Early Pathogenesis of Cystic Fibrosis Related Diabetes
John Engelhardt, PhD, Professor and Chair, Department of Anatomy and Cell Biology, and Andrew Norris, MD, PhD, Professor of Pediatrics and Biochemistry and Associate Director of the FOE Diabetes Research Center (DRC), have just been awarded a three-year, $4.5M research grant from the NIH’s National Institutes of Diabetes, Digestive and Kidney Diseases. The project will investigate the changes that occur in insulin producing cells that are affected by cystic fibrosis (CF).
CF is a life-threatening genetic condition that affects roughly 30,000 Americans. Over half of persons with cystic fibrosis will develop diabetes. Drs. Engelhardt and Norris recently discovered that humans and ferrets with CF experience a loss of beta-cells early in life followed by a reappearance of beta-cells. These “reborn” beta-cells often function for decades before diabetes eventually occurs. What is not known is how the beta-cells are reborn. To address this knowledge gap, the group has created new genetic models that enable cells of the ferret to be tracked over time. Possibilities include that the “reborn” beta-cells come from prior beta-cells or alternatively come from other pancreatic structures. Answering this question could provide insight into how new beta-cells can be formed and might help identify new therapies for other forms of diabetes. The University of Iowa team includes pancreas expert Dr. Aliye Uc, Chief of Pediatric Gastroenterology, and Dr. Xingshen Sun, Research Assistant Professor. To further the research, the grant will support collaboration with Dr. Lori Sussel, beta-cell biology expert and Research Director at the Barbara Davis Center for Childhood Diabetes located in Denver, Colorado.
The Connection Between Sleep Disturbances and Cardiometabolic Disorders
Congratulations to Huxing Cui, PhD, Assistant Professor of Neuroscience and Pharmacology and member of the FOEDRC, who is the recent recipient of a National Institutes of Health R01 grant. Cui’s grant funded by the National Heart, Lung, and Blood Institute provides $2,267,270 through March of 2025. The proposal is entitled: “Decoding brain circuit underlying metabolic regulation of sleep-wake behavior”.
Sleep disorders and obesity are inextricably linked – poor sleep quality and short sleep duration increase the risk of developing obesity, while obesity is an independent risk factor for chronic sleep disruption (CSD) and excessive daytime sleepiness (EDS). Despite a clear bidirectional and pernicious association between obesity and sleep disorders, the brain pathways linking poor sleep and obesity are largely unknown. Dr. Cui’s research program seeks to identify critical neural circuits linking metabolic alterations to CSD and EDS. They recently discovered that a hormone secreted from fat cells called leptin, promotes wakefulness. Using sophisticated tools (chemogenetic activation) Cui demonstrated that when of a subset of GABAergic neurons in the lateral hypothalamic area (LHA) expressing leptin receptor (LepR) were activated, sleep was completely disrupted in mice. The overall objective of this research proposal is to clarify how leptin acts on key hypothalamic neurons to affect normal sleep-wake cycle. His project will use the most advanced neuroscience techniques to answer these questions, including genetic manipulation, using light to target specific neurons with a technique known as optogenetics/chemogenetics, in vivo fiber photometry, and electrophysiology coupled with chronic wireless recording of EEG/EMG in freely moving animals. The proposed research is significant because it is expected to not only advance and our understanding of hypothalamic regulation of sleep-wake behavior but also shed light on largely unknown mechanisms that connect metabolic disorders to sleep-wake regulation. The proposed research is also innovative because it utilizes a combination of state-of-art neuroscience techniques coupled with sophisticated physiological measurements to address an important yet largely under-investigated question – what are the underlying neural circuits mediating CSD and EDS in obesity? Such knowledge may ultimately lead to the development of a novel strategy to effectively manage sleep problems associated with obesity in human patients.
Using Electromagnetic Fields to Treat Diabetes Attracts NIH Funding
Postdoctoral research scholar, Calvin Carter, PhD, member of the FOEDRC and recipient of the prestigious FOE Bridge to the Cure award, in collaboration with other FOEDRC researchers, has discovered a safe new way to manage blood sugar non-invasively. Exposing diabetic mice to a combination of static electric and magnetic fields for a few hours per day normalized blood glucose levels and reversed insulin resistance.
“The more we look, the more the transfer of electrons seems to underlie diabetes,” Carter said in a Q&A with the American Diabetes Association (ADA). That search was borne out last fall, when Carter and MD/PhD student Sunny Huang, PhD, published ground-breaking findings in Cell Metabolism, showing that static electric and magnetic fields (EMFs) can be used to normalize blood glucose in diabetic mice. Reactions in the press were excited and swift to the researchers’ evidence that blood sugar and insulin sensitivity could be controlled non-invasively.
A comprehensive piece by Jennifer Brown in the most recent issue of Medicine Iowa https://medicineiowa.org/spring-2021/next-wave-diabetes-care looks at the discovery’s origins and its implications. A combination of curiosity, luck, and the Iowa culture of collaboration may lit the initial spark, but it was a series of faculty mentors that gave Carter and Huang the time and support to follow that spark’s trail. These faculty have since included E. Dale Abel, MD, PhD, director of the Fraternal Order of Eagles Diabetes Research Center (FOEDRC); Val Sheffield, MD, PhD, FOEDRC member and professor in the Division of Medical Genetics; and Eric Taylor, PhD, director of the FOEDRC’s Metabolomics Core Facility and associate professor of Molecular Physiology and Biophysics.
And now, with Abel and Sheffield as principal investigators, and Carter and Taylor as co-investigators, the team will continue to follow that trail with the support of a five-year, $2.4M R01. The project will allow the researchers to examine more closely why certain molecules, reactive oxygen species (ROS), behave like “tiny magnetic antenna,” as Carter puts it. One ROS, a superoxide in the liver, has been receptive to EMFs in helping modulate insulin sensitivity. Its removal in mouse experiments negated the earlier observed effects that launched Carter and Huang’s work.
As Brown points out in her article, human trials are still to come, but preliminary tests on human liver cells are promising. She quotes Carter on the end goal: “Our dream is to create a new class of noninvasive medicines that remotely take control of cells to fight disease.”
“This grant is really the next inevitable step in the process,” Abel said. “All credit is due to Calvin and Sunny, who made the initial discovery, but also to the team-based environment of the FOEDRC and Carver College of Medicine. There are mentors around every corner ready to pitch in when something important comes up. We are all excited to see what is next, not only for this project, which could fundamentally change diabetes care, but also for Calvin and Sunny.”
The Next Wave of Diabetes Care
The Spring 2021 issue of the Carver College of Medicine Magazine “Medicine at Iowa”, circulated to all UI alumni, featured an important serendipitous breakthrough by scientists at the University of Iowa Fraternal Order of Eagles Diabetes Research Center (FOEDRC). FOEDRC scientists discovered at safe new way to manage blood sugar non-invasively with electromagnetic fields (EMFs). This discovery could have major benefits in diabetes care, particularly for patients whose current treatment plan is cumbersome and involves checking their blood sugar multiple times daily with finger sticks.
Exposing diabetic mice to a combination of static electric and magnetic fields for a few hours per day normalized two major hallmarks of type 2 diabetes, namely reducing blood glucose levels and preventing insulin resistance.
Electromagnetic fields are everywhere in modern society. Telecommunications, navigation and mobile devices all rely on electromagnetism to function. Medicine has also harnessed this fundamental force for diagnostic technologies, most notably MRI. While the diagnostic use of EMFs has rapidly expanded, therapeutic applications remain narrow due to a poor understanding of the biological effects. A team of FOEDRC scientists including Drs. Calvin Carter, Sunny Huang, Val Sheffield and E. Dale Abel et al. have been studying the biological effects of electromagnetic fields and made a groundbreaking discovery. The team demonstrated that a unique combination of EMFs, approximately 100x that found at the Earth’s surface, remotely controls blood sugar in animal models of type 2 diabetes. The treatment effects are rapid, reversing insulin resistance within three days and are equally effective when applied for just 7 hours per day during sleep. The treatment was safe, and caused no obvious side effects in these animals studies. The team found that electromagnetic fields activate “magnetic antennae” that are present in mammalian cells, to rebalance the body’s response to insulin. These findings represent a breakthrough in our understanding of how the body responds to EMFs and opens a new field of research into the therapeutic use of EMFs for the noninvasive management of type 2 diabetes. Drs. Carter and Huang have formed a startup company, Geminii, Inc. to translate this novel discovery into a wearable device for the noninvasive management of diabetes. Dr. Carter has also been the recipient of a Bridge to the Cure award from the FOE.
A link to the Medicine at Iowa article is included here. https://medicineiowa.org/spring-2021/next-wave-diabetes-care
These exciting new findings were also published Oct. 6 in the Journal Cell Metabolism.
New FOEDRC study reveals how too much fat in insulin producing cells in the pancrease may lead to type 2 diabetes
Pancreatic beta cells are only cells that can make insulin in humans. In type 2 diabetes, pancreatic beta cells are damaged and cannot make sufficient insulin to keep blood glucose levels normal. As overnutrition and obesity is a well-known risk factor for type 2 diabetes, it is important to find a way to protect beta cells from over nutrition.
In a recently published study in the scientific journal JCI Insight, led by Dr. Yumi Imai, Associate Professor of Internal Medicine and member of the FOEDRC, her laboratory has discovered that a protein known as Perilipin 2 plays an important role in protecting beta cells under nutritional challenge. Perilipin 2, regulates an organelle called lipid droplets that prevent toxic lipids from being released from these lipid droplets. When these lipids or fats are released into the cell, they will damage beta cells and reduce their ability to produce insulin. Diabetes increases the number of lipid droplets that accumulate in beta cells in the pancreas. Therefore, it is very important under these circumstances that more perilipin is available to prevent these lipid droplets from releasing toxic lipids. Their study showed that lowering the levels of perilipin 2 led to increased injury of beta cells and reduced insulin secretion. The study was performed through collaboration with other members of FOEDRC including, Drs. James Ankrum, Brian O’Neill, Samuel Stephens, William Sivitz, and Stefan Strack. Each of these researchers brought specific expertise to the project. For example, they visualized a previously unrecognized connection between perilipin 2 and another organelle the mitochondria (that makes energy for insulin release), using sophisticated techniques and in human islet cells. This study increases our understanding of why beta cells fail during states of overnutrition and identified a new target Perilipin, whose levels if increased can protect beta cells and reduce the risk of developing type 2 diabetes.
FOEDRC research discover a new brain pathway that regulates body weight gain that is independent of the complications of obesity such as diabetes and high blood pressure
Obesity has reached epidemic proportions in the US and around the world. This is a problem because being obese increases the likelihood of developing serious medical problems such as type 2 diabetes, high blood pressure and cardiovascular diseases such as heart attacks and heart failure. Obesity also increases the risks of complications from COVID-19 infections. We still do not understand all of the reasons why obesity develops and why some people develop complications and others do not. In work recently published in the Journal Molecular Metabolism, FOEDRC member Dr. Kamal Rahmouni, PhD, professor of Neuroscience, Pharmacology, and Internal Medicine, in collaboration with FOEDRC colleagues at the University of Iowa, identified a protein complex, called the BBSome. These are present in neurons (nerve cells) in a part of the brain called the hypothalamus. The hypothalamus is a small area in the brain that determines whether the calories derived from the food we eat is burned or stored in the form of fat. The BBsome in these nerve cells regulate body fat and development of obesity. Dr. Rahmouni’s team found when the BBSome was removed from neurons of the hypothalamus, animals progressively increased body fat and weight resulting in obesity. This is due to inability of the hypothalamus to properly send signals to peripheral tissues that burn calories. As a result, these animals had lower metabolic rates as indicated by reduced energy expenditure. Because of this, their bodies were burning less calories than they should. Therefore, most of the ingested calories were directed to the fat tissues for storage, which increased the mass of fat tissue leading to obesity. These findings indicate that defects in the BBSome could be a potential cause of obesity. Very interestingly, the obesity that resulted from absence of the BBSome in the hypothalamus did not lead to diabetes, insulin resistance or high blood pressure. These findings are very similar to what is seen in a small subset of obese humans, referred to as “healthy obese,” who do not develop type 2 diabetes and cardiovascular diseases. The Rahmouni group is now conducting follow up studies to further understand what confers this remarkable protection against obesity-related conditions. Answering this question will reveal how metabolic and cardiovascular disease develop in obesity and may lead to more specific ways to treat these complications, particularly in individuals who struggle to lose weight.
Rouabhi M, Guo DF, Morgan DA, Zhu Z, López M, Zingman L, Grobe JL, Rahmouni K.. BBSome Ablation in SF1 Neurons Causes Obesity without the Comorbidities. Mol Metab. 2021 Mar 12:101211. doi: 10.1016/j.molmet.2021.101211. Epub ahead of print. PMID: 33722691.
FOE Investigators invited to educate the diabetes research community on new hormones from the liver that regulate metabolism
FOEDRC member Matthew Potthoff, Ph.D., Associate Professor of Neuroscience and Pharmacology, and graduate student Sharon Jensen-Cody recently wrote a review article entitled: “Hepatokines and metabolism: Deciphering communication from the liver” that was published in the Journal Molecular Metabolism. This article was featured on the cover of the February issue of the Journal, that increased the visibility of their work. In that article Drs. Potthoff and Jensen-Cody note that the liver plays an important role in the regulation of the body’s energy metabolism. It is able to sense when nutrients are present in excess or are deficient. In response to these nutritional changes, the liver will release hormones that will instruct other tissues in the body how to respond. This means that the liver is now recognized as an endocrine organ (gland) that secretes hormones, which are now known as hepatokines. These liver-derived factors can signal to and communicate with distant tissues. In this review, Potthoff’s lab describe the growing list of hepatokines and their role in metabolic control. They also examine how each of these hepatokines function at the cellular and molecular level. They also discuss their potential to be used as as therapies for metabolic disorders such as diabetes and obesity. Dr. Potthoff’s laboratory in the FOEDRC has made major advances to this area of research, and his influence in this area is exemplified in this article.
FOEDRC Pioneering the Way
This month, the Spring 2021 issue of the Iowa Magazine devoted its cover and featured the University of Iowa Fraternal Order of Eagles Diabetes Research Center (FOEDRC). The heartwarming article shares real life testimonies of diabetic individuals, cared for at the University of Iowa and the impact of diabetes on their daily life. The desire for relief is real and certainly not lost on physicians and scientists at the FOEDRC. The Center’s mission is to improve the lives of individuals with the disease and find a cure. Every day dedicated FOEDRC scientists conduct a wide range of research projects to improve and benefit the lives of many.
In addition to featuring the work of specific FOEDRC members and highlighting the commitment of the FOEDRC to training the next generation of diabetes researchers, the article reminds us of the generous $25 million gift from the Fraternal Order of Eagles. Without the generosity of the Eagles, we would not have been able to make these wonderful strides in diabetes research. Thank you.
Below is the link to the Iowa Magazine article, I know you will enjoy reading it as much as I did.