucial support to be able to unravel the mechanism underlying these differences between individual incretin or incretin-like hormones and how they relate to the efficacy of their islet actions.

I think the emergence and application of new technologies such as genetically encoded sensors for calcium, cAMP and other second messengers will enable us to quantify the heterogeneity of incretin responses at multiple levels. Heterogeneity between different incretins that are commonly assumed to signal via the same second messenger pathways. Heterogeneity amongst individual beta cells within the same islet. And heterogeneity between individual subjects that plays into the variable efficacy that incretin mimetics have in different people with T2D. Our ability to deliver these genetically encoded biosensors efficiently and directly to human islets and islet cells opens up questions that were until recently not attainable. Validation of the insights we generate using these high precision tools in rodent models to the human condition has become possible with the much improved access to human islets because of organizations such as nPOD and IIDP. Coupled to continuing advances in next generation sequencing and the rapidly expanding Crispr toolbox to resolve pancreas-specific questions will enable us to conduct experiments that will allow us to really understand the mechanisms that control beta cell responses in response to different incretins and incretin-like drugs. I firmly believe that this allows us to be more effective in finding solutions that ultimately help determine which patients benefit from which diabetes medications.