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The ADA presented its 2022 National Scientific & Health Care Achievement Awards to a distinguished group of diabetes researchers, clinicians, and educators on Monday, June 6, at the 82nd Scientific Sessions in New Orleans. It’s the first time the awards have been presented in person since 2019 when the 79th Scientific Sessions were held in San Francisco.
Following the National Scientific & Health Care Achievement Awards Presentation, which was livestreamed and can be viewed on-demand at ADA2022.org, Anna L. Gloyn, DPhil, reviewed unpublished data from ongoing research into the genomic contributors to type 2 diabetes risk. Dr. Gloyn received the 2022 Outstanding Scientific Achievement Award for her groundbreaking research, which has identified novel therapeutic targets in type 2 diabetes.
“Diabetes is a complex jigsaw puzzle and human genetics is a powerful tool to help us find pieces of the puzzle,” said Dr. Gloyn, Professor of Pediatrics (Endocrinology) and Professor (by courtesy) of Genetics at Stanford University. “What we are looking for is pieces that have direct translational relevance.”
Dr. Gloyn began looking for pieces of the puzzle during her doctoral research into the adenosine triphosphate-sensitive potassium (KATP) channel that plays a key role in insulin secretion in specific monogenic forms of neonatal diabetes. Her work led to a dramatic change in clinical practice from the use of injected insulin to the use of oral sulfonylureas to treat the vast majority of children born with neonatal diabetes caused by KATP loss-of-function mutations.
“For me, it’s not just about finding the puzzle pieces, it’s about clinical translation,” she said. “We are discovering things of core importance to people with diabetes.”
Recognizing that sulfonylureas were originally developed to treat type 2 diabetes, she shifted her research focus from the puzzle of monogenic neonatal diabetes to the much larger puzzle of type 2 diabetes. The methodology remained the same. Identify DNA variants associated with diabetes risk, drill down to the key proteins and pathways involved in pathogenesis, and translate findings into clinical targets for drug development.
Genome-wide association studies have identified about 350 signals relevant to type 2 diabetes pathogenesis, Dr. Gloyn said, but most of those signals occur in noncoding DNA associated with gene regulation and expression. Studies have identified about 50% of the genetic risk for type 2 diabetes with 117 genes at active loci. Most of these genes affect beta-cell function, she said, but it’s not clear how. She likened the signals and genes to the snow in a winter scene.
“We don’t know if the snow is on trees, people, or buildings, but we know that gene regulation is highly context-specific,” she explained. “Activity depends on where, when, and under what stimulus. Snow looks like snow, but our genetic snow on the tree in front of the house is completely different from the snow on the tree behind the house.”
One shortcut is to look for coding variants associated with type 2 diabetes risk. The PAM (peptidylglycine alpha-amidating monooxygenase) gene, for example, has two variants associated with type 2 diabetes risk. PAM is the only enzyme known to create amide groups on glycine-extended peptide hormones, which affects the biological potency of neuroendocrine secretory granules such as insulin. PAM is widely expressed in human alpha and beta cells and other tissues.
Both variants lead to PAM loss-of-function, resulting in defective insulin secretion. Insulin itself is not amidated, Dr. Gloyn explained, but chromogranin A (CgA) is. Reducing CgA amidation affects the packaging of insulin, reducing both insulin secretion and insulin granule content.
PAM also plays a role in glucagon-like peptide-1 (GLP-1) activity. Individuals with PAM type 2 diabetes risk alleles have elevated GLP-1 levels with GLP-1 receptor resistance that can affect clinical activity of GLP-1 receptor agonists. Early data shows that 0% to 10% of individuals with PAM type 2 diabetes risk alleles reach A1C goals on incretin therapy compared to 30% of individuals who do not carry the risk alleles.
“This allele can make a big difference in whether you meet your A1C target,” Dr. Gloyn said. “It has direct clinical importance.”
More recently, Dr. Gloyn’s lab conducted knockout trials with the roughly 18,000 genes affecting human beta-cell activity to identify 580 genes that affect insulin content in human beta cells. About 20 of these genes also predict type 2 diabetes risk. One of them, CALCOCO2, has a known role in immune response. Dr. Gloyn’s lab identified a new role.
In human beta cells, loss of CALCOCO2 upregulates autophagy targeting immature and transitioning insulin granules. The result is reduced insulin content and a potential therapeutic target.
“There are emerging translational opportunities as we assemble the jigsaw puzzle of diabetes risk,” Dr. Gloyn said. “We are working with our pharma colleagues to move swiftly from scientific insights to clinical translation.”
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