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Rare Genetic Form of Diabetes, MODY, Reacts Poorly with Type 2 Oral Drugs, Study Reports

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Rare Genetic Form of Diabetes, MODY, Reacts Poorly with Type 2 Oral Drugs, Study Reports
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In a new study, researchers at Washington University School of Medicine in St. Louis reported that treatment of a rare and often misdiagnosed form of diabetes, maturity-onset diabetes of the young (MODY), with drugs given to type 2 diabetics can lead to the death of insulin-producing cells and to the much earlier dependence on insulin injections.

The article, “Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function,” was published in The Journal of Biological Chemistry.

MODY, a rare form of diabetes that is different from both types — 1 and 2 — of the disease, is caused by a mutation in a single gene, meaning that children of a parent has this gene have a 50 percent chance of developing the condition. The more common types of MODY are caused by mutations in the Hepatocyte Nuclear Factor 1-alpha (HNF1α), HNF4α, HNF1-beta, or glucokinase genes.

According to Diabetes UK, MODY is very rare compared to other forms of diabetes, accounting for only 1 percent to 2 percent of all diabetes cases in the United Kingdom. For this reason, it can go unrecognized and is often mistaken for type 2 diabetes, as some symptoms are similar between the diseases. However, the underlying pathogenic mechanisms in the genetic form of the disease are very different.

Researchers found that oral medications used to treat type 2 diabetes, which make insulin-secreting beta cells very active, can have very harmful effects in MODY patients, leading to the premature death of beta cells that regulate blood sugar. Patients with MODY usually transition from oral medications to insulin injections within 10 years of diagnosis, but type 2 oral drugs, researchers found, increase cellular stress levels, leading to cell death and an earlier need to switch to insulin.

Instead, they suggested that targeting specific pathways in the insulin-producing cells could have a more beneficial effect on this subset of diabetics. Researchers found that increasing expression of the transcription factor X-box Binding Protein-One (XBP1), which is decreased in the presence of the HNF4α mutation, was able to completely rescue the glucose-stimulated insulin secretion function of beta cells.

Doctors need to determine early if a particular patient has MODY or type 2 diabetes, the researchers said, as different treatment strategies could make a significant difference. “It’s important to diagnose patients as accurately as possible and to attempt to target the correct pathway,” concluded the study’s first author, Dr. Benjamin D. Moore, in a Washington University news release.

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