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.”

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.

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 16^th 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.”