type 2 diabetes 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

Diabetic patient is using glucometer to check glucose level

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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Exciting diabetes and obesity research highlights from Medical City

AuthorDeborah Robison
Date

May 22, 2017

diabetes wordcloud

Center for Metabolic Origins of Disease

With more than one-third of adults in the U.S. considered obese, scientists are searching for new ways to treat obesity and associated health problems such as type 2 diabetes. Four researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP) at Lake Nona have been invited to present new perspectives and insights at the American Diabetes Association’s 77th Scientific Sessions, to be held June 9-13, 2017, in San Diego. The conference is the world’s largest gathering of research experts and clinicians focused on diabetes research, prevention and care. The presentations will inform new treatment strategies for the nearly 30 million people diagnosed with diabetes.

Potential early therapeutic target for diabetes prevention
Obesity often leads to accumulation of fat in muscle and faulty machinery involved in taking up glucose from a meal to use it for energy, leading to type 2 diabetes. A recent advance from the laboratory of Daniel P. Kelly, MD, scientific director of SBP at Lake Nona, may lead to a way to stop this pre-diabetic state from advancing. Dr. Kelly will present findings on a recently discovered cellular glucose sensor in muscle that serves as a key connection between insulin resistance and accumulation of fat in muscle, which occurs in obesity-related diabetes. When the protein is inhibited in skeletal muscle cells, regulatory genes that influence glucose uptake and insulin signaling are enhanced. The team is now validating the pathway as a therapeutic target to prevent type 2 diabetes.

Fatty liver and type 2 diabetes
Peter Crawford, MD, PhD, director of SBP’s Cardiovascular Metabolism Program, is studying the root causes of nonalcoholic fatty liver disease (NAFLD), a condition that affects nearly 80 percent of people with type 2 diabetes. About 5 percent of NAFLD cases advance to liver cirrhosis – a disease characterized by scarring and fibrosis that could require liver transplant. Dr. Crawford is an expert on how the liver processes energy derived from food. At the ADA meeting, he will discuss how the interruption of normal fat metabolism can lead to enhanced scarring. Through ongoing research, he hopes to be able to specifically identify which diabetes patients are at risk of developing advanced liver disease and to develop therapies that protect against disease progression.

Brain nutrient sensors help maintain energy balance
Diabetes researcher Julio Ayala, PhD wants to understand how specialized regions in the brain control food intake, energy expenditure and body weight. His ADA presentation will focus on how nutrient-sensors that control the balance between energy-consuming and energy-producing processes in almost every cell in our bodies also play a very specific role in the brain. His research shows that hormones, such as glucagon-like peptide-1 (GLP-1) regulate the activities of these brain nutrient sensors to influence hunger, satiety and ultimately body weight. Defective sensors are implicated in obesity and could be a target for new therapeutic treatments.

Glucose Sensor in Macrophages
Insulin resistance is a key feature of type 2 diabetes. When present, the impairment prevents insulin from getting glucose into muscle where it’s used for energy, and instead causes blood sugars to become elevated. The events that drive the development and progression of insulin resistance are not known. Laszlo Nagy, MD, PhD, director of SBP’s Genomic Control of Metabolism Program, will present new research that suggests that the inflammatory process—and specifically a type of white blood cells called macrophages—are involved. He will present a novel hypothesis on the role of macrophages, defined in Greek as “big eaters”, and identify molecules involved in muscle growth and glucose metabolism. His research aims to reveal cellular interactions that could become new therapeutic targets to treat type 2 diabetes.

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Drug reverses type 2 diabetes in mice

AuthorJessica Moore
Date

March 30, 2017

insulin syringes

Type 2 diabetes is a massive public health challenge. About eight percent of the world’s adult population has it, and the complications are serious—increased risk of heart attack and stroke, kidney problems, hearing and vision loss and painful nerve damage. Managing blood sugar with diet, routine monitoring and insulin helps prevent these issues, but that takes more time and effort than many patients have.

A new experimental drug developed with the help of scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) may spell the end of insulin reliance. A study published in Nature Chemical Biology shows that the compound, which can be given as a pill, restores blood sugar control in a mouse model of diet-induced diabetes.

“By targeting an enzyme that controls insulin receptor signaling, we found a way to recover cells’ ability to respond to insulin,” says Anthony Pinkerton, PhD, director of medicinal chemistry at SBP’s Conrad Prebys Center for Chemical Genomics and a contributor to the research. “This could lead to a new treatment approach for type 2 diabetes.”

The candidate drug blocks an enzyme called low molecular weight protein tyrosine phosphatase (LMPTP), which regulates the insulin receptor. Human genetic studies suggested that individuals with lower LMPTP activity were protected from type 2 diabetes, but the mechanism of protection remained unclear.

The new investigation, led by Nunzio Bottini, MD, PhD, professor at UC San Diego, found that LMPTP has direct actions on the insulin receptor that reduce its signaling activity, making cells less sensitive to insulin. Turning off the LMPTP gene prevented mice from becoming diabetic when they were fed a high-fat diet, so the research team screened compounds to identify LMPTP inhibitors. Chemical improvements to the best compound gave a potent, orally available drug that improved glucose control in mice with type 2 diabetes.

“This is still a few steps away from clinical trials,” says Robert Liddington, PhD, professor at SBP who also collaborated on the study. “No adverse events were noted in mice who received the drug for a month, and the compound is highly selective for LMPTP, but considerably more optimization and testing has to be done to show that it’s safe when taken long-term and is likely to work in humans.”

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Long-term exercise makes fat better at burning calories, but doesn’t turn it brown

AuthorJessica Moore
Date

November 15, 2016

woman swimming on her back

Brown fat is good, white fat bad. That’s the impression given by recent metabolism research focused on how to make white fat, which stores energy, more like the rarer brown fat, which burns energy. However, a new study from the Florida Hospital Translational Research Institute for Metabolism and Diabetes (TRI-MD), an affiliate of Sanford Burnham Prebys Medical Discovery Institute (SBP), suggests that with regular exercise even white fat can be cajoled into burning more calories.

“Our findings reveal that even though exercise doesn’t turn white fat ‘beige’—that is, make some of it behave similarly to brown fat—it still has beneficial effects on metabolism in that tissue,” said Lauren M. Sparks, PhD, adjunct professor in the Integrative Metabolism Program at SBP in Lake Nona and an investigator at the TRI-MD. She led the research, recently published in the journal Obesity.

Prior to this investigation, not much was known about how exercise shapes the way human fat cells burn energy. One study suggested that endurance training does not change metabolism in white fat, but the experiments only assessed markers of ‘browning’. Sparks’ team aimed to examine the question more comprehensively by looking not only at browning markers, but also heat generation and the means by which most cells use energy—oxidizing fuels in mitochondria.

The researchers, including SBP’s Steven R. Smith, MD, scientific director of the TRI-MD, compared the abdominal fat of people who work out at least four hours per week at moderate to vigorous intensity to that of sedentary individuals. The levels of mitochondrial oxidation markers were higher in the fat of active people compared with the inactive group, the scientists found, However, markers of heat generation and conversion to ‘beige’ fat were similar between the groups.

“This work highlights the importance of studying metabolism in humans,” Smith said. “Because exercise training in rodents does cause white fat to burn calories as heat, these animals may not be ideal models for answering these kinds of questions.”

“Understanding the effects of exercise on metabolism at the molecular level is critical,” Sparks said. “It connects the dots between physical activity and disease, and it could help refine exercise programs that help people with metabolic problems such as type 2 diabetes and obesity get healthier.”

The paper is available online here.

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How your organs ‘taste’ sugar

Authorjmoore
Date

April 18, 2016

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You might be surprised to learn that the sensors for sweet-tasting molecules aren’t located only on your tongue—they’re also found in the gut, pancreas, fat tissue, and muscle. And new research from the laboratory of George Kyriazis, PhD, assistant professor in the Integrative Metabolism Program at Lake Nona, indicates just how important these sweet taste receptors are in regulating metabolism. Continue reading “How your organs ‘taste’ sugar”

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New links between heart hormones, obesity, and diabetes

AuthorGuest Blogger
Date

February 17, 2016

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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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SBP’s Sheila Collins’ diabetes research featured in Orlando Sentinel

Authorsgammon
Date

December 21, 2015

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“Obesity has reached epidemic proportions in the United States. Over 60 percent of the population can be classified as overweight or obese, placing them at risk for a large number of chronic diseases, including insulin resistance, cardiovascular disease, and type 2 diabetes,” says Sheila Collins, PhD, professor at SBP’s Lake Nona campus.

“There is a critical need for novel approaches to treating obesity—in particular, agents acting to increase energy expenditure would be valuable.”

Read the article in the Orlando Sentinel by Naseem S. Miller about how Collins is studying hormones produced by the heart to prevent obesity and possibly the myriad of disorders that come with it.

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Antioxidant-rich diet could help stave off type 2 diabetes

AuthorGuest Blogger
Date

November 12, 2015

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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

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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.