Tag: insulin resistance

Categories : Metabolic DisordersTags :

Probing an Outdated Diabetes Drug’s Insulin Resistance Lowering Abilities

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Thiazolidinediones (TZDs) are a class of drug that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main hallmarks of the disease. While TZDs were extremely popular in the 1990s and early 2000s, they have fallen out of use among physicians in recent decades because unwanted side effects emerged, including weight gain and excess fluid accumulation in body tissues.

Now, researchers at University of California San Diego School of Medicine are exploring how to isolate the positive effects of these drugs, which could help yield new treatments that don’t come with the old side effects.

In a new study published in Nature Metabolism, the researchers discovered how one of the most well-known TZD drugs works at the molecular level and were able to replicate its positive effects in mice without giving them the drug itself.

“For decades, TZDs have been the only drugs we have that can reverse insulin resistance, but we seldom use them anymore because of their side effects profile,” said Jerrold Olefsky, MD, a professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences.

“Impaired insulin sensitivity is the root cause of type 2 diabetes, so any treatment we can develop to safely restore this would be a major step forward for patients.”

The main driver of insulin resistance in type 2 diabetes is obesity. Obesity-related inflammation causes macrophages to accumulate in adipose tissue, where they can comprise up to 40% of the total number of cells in the tissue.

When adipose tissue is inflamed, these macrophages release tiny nanoparticles containing instructions for surrounding cells in the form of microRNAs. These microRNA-containing capsules, called exosomes, are released into the circulation and can travel through the bloodstream to be absorbed by other tissues, such as the liver and muscles. This can then lead to the varied metabolic changes associated with obesity, including insulin resistance.

To understand how TZD drugs, which restore insulin resistance, affect this exosome system, the researchers treated a group of obese mice with the TZD drug rosiglitazone. Those mice became more sensitive to insulin, but they also gained weight and retained excess fluid, known side effects of rosiglitazone.

However, by isolating exosomes from the adipose tissue macrophages of the mice who had received the drug and injecting them into another group of obese mice that had not received it, the researchers were able to deliver the positive effects of rosiglitazone without transferring the negative effects.

“The exosomes were just as effective in reversing insulin resistance as the drug itself but without the same side effects,” said Olefsky.

“This indicates that exosomes can ultimately link obesity-related inflammation and insulin resistance to diabetes. It also tells us that we may be able to leverage this system to boost insulin sensitivity.”

The researchers were also able to identify the specific microRNA within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone. This molecule, called miR-690, could eventually be leveraged into new therapies for type 2 diabetes.

“It’s likely not practical to develop exosomes themselves as a treatment because it would be difficult to produce and administer them, but learning what drives the beneficial effects of exosomes at the molecular level makes it possible to develop drugs that can mimic these effects,” said Olefsky. “There’s also plenty of precedent for using microRNAs themselves as drugs, so that’s the possibility we’re most excited about exploring for miR-690 going forward.”

Source: University of California – San Diego

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Liraglutide Results in Increased Insulin Sensitivity Independent of Weight Loss

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A new Vanderbilt University study published in the journal Diabetes demonstrates that a glucagon-like peptide-1 receptor (GLP-1R) agonist, a member of a class of medication used to treat Type 2 diabetes and obesity, can lead to a rapid improvement in insulin sensitivity.

Insulin sensitivity is how responsive cells are to insulin; reduced insulin sensitivity or insulin resistance is a feature of Type 2 diabetes, so improving it can reduce the risk of developing the disease or improve its treatment.

GLP-1R agonists are medications that influence metabolism, such as decreasing blood sugar levels by promoting insulin secretion. Dipeptidyl peptidase 4 (DPP-4) inhibitors block the degradation of the body’s own endogenous GLP-1, as well as other peptide hormones such as glucose-dependent insulinotropic peptide (GIP).

“We know that GLP-1R agonists promote weight loss, but we were surprised to find that the GLP-1R agonist liraglutide also has rapid effects on insulin sensitivity, independent from weight loss,” said Mona Mashayekhi MD, PhD, assistant professor of Medicine in the Division of Diabetes, Endocrinology and Metabolism.

“This effect requires activation of the GLP-1 receptor, but increasing the body’s own endogenous GLP-1 through the use of the DPP4 inhibitor sitagliptin does not achieve similar effects.”

“Our research suggests that liraglutide, and presumably other GLP-1R agonists, are having important metabolic effects in a way that’s different from increasing endogenous GLP-1 levels, even though they’re using the same receptor. Future research will focus on potential mechanisms of how GLP-1R agonists are improving insulin sensitivity independent of weight loss.”

Eighty-eight individuals with obesity and pre-diabetes were randomized for 14 weeks to receive the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin, or weight loss without drug using a low-calorie diet.

To further investigate the GLP-1R-dependent effects of the treatments, the GLP-1R antagonist exendin and a placebo were given in a two-by-two crossover study during mixed meal tests.

Crossover studies allow the response of a subject to treatment A to be compared with the same subject’s response to treatment B.

Liraglutide was shown to rapidly improve insulin sensitivity as well as decrease blood glucose within two weeks of beginning treatment and before any weight loss.

“GLP-1R agonists are an exciting class of medications, given their strong glucose-lowering effects combined with tremendous weight-loss benefits, and they have transformed how we manage diabetes and obesity in the clinic,” Mashayekhi said.

“Since the number of medications in this class is rapidly expanding, a deeper understanding of the mechanisms of benefit is crucial so we can design the right drugs for the desired effects in the right patients.”

The investigators’ prior research demonstrated that liraglutide, but not sitagliptin or diet, improves measures of heart disease and inflammation.

This matches the clinical findings of reduced cardiovascular disease with GLP-1R agonist treatment.

Future studies will continue to explore both receptor- and weight loss-dependent effects of GLP-1R agonists in humans.

Source: Vanderbilt University Medical Center

Categories : Metabolic Disorders NeurologyTags :

Liraglutide Boosts Associative Learning in People with Obesity

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Obesity leads to altered energy metabolism and reduced insulin sensitivity of cells. The so-called “anti-obesity drugs” such as liraglutide are increasingly used to treat obesity and have caused tremendous interest, especially in the USA. Researchers in Germany have now shown in people with obesity that reduced insulin sensitivity affects learning of sensory associations. The results, published in Nature Metabolism, showed that a single dose of liraglutide was able to normalise these changes and restore the underlying brain circuit function.

The brain must be able to form associations in order to control behaviour. This involves, for example, associating a neutral external stimulus with a consequence following the stimulus. In this way, the brain learns what the implication of handling of the first stimulus are. Associative learning is the basis for forming neural connections and gives stimuli their motivational force. It is essentially controlled by a brain region called the dopaminergic midbrain. This region has many receptors for the body’s signalling molecules, such as insulin, and can thus adapt behaviour to the body’s physiological needs.

But what happens when the body’s insulin sensitivity is reduced due to obesity? Does this change brain activity, ability to learn associations and thus behaviour? Researchers at the Max Planck Institute for Metabolism Research have now measured how well the learning of associations works in participants with normal body weight (high insulin sensitivity, 30 volunteers) and in participants with obesity (reduced insulin sensitivity, 24 volunteers), and if this learning process is influenced by the anti-obesity drug liraglutide.

Low insulin sensitivity reduces the brain’s ability to associate sensory stimuli.

In the evening, they injected the participants with either the drug liraglutide or a placebo in the evening. Liraglutide is a so-called GLP-1 agonist, which activates the GLP-1 receptor in the body, stimulating insulin production and producing a feeling of satiety. It is often used to treat obesity and type 2 diabetes and is given once a day. The next morning, the subjects were given a learning task that allowed the researchers to measure how well associative learning works. They found that the ability to associate sensory stimuli was less pronounced in participants with obesity than in those of normal weight, and that brain activity was reduced in the areas encoding this learning behaviour.

After just one dose of liraglutide, participants with obesity no longer showed these impairments, and no difference in brain activity was seen between participants with normal weight and obesity. In other words, the drug returned the brain activity to the state of normal-weight subjects.

“These findings are of fundamental importance. We show here that basic behaviours such as associative learning depend not only on external environmental conditions but also on the body’s metabolic state. So, whether someone has overweight or not also determines how the brain learns to associate sensory signals and what motivation is generated. The normalisation we achieved with the drug in subjects with obesity, therefore, fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” says study leader Marc Tittgemeyer from the Max Planck Institute for Metabolism Research.

“While it is encouraging that available drugs have a positive effect on brain activity in obesity, it is alarming that changes in brain performance occur even in young people with obesity without other medical conditions. Obesity prevention should play a much greater role in our healthcare system in the future. Lifelong medication is the less preferred option in comparison primary prevention of obesity and associated complications,” says Ruth Hanßen, first author of the study and a physician at the University Hospital of Cologne.

Source: Max Planck Institute for Biology of Ageing

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DNA Study Hints at How Insulin Resistance Develops after Glucose Challenge

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A study of the DNA of more than 55 000 people worldwide has shed light on what goes wrong in a glucose challenge that might lead to type 2 diabetes. The findings, published today in Nature Genetics, suggests that genetic changes relating to a protein called GLUT4 could be involved.

Several factors contribute to an increased risk of type 2 diabetes, such as older age, being overweight or having obesity, physical inactivity, and genetic predisposition. If untreated, type 2 diabetes can lead to complications, including eye and foot problems, nerve damage, and increased risk of heart attack and stroke.

Most studies to date of insulin resistance have focused on the fasting state when insulin is largely acting on the liver.  But most people’s time is spent in the fed state, when insulin acts on muscle and fat tissues.

It’s thought that the molecular mechanisms underlying insulin resistance after a so-called ‘glucose challenge’ play a key role in the development of type 2 diabetes. Yet these mechanisms are poorly-understood.

Professor Sir Stephen O’Rahilly, Co-Director of the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge, said: “We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it’s acting mostly on the liver, but very poorly after a meal, when it’s acting mostly on muscle and fat. What has not been clear is whether this sort of problem occurs more commonly in the wider population, and whether it’s relevant to the risk of getting type 2 diabetes.” 

To examine these mechanisms, an international team of scientists used genetic data from 28 studies, encompassing more than 55 000 participants (none of whom had type 2 diabetes), to look for key genetic variants that influenced insulin levels measured two hours after a sugary drink.

The team identified new 10 loci (genome regions) associated with insulin resistance after the sugary drink. Eight of these regions were also shared with a higher risk of type 2 diabetes, highlighting their importance.

One of these newly-identified loci was located within the gene that codes for GLUT4, the critical protein responsible for taking up glucose from the blood into cells after eating. This locus was associated with a reduced amount of GLUT4 in muscle tissue.

To look for additional genes that may play a role in glucose regulation, the researchers turned to cell lines taken from mice to study specific genes in and around these loci. This led to the discovery of 14 genes that played a significant role in GLUT 4 trafficking and glucose uptake – with nine of these never previously linked to insulin regulation.

Further experiments showed that these genes influenced how much GLUT4 was found on the surface of the cells, likely by altering the ability of the protein to move from inside the cell to its surface. The less GLUT4 that makes its way to the surface of the cell, the poorer the cell’s ability to remove glucose from the blood.

Dr Alice Williamson, who carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science, said: “What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work – and in particular how, when these mechanisms go wrong, they can lead to common diseases such as type 2 diabetes.”

Given that problems regulating blood glucose after a meal can be an early sign of increased type 2 diabetes risk, the researchers are hopeful that the discovery of the mechanisms involved could lead to new treatments in future.

Source: University of Cambridge

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Cold Temperatures Could Reduce Obesity-induced Inflammation

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In a new paper published in Nature Metabolism, researchers found that cold temperature exposure resolved obesity-induced inflammation while improving insulin sensitivity and glucose tolerance in diet-induced obese mice. The process depended on brown adipose tissue producing a molecule called Maresin 2 when stimulated by cold.

Brown adipose tissue is known to be an active endocrine orgain which helps dissipate stored energy and might promote weight loss and metabolic health.  

“Extensive evidence indicates that obesity and metabolic syndrome are linked with chronic inflammation that leads to systemic insulin resistance, so interrupting inflammation in obesity could offer promising therapies for obesity-related disease,” said co-corresponding author Yu-Hua Tseng, PhD, professor of medicine at Harvard Medical School.  “We discovered that cold exposure reduced inflammation and improved metabolism in obesity, mediated at least in part by the activation of brown adipose tissue. These findings suggest a previously unrecognized function of brown adipose tissue in promoting the resolution of inflammation in obesity.”

In two previous studies, Tseng and colleagues discovered that cold exposure could activate brown fat to produce specific lipid mediators that regulate nutrient metabolism. In the current study, the researchers identified a novel role for a lipid mediator produced from brown fat to resolve inflammation.

In the present study, the scientists created a mouse model that becomes obese when fed a typical high-fat, Western diet. When the animals were exposed to a cold environment (around 4°C), the researchers observed that the animals’ insulin sensitivity and glucose metabolism improved and their body weight decreased, compared to control animals maintained at a thermoneutral zone – the environmental temperature where the body does not need to produce heat for maintaining its core body temperature. What’s more, the scientists also noticed a profound improvement in inflammation, as measured by reduced levels of a major inflammatory marker. 

“We found that brown fat produces Maresin 2, which resolves inflammation systemically and in the liver,” said co-corresponding author Matthew Spite, PhD, a lead investigator at Brigham and Women’s Hospital and Associate Professor of Anesthesia at Harvard Medical School. “These findings suggest a previously unrecognized function of brown adipose tissue in promoting the resolution of inflammation in obesity via the production of this important lipid mediator.”

Moreover, these findings also suggest that Maresin 2 could have clinical applications as a therapy for patients with obesity, metabolic disease, or other diseases linked to chronic inflammation; however, the molecule itself breaks down quickly in the body. Tseng and colleagues seek a more stable chemical analog for clinical use.

The team notes a shortcut to improved metabolic health may already exist. Multiple human studies show that exposure to mild cold temperatures (10 to 13°C) have been shown to be sufficient to activate brown adipose tissue and improve metabolism, though the mechanisms are not well understood.

Source: EurekaAlert

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Moderate Light Levels During Sleep Increases Insulin Resistance

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Even exposure to moderate light levels during nighttime sleep, compared to sleeping in a dimly lit room, harms cardiovascular function during sleep and increases insulin resistance the following morning, according to a new study published in PNAS.

“The results from this study demonstrate that just a single night of exposure to moderate room lighting during sleep can impair glucose and cardiovascular regulation, which are risk factors for heart disease, diabetes and metabolic syndrome,” said senior study author Dr Phyllis Zee at Northwestern University. “It’s important for people to avoid or minimise the amount of light exposure during sleep.”

There is evidence that daytime light exposure increases heart rate via sympathetic nervous system activation, increasing heart rate and alertness to meet the day’s challenges.

“Our results indicate that a similar effect is also present when exposure to light occurs during nighttime sleep,” Dr Zee said.

“We showed your heart rate increases when you sleep in a moderately lit room,” said Dr Daniela Grimaldi, a co-first author and research assistant professor of neurology at Northwestern. “Even though you are asleep, your autonomic nervous system is activated. That’s bad. Usually, your heart rate together with other cardiovascular parameters are lower at night and higher during the day.”

The sympathetic and parasympathetic nervous systems regulate the body physiology during the day and night. Sympathetic takes charge during the day and parasympathetic is supposed to at night, when it conveys restoration to the entire body.

The researchers found signs of insulin resistance the morning after people slept in a light room. An earlier study examined a large population of healthy people who had exposure to light during sleep, and found they were more overweight and obese, Dr Zee said.

“Now we are showing a mechanism that might be fundamental to explain why this happens. We show it’s affecting your ability to regulate glucose,” Dr Zee said.

The study participants were unaware of the biological shift in their bodies at night.

“But the brain senses it,” A/Prof Grimaldi said. “It acts like the brain of somebody whose sleep is light and fragmented. The sleep physiology is not resting the way it’s supposed to.”

Night-time exposure to artificial light is widespread in the modern world, either from light-emitting devices indoors, or from outdoor sources such as street lights. Up to 40% of people sleep with a bedside lamp on or with a light on in the bedroom and/or keep the television on.

“In addition to sleep, nutrition and exercise, light exposure during the daytime is an important factor for health, but during the night we show that even modest intensity of light can impair measures of heart and endocrine health,” said co-first author Dr Ivy Mason.

The study tested the effect of sleeping with 100 lux (moderate light) compared to 3 lux (dim light) in participants over a single night. Moderate light exposure caused the body to go into sympathetic activation. In blood vessels, sympathetic activation constricts arteries and arterioles which increases vascular resistance and decreases distal blood flow. When this occurs throughout the body, the increased vascular resistance causes arterial pressure to increase.

“These findings are important particularly for those living in modern societies where exposure to indoor and outdoor nighttime light is increasingly widespread,” Dr Zee said.

Zee’s top tips for reducing light during sleep

1) Keep lights off. If a light is necessary (eg for older people’s safety), keep it dim and close to the floor.

2) Colour is important: amber or red/orange light stimulates the brain. Avoid white or blue light.

3) Blackout shades or eye masks are good if outdoor light can’t be controlled. Move your bed so the outdoor light isn’t shining on your face

As a rule of thumb, Dr Zee said that being able to see things really well means it’s too light.

Source: Northwestern University

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A Specific Type of Fat Cell Responds to Insulin

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While it was known that fat cells can influence insulin sensitivity, researchers have recently discovered that there are three different subtypes of mature fat cells in white adipose tissue and that it is only one of these, called AdipoPLIN, that responds to insulin. The findings, which were published in Cell Metabolism, may have implications for the treatment of metabolic diseases such as Type 2 diabetes. 

“These findings increase our knowledge about the function of fat tissue,” said co-corresponding author Niklas Mejhert, researcher at the Department of Medicine, Huddinge, at Karolinska Institutet. “They show that the overall capacity of fat tissue to respond to insulin is determined by the proportion and function of a specific fat cell subtype. This could have implications for diseases such as obesity, insulin resistance and Type 2 diabetes.”

The researchers identified 18 classes of cells that form clusters in white adipose tissue in humans. Of these, three constituted mature fat cells with distinct phenotypes.

To determine if a specific function was linked to the fat cell subtypes, the researchers measured how these subtypes in four people reacted to short-term increases in insulin levels. They found that insulin activated the gene expression in the AdipoPLIN subtype but did not affect the other two subtypes. The response to insulin stimulation was also proportional to the individual’s whole-body insulin sensitivity.

A challenge to the prevailing view
“Our findings challenge the current view of insulin resistance as a generally reduced response to insulin in the fat cells,” said co-corresponding author Mikael Rydén, professor in the same department. “Instead, our study suggests that insulin resistance, and possibly type 2 diabetes, could be due to changes in a specific subtype of fat cells. This shows that fat tissue is a much more complex tissue than previously thought. Like muscle tissue, people have several types of fat cells with different functions, which opens up for future interventions targeted at different fat cell types.”

The researchers employed spatial transcriptomics, which generates information about tissue organisation via microscopy and gene expression via RNA sequencing.

”This study is unique in that it is the first time we’ve applied spatial transcriptomics to fat tissue, which has a special set of characteristics and composition,” said third corresponding author Patrik Ståhl. “We are very happy that the technology continues to contribute to solving biologically complex questions in an increasing number of research areas.”

Source: Karolinska Institute