100, 100: JDRF Research Leads to a New Class of Glucose-Lowering Agents

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Woman taking an injection on her stomach

You’ve seen the ads: Victoza®. Ozempic®. Trulicity®.

They are for type 2 diabetes, and they lower your blood-sugar levels and cause the majority of people who use them to lose weight. And they can lower your risk of major cardiovascular events, such as heart attack and stroke.

But did you know that these drugs came about, in part, because of type 1 diabetes (T1D) research?

In honor of the 100th anniversary of the first administration of insulin, JDRF launched “100 Years, 100 JDRF Scientists,” to tell the story of scientists and their discoveries, which put together the vast knowledge that we have about diabetes today.

The next one: GLP-1 treatments.

Cloning the Hormone Glucagon

You read about the cloning and expression of insulin in our latest “100, 100,” but it does not stop with insulin. When she was a postdoctoral fellow working in the laboratory of Joel Habener, Ph.D., Pauline Kay Lund, Ph.D.—who would go on to receive a 1982-1985 JDRF Career Development Award—was the first to clone the hormone glucagon and discover two new hormones: glucagon-like peptide 1 (GLP-1) and 2 (GLP-2).

Said Lund, in an interview published in the Autumn 1985 issue of Countdown: “By understanding the factors which regulate glucagon gene activity and the production of glucagon, GLP-1, and GLP-2, it should be possible to predict the dietary and hormonal influences which best produce normal regulation of plasma glucose. This will aid in development of preventive and therapeutic measures to produce normal glucose regulation in patients with diabetes.”

In other words, understanding the protein could lead to the development of drugs that can help you reach a better blood-sugar range for people with diabetes.

Subsequent work revealed that GLP-1 encourages the release of insulin from the pancreas and reduces the release of glucagon, and clinical trials demonstrated that it was effective in treating type 2 diabetes.

In 2005, the FDA approved Byetta (exenatide). There are now seven GLP-1 medicines on the market.

JDRF Leadership

JDRF funded copious research in the 1980s and 1990s to understand the role of glucagon and glucagon-like peptide 1 in type 1 diabetes, including:

  • Patricia Brubaker, Ph.D., during her JDRF-funded postdoctoral fellowship in the laboratory of Mladen Vranic, M.D., D.Sc., between 1982-1985.
  • She would stay at the University of Toronto, working with Daniel Drucker, M.D., who held a JDRF grant from 1992-2009, on GLP function and development.
  • Louise Scrocchi, Ph.D., was a JDRF-funded postdoctoral fellow in the laboratory of Dr. Drucker, from 1996-1998, when she demonstrated the critical role of GLP-1 as an incretin hormone.

And there are many more JDRF investigators who had a hand in making this new class of agents a reality to the diabetes community.

JDRF Clinical Trials

When GLP-1 treatments came out, everyone in the type 1 space wanted to know if it worked for T1D. JDRF and others funded a number of clinical trials testing it with insulin, to see if it improved outcomes. Unfortunately, although it reduced HbA1c and total insulin dose, it increased the rates of low blood sugar (called hypoglycemia) and high blood sugar (hyperglycemia) events, thereby limiting its clinical use.

In the past few years, however, we have started to wonder whether three drugs (insulin + 2 other drugs) might work, and are now funding a trial to see if a GLP-1 therapy (semaglutide, brand name Ozempic, Rybelsus) and an SGLT therapy (dapagliflozin, brand name Farxiga), taken with insulin, can reach better blood sugar levels, compared with a dual therapy or insulin only.

Results won’t be out for another year or two, but stay tuned.

[1] Lund PK, Goodman RH, Habener JF. Intestinal glucagon mRNA identified by hybridization to a cloned islet cDNA encoding a precursor. Biochem Biophys Res Commun 1981; 100: 1659-1666. PMID: 7028035.

[2] Lund PK, Goodman RH, Habener JF. Pancreatic pre-proglucagons are encoded by two separate mRNAs. J Biol Chem 1981; 256: 6515-6518. PMID: 6165720.

[3] Lund PK, Goodman RH, Dee PC, Habener JF. Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem. Proc Natl Acad Sci USA 1982; 79: 345-349. PMID: 7043459 PMCID: PMC345726.

[4] Lund PK, Goodman RH, Montminy MR, Dee PC, Habener JF. Anglerfish islet pre-proglucagon II. Nucleotide and corresponding amino acid sequence of the cDNA. J Biol Chem 1983; 258: 3280-3284. PMID: 6338015.