Chemist designs diabetic treatment minus harmful side effects

February 9, 2018, Syracuse University
Chemist designs diabetic treatment minus harmful side effects
A 3-D illustration of the pancreas secreting insulin. Credit: sciencepics/Shutterstock.com

A chemist in the College of Arts and Sciences (A&S) has figured out how to control glucose levels in the bloodstream without the usual side effects of nausea, vomiting or malaise.

Robert Doyle, the Laura J. and L. Douglas Meredith Professor of Teaching Excellence and professor of chemistry, is the inventor of a new compound that triggers the secretion of insulin in the pancreas without associated nausea. Working with colleagues at the University of Pennsylvania (Penn), the Seattle Children's Hospital and SUNY Upstate Medical University, he has designed a conjugate of vitamin B12 that is bound to an FDA-approved drug known as Ex4.

Doyle expects his compound, called B12-Ex4, to offer a broader scope of available treatment options for because of its ability to improve glucose tolerance without the associated side effects.

His findings are part of a groundbreaking paper he has co-authored in Diabetes, Obesity and Metabolism (John Wiley & Sons, 2018). A related paper of his addressing glucoregulation and appetite suppression is scheduled to run in Scientific Reports.

"This represents an interesting new paradigm for the treatment of Type 2 diabetes, using so-called GLP1-R agonist drugs, which make up a multi-billion dollar industry," says Doyle, also an associate professor of medicine at SUNY Upstate. "Our findings highlight the potential clinical utility of B12-Ex4 conjugates as therapeutics to treat Type 2 diabetes, with reduced incidence of adverse effects."

Type 2 diabetes is marked by increased levels of glucose in the blood or urine, when the body is unable to use or produce enough insulin. Long-term complications include eye, kidney or nerve damage; heart attack or stroke; or problems with the wound-healing process.

Doyle's discovery stems from his work with exenatide, a drug that causes the pancreas to secrete insulin when are high. (Insulin is a hormone that moves glucose from the blood to various cells and tissues, where the sugar turns into energy.) Used to treat Type 2 diabetes, exenatide is part of a large class of medications called incretin mimetics. These injectable drugs bind to glucagon-like peptide receptors (GLP1-R) to stimulate the release of insulin.

A drawback of exenatide is that GLP1-R is found in the pancreas and brain. Stimulating the receptor in the pancreas leads to positive aspects of glucose control, but doing so in the hypothalamus (the part of the brain coordinating the nervous system and pituitary gland) causes malaise and nausea.

"We were able to mitigate the side effects of exenatide by preventing it from entering the brain, while allowing it to penetrate other areas of the body, such as the pancreas," says Doyle, whose research focuses on the chemistry of B12, exploiting its properties and dietary pathway for drug delivery. "Our ability to 'fix' Ex-4 as a proof of concept could impact obesity and cancer treatment, since we can use our drug system to prevent or modulate central nervous system [CNS]-mediated side effects. In the case of Ex-4, this [side effect] was chronic nausea."

Critical to Doyle's research are GLP-1R agonists—synthetic, peptide-based chemicals that bind to organs or cells, causing them to produce a biological response. These peptide conjugates of insulin are the only known hormones able to decrease blood-sugar levels by enhancing the secretion of . They do this by reducing food intake and body weight.

Doyle says these drugs are effective for treating obesity, but many Type 2 diabetics are not obese or overweight: "In fact, they should avoid losing weight altogether."

Add to that the prevalence of nausea or vomiting, and the chances of skipping doses or discontinuing treatment increase considerably. "These are surprisingly under-investigated, and they limit the full, widespread use and efficacy of GLP-1R agonists for the treatment of metabolic disease," he continues.

In response to critical need, Doyle's lab has spearheaded the development of a next-generation incretin therapeutic that controls blood sugar without causing a reduction in food intake or change in eating behavior. "This method of conjugation is ideal for the future treatment of Type 2 diabetes," says Doyle, adding that Syracuse University owns the patent on this work. "It also may be broadly beneficial to other therapeutics that would benefit from reduced CNS penetrance."

Explore further: Peptide improves glucose and insulin sensitivity, lowers weight in mice

More information: Elizabeth G. Mietlicki-Baase et al. A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without Associated Nausea or Hypophagia in Rodents, Diabetes, Obesity and Metabolism (2018). DOI: 10.1111/dom.13222

Related Stories

Peptide improves glucose and insulin sensitivity, lowers weight in mice

February 8, 2018
Treating obese mice with catestatin (CST), a peptide naturally occurring in the body, showed significant improvement in glucose and insulin tolerance and reduced body weight, report University of California San Diego School ...

Ozempic approved for type 2 diabetes

December 6, 2017
(HealthDay)—Ozempic (semaglutide) has been approved by the U.S. Food and Drug Administration as a weekly injection to treat type 2 diabetes in adults.

Targeting a microRNA shows potential to enhance effectiveness of diabetes drugs

November 7, 2017
Over the past 15 years, University of Alabama at Birmingham endocrinologist Anath Shalev, M.D., has unraveled a crucial biological pathway that malfunctions in diabetes.

Sugar sponges sop up and release glucose as needed

May 31, 2017
Many diabetes patients must inject themselves with insulin, sometimes several times a day, while others take medications orally to control blood sugar. The injections, as well as the side effects from both regimens, can be ...

Artificial pancreas performs well in clinical trial

October 16, 2017
During more than 60,000 hours of combined use of a novel artificial pancreas system, participants in a 12-week, multi-site clinical trial showed significant improvements in two key measures of well-being in people living ...

Recommended for you

Team provides insight into glucagon's role in diabetic heart disease

February 21, 2018
A UT Southwestern study reveals the hormone glucagon's importance to the development of insulin resistance and cardiac dysfunction during Type 2 diabetes, presenting opportunities to develop new therapies for diabetic diseases ...

Physical exercise reduces risk of developing diabetes: study

February 20, 2018
Exercising more reduces the risk of diabetes and could see seven million fewer diabetic patients across mainland China, Hong Kong and Taiwan, according to new research.

Some viruses produce insulin-like hormones that can stimulate human cells—and have potential to cause disease

February 19, 2018
Every cell in your body responds to the hormone insulin, and if that process starts to fail, you get diabetes. In an unexpected finding, scientists at Joslin Diabetes Center have identified four viruses that can produce insulin-like ...

Researchers discover link between gut and type 1 diabetes

February 19, 2018
Scientists have found that targeting micro-organisms in the gut, known as microbiota, could have the potential to help prevent type 1 diabetes.

Researchers find existing drug effective at preventing onset of type 1 diabetes

February 15, 2018
A drug commonly used to control high blood pressure may also help prevent the onset of type 1 diabetes in up to 60 percent of those at risk for the disease, according to researchers at the University of Colorado Anschutz ...

Chemist designs diabetic treatment minus harmful side effects

February 9, 2018
A chemist in the College of Arts and Sciences (A&S) has figured out how to control glucose levels in the bloodstream without the usual side effects of nausea, vomiting or malaise.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Anonym917177
not rated yet Feb 09, 2018
I was diagnosed with type 2 Diabetes and put on Metformin on June 26th, 2017. I started the ADA diet and followed it 100% for a few weeks and could not get my blood sugar to go below 140. Finally i began to panic and called my doctor, he told me to get used to it. He said I would be on metformin my whole life and eventually insulin. At that point i knew something wasn't right and began to do a lot of research. Then I found Lisa's diabetes story (google " How I freed myself from diabetes " ) I read that article from end to end because everything the writer was saying made absolute sense. I started the diet that day and the next week my blood sugar was down to 100 and now i have a fasting blood sugar between Mid 70's and the 80's. My doctor took me off the metformin after just three week of being on this lifestyle change. I have lost over 16 pounds and 3+ inches around my waist in a month. The truth is we can get off the drugs and help myself by trying natural methods

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.