The search for precision therapeutics in monogenic diabetes

“Monogenic diabetes is the poster disease for precision medicine,” said advanced Pediatric Endocrinology Fellow Maria Salguero Bermonth, MD, MSc. Salguero, who is completing a fellowship in clinical pharmacology and pharmacogenomics, hopes her research on maturity-onset diabetes of the young (MODY) will lead to targeted therapies for a disease that is often undiagnosed or mistreated. “There are many gaps in our understanding of how to treat MODY in kids and adolescents,” Salguero said. 

The University of Chicago’s Monogenic Diabetes Registry has enrolled the largest number of individuals with MODY in the U.S., making Salguero’s research in precision medicine possible. The goal of studying a disease caused by single gene mutations is to discover important insights into the mechanistic etiologies of diabetes, ultimately leading to precision therapeutics for children with MODY and also for children with type 2 and type 1 diabetes, she said. 

Salguero works with the Monogenic Diabetes Group under the mentorship of pediatric endocrinologist Rochelle Naylor, MD, and Louis Philipson, MD, PhD, Director of the Kovler Diabetes Center. Her research focuses on three different forms of MODY, each with a particular gene mutation that adversely affects insulin-producing beta cells. 

One form of MODY results from a mutation in the HNF1B gene. “Often individuals with MODY are misdiagnosed as having type 1 diabetes because they are thin and, therefore, they get treated with insulin,” said Salguero. “But insulin therapy doesn’t address the unique complications of this multi-organ disease.” Patients with HNF1B-MODY have renal anomalies and can develop chronic kidney disease that is different from the diabetic nephropathy that occurs in type 2 diabetes, for example. They also may develop very low levels of magnesium, liver abnormalities, pancreas dysfunction and genital tract malformations. 

Salguero’s hypothesis is that the antihyperglycemic agent SGLT2 inhibitors may reduce hypomagnesemia symptoms, improve blood pressure and delay renal disease progression in individuals with HNF1B-MODY, while improving glycemic control and providing cardioprotective benefits. “I believe there are better options than insulin to treat people with this form of MODY,” said Salguero. 

To that end, she has designed a pragmatic clinical trial that will evaluate how patients with HNF1B-MODY respond to SGLT2 inhibitors, starting first with adults and then enrolling adolescents. If the trial results are positive, she will study children with HNF1B-MODY on SGLT2 inhibitor therapy. “We may be able to reduce the dose of insulin these individuals take or even eliminate it, and they may not need infusions of magnesium every week,” said Salguero. “Therapy with SGLT2 inhibitors could be life-changing for these patients.”

Salguero recently received a grant to study adolescents with more common types of MODY caused by mutations in HNF1A and HNF4A genes. Although sulfonylureas are considered first-line therapy for HNF1A-MODY and HNF4A-MODY, adults exhibit hypersensitivity to the drug and develop hypoglycemia for reasons that are not completely understood. And there is no guidance on the appropriate dosing of sulfonylureas during the teenage years, which is often when these forms of MODY emerge. “We are extrapolating pediatric doses from the available adult literature,” said Salguero. She hopes to develop dosing guidelines and evidence-based recommendations to improve outcomes for pediatric patients, who are more vulnerable to recurrent hypoglycemia. 

Salguero’s research addresses important gaps in precision therapeutics for MODY, particularly in children and adolescents with monogenic diabetes. “My hope is that this work will ultimately further inform diabetes precision therapeutics for better management of all forms of diabetes,” she said.