insulin

Posted on Diabetes

UBC-developed oral insulin drops offer relief for diabetes patients.

Sublingual drops easily and efficiently absorbed by the body, potentially replacing insulin injections
Sublingual drops are easily and efficiently absorbed by the body, potentially replacing insulin injections.

Diabetes rates continue to rise, with 11.7 million Canadians living with diabetes or pre-diabetes. At UBC, scientists have created a pain-free drug delivery method to help people with diabetes manage the disease and maintain their health more easily.

Researchers at the Li Lab have developed oral insulin drops that, when placed under the tongue, are quickly and efficiently absorbed by the body, potentially replacing the need for insulin injections.

The drops contain a mixture of insulin and a unique cell-penetrating peptide (CPP) developed by Dr. Shyh-Dar Li and colleagues.

A little help from a peptide guide

“Insulin is a complicated molecule,” explains lead researcher Dr. Li, a professor in the faculty of pharmaceutical sciences. “In pill form, it’s easily destroyed in the stomach. Insulin must also be rapidly available in the blood, but as a large molecule, it cannot get through cells easily on its own.” The peptide, sourced from fish byproducts, opens a pathway for insulin to cross over.

Pre-clinical tests showed that insulin with the peptide effectively reaches the bloodstream, whereas, without the peptide, insulin remains stuck in the inside lining of the mouth.

“Think of it as a guide that helps insulin navigate through a maze to reach the bloodstream quickly. This guide finds the best routes, making it easier for insulin to get where it needs to go,” said Dr. Jiamin Wu, a postdoctoral researcher in the Li Lab.

Recent articles in the Journal of Controlled Release (here and here) describe two versions of the peptide. The UBC team is working to license the technology to a commercial partner.

Keeping medications on track

Healthy people naturally get insulin from the pancreas to regulate glucose after meals. Diabetes patients cannot produce sufficient insulin and need to get it from an outside source.

Unregulated glucose can be very dangerous, so diabetes patients must monitor their glucose levels and take insulin to lower it when necessary. While injections are the fastest way to get insulin into the blood, patients typically need at least three to four injections daily, affecting their quality of life. Adherence to this regimen is challenging, and over time, this can cause severe complications such as eye, kidney and nerve damage, potentially leading to limb amputations.

“My lab has been working on needle-free insulin alternatives these past three years,” said Dr. Li. “We tried nasal sprays before landing on oral drops, which are easy and convenient. Hopefully, the oral drops open up a new possibility for diabetes patients – making it easier to take their medications and regulate their blood glucose to maintain their health in the long run.”

Posted on Diabetes

Do sex differences in how we respond to insulin explain why type 2 diabetes is more common in men?

“In insulin resistance, fat cells are less sensitive to insulin and so both of these processes are impaired. This can lead to more fat circulating in the bloodstream, which raises the risk of T2D.
“In insulin resistance, fat cells are less sensitive to insulin, so both processes are impaired. This can lead to more fat circulating in the bloodstream, which raises the risk of diabetes.

New research could help explain why type 2 diabetes is more common in men than in women.

“Previous studies have shown that men develop type 2 diabetes ( at a younger age and a lower weight than women and, overall, men appear to be at higher risk of the condition,” says lead researcher Dr Daniel P Andersson, at the Department of Endocrinology, Karolinska University Hospital Huddinge, Stockholm, Sweden. “One reason for this may be differences in how the sexes’ adipose tissue responds to insulin. 

“Adipose tissue is the main organ for the storage of excess energy, and this is done in lipids called triglycerides, which consist of free fatty acids. When there is excess energy, insulin decreases the breakdown of triglycerides (lipolysis) releases free fatty acids to the blood and increases energy storage as triglycerides (lipogenesis) in fat cells.

“If the insulin resistance of adipose cells is more pronounced, or severe, in men than in women, this could help explain why T2D is more common in men than women.”

To explore this further, Dr Andersson measured the adipose insulin resistance index (AdipolR, a measure of insulin sensitivity of fat cells, with higher values indicating more insulin resistance) in 2,344 women and 787 men, with an average age of 44 years and BMI of 35 kg/m2.

Men had higher AdipoIR values than women, but only when obesity (body mass index 30 kg/m² or more) was present. This was the case both for physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine and not.

In a subgroup of 259 women and 54 men living with obesity, the researchers also took biopsies from the adipose tissue to study the effect of insulin on isolated fat cells.

This showed clear differences between the sexes. In men, compared to women, a 10-fold higher concentration of insulin was needed to block the breakdown of triglycerides to fatty acids, and the blockage was also less effective in men.

However, the storage capacity of the fat cells was similar for both sexes.

Dr Andersson explains: “In individuals who are living with obesity, you often have an excess of energy available in the body and insulin should decrease the release of fatty acids and increase the storage of lipids in adipose tissue to reduce the free fatty acids circulating in the blood.

“When looking at sex differences, we found that men who were living with obesity had increased adipose insulin resistance and higher levels of free fatty acids in the blood.

“The differences seen between men and women were mainly related to decreased ability of insulin to block the breakdown of fatty acids in fat cells from men rather than sex differences in storage capacity.

“Fatty acids in the bloodstream have effects in the liver, muscle and the pancreas and could lead to further local insulin resistance in these organs, creating a vicious circle that, over time, could lead to development of type 2 diabetes.”

The researchers conclude that in individuals who are living with obesity, adipose tissue insulin resistance is more severe in men than in women, which may partly explain why T2D is more common in men.

Posted on Diabetes

Drug manufacturers use FDA, patent strategies to keep insulin prices high

Drug manufacturers use FDA, patent strategies to keep insulin prices high

Researchers highlight how manufacturers have listed an increasing number of patents on insulin products over the years. CREDIT Towfiqu barbhuiya, Unsplash (CC0, https://creativecommons.org/publicdomain/zero/1.0/)

Over the last four decades, insulin manufacturers have extended their periods of market exclusivity on brand-name insulin products by employing several strategies, including filing additional patents on their products after FDA approval and obtaining many patents on delivery devices for their insulin products. That is the conclusion of a new analysis of FDA and patent records carried out by William Feldman of Brigham and Women’s Hospital, USA, and colleagues, and published November 16th in the open access journal PLOS Medicine.

Insulin is the primary, life-saving treatment for type 1 and some type 2 diabetes but remains costly in the US even though it was discovered more than a century ago. A 2021 Congressional report found that for decades, the three major manufacturers of insulin continuously raised prices, often in tandem with one another. These high prices are additionally sustained by patents and regulatory exclusivity that limit competition on brand-name products. Patents are government-granted monopolies that last 20 years and the Food and Drug Administration (FDA) cannot approve generic versions of drugs for marketing until patents have expired.

In the new study, researchers used publicly available U.S. FDA and patent data to track all insulin products approved in the U.S. from 1986 to 2019. During the study period, the FDA approved 56 brand-name insulin products.

The researchers found that protection on insulin was enhanced by patents obtained after FDA approval, which lengthened expected market exclusivity by a median of 6 years. Moreover, many patents were on the insulin delivery devices rather than the drugs themselves. In two-thirds of drug-device combinations, the device patents were the last to expire; these last-to-expire device patents extended protection for a median of 5.2 years. Overall, manufacturers secured a median of 16 years of protection on their insulin products through patents and exclusivities, surpassing the median of 14 years observed in other studies of top-selling small-molecule drugs. The insulin lines with the longest periods of expected protection from the first product approved to last-to-expire patent was Lantus (32.9 years), followed by Novolog (32.3 years) and Novolog 70/30 (30.9 years).

“Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have timely access to drugs at fair prices,” the authors say.

Feldman adds, “Our study highlights how manufacturers have listed an increasing number of patents on insulin products over the years. These patents can delay competition and keep prices high for patients.”

Posted on Obesity

Obesity is linked to neurodegeneration through insulin resistance.

Obesity linked to neurodegeneration through insulin resistance

Sugar fly. Artistic rendering generated by DALL.E the prompt used is “The drawing of the fruit fly Drosophila in a dark background in the style of Seurat”. The researchers fed fruit flies high sugar diets and examined the effect on brain function. CREDIT Akhila Rajan created this image using DALL-E and owns it. They are making it available under CC-BY 4.0 (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

Researchers led by Mroj Alassaf at the Fred Hutchinson Cancer Research Center in the United States have discovered a link between obesity and neurodegenerative disorders like Alzheimer’s disease. Using the common fruit fly, the research shows that a high-sugar diet — a hallmark of obesity — causes insulin resistance in the brain, which in turn reduces the ability to remove neuronal debris, thus increasing the risk of neurodegeneration. Publishing November 7th in the open access journal PLOS Biology, the research will impact therapies designed to reduce the risk of developing neurodegenerative diseases.

Although obesity is known to be a risk factor for neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease, exactly how one leads to the other remains a mystery. The new study focused on answering this question by taking advantage of the similarity between humans and fruit flies. Having previously shown that a high-sugar diet leads to insulin resistance in the peripheral organs of flies, the researchers now turned to their brains. Specifically, they examined glial cells because microglial dysfunction is known to lead to neural degeneration.

Levels of the protein PI3k indicate how much a cell is able to respond to insulin. The researchers found that the high sugar diet led to reduced PI3k levels in glial cells, indicating insulin resistance. They also looked at the fly equivalent of microglia, called ensheathing glia, whose primary function is to remove neural debris, such as degenerating axons. They observed that these glia had low levels of the protein Draper, indicating impaired function. Further tests revealed that artificial reduction of PI3k levels led to both insulin resistance and low Draper levels in ensheathing glia. Finally, they showed that after actually damaging olfactory neurons, the ensheathing glia could not remove the degenerating axons in the flies on the high sugar diet because their Draper levels did not increase.

The authors add, “Using fruit flies, the authors establish that high-sugar diets trigger insulin resistance in glia, disrupting their ability to clear neuronal debris. This study provides insight into how obesity-inducing diets potentially contribute to the increased risk of neurodegenerative disorders.”

Posted on Diabetes, Patient Talk

A step closer to injection-free diabetes care: U of A’s innovation in insulin-producing cells

Using a patient’s own stem cells to replace insulin-producing cells “the horizon” for treating diabetes, says researcher
Using a patient’s own stem cells to replace insulin-producing cells “the horizon” for treating diabetes, says researcher

A University of Alberta team has developed a new step to improve the process for creating insulin-producing pancreatic cells from a patient’s own stem cells, bringing the prospect of injection-free treatment closer for people with diabetes.

The researchers take stem cells from a single patient’s blood and chemically wind them back in time, then forward again in a process called “directed differentiation,” to eventually become insulin-producing cells.

In research published this month, the team treated pancreatic progenitor cells with an anti-tumour drug known as AKT/P70 inhibitor AT7867. They report the method produced the desired cells at a rate of 90 per cent, compared with previous methods that produced just 60 per cent target cells. The new cells were less likely to produce unwanted cysts and led to insulin injection-free glucose control in half the time when transplanted into mice. The team believes its efforts will soon be able to eliminate the final five to 10 per cent of cells that do not result in pancreatic cells.

“We need a stem cell solution that provides a potentially limitless source of cells,” says James Shapiro, Canada Research Chair in Transplant Surgery and Regenerative Medicine and head of the Edmonton Protocol, which has allowed 750 transplantations of donated islet cells since it was first developed 21 years ago. “We need a way to make those cells so that they can’t be seen and recognized as foreign by the body’s immune system.”

The researchers suggest this safer and more reliable way to grow insulin-producing cells from a patient’s own blood could eventually allow transplants without the need for anti-rejection drugs. Recipients of donated cells must take anti-rejection drugs for life, and the therapy is limited by the small number of donated organs available. 

Shapiro says further safety and efficacy studies will need to be carried out before transplantation of stem-cell-derived islet cells is ready for human trials, but he is excited by the progress.

“What we’re trying to do here is peer over the horizon and try to imagine what diabetes care is going to look like 15, 20, 30 years from now,” he says. “I don’t think people will be injecting insulin anymore. I don’t think they’ll be wearing pumps and sensors.”