Diabetes and Obesity Archives - Sanford Burnham Prebys
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Scientists discover an early sign of type 2 diabetes: Misfolded proinsulin

AuthorMonica May
Date

March 19, 2020

The findings could lead to tests or treatments that help prevent type 2 diabetes.

Misfolded proinsulin—a protein the body normally processes into insulin—is an early sign of type 2 diabetes, according to a study by scientists at Sanford Burnham Prebys and the University of Michigan Medical School. The discovery, published in eLife, could lead to tests or treatments that help prevent people from developing type 2 diabetes.

“Understanding the molecular events that occur as prediabetes progresses to diabetes opens new avenues for us to detect or interrupt these processes,” says Randal Kaufman, PhD, director and professor in the Degenerative Diseases Program at Sanford Burnham Prebys and co-corresponding author of the study. “With this information, we can start to find interventions that might spare millions of people from a serious, lifelong condition.”

More than one in three Americans, or approximately 88 million people, have prediabetes—which is characterized by elevated blood sugar. If left untreated, within four years nearly 40% of people with prediabetes develop type 2 diabetes, which occurs when the body doesn’t use insulin properly. In 2017, the cost of treating diabetes exceeded $327 billion, according to the American Diabetes Association. Due to increasing obesity rates, the number of people with the condition—particularly children—is on the rise.

Identifying the molecular events that occur during progression from prediabetes to full-blown diabetes remains one of the most perplexing problems in diabetes research. In the study, the scientists set out to answer this question by tracking proinsulin folding in the beta cells of humans and mice that are healthy, prediabetic and diabetic.

These studies revealed that instead of undergoing its normal folding process, proinsulin proteins were abnormally linked to each other. Levels of the abnormal proinsulin accumulated as prediabetes progressed to type 2 diabetes. Obese mice in the earliest stages of diabetes had the highest levels of abnormal proinsulin in their beta cells.

“Proinsulin misfolding is the earliest known event that may contribute to the progression from prediabetes to diabetes,” says Kaufman. “Together, these studies show that abnormally linked proinsulin holds promise as a potential measure of how close someone may be to developing type 2 diabetes.”

Now, the researchers are set to uncover more details about this process, such as the proteins that interact with the misfolded proinsulin.

“Understanding the fundamental molecular events that lead to type 2 diabetes is critical as the number of people with prediabetes continues to rise,” says Kaufman. “If we don’t find preventive measures, we will soon have a diabetes epidemic.”

The study’s first author is Anoop Arunagiri, PhD; and the study’s senior author is Peter Arvan, both of the University of Michigan Medical School.

Additional authors include Leena Haataja and Fawnnie Pamenan of the University of Michigan Medical School; Ming Liu of the University of Michigan Medical School and Tianjin Medical University in China; Anita Pottekat and Pamela Itkin-Ansari of Sanford Burnham Prebys; Soohyun Kim of Konkuk University in South Korea; Lori M. Zeltser of Columbia University; Adrienne W. Paton and James C. Paton of the University of Adelaide in Australia; and Billy Tsai of the University of Michigan.

The study’s DOI is 10.7554/eLife.44532.

This work was supported by the National Institutes of Health (R01DK111174, R24DK110973 and R01DK48280) and the Juvenile Diabetes Research Foundation International (2-SRA-2018-539-A-B).

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SBP scientists reflect on progress in diabetes research

AuthorDeborah Robison
Date

June 23, 2016

“The most significant advances in diabetes treatment, which were underscored at the ADA meeting, is the clinical evidence that two newer classes of anti-diabetic drugs significantly improve cardiovascular outcomes and overall mortality. These drug families are insulin secretion enhancers such as liraglutide (LEADER trial) and drugs that promote glucose elimination in the urine, such as canagliflozin and empagliflozin (EMPA-REG OUTCOME trial). This has major impact because reducing the risk of heart disease is always the end goal in treating diabetes—the association with heart disease is what makes type 2 diabetes so serious. These trials also present a remarkable opportunity for basic researchers—many of us, including several here in Lake Nona, study how drugs in these classes affect metabolism. The answers to those questions should lead to new drug targets that are even more specific and precision-oriented.”

Peter Crawford, MD, PhD
Associate Professor and Director
Cardiovascular Metabolism Program

“From the sessions that I saw, there was a significant emphasis on combination treatments—either combining two or more already approved drugs that have related functions or generating fusions of multiple protein drugs. An example of the former is the combination of basal insulin and glucagon-like peptide-1 receptor agonists to control fasting and post-meal glucose levels, respectively. With regards to fusion proteins, there were many posters and presentations highlighting efforts to generate dual and triple combinations that would lower glucose and aid weight loss. These approaches may reduce the need for patients to take multiple drugs and therefore improve efficacy and patient adherence.”

Julio Ayala, PhD
Associate Professor
Integrative Metabolism Program
ADA Thomas R. Lee Career Development Award Recipient ’14

“During the ADA meeting two symposia and numerous other presentations examined evidence implicating gut microbiota in the development of type 1 and type 2 diabetes. I am personally enthusiastic about the potential of novel therapeutic strategies that either prevent harmful changes in gut microbiota or even directly transplant “therapeutic” microbial species. Nevertheless, our current understanding of the potential mechanisms is very limited due to the complex factors affecting the microbiome such as the host’s genetics and the environment (diet, antibiotic use, history of infections etc.).”

George Kyriazis, PhD
Assistant Professor
Integrative Metabolism Program

“Of particular interest to me were the symposia on experimental strategies for understanding how the brain controls metabolism. Specifically, optogenetics and magnetogenetics are emerging as two powerful research tools for this purpose, and involve genetically modifying neurons to express either light- or magnetic field-sensitive proteins so that their activity can be controlled with fiber optic light or magnets, respectively. These sophisticated techniques will help investigators delineate which regions in the brain play a critical role in regulating blood glucose, which could lead to more effective therapies for diabetes and obesity.”

Melissa Burmeister, PhD
Staff Scientist
Dr. Julio Ayala Lab

 

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Why the “Biggest Losers” don’t win

AuthorJessica Moore
Date

May 12, 2016

Following a recent publication on the long-term effects of participation in TV’s “Biggest Loser” competition, Steven Smith, MD, professor in SBP’s Integrative Metabolism Program and director of the Translational Research Institute for Metabolism and Diabetes at Florida Hospital, was interviewed by NBC WESH TV Orlando reporter Amanda Ober. Smith explained why nearly all of the “Biggest Losers” regained large proportions of the weight they had lost, and sometimes even more. Continue reading “Why the “Biggest Losers” don’t win”

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New links between heart hormones, obesity, and diabetes

AuthorGuest Blogger
Date

February 17, 2016

New research from SBP’s Sheila Collins, PhD, and Richard Pratley, MD, has revealed an important relationship between proteins secreted by the heart and obesity, glucose intolerance, and insulin resistance. The findings, published in Obesity, offer a new approach to treating metabolic disorders, including type 2 diabetes, by targeting the pathway that controls the proteins’ concentration in the blood. Continue reading “New links between heart hormones, obesity, and diabetes”

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New method to identify bacteria in the gut may facilitate development of probiotics

Authorjmoore
Date

January 19, 2016

The gut microbiome, the community of bacteria living in the intestines, has an enormous impact on human health, affecting risk for obesity, inflammatory bowel disease (IBD), neurological disorders, and even cancer. Accordingly, there has been an explosion of research in this area in the past ten years, with the long-term goal of developing ways to manipulate the microbiome to promote the survival of bacteria that promote health and/or eliminate those associated with disease. Continue reading “New method to identify bacteria in the gut may facilitate development of probiotics”

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Can your heart prevent diabetes?

AuthorGuest Blogger
Date

November 19, 2015

This article was written by guest blogger Crystal Woodard, PhD

Can your heart prevent diabetes? Being overweight or obese is currently deemed the single best predictor of type 2 diabetes. With the prevalence of obesity on the rise, estimates suggest that one in three American adults could have type 2 diabetes by 2050. Weight loss is key to preventing this epidemic. At SBP, scientists are investigating how hormones released by the heart may help the body burn more calories to prevent obesity and type 2 diabetes.

What color is your fat? All fat is not created equal. Excess weight is held in energy-storing fat cells called white adipose tissue as well as energy-burning fat cells called brown adipose tissue. Increasing a person’s brown fat could improve the risks associated with obesity.

Two compounds released by the heart in response to high blood pressure—human atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)—have been found to play a direct role in “browning” white adipose tissue. By browning, white fat starts to burn more calories, mimicking what occurs in brown fat. Sheila Collins, PhD, professor in the Integrative Metabolism Program and her research team, are investigating how these natriuretic peptides activate fat browning with the goal of tapping into the process to help promote weight loss and prevent diabetes.

In collaboration with Dr. Richard Pratley at the Florida Hospital – SBP Translational Research Institute for Metabolism and Diabetes, the teams are conducting clinical trials with obese and lean volunteers to test whether BNP can increase energy expenditure and improve glucose tolerance. Since recombinant human BNP is an FDA-approved drug prescribed for acute heart failure patients, the costs, and development and approval times for using BNP for these conditions may be reduced.

How does BNP work? Investigators in Italy almost 20 years ago discovered that binding sites for BNP, called natriuretic peptide receptors (NPRs), were expressed in human adipose tissue. The natriuretic peptide ‘signaling’ receptor, NPRA, binds the natriuretic peptides, while the natriuretic peptide ‘clearance’ receptor, NPRC, removes them from circulation. Since then, several studies have reported that BNP levels are lower in the blood of obese patients compared to their lean counterparts. Additional research suggests BNP can lead to increased release of adiponectin, an insulin-sensitizing hormone produced by fat cells and that low levels of BNP in the bloodstream might contribute to insulin resistance.

According to Collins, “Early studies proposed that increased clearance is responsible for the lower peptide levels observed in obese individuals in comparison to lean individuals; however, there are no definitive studies to actually prove this or not. Important efforts are currently underway to understand how NPRs are regulated and how the peptides can be best used for their fat-burning capacity.”

Dr. Sheila Collins is a professor at Sanford Burnham Prebys Medical Discovery Institute (SBP) in Lake Nona, Fla. and a recipient of an American Diabetes Association research award. Dr. Richard Pratley is a senior investigator at the Florida Hospital – SBP Translational Research Institute, Medical Director of the Florida Hospital Diabetes Institute, and adjunct professor at SBP in Lake Nona. This post was written by Crystal Woodard, PhD, a post-doctoral fellow in Dr. Collins’s lab.

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Antioxidant-rich diet could help stave off type 2 diabetes

AuthorGuest Blogger
Date

November 12, 2015

Type 2 diabetes affects about 8% of all adults and is a leading cause of death worldwide. Despite its prevalence, relatively little is known about underlying molecular causes of the disease. SBP researchers now show that defects in a major cell stress pathway play a key role in the failure of pancreatic beta cells, leading to signs of diabetes in mice. The findings, published recently in PLOS Biology, also suggest that a diet rich in antioxidants could help to prevent or treat type 2 diabetes.

“The findings open new therapeutic options to preserve beta cell function and treat diabetes,” said senior study author Randal Kaufman, PhD, director of the Degenerative Diseases Program at SBP. “Because the same cell stress response is implicated in a broad range of diseases, our findings suggest that antioxidant treatment may be a promising therapeutic approach not only for metabolic disease, but also neurodegenerative diseases, inflammatory diseases, and cancer.”

Excess cell stress

Type 2 diabetes is caused by the failure of pancreatic beta cells to produce enough insulin—a hormone that helps to move a blood sugar called glucose into cells to be stored for energy. A major cause of type 2 diabetes is obesity, which can lead to abnormalities in insulin signaling and high blood glucose levels. Beta cells try to compensate by producing up to 10 times the usual amount of insulin, but this puts extra stress on a cell structure called the endoplasmic reticulum to properly fold, process, and secrete the hormone.

An increase in protein synthesis in beta cells also causes oxidative stress—a process that can lead to cell damage and death through the build-up of toxic molecules called reactive oxygen species. If the stress is too great, the beta cells will eventually fail. Approximately one-third of individuals with abnormal insulin signaling eventually develop beta cell failure and diabetes.

In the new study, Kaufman and his collaborators discovered that beta cell failure is caused by deficiency in a protein called IRE1α, which would otherwise help to protect cells against the stress of increased insulin production. Mice that lacked IRE1α in pancreatic beta cells did not produce enough insulin and developed high blood glucose levels, similar to patients with type 2 diabetes. IRE1α deficiency also caused inflammation and oxidative stress, which was the primary cause of beta cell failure. But treatment with antioxidants, which prevented the production of reactive oxygen species, significantly reduced metabolic abnormalities, inflammation and oxidative stress in these mice.

Taken together, the findings suggest that IRE1α evolved to expand the capacity of beta cells to produce insulin in response to increases in blood glucose levels. The study also implicates this major cell stress pathway in the development of type 2 diabetes and suggests that a diet rich in antioxidants could help to prevent or reduce the severity of the disease.

“Currently, we are testing the effects of antioxidants on glucose levels and beta cell function in mice,” Kaufman said. “If these studies prove successful, they could pave the way for clinical trials in humans and eventually lead to a new therapeutic approach for dealing with a major pandemic of the 21st century.”

This post was written by guest blogger Janelle Weaver, PhD

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Is there a type 3 diabetes?

AuthorGuest Blogger
Date

November 10, 2015

This article was written by guest blogger Jessica Frisch-Daiello, PhD

People with type 2 diabetes are twice as likely to develop Alzheimer’s disease—a type of dementia affecting behavior, memory, and cognitive functions. According to the Centers for Disease Control and Prevention, in 2013 Alzheimer’s ranked sixth and diabetes was seventh as the leading causes of death in the United States. Recent studies are suggesting a link between insulin resistance in the brain and Alzheimer’s disease, prompting some researchers to consider a new classification for the disease: type 3 diabetes.

People with diabetes can’t effectively break down blood sugar. Either their bodies don’t produce enough insulin (type 1 diabetes) or their bodies become desensitized to insulin (type 2 diabetes).

The exact mechanisms between insulin resistance and Alzheimer’s disease are not well understood and research is on-going. However, studies suggest that insulin resistance in the brain leads to the formation of two pathological hallmarks of Alzheimer’s disease—the formation of tau tangles and the build-up of clusters of beta amyloid peptides called plaques in the brain. The degree of insulin resistance is correlated with the amount of plaques deposited between nerve cells. Plaques create a blockade that inhibits cell-to-cell signaling in the brain. Additionally, insulin dysfunction has also been shown to affect the formation of tau tangles by mediating the activity of an important enzyme in the body, GSK-3β (glycogen synthase kinase 3).

Juan Pablo Palavicini, PhD, an SBP postdoctoral fellow in the lab of Xianlin Han, PhD, is studying the role of a particular class of molecules found in the body that might give more clues to the mechanisms connecting these two seemingly disparate diseases. According to Palavicini, “We have found that a specific lipid class called sulfatide is severely deficient in the brains of both Alzheimer’s disease patients and type 2 diabetics. Moreover, our research shows that when sulfatide is removed, there is a dramatic change in insulin levels, beta amyloid peptides, and tau tangles. We are currently exploring therapeutic techniques to restore sulfatide content as a treatment for both diseases.”

Sulfatide serves many functions in the body, including aiding neural plasticity and memory. It also plays a role in insulin secretion. A change in the expression of sulfatide has been associated with a number of conditions, including Alzheimer’s disease, Parkinson’s disease, and diabetes.

Given the association between Alzheimer’s disease and diabetes, it is important for people to incorporate healthy habits in everyday life. Both the American Diabetes Association and the Alzheimer’s Association say that daily exercise, social interaction, and a diet emphasizing fruits, vegetables, and whole grains may reduce the risk of developing, or slowing the progression of, these diseases.

Dr. Palavicini and Dr. Han are pursuing this research as part of a mentor-based postdoctoral fellowship awarded by the American Diabetes Association. This article was written by Dr. Jessica Frisch-Daiello, a postdoctoral associate in Dr. Han’s laboratory at SBP.

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The Diabetes Story: Will new treatments lead to novel weight loss drugs?

AuthorGuest Blogger
Date

November 3, 2015

Written by Jing Ping Lu, PhD

November is American Diabetes Month. Throughout the month, we will be highlighting our research contributions to this increasingly prevalent disease.

The growing epidemic of diabetes presents significant challenges for health care. It ranks 7th among the leading causes of death, and about one tenth of all health care dollars are spent on diabetes and its complications. According to the American Diabetes Association, 29.1 million Americans have been diagnosed with this metabolic disorder, and 1.4 million new cases were reported in 2013. With these statistics, the burden diabetes has on the health care system will continue to rise.

Opportunities to research the disease have also increased with the growing diabetic population. One particular area of emphasis is in understanding how glucose—a type of sugar—is broken down, or metabolized, in diabetic patients. Glucose is the major energy source our body uses to carry out activities. Glucose levels in the blood are kept constant by a hormone called insulin. After eating, the glucose level in the blood rises and signals insulin release. Insulin is like a key that opens up the locks on our cells so that glucose can enter. Glucose can then be stored in the form of glycogen and used later for energy. If our body does not make enough insulin, or insulin is not well recognized by the cell, then glucose levels will build up in the blood stream causing diabetes and other long-term complications.

Treating Diabetes Diabetic treatments are primarily developed to lower the amount of blood glucose by restoring the secretion of insulin or enhancing how well insulin works to promote the entry of glucose into cells. Another hormone called glucagon-like-peptide-1(GLP-1) has been shown to increase glucose-dependent stimulation of insulin release, and GLP-1 based drugs are used to treat diabetes. Julio Ayala, PhD, and his research team are working on projects that utilize GLP-1 based drugs to stimulate insulin secretion. These drugs come in two categories, GLP-1 analogs that mimic the action of GLP-1 and dipeptidyl peptidase 4 (DPP-4) inhibitors that prevent the breakdown of GLP-1 made in the body. Although both drugs can effectively lower glucose levels, one promotes weight loss while the other does not.

A new avenue for weight loss? Preliminary research performed in Ayala’s lab confirmed that the two drugs have different effects on food intake. “Interestingly, when targeted to specific regions in the brain, GLP-1 analogs reduce food intake to a greater degree than does native (natural) GLP-1. This may partly explain why GLP-1 analogs promote weight loss while DPP-4 inhibitors that increase native GLP-1 levels do not,” Ayala explained. “This leads us to speculate that even though both drugs bind to the same receptor in the feeding centers of the brain, they activate different molecular mechanisms in cells of the brain and this eventually results in different effects on food intake, and therefore, weight loss.”

As Ayala’s team continues to explore the mechanism of action, they hope to identify the critical steps that lead to the reduction in food intake. “Obesity is a leading risk factor for developing Type 2 diabetes. If we can discover the steps that GLP-1 analogs engage to promote weight loss, then drugs can be designed to specifically target these steps. This would provide a new avenue for designing drugs to treat obesity,” Ayala added, “and that could deliver a greater benefit to diabetes patients and contribute to decreasing the rise in Type 2 diabetes. We are excited to see the possibilities.”

Dr. Julio Ayala is an assistant professor at Sanford Burnham Prebys Medical Discovery Research Institute in Lake Nona, Fla and a recipient of an American Diabetes Association research award.

This post was written by Jing Ping Lu, PhD, a post-doctoral associate in Dr. Rastinejad’s lab in Lake Nona.

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Ketogenesis prevents fatty liver disease

Authorsgammon
Date

January 12, 2015

A new study, published in the Journal of Clinical Investigation, suggests that ketogenesis may prevent non-alcoholic fatty liver disease (NAFLD). NAFLD is term used to describe the accumulation of fat in the liver of people who drink little or no alcohol. It affects approximately one billion individuals worldwide, has become a leading cause of cirrhosis, and increases the risk of cardiovascular disease, including heart attacks and stroke. Continue reading “Ketogenesis prevents fatty liver disease”