Targeting New Pathway May Be Beneficial in Mature-Onset Diabetes of the Young
Patients with mature-onset diabetes of the young 1 are often misdiagnosed with type 2 diabetes.
(HealthDay News) — Patients with maturity-onset diabetes of the young 1 (MODY1) are often misdiagnosed as having type 2 diabetes, but patients with MODY1 might benefit from therapies that target a specific pathway that appears to be essential to the function of insulin-secreting cells, according to an experimental study published in the Journal of Biological Chemistry.
"People diagnosed with type 2 diabetes are treated with oral medications that make insulin-secreting beta cells very active," first author Benjamin D. Moore, PhD, said in a Washington University news release. Dr Moore is a former postdoctoral fellow at Washington University in St. Louis who is now at Massachusetts General Hospital in Boston. "But the MODY1 pathway we've uncovered shows that stimulating those cells with those drugs can lead to beta cell death. That means these patients can become dependent on insulin injections much sooner."
The researchers demonstrated that Hepatocyte Nuclear Factor 4α (HNF4α) directly induced XBP1 expression. HNF4α mutations caused MODY1, characterized by diminished glucose-stimulated insulin secretion (GSIS). Using dominant negative and human-disease-allele point mutants or knock-out or knockdown models, disruption of HNF4α caused decreased XBP1 expression and reduced cellular ER networks in mouse models, cell lines, and ex vivo islets. Diminished XBP1 and/or HNF4α in beta cells correlated with impaired ER Ca2+ hemostasis. In HNF4α-deficient beta cells, restoring XBP1 expression was sufficient to completely rescue GSIS.
The researchers are continuing to conduct experiments to determine whether the same pathways are active in different types of secretory cells. They assert that physicians need to determine whether their patients have the MODY1 form of the disorder before moving ahead with treatment.
"It's important to diagnose patients as accurately as possible and to attempt to target the correct pathway," Dr Moore said.
One author disclosed employment by Roche Pharma Research and Early Development.