Diabetes

Stern lab research aims to understand the role of glucagon signaling in the pathogenesis of obesity, type II diabetes mellitus, and aging. Glucagon Signaling in Obesity and Type II Diabetes: Insulin resistance and elevated insulin are key to the metabolic disturbances in type II diabetes mellitus (T2DM). Yet, elevated glucagon, common to diabetes, may be equally important in the metabolic abnormalities in T2DM. Dr. Stern has shown that nutritional state differentially affects glucagon secretion in obesity. In turn, the glucagon:insulin ratio is dysregulated in obesity. Current Stern lab research aims to understand the metabolic consequences of a dysregulated glucagon response to fasting and re-feeding. Glucagon Signaling and Aging: More than 25% of the U.S. population greater than 65 years old has Type II diabetes mellitus, representing the highest prevalence of diabetes of any age group. Most research aimed at understanding the consequences of obesity in aging have focused on insulin and downstream signaling cascades, overlooking a potential role for glucagon. Given that many prominent diabetes treatments target glucagon or glucagon signaling pathways, it is essential to understand the role of glucagon in aging. Stern lab research examines 1) the tissue specific effects of glucagon signaling, 2) the role of glucagon signaling in obesity-accelerated aging, and 3) the role of glucagon signaling in healthspan extension promoted by calorie restriction. This work will close a significant gap in our understanding of how glucagon alters aging, while allowing us to assess the potential risks associated with inhibition of glucagon signaling. Other Stern Lab Research Foci: Sleep disturbance and metabolic dysfunction Obesity related cancer development and progression

CURRENT AND FUTURE RESEARCH PLANS Renquist lab research can be broken into 4 foci that target the pathophysiologies of obesity (insulin resistance, hypertension, and cancer) or aim to better understand energy balance (food intake and energy expenditure) to combat the obesity epidemic. 1) Metabolic Syndrome: Excess hepatic lipid accumulation, common in obesity, is directly related to the incidence and severity of Type II Diabetes Mellitus and hypertension. Hepatic lipid accumulation depolarizes the hepatocyte. To understand the role of hepatocyte membrane potential in mediating the pathophysiologies of obesity, we use tissue specific knockout, pharmacological, and mouse models with adenovirus induced ion channel expression. Through this research we have found that obesity changes hepatocyte neurotransmitter release to affect activity of the hepatic vagal afferent nerve. This research has been supported by competitive grants from the Arizona Biomedical Research Commission and The American Heart Association. Primary hypothesis: Hepatic membrane potential is communicated through the peripheral nervous system to affect serum glucoregulatory hormones, peripheral tissue glucose uptake, and blood pressure. 2) Targeted cell ablation. In two grants funded by Found Animals Foundation, we have focused on inducing permanent sterility by selectively delivering a GnRH targeted toxin to GnRH receptive gonadotropes (A strategy developed by Terry Nett, CSU). The cancer field is demanding delivery systems that improve ligand or antibody directed therapeutics. Many cancers (e.g. breast, ovarian, melanoma, pancreatic, and colorectal) express GnRH receptors. Thus, effective GnRH-targeted toxins can also be directed to target cancer. Two issues have limited the application of GnRH targeted toxins. First, the potential for effects in ‘non-targeted’ GnRH expressing cells. Second, the endosomal sequestration of internalized toxins. By separately targeting an endosome disrupter with one G-protein coupled receptor (GPCR) ligand and the toxin with another GPCR ligand, we eliminate both limitations. By using this modification of the delivery system to maximize endosome escape, we have increased in vitro efficacy more than 1,000,000,000 times. This improvement in efficacy helped our research team to secure a DoD grant aimed applying this strategy to prostate cancer. Importantly, GnRH targeted doxorubicin has recently been approved by the FDA for treatment of cancer. We fully expect that our targeted endosome disrupters would enhance the efficacy of this FDA approved treatment while improving specificity and decreasing the potential for side effects. Primary hypothesis: Optimizing GnRH-toxin conjugates to enhance endosome escape will allow for selective ablation of target cells encouraging the development of improved ligand directed chemotherapeutics and an injectable sterilant 3) Control of food intake and milk production. Understanding the mechanisms that regulate food intake under differing environmental conditions provides opportunities to pharmacologically manipulate phagic drive to treat obesity. Heat stress depresses food intake dependent on histamine signaling. My lab aims to understand how the neuroendocrine/endocrine suppression of visceral blood flow, a physiological adaptation to encourage heat loss by increasing cutaneous blood flow, depresses phagic drive. This USDA NIFA funded project is focused on the dairy cow as our target species, but we employ mouse models and see this as an opportunity to better understand the control of food intake. We use mice that lack histamine receptors to focus on the role of central nervous system histamine signaling in the control of blood flow to the digestive tract and mammary gland. Therapeutics aimed at suppressing visceral blood flow may have application in addressing the obesity epidemic. Primary hypothesis: A decrease in blood flow to the digestive tract and mammary gland is responsible for a decrease in food intake and milk production common to heat stress. 4) Energy Expenditure. I developed an assay to measure the metabolic rate of embryonic zebrafish for application in drug and gene discovery. Since joining the University of Arizona, I have secured funding from USDA Western Regional Aquaculture Center and USDA NIFA funding to apply this assay to identify fish that are genetically superior for growth. We further showed that by measuring the metabolic rate of skeletal muscle biopsies from adult fish, we could identify the fish that were more feed efficient. Skeletal muscle biopsies from adult feed efficient fish were less metabolically active. Recently, we have initiated studies using tissue biopsies from homeothermic mice. This research will allow us to assess the tissue specific response to physiological perturbations (e.g. exercise, diet, obesity, fasting). Since insulin and leptin both increase energy expenditure, we expect that assays performed in tissue explant from homeotherms may allow for screening of insulin and leptin sensitizers in a more physiologically relevant model. We further propose this this assay could be a tool to assess insulin or leptin resistance and drug response in patient biopsies. Primary hypothesis: This assay designed for high throughput metabolic rate determination may be applied to improve growth and feed efficiency in production animals, improve drug development and gene discovery in biomedical models, or personalize medicine for patients. Keywords: Obesity, Metabolic Syndrome, Cancer

I have spent the past 21 years of his research career studying the properties of insulin-secreting tissue and their relationship to viability and function. I have worked on the development and validation of assays (especially ones based on mitochondrial function such as oxygen consumption rate) for the real-time, objective assessment of islet quality prior to transplantation. In particular the assay based on oxygen consumption rate has been recently validated based on its ability to predict diabetes reversal in mice and clinical human islet auto transplants in patients with chronic pancreatitis. I have used these assays along with engineering principles to optimize the islet transplantation process from pancreas procurement to islet infusion to the recipient. My group has also developed tools for the real time non-invasive assessment of pancreases and other organs during preservation, and i am actively involved in research for improvements in organ preservation technology aiming at extending the allowable time window from procurement to transplantation and the utilization of organs from expanded criteria donors without compromising clinical outcomes. I have had continuous NIH funding for the past 7 years in the area of pancreas preservation and I have spearheaded the effort for the development of humidified oxygen gas perfusion (persufflation) of the pancreas using novel technology for portable in situ oxygen generation from water via electrochemistry. I am also actively collaborating with leaders in the liquid perfusion field on NIH sponsored projects aiming at improving oxygenation.

Sean W. Limesand, PhD, is an Associate Professor in the School of Animal and Comparative Biomedical Sciences at the University of Arizona in the College of Agriculture and Life Sciences. He is also a member of the UA’s BIO5 Institute and Department of Obstetrics and Gynecology. Dr. Limesand is nationally and internationally recognized for his work studying fetal endocrinology and metabolism in pregnancy and in pregnancies compromised by pathology such as intrauterine growth restriction and diabetes. His research is focused on defining developmental consequences resulting from a compromised intrauterine environment. Specifically, he is focused on fetal adaptations in insulin secretion and action that when altered in utero create lifelong metabolic complications. Dr. Limesand has lead the charge on prenatal origins of –cell dysfunction as the Principal Investigator for a number of federal and foundation grant awards and published more than 40 peer-reviewed articles on topics related to this research. Keywords: Diabetes, Pregnancy, Perinatal Biology

Yann C. Klimentidis, PhD, is an Associate Professor in the Department of Epidemiology and Biostatistics in the Mel and Enid Zuckerman College of Public Health at the University of Arizona. His research centers on improving our understanding of the links between genetic variation, lifestyle factors, metabolic disease, and health disparities. In the past, he has used measures of genetic admixture and genomic tests of natural selection to understand the genetic basis of population differences in disease susceptibility. His most recent work examines the use various statistical approaches for the analysis of high-dimensional genetic data for improving prediction of genetic susceptibility to type-2 diabetes. In addition, his work examines gene-by-lifestyle interactions in type-2 diabetes, as well as understanding the causal links between metabolic traits such as dyslipidemia and type-2 diabetes. Keywords: Genetics, epidemiology, Cardiometabolic disease, Physical activity

Dr. Bonnie Hurwitz is an Assistant Professor of Biosystems Engineering at the University of Arizona and BIO5 Research Institute Fellow. She has worked as a computational biologist for nearly two decades on interdisciplinary projects in both industry and academia. Her research on the human/earth microbiome incorporates large-scale –omics datasets, high-throughput computing, and big data analytics towards research questions in “One Health”. In particular, Dr. Hurwitz is interested in the relationship between the environment, microbial communities, and their hosts. Dr. Hurwitz is well-cited for her work in computational biology in diverse areas from plant genomics to viral metagenomics with over 1200 citations

Identify and understand determinants of behavioral, weight-related, and metabolic outcomes in children, adolescents, and families, including how and why so-called “obesogenic behaviors” (unhealthy dietary habits, sedentary behaviors) are initiated and sustained. Develop and test novel approaches to motivate healthy lifestyle changes in children, adolescents, and families, including development, testing, and assessment of face-to-face and mobile device-based interventions.

Janet L. Funk, MD, FACP, is a Professor of Medicine at the University of Arizona College of Medicine. Dr. Funk leads a federally-funded research team that is focused on identifying new treatments for chronic diseases that have strong inflammatory components, including metabolic bone diseases, such as arthritis, bone tumors and osteoporosis, and cardiovascular diseases, including diabetes. Recent studies have focused on the use of medicinal plants that have historically been used to treat inflammatory conditions, such as arthritis. By understanding whether and how these plants work in blocking inflammatory pathways in the body, we are striving to harness the power of nature and the wisdom of our ancestors to indentify new treatments for diseases that are common in our modern society. Discoveries we have made at the lab bench have allowed us to move forward into the clinics, building upon the old to discover the new.

The broad goal of research in our laboratory is to understand how inhibitory inputs influence neuronal signaling and sensory signal processing in the healthy and diabetic retina. Neurons in the brain receive inputs that are both excitatory, increasing neural activity, and inhibitory, decreasing neural activity. Inhibitory and excitatory inputs to neurons must be properly balanced and timed for correct neural signaling to occur. To study sensory inhibition we use the retina, a unique preparation which can be removed intact and can be activated physiologically, with light, in vitro. Thus using the retina as a model system, we can study how inhibitory synaptic physiology influences inhibition in visual processing. This intact system also allows us to determine the mechanisms of retinal damage in early diabetes. Keywords: neuroscience, diabetes, vision, electrophysiology, light

An overwhelming obesogenic environment, the backdrop to a globally-expanding western lifestyle, has led to a ‘diabesity’ pandemic that represents a costly and urgent global health crisis. The success of gastric bypass surgery and gut-derived diabetes/obesity treatments highlight the major role of the gastrointestinal (GI) tract in metabolic diseases. My research aims to better understand the complex intestinal signaling mechanisms involved in the regulation of energy and glucose homeostasis in physiological and pathophysiological states. My work to date has focused on elucidating how nutrients are sensed by the gut, and how changes in these mechanisms lead to a reduction in food intake and/or a reduction in endogenous hepatic glucose production via a gut-brain neuronal axis. More specifically, my work focused on alterations in intestinal detection of fats and carbohydrates and paracrine gut peptide signaling (CCK and GLP-1) during high-fat feeding, the influence of the gut microbiota on these pathways, and how these contribute to the development of obesity and diabetes. As such, I plan to continue to decipher this complex interaction between gut-sensing mechanisms and the gut microbiota, as a better understanding of these pathways are crucial for the development of successful, gut-targeted therapeutic options in the treatment of metabolic diseases. Given the rapid rise of obesity/diabetes in only several generations, obesity cannot be attributed to genomic alterations, but more likely results from a complex set of interactions between genetic risk factors and environmental changes. Importantly, studies suggest the development of adult phenotypes (obesity and diabetes) results from early, transient environmental interactions, coined ‘early life programming,’ which has been partly attributed to epigenetic changes. Gut microbiota development is also crucial during this time, and differing modes of development (i.e. maternal microbiota, type of delivery, breastfeeding vs. formula feeding, etc.) can lead to later metabolic dysfunctions. Therefore, using animals models prone to the development of obesity and/or diabetes from polygenetic inheritance and transgenerational, epigenetic, changes in gene activity, I am studying how varying environmental factors (diet, housing, exercise, pre/post-natal environment, etc.) result in differential effects on the gut microbiota, intestinal nutrient sensing, and whole body energy and glucose homeostasis. A better understanding of how early changes in the gut microbiota can impact the development of metabolic regulation, and vice versa, is vital for developing successful strategies to curb diabetes and obesity.