Intranasal insulin induces an increase in the [11C] raclopride binding potential in the striatum, which indicates a decrease in the synaptic dopamine level. © IDM

In the human brain, the hormone insulin also acts on the most important neurotransmitter for the reward system, dopamine. This was shown by researchers from the German Center for Diabetes Research (DZD) in Tübingen. Insulin lowers the dopamine level in a specific region of the brain (striatum *) that regulates reward processes and cognitive functions, among other things. This interaction can be an important driver of the brain’s regulation of glucose metabolism and eating behavior. The study has now been published in the Journal of Clinical Endocrinology & Metabolism.  

Worldwide, more and more people are developing obesity and type 2 diabetes. Studies show that the brain plays an important role in causing these diseases. Dopamine is the most important neurotransmitter for the reward system. The hormone insulin is released after eating and regulates the metabolism in the human body (homeostatic system). It is not yet known how these two systems interact. However, changes in these systems have been linked to obesity and diabetes. In the current study, researchers from the Institute of Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, a partner of the DZD, and Tübingen University Hospital (Innere IV, Director: Prof. Andreas Birkenfeld) examined how the two systems interact specifically in the reward center of the brain, the striatum.  

“Our eating behavior is regulated by the interaction between the reward system and homeostatic systems. Studies indicate that insulin also acts in dopamine-driven reward centers in the brain. It has also been shown that obesity leads to changes in the signaling of the brain that have a negative effect on the glucose metabolism in the whole body,” said first author Stephanie Kullmann. “We now wanted to decipher the interaction between the two systems in humans and find out how insulin regulates the dopamine system.” 

For this purpose, ten healthy, normal-weight men received insulin or a placebo via a nasal spray (randomized, placebo-controlled, blinded crossover study). When insulin is absorbed via the nose, it reaches the brain directly. To study the interaction between insulin and dopamine, the researchers used a unique measurement technique: they combined magnetic resonance imaging to assess functional brain activity and positron emission tomography to assess dopamine levels.   

Analysis of the study showed that the intranasal administration of insulin lowered dopamine levels and led to changes in the brain’s network structure. “The study provides direct evidence of how and where in the brain signals triggered after eating – such as insulin release and the reward system – interact,” said Professor Martin Heni, last author of the study, summarizing the results. “We were able to show that insulin is able to decrease dopamine levels in the striatum in normal-weight individuals. The insulin-dependent change in dopamine levels was also associated with functional connectivity changes in whoe-brain networks. Changes in this system may be an important driver of obesity and related diseases.” 

In further studies, the researchers want to investigate changes in the interaction of dopamine and insulin in obese or diabetic participants. These people often suffer from insulin resistance in the brain. The researchers therefore assume that this resistance prevents the normal insulin-induced regulation of dopamine levels in the reward center. In further steps, they want to restore the normal action of insulin in the brain by behavioral and/or pharmaceutical interventions. 

Insulin is one of the most well known hormones in the human body for its role in regulating blood glucose. While its absence or inaction causes diabetes (Type-I and Type-II), it is also associated with several metabolic disorders such as obesity, hypertension, cancer and aging. Levels of insulin, produced by the pancreas, fluctuate between fasted and fed states in a normal healthy individual. However, abnormally high amounts of insulin could be found either in hyper-insulinemic states (pre-/early-diabetic) or during treatments with clinically administered insulin (for both types of diabetes).

Diabetes is often associated with tissue damage resulting in neuropathy, nephropathy and myopathy among others. This is linked to insulin (in)action since besides its essentiality for maintaining glycemic index, it is critical for controlling tissue growth and repair.

Insulin dependent effects are mediated by an intricate and elaborate network of molecules that convey information, inside all cells, about the presence and concentrations of insulin and constitute the insulin signaling cascade. The flow of information within the different components of insulin signaling cascade dictates the uptake and utilization of glucose for metabolism and tissue growth.

Albeit decades of work elucidated the molecular components of the insulin signaling cascade, how information is conveyed amongst these different molecules in response to varied insulin inputs is still unknown. Besides being fundamentally important to our understanding of action of insulin under fed and fasted states, this is relevant in the context of diabetes, both emergence and treatment.

Moreover, with excess consumption of high calorie diets and aberrant or uncontrolled feeding habits, if/how perturbed information flow in insulin signaling cascade, under these conditions, lead to ‘insulin resistance’ has not been addressed thus far.

The study illustrates robustness of information flow in the signaling cascade in response to normal and abnormal insulin inputs. It demonstrates the importance of normal feed-fast cycles with the discovery of fasted insulin inputs leading to better response to fed insulin inputs. The findings also elucidate the detrimental impact of constant high insulin as in the case of uncontrolled feeding habits, without a fasting phase, and effects on signaling molecules that govern tissue maintenance and growth. The study identifies potential novel regulatory components and parameters whose modulation could lead to better therapeutic interventions in the future to reduce tissue damage, beyond the usual impact on blood glucose.

The study uncovers hitherto unknown mechanisms that regulate robustness of information flow through insulin signaling. In addition to highlighting the importance of normal insulin cycles (during feeding and fasting), it identifies components that could perturb the signaling cascade under situations of hyper-insulinemia as in diabetes and clinical insulin administration. The study also raises the possibility of re-evaluation of insulin dosing (amounts and frequency) to ascertain its impact on molecular components that protect tissues from damage, beyond maintenance of blood glucose levels.

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In purple, the tanycytes that form the brain’s cellular gateway to the hormone leptin; in yellow, the appetite-inducing neurons and, in blue, the appetite-suppressing neurons. Leptin targets both neuron types, inhibiting the former and using its appetite-suppressant signal to activate the latter. CREDIT Inserm/Vincent Prévot

Leptin, the satiety or appetite-suppressant hormone, is secreted by the adipose tissue at levels proportional to the body’s fat reserves and regulates appetite by controlling the feeling of fullness.  It is transported to the brain by tanycytes – cells which it enters by attaching to the LepR receptors. Tanycytes are therefore leptin’s gateway to the brain, helping it to cross the blood-brain barrier and deliver satiety information to the neurons.

Previous research has revealed that such transport is impaired in subjects who are obese or overweight. This goes some way to explaining their dysfunctional appetite regulation given that it is more difficult for the information on satiety to reach the brain. In their new study, the researchers took a closer look at this transport mechanism, and more precisely the role played by the LepR receptors.

The key role of satiety hormone receptors in glucose management

In mouse models, the researchers removed the LepR receptor that is located on the surface of the tanycytes. After three months, the mice experienced a marked increase in their fat mass (which doubled over the period) as well as a loss of muscle mass (reduced by more than half). The total amount of weight gained was only fairly moderate. The scientists also regularly measured the animals’ blood sugar levels following the injection of glucose.

They found that in order to maintain blood sugar at normal levels (between 0.70 and 1.10 g/L), the mice secreted more insulin during the first four weeks of the experiment. Three months after removing the receptor, their ability to secrete insulin from the pancreas appeared to be exhausted.

Removing the LepR receptors and impairing leptin transport to the brain therefore led the mice to initially develop a pre-diabetic state. This occurs when the body releases more insulin than usual in order to control blood sugar. Then, in the longer term, the mice became unable to secrete insulin and as such unable to control their blood sugar levels. These data therefore suggest that impaired leptin transport to the brain via the LepR receptors plays a role in the development of type 2 diabetes.

In the last part of their research, the scientists reintroduced leptin to the brain and observed the immediate resumption of its pancreatic function-promoting action – particularly the ability of the pancreas to secrete insulin to regulate blood sugar. The mice quickly regained a healthy metabolism.

This study therefore elucidates the brain’s role in type 2 diabetes and also helps to further research into a disease that until then had not been considered to involve the central nervous system.

“We show that the brain’s perception of leptin is essential for the management of energy homeostasis[1] and blood sugar. We also show that blocking the transport of leptin to the brain impairs the functioning of the neurons that control pancreatic insulin secretion,” concludes Vincent Prévot, research director at Inserm and last author of the study.

To 3D print vascularized hydrogels that can be turned into living tissue, Rice University bioengineers use (top left) a nontoxic liquid polymer that is (top middle) solidified one layer at a time by blue light. Yellow food coloring absorbs the light, allowing for the creation of passageways for flowing blood. Postdoctoral researcher Kristen Means (top right) displays a printed hydrogel that was secured (bottom right and middle) in a plastic housing for graduate student Madison Royse’s (bottom left) blood-flow demonstration using liquid dye. CREDIT Photos by Jeff Fitlow/Rice University

Rice University bioengineers are using 3D printing and smart biomaterials to create an insulin-producing implant for Type 1 diabetics.

The three-year project is a partnership between the laboratories of Omid Veiseh and Jordan Miller that’s supported by a grant from JDRF, the leading global funder of diabetes research. Veiseh and Miller will use insulin-producing beta cells made from human stem cells to create an implant that senses and regulates blood glucose levels by responding with the correct amount of insulin at a given time.

Veiseh, an assistant professor of bioengineering, has spent more than a decade developing biomaterials that protect implanted cell therapies from the immune system. Miller, an associate professor of bioengineering, has spent more than 15 years researching techniques to 3D print tissues with vasculature, or networks of blood vessels.

“If we really want to recapitulate what the pancreas normally does, we need vasculature,” Veiseh said. “And that’s the purpose of this grant with JDRF. The pancreas naturally has all these blood vessels, and cells are organized in particular ways in the pancreas. Jordan and I want to print in the same orientation that exists in nature.”

Type 1 diabetes is an autoimmune disease that causes the pancreas to stop producing insulin, the hormone that controls blood-sugar levels. About 1.6 million Americans live with Type 1 diabetes, and more than 100 cases are diagnosed each day. Type 1 diabetes can be managed with insulin injections. But balancing insulin intake with eating, exercise and other activities is difficult. Studies estimate that fewer than one-third of Type 1 diabetics in the U.S. consistently achieve target blood glucose levels.

Veiseh’s and Miller’s goal is to show their implants can properly regulate blood glucose levels of diabetic mice for at least six months. To do that, they’ll need to give their engineered beta cells the ability to respond to rapid changes in blood sugar levels.

“We must get implanted cells in close proximity to the bloodstream so beta cells can sense and respond quickly to changes in blood glucose,” Miller said.

Ideally, insulin-producing cells will be no more than 100 microns from a blood vessel, he said.

“We’re using a combination of pre-vascularization through advanced 3D bioprinting and host-mediated vascular remodeling to give each implant several shots at host integration,” Miller said.

The insulin-producing cells will be protected with a hydrogel formulation developed by Veiseh, who is also a Cancer Prevention and Research Institute of Texas Scholar. The hydrogel material, which has proven effective for encapsulating cell treatments in bead-sized spheres, has pores small enough to keep the cells inside from being attacked by the immune system but large enough to allow passage of nutrients and life-giving insulin.

“Blood vessels can go inside of them,” Veiseh said of the hydrogel compartments. “At the same time, we have our coating, our small molecules that prevent the body from rejecting the gel. So it should harmonize really well with the body.”

If the implant is too slow to respond to high or low blood sugar levels, the delay can produce a roller coaster-like effect, where insulin levels repeatedly rise and fall to dangerous levels.

“Addressing that delay is a huge problem in this field,” Veiseh said. “When you give the mouse — and ultimately a human — a glucose challenge that mimics eating a meal, how long does it take that information to reach our cells, and how quickly does the insulin come out?”

By incorporating blood vessels in their implant, he and Miller hope to allow their beta-cell tissues to behave in a way that more closely mimics the natural behavior of the pancreas.

A transplant of healthy gut microbes followed by fibre supplements benefits patients with severe obesity and metabolic syndrome, according to University of Alberta clinical trial findings published today in Nature Medicine.

Patients who were given a single-dose oral fecal microbial transplant followed by a daily fibre supplement were found to have better insulin sensitivity and higher levels of beneficial microbes in their gut at the end of the six-week trial. Improved insulin sensitivity allows the body to use glucose more effectively, reducing blood sugar.

“They were much more metabolically healthy,” said principal investigator Karen Madsen, professor of medicine in the Faculty of Medicine & Dentistry and director of the Centre of Excellence for Gastrointestinal Inflammation and Immunity Research.

“These patients were on the best known medications (for metabolic syndrome) and we could improve them further, which shows us there is an avenue for improvement by targeting these different pathways in the microbiome.”

Sixty-one patients with a body mass index of 40 or higher completed the double-blind, randomized trial. Recruited from the bariatric surgery waitlist in Edmonton, all had metabolic syndrome, a condition that includes insulin resistance, high blood glucose, high blood pressure and other complications. It can eventually lead to diabetes.

The microbiome is all of the bugs–micro-organisms, bacteria, viruses, protozoa and fungi–found in the gastrointestinal tract. People with various diseases are known to have altered microbial contents. It is not fully understood whether microbiome changes cause disease or whether disease causes changes in the gut, but it is likely a bit of both, Madsen said. It is known that replacing unhealthy bacteria with healthy bacteria can lead to improved health.

Fecal transplants, which contain microbes from healthy stool donors, are currently used extensively for treating Clostridium difficile, or C. difficile, bacterial infections, and research is underway to test their usefulness in treating other illnesses such as inflammatory bowel disease, mental health and metabolic disorders.

“We know that the gut microbiome affects all of these processes–inflammation, metabolism, immune function,” said Madsen, who is a member of the Women and Children’s Health Research Institute and is one of the University of Alberta leads for the national Microbiome Research Core (IMPACTT).

“The potential for improving human health through the microbiome is immense,” Madsen said. “We are only scratching the surface at the moment.”

This is the first study to show that oral delivery of fecal transplantation is effective in patients with obesity-related metabolic syndrome.

A previous study done in Europe on a small number of male patients with obesity and metabolic syndrome had shown promising results, but the transplants in that study were given through an invasive endoscopy (a tube down the throat) and the patients had milder disease.

The fecal microbial transplants in this study were from four lean, healthy donors, and were taken by mouth in a single dose of about 20 capsules prepared in a U of A lab. The capsules have no taste or odour.

The fibre supplements following the transplant were key to the success, Madsen said.

“When you transplant beneficial microbes, you need to feed them to keep them around,” Madsen explained. “If you give a new microbe and you don’t feed it, if you continue to eat a diet of processed foods and no fibre, then that microbe will likely die.”

Our bodies do not naturally produce the enzymes needed to break down fibre, but that’s what healthy bacteria in the microbiome need to live, thus the supplements. The team experimented with fermentable fibre (the kind found in beans, which produce gas) and non-fermentable fibre (essentially cellulose, found in whole grains).

“Non-fermentable fibre can change gut motility–how fast things move through–as well as acting as a bulking and binding agent that can change levels of bile acids, which could help explain our results,” Madsen explained.

Madsen said the next step will be to do a longer study with more participants in multiple centres to learn how the transplant/fibre combination works and to monitor for changes in medication requirements, weight loss and other indicators. If results continue to show benefit, she said the pills could be available as a potential therapy within five years.

While scientists continue to narrow down which bacteria are the most beneficial for us, Madsen recommends we support the health of our own gut microbiome by eating fewer processed foods and more foods that contain fibre, such as whole grains, fruits and vegetables.